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Wnt pharmaceutics

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https://www.readbyqxmd.com/read/28474989/discovery-of-small-molecule-inhibitors-of-the-wnt-%C3%AE-catenin-signaling-pathway-by-targeting-%C3%AE-catenin-tcf4-interactions
#1
REVIEW
Maocai Yan, Guanqun Li, Jing An
The Wnt/β-catenin signaling pathway typically shows aberrant activation in various cancer cells, especially colorectal cancer cells. This signaling pathway regulates the expression of a variety of tumor-related proteins, including c-myc and cyclin D1, and plays essential roles in tumorigenesis and in the development of many cancers. Small molecules that block the interactions between β-catenin and Tcf4, a downstream stage of activation of the Wnt/β-catenin signaling pathway, could efficiently cut off this signal transduction and thereby act as a novel class of anticancer drugs...
June 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28460416/the-skeletal-cell-derived-molecule-sclerostin-drives-bone-marrow-adipogenesis
#2
Heather Fairfield, Carolyne Falank, Elizabeth Harris, Victoria Demambro, Michelle McDonald, Jessica A Pettitt, Sindhu T Mohanty, Peter Croucher, Ina Kramer, Michaela Kneissel, Clifford J Rosen, Michaela R Reagan
The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi-potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic-induced fracture, systemic adiposity, and the presence of bone-homing cancers...
April 29, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28416592/-wnt-er-is-coming-wnt-signalling-in-chronic-lung-diseases
#3
H A Baarsma, M Königshoff
Chronic lung diseases represent a major public health problem with only limited therapeutic options. An important unmet need is to identify compounds and drugs that target key molecular pathways involved in the pathogenesis of chronic lung diseases. Over the last decade, there has been extensive interest in investigating Wingless/integrase-1 (WNT) signalling pathways; and WNT signal alterations have been linked to pulmonary disease pathogenesis and progression. Here, we comprehensively review the cumulative evidence for WNT pathway alterations in chronic lung pathologies, including idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma and COPD...
August 2017: Thorax
https://www.readbyqxmd.com/read/28332354/cyclized-oligopeptide-targeting-lrp5-6-dkk1-interaction-reduces-the-growth-of-tumor-burden-in-a-multiple-myeloma-mouse-model
#4
Bo Mi Park, Eun Jin Kim, Hee Jin Nam, Dongdong Zhang, Chu Hyun Bae, Myeongmo Kang, Heeyoun Kim, Weontae Lee, Bjarne Bogen, Sung Kil Lim
PURPOSE: Dickkopf 1 (DKK1) has been extensively investigated in mouse models of multiple myeloma, which results in osteolytic bone lesions. Elevated DKK1 levels in bone marrow plasma and serum inhibit the differentiation of osteoblast precursors. Present pharmaceutical approaches to target bone lesions are limited to antiresorptive agents. In this study, we developed a cyclized oligopeptide against DKK1-low density lipoprotein receptor-related protein (LRP) 5/6 interaction and tested the effects of the oligopeptide on tumor burden...
May 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/28244648/salvianolic-acid-b-regulates-gene-expression-and-promotes-cell-viability-in-chondrocytes
#5
Xiaohong Yang, Shaojie Liu, Siming Li, Pengzhen Wang, Weicong Zhu, Peihong Liang, Jianrong Tan, Shuliang Cui
Articular chondrocytes reside in lacunae distributed in cartilage responsible for the remodelling of the tissue with limited ability of damage repairing. The in vitro expanded chondrocytes enhanced by factors/agents to obtain large numbers of cells with strengthened phenotype are essential for successful repair of cartilage lesions by clinical cell implantation therapies. Because the salvianolic acid B (Sal B), a major hydrophilic therapeutic agent isolated from Salvia miltiorrhiza, has been widely used to treat diseases and able to stimulate activity of cells, this study examines the effects of Sal B on passaged chondrocytes...
