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Cathepsin k inhibitors

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https://www.readbyqxmd.com/read/28087651/frontline-science-multiple-cathepsins-promote-inflammasome-independent-particle-induced-cell-death-during-nlrp3-dependent-il-1%C3%AE-activation
#1
Gregory M Orlowski, Shruti Sharma, Jeff D Colbert, Matthew Bogyo, Stephanie A Robertson, Hiroshi Kataoka, Francis K Chan, Kenneth L Rock
Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3...
January 13, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28064012/effect-of-a-novel-quaternary-ammonium-silane-on-dentin-protease-activities
#2
D Umer, C K Y Yiu, M F Burrow, L-N Niu, F R Tay
OBJECTIVES: Demineralized dentin collagen release C-terminal cross-linked telopeptide (ICTP) and C-terminal peptide (CTX) during degradation. The present study evaluated the effects of dentin pre-treatment with K21, a quaternary ammonium silane (QAS), on matrix metalloproteinase (MMP) and cathepsin K-mediated collagen degradation. METHODS: Dentin beams were demineralized with 10% H3PO4 for 24h. After baseline dry mass measurements, the beams were divided into 5 groups (N=10) according to protease inhibitors...
January 4, 2017: Journal of Dentistry
https://www.readbyqxmd.com/read/28049758/identification-of-mouse-cathepsin-k-structural-elements-that-regulate-the-potency-of-odanacatib
#3
Simon Law, Pierre-Marie Andrault, Adeleke Aguda, Nham Nguyen, Natasha Kruglyak, Gary Brayer, Dieter Bromme
Cathepsin K (CatK) is the predominant mammalian bone-degrading protease and thus an ideal target for anti-osteoporotic drug development. Rodent models of osteoporosis are preferred due to their close reflection of the human disease and their ease of handling, genetic manipulation, and economic affordability.  However, large differences in the potency of CatK inhibitors for the mouse/rat versus the human protease orthologues have made it impossible to use rodent models. This is even more of a problem considering that the most advanced CatK inhibitors including odanacatib and balicatib failed in human clinical trials due to side effects and rodent models are not available to investigate the mechanism of these failures...
January 3, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28045523/design-of-potent-and-selective-cathepsin-g-inhibitors-based-on-the-sunflower-trypsin-inhibitor-1-scaffold
#4
Joakim E Swedberg, Choi Yi Li, Simon J de Veer, Conan K Wang, David J Craik
Neutrophils are directly responsible for destroying invading pathogens via reactive oxygen species, antimicrobial peptides, and neutrophil serine proteases (NSPs). Imbalance between NSP activity and endogenous protease inhibitors is associated with chronic inflammatory disorders, and engineered inhibitors of NSPs are a potential therapeutic pathway. In this study we characterized the extended substrate specificity (P4-P1) of the NSP cathepsin G using a peptide substrate library. Substituting preferred cathepsin G substrate sequences into sunflower trypsin inhibitor-1 (SFTI-1) produced a potent cathepsin G inhibitor (Ki = 0...
January 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28040478/cathepsin-k-cleavage-of-sdf-1%C3%AE-inhibits-its-chemotactic-activity-towards-glioblastoma-stem-like-cells
#5
Vashendriya V V Hira, Urška Verbovšek, Barbara Breznik, Matic Srdič, Marko Novinec, Hala Kakar, Jill Wormer, Britt Van der Swaan, Brigita Lenarčič, Luiz Juliano, Shwetal Mehta, Cornelis J F Van Noorden, Tamara T Lah
Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches...
December 28, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28034583/differential-hypertensive-protease-expression-in-the-thoracic-versus-abdominal-aorta
#6
Jean Marie Ruddy, Adam W Akerman, Denise Kimbrough, Elizabeth K Nadeau, Robert E Stroud, Rupak Mukherjee, John S Ikonomidis, Jeffrey A Jones
BACKGROUND: Hypertension (HTN), which is a major risk factor for cardiovascular morbidity and mortality, can drive pathologic remodeling of the macro- and microcirculation. Patterns of aortic pathology differ, however, suggesting regional heterogeneity of the pressure-sensitive protease systems triggering extracellular matrix remodeling in the thoracic (TA) and abdominal aortas (AA). This study tested the hypothesis that the expression of two major protease systems (matrix metalloproteinases [MMPs] and cathepsins) in the TA and AA would be differentially affected with HTN...
December 26, 2016: Journal of Vascular Surgery
https://www.readbyqxmd.com/read/28033540/cathepsin-s-inhibition-changes-regulatory-t-cell-activity-in-regulating-bladder-cancer-and-immune-cell-proliferation-and-apoptosis
#7
Xiang Yan, Chun Wu, Tao Chen, Marcela M Santos, Cong-Lin Liu, Chongzhe Yang, Lijun Zhang, Jingyuan Ren, Sha Liao, Hongqiang Guo, Galina K Sukhova, Guo-Ping Shi
Regulatory T cells (Tregs) are immune suppressive cells, but their roles in tumor growth have been elusive, depending on tumor type or site. Our prior study demonstrated a role of cathepsin S (CatS) in reducing Treg immunosuppressive activity. Therefore, CatS inhibition in Tregs may exacerbate tumor growth. Using mouse bladder carcinoma MB49 cell subcutaneous implant tumor model, we detected no difference in tumor growth, whether mice were given saline- or CatS inhibitor-treated Tregs. However, mice that received inhibitor-treated Tregs had fewer splenic and tumor Tregs, and lower levels of tumor and splenic cell proliferation than mice that received saline-treated Tregs...
