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Philip Stashenko - One of the best experts on this subject based on the ideXlab platform.
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il 17 receptor a signaling is protective in infection stimulated periapical Bone Destruction
Journal of Immunology, 2013Co-Authors: Emad Alshwaimi, Philip Stashenko, Justine M Dobeck, Ellen Berggreen, Hisako Furusho, Jonathan Caleb Rossall, Subbiah YoganathanAbstract:IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on Bone Destruction. In this study we determined the role of IL-17RA signal in Bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased Bone Destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both α and β isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1β and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and Bone Destruction via suppression of neutrophil and mononuclear inflammation.
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interleukin 6 deficiency increases inflammatory Bone Destruction
Infection and Immunity, 2001Co-Authors: Hajime Sasaki, Khaled Balto, Philip StashenkoAbstract:Periapical Bone Destruction occurs as a consequence of pulpal infection. In previous studies, we showed that interleukin-1 (IL-1) is the primary stimulator of Bone Destruction in this model. IL-6 is a pleiotropic cytokine that is induced in these infections and has both pro- and anti-inflammatory activities. In the present study, we determined the role of IL-6 in regulating IL-1 expression and Bone resorption. The first molars of IL-6 knockouts (IL-6(-/-)) and wild-type mice were subjected to surgical pulp exposure and infection with a mixture of four common pulpal pathogens, including Prevotella intermedia, Fusobacterium nucleatum, Peptostreptococcus micros, and Streptococcus intermedius. Mice were killed after 21 days, and Bone Destruction and cytokine expression were determined. Surprisingly, Bone Destruction was significantly increased in IL-6(-/-) mice versus that in wild-type mice (by 30%; P < 0.001). In a second experiment, the effects of chronic (IL-6(-/-)) IL-6 deficiency and short-term IL-6 deficiency induced by in vivo antibody
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toll like receptor 4 deficient mice have reduced Bone Destruction following mixed anaerobic infection
Infection and Immunity, 2000Co-Authors: Hajime Sasaki, Philip StashenkoAbstract:Innate recognition of bacterial products constitutes a principal bulwark of host defense against infection. Innate mechanisms, including phagocytic leukocytes and cytokines, play a central role in the pathogenesis of oral infections (5, 17). Strong links have been shown between defects in polymorphonuclear leukocytes and increased periapical and periodontal disease (12, 26). Other responses, particularly the production of proinflammatory cytokines such as interleukin 1 (IL-1) and tumour necrosis factor alpha (TNF-α), mediate tissue Destruction, including Bone resorption (2, 29). Therefore, modulation of innate responses to decrease the expression and activity of inflammatory cytokines represents a potential way of ameliorating alveolar Bone Destruction. The recently identified family of Toll-like receptors (TLRs), homologous to Drosophila Toll, are key participants in innate recognition of pathogens (16). TLRs are characterized structurally by an extracellular leucine-rich repeat domain and a cytoplasmic domain that is homologous to the signaling domain of the IL-1 receptor (IL-1R). Moreover, the signal transduction pathway for TLRs and IL-1R that leads to cytokine expression is also intertwined with TNF receptor signaling pathways (16). To date, the sequences of seven TLRs have been reported in humans and mice (24). There is evidence that both TLR2 and TLR4 are involved in responses to bacterial lipopolysaccharide (LPS), leading to the expression of proinflammatory cytokines IL-1, TNF-α, IL-6, and IL-8 (10, 14, 19, 43). Recently, TLR2 has also been shown to mediate responses to gram-positive bacterial cell wall components, including peptidoglycan (34) and lipoteichoic acid (27, 44). To date, the role of TLRs in responses to oral pathogens and in alveolar Bone Destruction is unknown. The LPS hyporesponsive mouse strains C3H/HeJ and C57BL/10ScCr have mutations that map to a single autosomal lps locus (42). The consequence of this hyporesponsiveness is decreased susceptibility to septic shock (41) and enhanced susceptibility to challenge with some gram-negative pathogens (21). Recently, C3H/HeJ mice were shown to have an inactivating point mutation within the signal transducing domain of the Tlr4 gene (22), whereas C57BL/10ScCr mice exhibit a deletion of Tlr4 (23). In the present study, we compared infection-stimulated infraosseous Bone resorption and dentoalveolar abscess formation in TLR4-deficient LPS-hyporesponsive C3H/HeJ and wild-type control C3H/HeOuJ mice. The results demonstrate that TLR4 function significantly enhances inflammatory responses and Bone Destruction in this model.