February 28, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28094799/activation-of-wnt-%C3%AE-catenin-signalling-via-gsk3-inhibitors-direct-differentiation-of-human-adipose-stem-cells-into-functional-hepatocytes
#6
Jieqiong Huang, Xinyue Guo, Weihong Li, Haiyan Zhang
The generation of hepatocytes that are derived from human adipose stem cells (hASCs) represents an alternative to human hepatocytes for individualized therapeutic and pharmaceutical applications. However, the mechanisms facilitating hepatocyte differentiation from hASCs are not well understood. Here, we show that upon exposure to glycogen synthase kinase 3 (GSK3) inhibitors alone, the expression of definitive endoderm specific genes GATA4, FOXA2, and SOX17 in hASCs significantly increased in a manner with activation of Wnt/β-catenin signalling...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27567978/wnt-%C3%AE-catenin-signaling-inhibitor-icg-001-enhances-pigmentation-of-cultured-melanoma-cells
#7
Kyung-Il Kim, Do-Sun Jeong, Eui Chang Jung, Jeung-Hoon Lee, Chang Deok Kim, Tae-Jin Yoon
BACKGROUND: Wnt/β-catenin signaling is important in development and differentiation of melanocytes. OBJECTIVE: The object of this study was to evaluate the effects of several Wnt/β-catenin signaling inhibitors on pigmentation using melanoma cells. METHODS: Melanoma cells were treated with Wnt/β-catenin signaling inhibitors, and then melanin content and tyrosinase activity were checked. RESULTS: Although some inhibitors showed slight inhibition of pigmentation, we failed to observe potential inhibitory effect of those chemicals on pigmentation of HM3KO melanoma cells...
November 2016: Journal of Dermatological Science
https://www.readbyqxmd.com/read/27500408/large-scale-production-of-cardiomyocytes-from-human-pluripotent-stem-cells-using-a-highly-reproducible-small-molecule-based-differentiation-protocol
#8
Hananeh Fonoudi, Hassan Ansari, Saeed Abbasalizadeh, Gillian M Blue, Nasser Aghdami, David S Winlaw, Richard P Harvey, Alexis Bosman, Hossein Baharvand
Maximizing the benefit of human pluripotent stem cells (hPSCs) for research, disease modeling, pharmaceutical and clinical applications requires robust methods for the large-scale production of functional cell types, including cardiomyocytes. Here we demonstrate that the temporal manipulation of WNT, TGF-β, and SHH signaling pathways leads to highly efficient cardiomyocyte differentiation of single-cell passaged hPSC lines in both static suspension and stirred suspension bioreactor systems. Employing this strategy resulted in ~ 100% beating spheroids, consistently containing > 80% cardiac troponin T-positive cells after 15 days of culture, validated in multiple hPSC lines...
2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27397144/astragaloside-i-stimulates-osteoblast-differentiation-through-the-wnt-%C3%AE-catenin-signaling-pathway
#9
Xun Cheng, Biaofang Wei, Lijuan Sun, Xiaofang Hu, Jichao Liang, Yong Chen
Astragaloside I (As-I), one of the main active ingredients in Astragalus membranaceus, is believed to have osteogenic properties, but this hypothesis has not been investigated in detail. In the present work, the As-I-induced osteogenic effects and its underlying mechanism were studied in MC3T3-E1 cells. The results indicated that the cellular levels of ALP and extracellular matrix calcium increased in a dose-dependent manner by As-I. To clarify the mechanisms involved in this process, the effect of As-I on the key osteogenic-related genes was investigated...
October 2016: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/27351373/pentoxifylline-inhibits-wnt-signalling-in-%C3%AE-cateninhigh-patient-derived-melanoma-cell-populations
#10
Beata Talar, Anna Gajos-Michniewicz, Marcin Talar, Salem Chouaib, Malgorzata Czyz
BACKGROUND: The heterogeneity of melanoma needs to be addressed and combination therapies seem to be necessary to overcome intrinsic and acquired resistance to newly developed immunotherapies and targeted therapies. Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized. Using patient-derived melanoma cell populations, we investigated the influence of pentoxifylline on melanoma cells with either high or low expression of β-catenin...