December 26, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/28032341/nlrp3-inflammasome-mediates-il-1%C3%AE-production-in-immune-cells-in-response-to-acinetobacter-baumannii-and-contributes-to-pulmonary-inflammation-in-mice
#8
Min-Jung Kang, Sung-Gang Jo, Dong-Jae Kim, Jong-Hwan Park
Acinetobacter baumannii is a multi-drug resistant gram-negative bacteria, and infection with this organism is one of the major causes of mortality in intensive care units. Inflammasomes are multiprotein oligomers that include caspase-1, and their activation is required for maturation of IL-1β. Inflammasome signaling is involved in host defenses against various microbial infection, but the precise mechanism by which A. baumannii activates inflammasomes and the roles of relevant signals in host defense against pulmonary A...
December 29, 2016: Immunology
https://www.readbyqxmd.com/read/27999266/discovery-of-a-new-class-of-cathepsin-k-inhibitors-in-rhizoma-drynariae-as-potential-candidates-for-the-treatment-of-osteoporosis
#9
Zuo-Cheng Qiu, Xiao-Li Dong, Yi Dai, Gao-Keng Xiao, Xin-Luan Wang, Ka-Chun Wong, Man-Sau Wong, Xin-Sheng Yao
Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis...
December 16, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27920423/de-novo-renal-neoplasia-after-kidney-transplantation-according-to-new-2016-who-classification-of-renal-tumors
#10
Albino Eccher, Luigino Boschiero, Brett Delahunt, Luca Cima, Francesca Fior, Francesco Nacchia, Momo Rostand, Amedeo Carraro, Umberto Tedeschi, Gianluigi Zaza, Marilena Casartelli Liviero, Laura Zampicinini, Marco Chilosi, Giuseppe Feltrin, Claudio Rago, Antonietta D'Errico, Claudio Ghimenton, Guido Martignoni, Matteo Brunelli
BACKGROUND De novo renal neoplasia developing after kidney transplantation at Verona Kidney Transplant Center were reviewed according to new 2016 WHO Renal Tumor Classification. MATERIAL AND METHODS Primary renal tumors developed in native or transplanted kidneys de novo following renal transplantation were retrieved and histologically reviewed by three expert uropathologists. Immunoexpression of the diagnostic antigens CD13, CD10, CK7, CK34bE12, AMACR, CAIX, AE1/AE3, CK14, GATA-3, HMB-45, cathepsin-k, S100A1, and parvalbumin was assessed...
December 6, 2016: Annals of Transplantation: Quarterly of the Polish Transplantation Society
https://www.readbyqxmd.com/read/27913299/the-inhibitory-effect-of-beta-lapachone-on-rankl-induced-osteoclastogenesis
#11
Dong Ryun Gu, Joon No Lee, Gi-Su Oh, Hyung Jin Kim, Min Seuk Kim, Seoung Hoon Lee
β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27885686/repeated-oral-administration-of-a-cathepsin-k-inhibitor-significantly-suppresses-bone-resorption-in-exercising-horses-with-evidence-of-increased-bone-formation-and-maintained-bone-turnover
#12
H Hussein, J Dulin, L Smanik, W T Drost, D Russell, M Wellman, A Bertone
Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle...
November 24, 2016: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27876137/cathepsin-k-the-association-between-cathepsin-k-expression-and-sphenoid-sinus-invasion-of-pituitary-adenomas
#13
Hongyan Liu, Guoqi Wang, Weijun Gu, Yiming Mu
Pituitary adenomas with sphenoid sinus or clivus invasion are not uncommon, but the pathogenesis responsible for this phenomenon remains unclear. Cathepsin K, expressed predominantly in osteoclasts, can degrade type I collagen and plays an essential role in bone resorption. Recent studies reported the expression of Cathepsin K in various malignant tumors, such as bone, breast, lung and prostate cancers, and its expression is further increased in bone metastasis or invasive subpopulations. In addition, cathepsin K inhibitors (CatKi) were demonstrated to effectively prevent or reduce osteolytic lesions in breast cancers with bone metastasis...
December 2016: Medical Hypotheses
https://www.readbyqxmd.com/read/27856662/therapeutic-implications-of-suppressing-osteoclast-formation-versus-function
#14
REVIEW
Steven L Teitelbaum
Anti-resorptive therapy is the principal means of treating osteoporotic disorders. The two families of presently available anti-resorptive drugs, namely bisphosphonates and denosumab, dampen activity of osteoclasts by reducing their number. In consequence, these agents also arrest bone remodelling eventuating suppressed formation as well as resorption. Evidence exists that osteoclasts recruit osteoblasts to sites of bone remodelling by mobilizing chemotactic proteins from matrix and direct secretion of such proteins that attract osteoblast precursors...
