Read by QxMD icon Read

Cathepsin k inhibitors

Naira F Z Schneider, Claudia Cerella, Jin-Young Lee, Aloran Mazumder, Kyung Rok Kim, Annelise de Carvalho, Jennifer Munkert, Rodrigo M Pádua, Wolfgang Kreis, Kyu-Won Kim, Christo Christov, Mario Dicato, Hyun-Jung Kim, Byung Woo Han, Fernão C Braga, Cláudia M O Simões, Marc Diederich
Cardiac glycosides (CGs) are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV) out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+ /K+ -ATPase α subunit, assessed by computational docking...
2018: Frontiers in Pharmacology
Youngil Kwon, Hyunjung Ko, Soojung Kim, Miri Kim
BACKGROUND/AIM: Continuous research efforts have been focusing on promoting healing of delayed replantation of avulsed teeth. The aim of this in vivo study was to assess the effect of cathepsin K inhibitor surface treatment on delayed tooth replantation.Materials and Methods Thirty-four premolar roots of four beagle dogs were extracted and conventional root canal treatment was performed. The canals were filled with gutta-percha and cement. All extracted teeth were air-dried for 1 h. Teeth were divided into two groups according to the root surface treatment prior to replantation: control (n = 13) and cathepsin K inhibitor (n = 21)...
March 13, 2018: Dental Traumatology: Official Publication of International Association for Dental Traumatology
Erik Lindström, Biljana Rizoska, Karin Tunblad, Charlotte Edenius, Alison M Bendele, Don Maul, Michael Larson, Neha Shah, Valerie Yoder Otto, Chris Jerome, Urszula Grabowska
BACKGROUND: MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). METHODS: Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks...
March 9, 2018: Journal of Translational Medicine
Bhavita Walia, Elizabeth Lingenheld, Le Duong, Archana Sanjay, Hicham Drissi
Osteoporosis management is currently centered around bisphosphonates, which inhibit osteoclast (OC) bone resorption but do not affect bone formation. This reduces fracture risk, but fails to restore healthy bone remodeling. Studies in animal models showed that cathepsin K (CatK) inhibition by genetic deletion or chemical inhibitors maintained bone formation while abrogating resorption during bone remodeling and stimulated periosteal bone modeling. Recently, periosteal mononuclear tartrate-resistant acid phosphatase-positive (TRAP+ ) osteoclast precursors (OCPs) were shown to augment angiogenesis-coupled osteogenesis...
February 26, 2018: Annals of the New York Academy of Sciences
Alanna M Dubrovsky, Mie Jin Lim, Nancy E Lane
Osteoporosis in rheumatic diseases is a very well-known complication. Systemic inflammation results in both generalized and localized bone loss and erosions. Recently, increased knowledge of inflammatory process in rheumatic diseases has resulted in the development of potent inhibitors of the cytokines, the biologic DMARDs. These treatments reduce systemic inflammation and have some effect on the generalized and localized bone loss. Progression of bone erosion was slowed by TNF, IL-6 and IL-1 inhibitors, a JAK inhibitor, a CTLA4 agonist, and rituximab...
February 22, 2018: Calcified Tissue International
N Binkley, D Krueger, A E de Papp
INTRODUCTION: Case reports of women sustaining multiple vertebral fractures (VF) soon afterdenosumab discontinuation are accumulating. METHODS: We report a woman with five new vertebral fractures in ~8 months following discontinuation of long-term odanacatib (ODN), an experimental cathepsin K inhibitor. RESULTS: DXA examination demonstrated an ~12% decline in bone mineral density (BMD) and ~9% decline in trabecular bone score (TBS) since ODN discontinuation...
