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Cathepsin k inhibitors

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https://www.readbyqxmd.com/read/29089436/protease-mediated-suppression-of-drg-neuron-excitability-by-commensal-bacteria
#1
Jessica L Sessenwein, Corey C Baker, Sabindra Pradhananga, Megan E Maitland, Elaine O Petrof, Emma Allen-Vercoe, Curtis Noordhof, David E Reed, Stephen J Vanner, Alan E Lomax
Peripheral pain signaling reflects a balance of pro and anti-nociceptive influences; the contribution by the gastrointestinal (GI) microbiota to this balance has received little attention. Disorders such as inflammatory bowel disease and irritable bowel syndrome are associated with exaggerated visceral nociceptive actions that may involve altered microbial signaling, particularly given the evidence for bacterial dysbiosis. Thus, we tested whether a community of commensal GI bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse dorsal root ganglion (DRG) neurons...
October 31, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29058826/cathepsin-k-activity-controls-cardiotoxin-induced-skeletal-muscle-repair-in-mice
#2
Shinyu Ogasawara, Xian Wu Cheng, Aiko Inoue, Lina Hu, Limei Piao, Chenglin Yu, Hiroki Goto, Wenhu Xu, Guangxian Zhao, Yanna Lei, Guang Yang, Kaoru Kimura, Hiroyuki Umegaki, Guo-Ping Shi, Masafumi Kuzuya
BACKGROUND: Cathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non-enzymatic functions in signalling. Here, we examined whether CatK-deficiency (CatK(-/-) ) would mitigate injury-related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis. METHODS: Cardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild-type (CatK(+/+) ) and CatK(-/-) mice, and the mice were processed for morphological and biochemical studies...
October 23, 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/29032174/c-ebp%C3%AE-and-pu-1-exhibit-different-responses-to-rank-signaling-for-osteoclastogenesis
#3
Joel Jules, Wei Chen, Yi-Ping Li
The transcription factors C/EBPα and PU.1 are upregulated by RANKL through activation of its receptor RANK during osteoclastogenesis and are critical for osteoclast differentiation. Herein we investigated the mechanisms underlying how C/EBPα and PU.1 regulate osteoclast differentiation in response to RANK signaling. We showed that C/EBPα or PU.1 overexpression could initiate osteoclastogenesis and upregulate the expressions of the osteoclast genes encoding the nuclear factor of activated T-cells, C1, cathepsin K, and tartrate-resistant acid phosphatase independently of RANKL...
October 11, 2017: Bone
https://www.readbyqxmd.com/read/28983590/i%C3%A2-bet151-inhibits-osteoclastogenesis-via-the-rankl-signaling-pathway-in-raw264-7-macrophages
#4
Jing Cheng, Jifu Zheng, Ninghong Guo, Fuming Zi
Excessive bone resorption mediated by osteoclasts may lead to the risk of various lytic bone diseases. In the present study, the effects of I‑BET151, a bromodomain and extra terminal domain protein inhibitor, on osteoclastogenesis in RAW264.7 cells and the underlying mechanism of this process was investigated. Cells were divided into 6 groups, including the control group, receptor activator of nuclear factor‑κB ligand (RANKL) group and 4 other groups containing RANKL and I‑BET151 at different concentrations...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28978867/cysteine-protease-cathepsins-in-atherosclerotic-cardiovascular-diseases
#5
Hongxian Wu, Qiuna Du, Qiuyan Dai, Junbo Ge, Xianwn Cheng
Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease characterized by extensive arterial wall matrix protein degradation. Cysteine protease cathepsins play a pivotal role in extracellular matrix (ECM) remodeling and have been implicated in the development and progression of atherosclerosis-based cardiovascular diseases. An imbalance in expression between cathepsins (such as cathepsins S, K, L, C) and their inhibitor cystatin C may favor proteolysis of ECM in the pathogenesis of cardiovascular disease such as atherosclerosis, aneurysm formation, restenosis, and neovascularization...
October 5, 2017: Journal of Atherosclerosis and Thrombosis
https://www.readbyqxmd.com/read/28953929/class-ii-and-iv-hdacs-function-as-inhibitors-of-osteoclast-differentiation
#6
Nicholas C Blixt, Bora K Faulkner, Kristina Astleford, Rosemary Lelich, Jacob Schering, Ekaterina Spencer, Rajaram Gopalakrishnan, Eric D Jensen, Kim C Mansky
Histone deacetylases (HDACs) are negative regulators of transcription and have been shown to regulate specific changes in gene expression. In vertebrates, eighteen HDACs have thus far been identified and subdivided into four classes (I-IV). Key roles for several HDACs in bone development and biology have been elucidated through in vitro and in vivo models. By comparison, there is a paucity of data on the roles of individual HDACs in osteoclast formation and function. In this study, we investigated the gene expression patterns and the effects of suppressing individual class II (Hdac4, 5, 6, 9, and 10) and class IV (Hdac11) HDACs during osteoclast differentiation...