2016: PloS One
https://www.readbyqxmd.com/read/27294914/protective-effect-of-ginsenoside-rg1-on-hematopoietic-stem-progenitor-cells-through-attenuating-oxidative-stress-and-the-wnt-%C3%AE-catenin-signaling-pathway-in-a-mouse-model-of-d-galactose-induced-aging
#11
Jing Li, Dachuan Cai, Xin Yao, Yanyan Zhang, Linbo Chen, Pengwei Jing, Lu Wang, Yaping Wang
Stem cell senescence is an important and current hypothesis accounting for organismal aging, especially the hematopoietic stem cell (HSC). Ginsenoside Rg1 is the main active pharmaceutical ingredient of ginseng, which is a traditional Chinese medicine. This study explored the protective effect of ginsenoside Rg1 on Sca-1⁺ hematopoietic stem/progenitor cells (HSC/HPCs) in a mouse model of d-galactose-induced aging. The mimetic aging mouse model was induced by continuous injection of d-gal for 42 days, and the C57BL/6 mice were respectively treated with ginsenoside Rg1, Vitamin E or normal saline after 7 days of d-gal injection...
June 9, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27143851/baicalein-suppresses-metastasis-of-breast-cancer-cells-by-inhibiting-emt-via-downregulation-of-satb1-and-wnt-%C3%AE-catenin-pathway
#12
Xingcong Ma, Wanjun Yan, Zhijun Dai, Xiaoyan Gao, Yinan Ma, Quntao Xu, Jiantao Jiang, Shuqun Zhang
BACKGROUND: The flavonoid baicalein, a historically used Chinese herbal medicine, shows a wide range of biological and pharmaceutical effects, among which its potent antitumor activity has raised great interest in recent years. However, the molecular mechanism involved in the antimetastatic effect of baicalein remains poorly understood. This study aimed to verify the inhibitory effects of baicalein on metastasis of MDA-MB-231 human breast cancer cells both in vitro and in vivo, as well as to investigate the related mechanisms...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27142748/effects-of-quercetin-a-natural-phenolic-compound-in-the-differentiation-of-human-mesenchymal-stem-cells-msc-into-adipocytes-and-osteoblasts
#13
Antonio Casado-Díaz, Jaouad Anter, Gabriel Dorado, José Manuel Quesada-Gómez
Natural phenols may have beneficial properties against oxidative stress, which is associated with aging and major chronic aging-related diseases, such as loss of bone mineral mass (osteoporosis) and diabetes. The main aim of this study was to analyze the effect of quercetin, a major nutraceutical compound present in the "Mediterranean diet", on mesenchymal stem-cell (MSC) differentiation. Such cells were induced to differentiate into osteoblasts or adipocytes in the presence of two quercetin concentrations (0...
June 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/26626076/the-role-of-wnt-regulation-in-heart-development-cardiac-repair-and-disease-a-tissue-engineering-perspective
#14
REVIEW
Aric Pahnke, Genna Conant, Locke Davenport Huyer, Yimu Zhao, Nicole Feric, Milica Radisic
Wingless-related integration site (Wnt) signaling has proven to be a fundamental mechanism in cardiovascular development as well as disease. Understanding its particular role in heart formation has helped to develop pluripotent stem cell differentiation protocols that produce relatively pure cardiomyocyte populations. The resultant cardiomyocytes have been used to generate heart tissue for pharmaceutical testing, and to study physiological and disease states. Such protocols in combination with induced pluripotent stem cell technology have yielded patient-derived cardiomyocytes that exhibit some of the hallmarks of cardiovascular disease and are therefore being used to model disease states...
May 6, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26613980/2-amino-4-3-4-methylenedioxy-benzylamino-6-3-methoxyphenyl-pyrimidine-is-an-anti-inflammatory-tlr-2-4-and-5-response-mediator-in-human-monocytes
#15
Huizhi Wang, Mark W Graves, Huaxin Zhou, Zhen Gu, Richard J Lamont, David A Scott
OBJECTIVE AND DESIGN: To elucidate the influence of 2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP), a canonical Wnt/β-catenin pathway activator, on the inflammatory response of TLR-engaged innate cells in vitro. MATERIAL OR SUBJECT: Primary human monocytes. TREATMENT: AMPMB (0-10 μM), LPS (0-1.0 μg/ml), Pam3CSK4, FSL-1, or S. typhimurium flagellin (0-0.25 μg/ml). METHODS: TLR-induced cytokine release (TNF, IL-6, IL-12 p40) was monitored by ELISA while Wnt-related signals (GSK3β, p65, IκB, β-catenin) were assessed by Western blot, pharmaceutical inhibition and gene silencing...