February 18, 2018: Osteoporosis International
Shijun Li, Ming Wang, David M Ojcius, Bijun Zhou, Weilin Hu, Ying Liu, Qing Ma, Guangpeng Tang, Dingming Wang, Jie Yan
Leptospirosis is a worldwide zoonosis caused by spirochetes from the genus Leptospira. Although there is a large diversity of clinical signs and symptoms, a severe inflammatory response is common to all leptospirosis patients. The mechanism of IL-1βß secretion during Leptospira infection has been previously studied in mouse macrophages. However, the outcome of Leptospira infection is very different in human and murine macrophages, and the mechanisms responsible for IL-1β secretion in human macrophages had not been investigated...
February 9, 2018: Microbes and Infection
Kristie N Tu, Janette D Lie, Chew King Victoria Wan, Madison Cameron, Alaina G Austel, Jenny K Nguyen, Kevin Van, Diana Hyun
Approximately 10 million men and women in the U.S. have osteoporosis,1 a metabolic bone disease characterized by low bone density and deterioration of bone architecture that increase the risk of fractures.2 Osteoporosis-related fractures can increase pain, disability, nursing home placement, total health care costs, and mortality.3 The diagnosis of osteoporosis is primarily determined by measuring bone mineral density (BMD) using noninvasive dual-energy x-ray absorptiometry. Osteoporosis medications include bisphosphonates, receptor activator of nuclear factor kappa-B ligand inhibitors, estrogen agonists/antagonists, parathyroid hormone analogues, and calcitonin...
February 2018: P & T: a Peer-reviewed Journal for Formulary Management
Preety Panwar, Simon Law, Andrew Jamroz, Pouya Azizi, Dongwei Zhang, Marco Ciufolini, Dieter Brömme
BACKGROUND AND PURPOSE: Attempts to generate active site-directed cathepsin K (CatK) inhibitors for the treatment of osteoporosis have failed because of side effects. We have previously shown that an ectosteric tanshinone CatK inhibitor isolated from Salvia miltiorrhiza blocked selectively the collagenase activity of CatK without affecting the active site and demonstrated its in-vivo bone-preserving activity. Here, we characterize the antiresorptive potential of tanshinones, which may provide a scaffold for side effect-free CatK inhibitors...
December 26, 2017: British Journal of Pharmacology
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Cindy Sander, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Paul Dent
The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET and mutant K-RAS via autophagic degradation. In the present studies, in a dose-dependent fashion, neratinib reduced the expression levels of mutant K-RAS or of mutant N-RAS, which was augmented in an additive to greater than additive fashion by the HDAC inhibitors sodium valproate and AR42. Neratinib could reduce PDGFRα levels in GBM cells, that was enhanced by sodium valproate...
February 1, 2018: Cancer Biology & Therapy
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Paul Dent
Patients whose NSCLC tumors become afatinib resistant presently have few effective therapeutic options to extend their survival. Afatinib resistant NSCLC cells were sensitive to clinically relevant concentrations of the irreversible pan-HER inhibitor neratinib, but not by the first generation ERBB1/2/4 inhibitor lapatinib. In multiple afatinib resistant NSCLC clones, HDAC inhibitors reduced the expression of ERBB1/3/4, but activated c-SRC, which resulted in higher total levels of ERBB1/3 phosphorylation. Neratinib also rapidly reduced the expression of ERBB1/2/3/4, c-MET and of mutant K-/N-RAS; K-RAS co-localized with phosphorylated ATG13 and with cathepsin B in vesicles...
October 27, 2017: Oncotarget
Justin B Schaal, Dat Q Tran, Akshay Subramanian, Reshma Patel, Teresina Laragione, Kevin D Roberts, Katie Trinh, Prasad Tongaonkar, Patti A Tran, Dmitriy Minond, Gregg B Fields, Paul Beringer, André J Ouellette, Percio S Gulko, Michael E Selsted
θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture...
2017: PloS One
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 pronociceptive and antinociceptive influences; the contribution by the gastrointestinal 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 gastrointestinal bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse DRG neurons...
November 29, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
Joel Jules, Yi-Ping Li, Wei Chen
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...
February 2018: Bone
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
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
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
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
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
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"