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Cathepsin k inhibitors

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https://www.readbyqxmd.com/read/28209487/lipoxin-a4-suppresses-osteoclastogenesis-in-raw264-7-cells-and-prevents-ovariectomy-induced-bone-loss
#1
Changyu Liu, Hanfeng Guan, Cong Cai, Feng Li, Jun Xiao
Lipoxin A4 (LXA4; 5S, 6R, 15Strihydroxy- 7,9,13-trans-11-eicosatetraenoic acid) is a metabolic product of arachidonic acid under the action of lipoxidase. This lipid molecule plays important roles in several biological functions, especially inflammatory processes. In vivo, LXA4 regulates the inflammatory response through several signaling pathways. Its mechanism suggests that it might have an effect on osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, it was here observed that LXA4 could significantly inhibit the formation and function of osteoclasts and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4)...
February 13, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28199790/an-integrated-microfluidic-processor-for-dna-encoded-combinatorial-library-functional-screening
#2
Andrew B MacConnell, Alexander K Price, Brian M Paegel
DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables whole-library functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits...
February 15, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28196851/inhibition-of-lipopolysaccharide-induced-osteoclast-formation-and-bone-resorption-in-vitro-and-in-vivo-by-cysteine-proteinase-inhibitors
#3
Fredrik Strålberg, Ali Kassem, Franciszek Kasprzykowski, Magnus Abrahamson, Anders Grubb, Catharina Lindholm, Ulf H Lerner
Inflammation-induced bone destruction is a major treatment target in many inflammatory skeletal diseases. The aim of this study was to investigate if the cysteine proteinase inhibitors cystatin C, fungal cysteine proteinase inhibitor (E-64), and N-benzyloxycarbonyl-arginyl-leucyl-valyl-glycyl-diazomethane acetate (Z-RLVG-CHN2) can inhibit LPS-induced osteoclast formation. Mouse bone marrow macrophages (BMMs) were isolated and primed with receptor activator of NF-κB ligand (RANKL) for 24 h, followed by stimulation with LPS, with and without inhibitors...
February 14, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28174118/molecular-and-structural-characterization-of-novel-cystatins-from-the-taiga-tick-ixodes-persulcatus
#4
Carolina K Rangel, Luís F Parizi, Gabriela A Sabadin, Evenilton P Costa, Nelilma C Romeiro, Masayoshi Isezaki, Naftaly W Githaka, Adriana Seixas, Carlos Logullo, Satoru Konnai, Kazuhiko Ohashi, Itabajara da Silva Vaz
Cystatins are cysteine peptidase inhibitors that in ticks mediate processes such as blood feeding and digestion. The ixodid tick Ixodes persulcatus is endemic to the Eurasia, where it is the principal vector of Lyme borreliosis. To date, no I. persulcatus cystatin has been characterized. In the present work, we describe three novel cystatins from I. persulcatus, named JpIpcys2a, JpIpcys2b and JpIpcys2c. In addition, the potential of tick cystatins as cross-protective antigens was evaluated by vaccination of hamsters using BrBmcys2c, a cystatin from Rhipicephalus microplus, against I...
January 31, 2017: Ticks and Tick-borne Diseases
https://www.readbyqxmd.com/read/28173850/new-horizons-in-treatment-of-osteoporosis
#5
REVIEW
Ozra Tabatabaei-Malazy, Pooneh Salari, Patricia Khashayar, Bagher Larijani
BACKGROUND: Prevalence of osteoporosis is increasing both in developed and developing countries. Due to rapid growth in the burden and cost of osteoporosis, worldwide, it seems reasonable to focus on the reduction of fractures as the main goal of treatment. Although, efficient pharmacological agents are available for the treatment of osteoporosis, there still remains a need to more specific drugs with less adverse effects. MAIN BODY: This review article provides a brief update on the pathogenesis, presenting current pharmacological products approved by the US Food and Drug Administration (FDA) or Europe, and also newer therapeutic agents to treat osteoporosis according to the clinical trial data available at PubMed, UpToDate, International Osteoporosis Foundation (IOF), and clinical practice guidelines...
February 7, 2017: Daru: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences
https://www.readbyqxmd.com/read/28150528/theoretical-studies-on-the-interaction-between-the-nitrile-based-inhibitors-and-the-catalytic-triad-of-cathepsin-k
#6
C Pitchumani Violet Mary, R Shankar, S Vijayakumar
Computational studies on the interaction of novel inhibitor compounds with the Cathepsin K protease has been performed to study the inhibition properties of the inhibitor compounds. The quantum chemical calculations have been performed to analyze the molecular geometries, structural stability, reactivity, nature of interaction and the charge transfer properties using B3LYP level of theory by implementing 6-311g(d,p) basis set. The calculated C-S and N-H...N bond lengths of the inhibitor-triad complexes are found to agree well with the previous literature results...
February 2, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28128866/cyclin-dependent-kinase-inhibitor-1-deficient-mice-are-susceptible-to-osteoarthritis-associated-with-enhanced-inflammation
#7
Shinsuke Kihara, Shinya Hayashi, Shingo Hashimoto, Noriyuki Kanzaki, Koji Takayama, Tomoyuki Matsumoto, Nobuaki Chinzei, Kenjiro Iwasa, Masahiko Haneda, Kazuhiro Takeuchi, Kotaro Nishida, Ryosuke Kuroda
Osteoarthritis (OA) is a multifactorial disease, and recent data suggested that cell cycle-related proteins play a role in OA pathology. Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates activation of other CDKs, and recently, we reported that p21 deficiency induced susceptibility to OA induced by destabilization of the medial meniscus (DMM) surgery through STAT3-signaling activation. However, the mechanisms associated with why p21 deficiency led to susceptibility to OA by the STAT3 pathway remain unknown...
January 27, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28117540/cathepsin-k-modulates-invasion-migration-and-adhesion-of-oral-squamous-cell-carcinomas-in-vitro
#8
Kentaro Yamashita, Mayumi Iwatake, Kuniaki Okamoto, Shin-Ichi Yamada, Masahiro Umeda, Takayuki Tsukuba
OBJECTIVE: Cathepsin K was initially discovered as an osteoclast-specific cysteine proteinase, but the enzyme is also expressed in various cancers including oral squamous cell carcinomas. The present study aimed to clarify the function of cathepsin K in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of cathepsin K were examined in six types of cell carcinomas. Carcinomas overexpressing cathepsin K were constructed. Effects of cathepsin K overexpression and treatment with odanacatib, a specific cathepsin K inhibitor, on cell invasion, migration, and adhesion were analysed...
January 24, 2017: Oral Diseases
https://www.readbyqxmd.com/read/28106828/bajijiasu-abrogates-osteoclast-differentiation-via-the-suppression-of-rankl-signaling-pathways-through-nf-%C3%AE%C2%BAb-and-nfat
#9
Guoju Hong, Lin Zhou, Xuguang Shi, Wei He, Haibin Wang, Qiushi Wei, Peng Chen, Longkai Qi, Jennifer Tickner, Li Lin, Jiake Xu
Pathological osteolysis is commonly associated with osteoporosis, bone tumors, osteonecrosis, and chronic inflammation. It involves excessive resorption of bone matrix by activated osteoclasts. Suppressing receptor activator of NF-κB ligand (RANKL) signaling pathways has been proposed to be a good target for inhibiting osteoclast differentiation and bone resorption. Bajijiasu-a natural compound derived from Morinda officinalis F. C. How-has previously been shown to have anti-oxidative stress property; however, its effect and molecular mechanism of action on osteoclastogenesis and bone resorption remains unclear...
January 19, 2017: International Journal of Molecular Sciences
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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