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quantification of periapical Bone Destruction in mice by micro computed tomography
Journal of Dental Research, 2000Co-Authors: Khaled Balto, Ralph Muller, D C Carrington, Justine M Dobeck, Philip StashenkoAbstract:Bacterial infections of the dental pulp result in tissue Destruction and periapical Bone resorption. The availability of genetically engineered mouse strains is a major advantage in the use of this model system for studies of periapical pathogenesis. The main limitation of the mouse model is its small size, and the necessity for laborious histologic analyses to quantify periapical Bone Destruction. In the present study, we evaluated the use of a new technology, high-resolution micro-computed tomography (micro-CT), for the rapid and non-invasive quantification of periapical Bone Destruction. Periapical lesions were induced in the lower first molars of mice by exposing the pulp to the oral environment. Mandibles were harvested on day 21 after pulp exposure, and were subjected to micro-CT analysis, with 17-μm-thick radiographic sections. Samples were then decalcified, embedded, and sectioned for histology. The cross-sectional area of periapical lesions was determined by image analysis of corresponding micro-...
Olivier Huck - One of the best experts on this subject based on the ideXlab platform.
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akkermansia muciniphila reduces porphyromonas gingivalis induced inflammation and periodontal Bone Destruction
Journal of Clinical Periodontology, 2020Co-Authors: George Rubin, Zev Kizelnik, Nasreen S Haque, Olivier Huck, Hannah Mulhall, Radha Iyer, John D Perpich, Patrice D Cani, Salomon AmarAbstract:Aim: Akkermansia muciniphila is a beneficial gut commensal, whose anti-inflammatory properties have recently been demonstrated. This study aimed to evaluate the effect of A. muciniphila on Porphyromonas gingivalis elicited inflammation. Material and Methods: In lean and obese mice, A. muciniphila was administered in P. gingivalis-induced calvarial abscess and in experimental periodontitis model (EIP). Bone Destruction and inflammation were evaluated by histomorphometric analysis. In vitro, A. muciniphila was co-cultured with P. gingivalis, growth and virulence factor expression was evaluated. Bone marrow macrophages (BMMϕ) and gingival epithelial cells (TIGK) were exposed to both bacterial strains, and the expression of inflammatory mediators, as well as tight junction markers, was analysed. Results: In a model of calvarial infection, A. muciniphila decreased inflammatory cell infiltration and Bone Destruction. In EIP, treatment with A. muciniphila resulted in a decreased alveolar Bone loss. In vitro, the addition of A. muciniphila to P. gingivalis-infected BMMϕ increased anti-inflammatory IL-10 and decreased IL-12. Additionally, A. muciniphila exposure increases the expression of junctional integrity markers such as integrin-β1, E-cadherin and ZO-1 in TIGK cells. A. muciniphila co-culture with P. gingivalis reduced gingipains mRNA expression. Discussion: This study demonstrated the protective effects of A. muciniphila administration and may open consideration to its use as an adjunctive therapeutic agent to periodontal treatment.
Salomon Amar - One of the best experts on this subject based on the ideXlab platform.
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akkermansia muciniphila reduces porphyromonas gingivalis induced inflammation and periodontal Bone Destruction
Journal of Clinical Periodontology, 2020Co-Authors: George Rubin, Zev Kizelnik, Nasreen S Haque, Olivier Huck, Hannah Mulhall, Radha Iyer, John D Perpich, Patrice D Cani, Salomon AmarAbstract:Aim: Akkermansia muciniphila is a beneficial gut commensal, whose anti-inflammatory properties have recently been demonstrated. This study aimed to evaluate the effect of A. muciniphila on Porphyromonas gingivalis elicited inflammation. Material and Methods: In lean and obese mice, A. muciniphila was administered in P. gingivalis-induced calvarial abscess and in experimental periodontitis model (EIP). Bone Destruction and inflammation were evaluated by histomorphometric analysis. In vitro, A. muciniphila was co-cultured with P. gingivalis, growth and virulence factor expression was evaluated. Bone marrow macrophages (BMMϕ) and gingival epithelial cells (TIGK) were exposed to both bacterial strains, and the expression of inflammatory mediators, as well as tight junction markers, was analysed. Results: In a model of calvarial infection, A. muciniphila decreased inflammatory cell infiltration and Bone Destruction. In EIP, treatment with A. muciniphila resulted in a decreased alveolar Bone loss. In vitro, the addition of A. muciniphila to P. gingivalis-infected BMMϕ increased anti-inflammatory IL-10 and decreased IL-12. Additionally, A. muciniphila exposure increases the expression of junctional integrity markers such as integrin-β1, E-cadherin and ZO-1 in TIGK cells. A. muciniphila co-culture with P. gingivalis reduced gingipains mRNA expression. Discussion: This study demonstrated the protective effects of A. muciniphila administration and may open consideration to its use as an adjunctive therapeutic agent to periodontal treatment.
Won Yoon Chung - One of the best experts on this subject based on the ideXlab platform.