2017: PloS One
https://www.readbyqxmd.com/read/28914985/cherubism-mice-also-deficient-in-c-fos-exhibit-inflammatory-bone-destruction-executed-by-macrophages-that-express-mmp14-despite-the-absence-of-trap-osteoclasts
#7
Mizuho Kittaka, Kotoe Mayahara, Tomoyuki Mukai, Tetsuya Yoshimoto, Teruhito Yoshitaka, Jeffrey P Gorski, Yasuyoshi Ueki
Currently, it is believed that osteoclasts positive for tartrate-resistant acid phosphatase (TRAP+) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2(KI/KI) ) with a homozygous gain-of-function mutation in the SH3-domain binding protein 2 (SH3BP2) was shown to develop auto-inflammatory joint destruction. Here, we demonstrate that Sh3bp2(KI/KI) mice also deficient in the FBJ osteosarcoma oncogene (c-Fos) still exhibit noticeable bone erosion at the distal tibia even in the absence of osteoclasts at 12 weeks old...
September 15, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28884622/ex-vivo-and-in-vivo-noninvasive-imaging-of-epidermal-growth-factor-receptor-inhibition-on-colon-tumorigenesis-using-activatable-near-infrared-fluorescent-probes
#8
Shengli Ding, Randall E Blue, Emily Moorefield, Hong Yuan, Pauline K Lund
BACKGROUND: Near-infrared fluorescence (NIRF) imaging combined with enzyme-activatable NIRF probes has yielded promising results in cancer detection. OBJECTIVE: To test whether 3-dimensional (3-D) noninvasive in vivo NIRF imaging can detect effects of epidermal growth factor receptor (EGFR) inhibitor on both polypoid and flat tumor load in azoxymethane (AOM)-induced colon tumors or tumors in Apc(Min/+) mice. METHODS: The AOM-injected KK-HIJ mice received EGFR inhibitor diet or chow diet...
January 2017: Molecular Imaging
https://www.readbyqxmd.com/read/28874760/zinc-depletion-promotes-apoptosis-like-death-in-drug-sensitive-and-antimony-resistance-leishmania-donovani
#9
Shalini Saini, Kavita Bharati, Chandrima Shaha, Chinmay K Mukhopadhyay
Micronutrients are essential for survival and growth for all the organisms including pathogens. In this manuscript, we report that zinc (Zn) chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethylenediamine (TPEN) affects growth and viability of intracellular pathogen Leishmania donovani (LD) by a concentration and time dependent manner. Simultaneous addition of zinc salt reverses the effect of TPEN. Further experiments provide evidence of apoptosis-like death of the parasite due to Zn-depletion. TPEN treatment enhances caspase-like activity suggesting increase in apoptosis-like events in LD...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821796/cathepsin-k-knockout-protects-against-cardiac-dysfunction-in-diabetic-mice
#10
Rui Guo, Yinan Hua, Olivia Rogers, Travis E Brown, Jun Ren, Sreejayan Nair
Diabetes is a major risk factor for cardiovascular disease and the lysosomal cysteine protease cathepsin K plays a critical role in cardiac pathophysiology. To expand upon our previous findings, we tested the hypothesis that, knockout of cathepsin K protects against diabetes-associated cardiac anomalies. Wild-type and cathepsin K knockout mice were rendered diabetic by streptozotocin (STZ) injections. Body weight, organ mass, fasting blood glucose, energy expenditure, cardiac geometry and function, cardiac histomorphology, glutathione levels and protein levels of cathepsin K and those associated with Ca(2+) handling, calcineurin/NFAT signaling, insulin signaling, cardiac apoptosis and fibrosis were determined...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28802000/pmepa1-induced-by-rankl-p38-mapk-pathway-has-a-novel-role-in-osteoclastogenesis
#11
Noboru Funakubo, Xianghe Xu, Toshio Kukita, Seiji Nakamura, Hiroshi Miyamoto, Akiko Kukita
Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here, we have analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-β and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking...
August 12, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28745432/an-ectosteric-inhibitor-of-cathepsin-k-inhibits-bone-resorption-in-ovariectomized-mice
#12
Preety Panwar, Liming Xue, Kent Søe, Kamini Srivastava, Simon Law, Jean-Marie Delaisse, Dieter Brömme
The potent cathepsin K (CatK) inhibitor, Tanshinone IIA Sulfonic Sodium (T06), was tested for its in vitro and in vivo antiresorptive activities. T06 binds in an ectosteric site of CatK remote from its active site and selectively inhibits collagen degradation with an IC50 value of 2.7±0.2 μM (CatK:T06 molar ratio of 1:5). However, it does not suppress fluorogenic peptide cleavage and gelatinolysis at a 2,500-fold molar excess. Contrary to active site-directed CatK inhibitors, such as odanacatib, T06 suppresses bone resorption in both human and mouse osteoclasts equally well (IC50 value for human and mouse osteoclasts: 237±60 nM and 245±55 nM, respectively) and its antiresorptive activity is fully reversible in both cell types...
