Read by QxMD icon Read

Cathepsin k inhibitors

Jingsong He, Qingxiao Chen, Huiyao Gu, Jing Chen, Enfan Zhang, Xing Guo, Xi Huang, Haimeng Yan, DongHua He, Yang Yang, Yi Zhao, Gang Wang, Huang He, Qing Yi, Zhen Cai
Histone deacetylases are promising therapeutic targets in hematological malignancies. In the present work, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myeloma and its associated bone diseases using different models. The cytotoxicity of chidamide toward myeloma is due to its induction of cell apoptosis and cell cycle arrest by increasing the levels of caspase family proteins, including p21 and p27, among others...
May 17, 2018: Haematologica
Yaxian Ma, Xiaoyong Qiao, Rujun Zeng, Ran Cheng, Jun Zhang, Yunyao Luo, Ying Nie, Ying Hu, Zhilan Yang, Jing Zhang, Lin Liu, Wenming Xu, Charles C Xu, Liangzhi Xu
The receptor activator of NF-κB ligand-induced osteoclast differentiation has a critical role in the process of bone metabolism. Overactivation of osteoclastogenesis may result in a series of diseases. Irisin, a novel myokine, which was first reported in 2012, has been proposed to mediate the beneficial metabolic effects of exercise. Studies have demonstrated that irisin targets osteoblasts by promoting osteoblast proliferation and differentiation; however, the underlying mechanism regarding the effect of irisin on osteoclasts remains elusive...
May 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Erik Lindström, Biljana Rizoska, Ian Henderson, Ylva Terelius, Markus Jerling, Charlotte Edenius, Urszula Grabowska
BACKGROUND: Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. METHODS: The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts...
May 9, 2018: Journal of Translational Medicine
Thomas N Rohrabaugh, Kelsey A Collins, Congcong Xue, Jessica K White, Jeremy J Kodanko, Claudia Turro
A new complex, [Ru(tpy)(dppn)(Cbz-Leu-NHCH2CN)]2+ (1, tpy = 2,2':6',2''-terpyridine, dppn = benzo[i]dipyrido[3,2-a:2',3'-c]phenazine) was synthesized and its photochemical properties were investigated. This complex undergoes photorelease of the Cbz-Leu-NHCH2CN ligand, a known cathepsin K inhibitor, with a quantum yield, Φ450, of 0.0012(4) in water (λirr = 450 nm). In addition, 1 sensitizes the production of singlet oxygen upon visible light irradiation with quantum yield, ΦΔ, of 0.64(3) in CH3OH. The photophysical properties of 1 were compared with those of [Ru(tpy)(bpy)(Cbz-Leu-NHCH2CN)]2+ (2, bpy = 2,2'-bipyridine), [Ru(tpy)(dppn)(CH3CN)]2+ (3), and [Ru(tpy)(bpy)(CH3CN)]2+ (4) to evaluate the effect of the release of the Cbz-Leu-NHCH2CN inhibitor relative to the CH3CN ligand, as well as the role of dppn as the bidentate ligand for 1O2 production instead of bpy...
May 9, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Tomonari Kajita, Wataru Ariyoshi, Toshinori Okinaga, Sho Mitsugi, Kazuhiro Tominaga, Tatsuji Nishihara
Several growth factors in bone tissues are reported to be associated with osteoclastogenesis. Activin-A, a member of the transforming growth factor-β (TGF-β) family is known to be present in bone tissues and an important regulator in osteoclastogenesis with SMAD-mediated signaling being crucial for inducing osteoclast differentiation. In the present study, we examined the effect and underlying mechanisms of activin-A on osteoclast formation in vitro culture systems. Activin-A enhanced osteoclast formation in both mouse bone marrow cells and monocyte/macrophage cell line RAW 264...
May 8, 2018: Journal of Cellular Biochemistry
Jun Lu, Maolin Wang, Ziyue Wang, Zhongqi Fu, Aiping Lu, Ge Zhang
Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a target of medicinal chemistry efforts for its role in bone matrix degradation. Inhibition of the Cat K enzyme reduces bone resorption and thus, has rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. Over the past decades, considerable efforts have been made to design and develop highly potent, excellently selective and orally applicable Cat K inhibitors...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
H M Suranji Wijekoon, Eugene C Bwalya, Jing Fang, Sangho Kim, Kenji Hosoya, Masahiro Okumura
BACKGROUND: Sodium pentosan polysulfate (NaPPS) was testified as a chondroprotective drug in with a detailed rationale of the disease-modifying activity. This study was undertaken to determine whether anti-osteoarthritis drug, NaPPS inhibited osteoclasts (OC) differentiation and function. Canine bone marrow mononuclear cells (n = 6) were differentiated to OC by maintaining with receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) for up to 7 days with the treatment of NaPPS at concentration of 0, 0...