January 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/26554834/missense-mutations-in-lrp5-associated-with-high-bone-mass-protect-the-mouse-skeleton-from-disuse-and-ovariectomy-induced-osteopenia
#16
Paul J Niziolek, Whitney Bullock, Matthew L Warman, Alexander G Robling
The low density lipoprotein receptor-related protein-5 (LRP5), a co-receptor in the Wnt signaling pathway, modulates bone mass in humans and in mice. Lrp5 knock-out mice have severely impaired responsiveness to mechanical stimulation whereas Lrp5 gain-of-function knock-in and transgenic mice have enhanced responsiveness to mechanical stimulation. Those observations highlight the importance of Lrp5 protein in bone cell mechanotransduction. It is unclear if and how high bone mass-causing (HBM) point mutations in Lrp5 alter the bone-wasting effects of mechanical disuse...
2015: PloS One
https://www.readbyqxmd.com/read/26522946/the-use-of-porcupine-inhibitors-to-target-wnt-driven-cancers
#17
REVIEW
Soo Yei Ho, Thomas H Keller
Over the past decade, academic groups and pharmaceutical companies have uncovered several components and targets for intervention in the Wnt pathway. One approach is to block Wnt signalling through the use of orally bioavailable small molecules that prevent Wnt ligand secretion. In recent years, the membrane bound O-acyl transferase (MBOAT) porcupine (PORCN) has emerged as a molecular target of interest in the search for clinical options to treat Wnt-driven cancers. This review shall provide an overview of the reported small molecule inhibitors for PORCN and discuss the progress made in identifying human disease models that are responsive to PORCN inhibitors...
December 1, 2015: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26511653/a-universal-and-robust-integrated-platform-for-the-scalable-production-of-human-cardiomyocytes-from-pluripotent-stem-cells
#18
Hananeh Fonoudi, Hassan Ansari, Saeed Abbasalizadeh, Mehran Rezaei Larijani, Sahar Kiani, Shiva Hashemizadeh, Ali Sharifi Zarchi, Alexis Bosman, Gillian M Blue, Sara Pahlavan, Matthew Perry, Yishay Orr, Yaroslav Mayorchak, Jamie Vandenberg, Mahmood Talkhabi, David S Winlaw, Richard P Harvey, Nasser Aghdami, Hossein Baharvand
UNLABELLED: Recent advances in the generation of cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs), in conjunction with the promising outcomes from preclinical and clinical studies, have raised new hopes for cardiac cell therapy. We report the development of a scalable, robust, and integrated differentiation platform for large-scale production of hPSC-CM aggregates in a stirred suspension bioreactor as a single-unit operation. Precise modulation of the differentiation process by small molecule activation of WNT signaling, followed by inactivation of transforming growth factor-β and WNT signaling and activation of sonic hedgehog signaling in hPSCs as size-controlled aggregates led to the generation of approximately 100% beating CM spheroids containing virtually pure (∼90%) CMs in 10 days...
December 2015: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/26478571/berberine-promotes-bone-marrow-derived-mesenchymal-stem-cells-osteogenic-differentiation-via-canonical-wnt-%C3%AE-catenin-signaling-pathway
#19
Ke Tao, Deming Xiao, Jian Weng, Ao Xiong, Bin Kang, Hui Zeng
Berberine (BBR) has recently been reported to be extensively used for musculoskeletal disorders such as osteoporosis through enhancing osteogenic differentiation, inhibiting osteoclastogenesis and bone resorption and repressing adipogenesis. Although canonical Wnt signaling plays a crucial role in suppressing bone marrow-derived mesenchymal stem cells (MSCs) commitment to the chondrogenic and adipogenic lineage and enhancing osteogenic differentiation, no previous reports have shown an association between BBR-induced osteogenesis and Wnt/β-catenin signaling pathway...
January 5, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/26439805/targeting-the-wnt-signaling-pathway-in-colorectal-cancer
#20
REVIEW
Masaaki Sawa, Mari Masuda, Tesshi Yamada
INTRODUCTION: The treatment of patients with advanced colorectal cancer still remains challenging, and identification of new target molecules and therapeutic avenues remains a priority. The great majority of colorectal cancers have mutations in one of two genes involved in the Wnt signaling pathway: the adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes. Up to now, however, no therapeutics for targeting this pathway have been established. AREAS COVERED: This review article begins with a brief summary of Wnt signaling from the viewpoints of genetics, cancer stem cell biology, and drug development...
2016: Expert Opinion on Therapeutic Targets
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