July 26, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28707576/new-strategies-for-the-prevention-and-treatment-of-systemic-and-local-bone-loss-from-pathophysiology-to-clinical-application
#13
A Fassio, Maurizio Rossini, Ombretta Viapiana, Luca Idolazzi, Camilla Benini, Elisabetta Vantaggiato, Davide Gatti
Bone loss is the result of a negative unbalance between bone formation ad bone resorption. In the last years, the studies on the Wnt canonical pathway have highlighted its crucial role in bone balance through its influence on the activity and maturation of the osteoblast line and in the Receptor Activator of Nuclear Factor κ B (RANK) - RANK ligand (RANKL)/Osteoprotegerin (OPG) system. These mechanisms are involved not only in the pathological processes inducing not only systemic bone loss (ie. Postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, etc...
July 13, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28699744/design-synthesis-and-pharmacokinetics-of-a-bone-targeting-dual-action-prodrug-for-the-treatment-of-osteoporosis
#14
Haibo Xie, Gang Chen, Robert N Young
A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA)...
August 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28692065/increased-cathepsin-s-in-prdm1-dendritic-cells-alters-the-tfh-cell-repertoire-and-contributes-to-lupus
#15
Sun Jung Kim, Sebastian Schätzle, S Sohail Ahmed, Wolfgang Haap, Su Hwa Jang, Peter K Gregersen, George Georgiou, Betty Diamond
Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules...
September 2017: Nature Immunology
https://www.readbyqxmd.com/read/28683495/osteoimmunology-influence-of-the-immune-system-on-bone-regeneration-and-consumption
#16
Andreas Limmer, Dieter C Wirtz
Background Stimulating bone regeneration is a central aim in orthopaedic and trauma surgery. Although the replacement of bone with artificial materials like cement or apatite helps to keep up bone stability, new bone often cannot be regenerated. Increasing research efforts have led to the clinical application of growth factors stimulating bone growth (e.g. bone morphogenic protein, BMP) and inhibitors preventing bone consumption (e.g. RANKL blocking antibodies). These factors mostly concentrate on stimulating osteoblast or preventing osteoclast activity...
June 2017: Zeitschrift Für Orthopädie und Unfallchirurgie
https://www.readbyqxmd.com/read/28651365/cathepsin-k-inhibitors-for-osteoporosis-biology-potential-clinical-utility-and-lessons-learned
#17
Matthew T Drake, Bart L Clarke, Merry Jo Oursler, Sundeep Khosla
Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast-bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for ≤5 years of treatment and improves bone strength at the spine and hip...
August 1, 2017: Endocrine Reviews
https://www.readbyqxmd.com/read/28629344/antiresorptive-effect-of-a-cathepsin-k-inhibitor-ono-5334-and-its-relationship-to-bmd-increase-in-a-phase-ii-trial-for-postmenopausal-osteoporosis
#18
Makoto Tanaka, Yoshitaka Hashimoto, Chihiro Hasegawa, Steve Deacon, Richard Eastell
BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship...
June 19, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28623674/cathepsin-k-in-lymphangioleiomyomatosis-lam-cell-fibroblast-interactions-enhance-protease-activity-by-extracellular-acidification
#19
Arundhati Dongre, Debbie Clements, Andrew J Fisher, Simon R Johnson
Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells and fibroblasts form lung nodules and it is hypothesized that LAM nodule-derived proteases cause cyst formation and tissue damage. On protease gene expression profiling in whole lung tissue, cathepsin K gene expression was 40-fold overexpressed in LAM compared with control lung tissue (P ≤ 0.0001). Immunohistochemistry confirmed cathepsin K protein was expressed in LAM but not control lungs. Cathepsin K gene expression and protein and protease activity were detected in LAM-associated fibroblasts but not the LAM cell line 621-101...
August 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28605601/a-new-sugarcane-cystatin-strongly-binds-to-dental-enamel-and-reduces-erosion
#20
A C Santiago, Z N Khan, M C Miguel, C C Gironda, A Soares-Costa, V T Pelá, A L Leite, J M Edwardson, M A R Buzalaf, F Henrique-Silva
Cystatin B was recently identified as an acid-resistant protein in acquired enamel pellicle; it could therefore be included in oral products to protect against caries and erosion. However, human recombinant cystatin is very expensive, and alternatives to its use are necessary. Phytocystatins are reversible inhibitors of cysteine peptidases that are found naturally in plants. In plants, they have several biological and physiological functions, such as the regulation of endogenous processes, defense against pathogens, and response to abiotic stress...
August 2017: Journal of Dental Research
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