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abstract 2147 the effects of artemisinin dihydroartemisinin and artemisinin glycolipid on non small cell lung cancer induced Bone Destruction
Cancer Research, 2014Co-Authors: Kwang Kyun Park, Won Yoon ChungAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Lung cancer is the major cause of cancer-related death in males worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of entire lung cancer and largely metastasizes to Bone. Bone consistently maintains the balance between osteoclasts and osteoblasts, but NSCLC metastasized to Bone interacts with normal Bone cells and abnormally enhances osteoclasts-mediated Bone resorption. As a result, enhanced Bone resorption results in the release of transforming growth factor-beta (TGF-β) and insulin-like growth factor -1 (IGF-1) which promote cancer progression. Plant-derived compounds have been received attention as therapeutic agents for many human diseases. Artemisinin (ART) which is isolated from chinese medicinal herb, Artemisia annua and its derivative dihydroartemisinin (DHA) have been known as outstanding anti-malarial agents and have also potent anti-cancer activities. ART-glycolipid is ART's derivative that combined ART with the glycolipid daumone in order to enhance anti-cancer activity. We found that cell viability was decreased in A549 cells treated with ART, DHA and ART-glycolipid. ART, DHA and ART-glycolipid decreased the migration of A549 cells treated with or without TGF- β1 and IGF-1 which are highly discovered in Bone metastasis of NSCLC. In addition, they inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in Bone marrow macrophages (BMMs). In particular, ART-glycolipid showed the most potent inhibitory effect. Therefore, we expect that ART, DHA and ART-glycolipid can inhibit metastatic ability of A549 cells and Bone resorbing activity of osteoclasts by reducing secretion of matrix metalloproteinases- 9 (MMP-9) and cathepsin K activities in BMM. These results indicate that ART, DHA and ART-glycolipid may serve as useful agents for attenuating NSCLC induced Bone Destruction. Citation Format: Gwang-Taek Ma, Kwang-Kyun Park, Won-Yoon Chung. The effects of artemisinin, dihydroartemisinin and artemisinin-glycolipid on non-small cell lung cancer induced Bone Destruction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2147. doi:10.1158/1538-7445.AM2014-2147
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Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated Bone Destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts
Investigational New Drugs, 2014Co-Authors: Kwang Kyun Park, Won Yoon ChungAbstract:Breast cancer frequently spreads to Bone. The interaction between Bone metastases and microenvironment, referred as the “vicious cycle”, increases both tumor burden and Bone Destruction. Therefore, inhibition at any point in this “vicious cycle” can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated Bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-β-stimulated cell viability, migration, and invasion and decreased TGF-β-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse Bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced Bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated Bone Destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the “vicious cycle” between breast cancer metastases and Bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic Bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced Bone Destruction in breast cancer patients.
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the inhibitory effect of roasted licorice extract on human metastatic breast cancer cell induced Bone Destruction
Phytotherapy Research, 2013Co-Authors: Sun Kyoung Lee, Kwang Kyun Park, Jung Han Yoon Park, Soon Sung Lim, Won Yoon ChungAbstract:The aim of this study was to determine whether the ethanol extract of roasted licorice (rLE) could inhibit breast cancer-mediated Bone Destruction. rLE treatment reduced the viability of MDA-MB-231 human metastatic breast cancer cells but did not show any cytotoxicity in hFOB1.19 human osteoblastic cells and murine Bone marrow-derived macrophages (BMMs). rLE inhibited expression and secretion of receptor activator of nuclear factor κB ligand (RANKL) as well as the mRNA and protein expression of cyclooxygenase-2 in osteoblastic cells exposed to the conditioned medium of breast cancer cells. rLE dramatically inhibited RANKL-induced osteoclastogenesis in BMMs, thereby reducing osteoclast-mediated pit formation. Moreover, treatment with licochalcone A and isoliquiritigenin as the active components, whose contents are increased by the roasting process, remarkably suppressed RANKL-induced osteoclast formation in BMMs, respectively. Furthermore, orally administered rLE substantially blocked tumor growth and Bone Destruction in mice inoculated with breast cancer cells in the tibiae. Serum levels of tartrate-resistant acid phosphatase and C-terminal cross-linking telopeptide of type I collagen and trabecular Bone morphometric parameters were reversed to almost the same levels as the control mice by the rLE treatment. In conclusion, rLE may be a beneficial agent for preventing and treating Bone Destruction in patients with breast cancer. Copyright © 2013 John Wiley & Sons, Ltd.
Jing Yang - One of the best experts on this subject based on the ideXlab platform.