May 2, 2018: BMC Veterinary Research
Cong-Lin Liu, Junli Guo, Xian Zhang, Galina K Sukhova, Peter Libby, Guo-Ping Shi
Cysteine protease cathepsins have traditionally been considered as lysosome-restricted proteases that mediate proteolysis of unwanted proteins. However, studies from the past decade demonstrate that these proteases are localized not only in acidic compartments (endosomes and lysosomes), where they participate in intracellular protein degradation, but also in the extracellular milieu, plasma membrane, cytosol, nucleus, and nuclear membrane, where they mediate extracellular matrix protein degradation, cell signalling, and protein processing and trafficking through the plasma and nuclear membranes and between intracellular organelles...
April 20, 2018: Nature Reviews. Cardiology
Zhen-Yu Cai, Bo Yang, Ying-Xu Shi, Wei-Lin Zhang, Fei Liu, Wei Zhao, Mao-Wei Yang
Diabetes is a chronic disease that disrupts the balance between bone formation and bone desorption, which can lead to osteoporosis, increasing the risk of fracture. However, compared with osteoblasts, the biological effects of hyperglycemia on osteoclastogenesis remain to be elucidated. Therefore, we investigated the impact of glucose at different concentrations (5.5, 10.5, 15.5, 20.5, 25.5, and 30.5 mM) on osteoclastogenesis using RAW264.7 cells. Cell proliferation was measured with the cell counting kit-8 assay, and osteoclastogenesis was detected with tartrate-resistant acid phosphatase staining and bone resorption assays, as well as protein cathepsin K expression...
April 9, 2018: Biochemical and Biophysical Research Communications
Svenja Memmert, Marjan Nokhbehsaim, Anna Damanaki, Andressa V B Nogueira, Alexandra K Papadopoulou, Christina Piperi, Efthimia K Basdra, Birgit Rath-Deschner, Werner Götz, Joni A Cirelli, Andreas Jäger, James Deschner
BACKGROUND: Cathepsin S is a cysteine protease, which is expressed in human periodontal ligament (PDL) cells under inflammatory and infectious conditions. This in vitro study was established to investigate the effect of cathepsin S on PDL cell wound closure. METHODS: An in vitro wound healing assay was used to monitor wound closure in wounded PDL cell monolayers for 72 h in the presence and absence of cathepsin S. In addition, the effects of cathepsin S on specific markers for apoptosis and proliferation were studied at transcriptional level...
April 5, 2018: BMC Oral Health
Emanuela Nizi, Alessio Sferrazza, Danilo Fabbrini, Valentina Nardi, Matteo Andreini, Rita Graziani, Nadia Gennari, Alberto Bresciani, Giacomo Paonessa, Steven Harper
Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine proteases (that include cathepsins B, K, L and S) is likely to be required for the development of agents targeting FP2. Here we describe a series of P2-modified aminonitrile based inhibitors of FP2 that provide a clear strategy toward addressing selectivity for the P...
March 26, 2018: Bioorganic & Medicinal Chemistry Letters
Brian T O'Neill, Elizabeth M Beck, Christopher R Butler, Charles E Nolan, Cathleen Gonzales, Lei Zhang, Shawn D Doran, Kimberly Lapham, Leanne M Buzon, Jason K Dutra, Gabriela Barreiro, Xinjun Hou, Luis A Martinez-Alsina, Bruce N Rogers, Anabella Villalobos, John C Murray, Kevin Ogilvie, Erik A LaChapelle, Cheng Chang, Lorraine F Lanyon, Claire M Steppan, Ashley Robshaw, Katherine Hales, Germaine G Boucher, Karamjeet Pandher, Christopher Houle, Claude W Ambroise, David Karanian, David Riddell, Kelly R Bales, Michael A Brodney
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically has only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype...
April 3, 2018: Journal of Medicinal Chemistry
Chang-Hong Li, Lin-Lin Xu, Lei-Lei Jian, Ruo-Han Yu, Jin-Xia Zhao, Lin Sun, Guo-Hong Du, Xiang-Yuan Liu
Tofacitinib, a small molecule JAK inhibitor, has been widely used to reduce inflammation and inhibit progression of bone destruction in rheumatoid arthritis. STAT3, a downstream signaling molecule of JAK, plays a key role in the activation of signaling in response to inflammatory cytokines. Thus, targeting STAT3 may be an inspiring strategy for treating osteoclast-related diseases such as rheumatoid arthritis. In this study, we first investigated the effects of Stattic, a STAT3 inhibitor, on receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis...
March 24, 2018: International Immunopharmacology
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 4 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 hour...
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...
March 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...
May 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...
April 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-1β 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...
April 2018: Microbes and Infection
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"