December 2016: Rheumatology
https://www.readbyqxmd.com/read/27856256/pulsed-electromagnetic-field-inhibits-rankl-dependent-osteoclastic-differentiation-in-raw264-7-cells-through-the-ca-2-calcineurin-nfatc1-signaling-pathway
#15
Jie Zhang, Haixia Xu, Zhongyu Han, Ping Chen, Qiang Yu, Yutian Lei, Zongze Li, Ming Zhao, Jing Tian
Pulsed electromagnetic field (PEMF) has been reported to improve bone healing in osteoporosis patients. However, the precise mechanism has remained largely unknown. This study aimed to investigate the effects of PEMF on nuclear factor κB ligand (RANKL)-dependent osteoclastic differentiation and the Ca(2+)-calcineurin-NFATc1 signaling pathway in RAW264.7 cells in vitro. Treating RAW264.7 cells with RANKL for 4 days induced osteoclastic differentiation in vitro, and the formation of multinucleated osteoclasts, bone resorption-pit formation, tartrate-resistant acid phosphatase (TRAP) activity and the protein levels of cathepsin K, TRAP, Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and matrix metalloproteinase 9 (MMP-9) were significantly decreased...
January 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27711349/caging-the-uncageable-using-metal-complex-release-for-photochemical-control-over-irreversible-inhibition
#16
Matthew Huisman, Jessica K White, Veronica G Lewalski, Izabela Podgorski, Claudia Turro, Jeremy J Kodanko
Photochemical control over irreversible inhibition was shown using Ru(ii)-caged inhibitors of cathepsin L. Levels of control were dependent on where the Ru(ii) complex was attached to the organic inhibitor, reaching >10 : 1 with optimal placement. A new strategy for photoreleasing Ru(ii) fragments from inhibitor-enzyme conjugates is also reported.
October 18, 2016: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27677962/loss-of-second-and-sixth-conserved-cysteine-residues-from-trypsin-inhibitor-like-cysteine-rich-domain-type-protease-inhibitors-in-bombyx-mori-may-induce-activity-against-microbial-proteases
#17
Youshan Li, Huawei Liu, Rui Zhu, Qingyou Xia, Ping Zhao
Previous studies have indicated that most trypsin inhibitor-like cysteine-rich domain (TIL)-type protease inhibitors, which contain a single TIL domain with ten conserved cysteines, inhibit cathepsin, trypsin, chymotrypsin, or elastase. Our recent findings suggest that Cys(2nd) and Cys(6th) were lost from the TIL domain of the fungal-resistance factors in Bombyx mori, BmSPI38 and BmSPI39, which inhibit microbial proteases and the germination of Beauveria bassiana conidia. To reveal the significance of these two missing cysteines in relation to the structure and function of TIL-type protease inhibitors in B...
December 2016: Peptides
https://www.readbyqxmd.com/read/27664516/neohesperidin-suppresses-osteoclast-differentiation-bone-resorption-and-ovariectomised-induced-osteoporosis-in-mice
#18
Zhen Tan, Jianwen Cheng, Qian Liu, Lin Zhou, Jacob Kenny, Tao Wang, Xixi Lin, Jinbo Yuan, Julian M W Quinn, Jennifer Tickner, Guoju Hong, An Qin, Jinmin Zhao, Jiake Xu
Excessive bone resorption by osteoclasts plays an important role in osteoporosis. Bone loss occurs in ovariectomised (OVX) mice in a similar manner to that in humans, so this model is suitable for evaluating potential new therapies for osteoporosis. Neohesperidin (NE) is a flavonoid compound isolated from citrus fruits. Its role in bone metabolism is unknown. In this study we found that neohesperidin inhibits osteoclast differentiation, bone resorption and the expression of osteoclast marker genes, tartrate-resistant acid phosphatase and cathepsin K...
September 21, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27639811/odanacatib-effects-of-16-month-treatment-and-discontinuation-of-therapy-on-bone-mass-turnover-and-strength-in-the-ovariectomized-rabbit-model-of-osteopenia
#19
Le T Duong, Randy Crawford, Kevin Scott, Christopher T Winkelmann, Gouxin Wu, Pete Szczerba, Michael A Gentile
Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7...
September 15, 2016: Bone
https://www.readbyqxmd.com/read/27630170/human-macrophage-cathepsin-b-mediated-c-terminal-cleavage-of-apolipoprotein-a-i-at-ser228-severely-impairs-antiatherogenic-capacity
#20
Donna Lee M Dinnes, Melanie Y White, Maaike Kockx, Mathew Traini, Victar Hsieh, Mi-Jurng Kim, Liming Hou, Wendy Jessup, Kerry-Anne Rye, Morten Thaysen-Andersen, Stuart J Cordwell, Leonard Kritharides
Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I, such as chlorination, nitration, oxidation, and proteolysis, can impair its antiatherogenic function, although it is unknown whether macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDMs) were incubated with human apoA-I under conditions used to induce cholesterol export...
December 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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