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c reactive protein promotes Bone Destruction in human myeloma through the cd32 p38 mapk twist axis
Science Signaling, 2017Co-Authors: Jing Yang, Zhiqiang Liu, Huan Liu, Jianling Yang, Pei Lin, Qiang Wang, Zheng Yin, Eric DavisAbstract:Bone Destruction is a hallmark of myeloma and affects 80% of patients. Myeloma cells promote Bone Destruction by activating osteoclasts. In investigating the underlying mechanism, we found that C-reactive protein (CRP), a protein secreted in increased amounts by hepatocytes in response to myeloma-derived cytokines, activated myeloma cells to promote osteoclastogenesis and Bone Destruction in vivo. In mice bearing human Bone grafts and injected with multiple myeloma cells, CRP bound to surface CD32 (also known as FcγRII) on myeloma cells, which activated a pathway mediated by the kinase p38 MAPK and the transcription factor Twist that enhanced the cells’ secretion of osteolytic cytokines. Furthermore, analysis of clinical samples from newly diagnosed myeloma patients revealed a positive correlation between the amount of serum CRP and the number of osteolytic Bone lesions. These findings establish a mechanism by which myeloma cells are activated to promote Bone Destruction and suggest that CRP may be targeted to prevent or treat myeloma-associated Bone disease in patients.
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c reactive protein promotes Bone Destruction in human myeloma by stimulating myeloma cell production of osteolytic cytokines via the cd32 fcγrii p38mapk twist axis
Blood, 2017Co-Authors: Jing Yang, Zhiqiang Liu, Huan Liu, Jianling Yang, Pei Lin, Qiang Wang, Robert Z Orlowski, Richard E Davis, Jian HouAbstract:More than 80% of patients with multiple myeloma develop Bone Destruction that causes pathological fractures, severe Bone pain, spinal cord compression, and hypercalcemia. The normally balanced act between Bone-resorbing osteoclasts and Bone-forming osteoblasts is disrupted in those patients. It is well established that myeloma cells mediate Bone Destruction by activating osteoclasts. Studies have been shown that myeloma cells produce a number of cytokines such as nuclear factor kappa-B ligand (RANKL), macrophage inflammatory protein (MIP)-1α, and monocyte chemoattractant protein (MCP)-1, which increase osteoclast differentiation and Bone resorption activity. Yet the mechanism how myeloma cells are regulated to do so is unknown. Here we show that C-reactive protein (CRP), a protein secreted in elevated amounts by hepatocytes in response to myeloma-derived cytokines, may be responsible for activating myeloma cells to promote osteoclastogenesis and inducing Bone Destruction in vivo . Using both SCID and SCID-hu models, we found that injection of human CRP into myeloma-bearing, but not myeloma-free, mice accelerated the induction of Bone Destruction in both murine and human Bones, and significantly more osteoclasts were detected in the Bone-tumor interface in CRP-injected mice as compared with controls. Mechanistic studies show that CRP binds to surface CD32/FcγRII, activates p38MAPK-twist pathways, and upregulates the secretion of osteolytic cytokines by myeloma cells. Furthermore, clinical studies revealed a highly positive correlation between the level of serum CRP and the number of osteolytic Bone lesions in newly diagnosed myeloma patients. These findings establish a novel mechanism by which myeloma cells are activated to promote Bone Destruction in patients and suggest that CRP may be targeted to prevent or treat myeloma-associated Bone disease. Disclosures Yang: Poseida Therapuetics: Research Funding; Cellectis: Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity9s Board of Directors or advisory committees.
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p38 mapk in myeloma cells regulates osteoclast and osteoblast activity and induces Bone Destruction
Cancer Research, 2012Co-Authors: Zhiqiang Liu, Pei Lin, Yuhuan Zheng, Jianfei Qian, Bangxing Hong, Mingjun Zhang, Zhen Cai, Robert Z Orlowski, Larry W Kwak, Jing YangAbstract:p38 mitogen-activated protein kinase (MAPK), which is constitutively activated in human myeloma, has been implicated in Bone Destruction by this cancer, but the processes it recruits are obscure. In this study, we show that p38 activity in myeloma inhibits osteoblast differentiation and Bone formation, but also enhances osteoclast maturation and Bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Attenuating p38, DKK-1, or MCP-1 were each sufficient to reduce Bone lesions in vivo. Although it is well known that DKK-1 inhibits osteoblast differentiation, we found that together with MCP-1, it could also promote osteoclast differentiation and Bone resorption. The latter effects were mediated by enhancing expression of RANK in osteoclast progenitor cells and by upregulating secretion of its ligand RANKL from stromal cells and mature osteoblasts. In summary, our study defined the mechanisms by which p38 signaling in myeloma cells regulates osteoblastogenesis, osteoclastogenesis, and Bone Destruction. Our findings, which may have implications for Bone invasion by other cancers where p38 is elevated, strongly suggests that targeting p38 for inhibition may offer an effective therapeutic approach to treat osteolytic Bone lesions in patients with myeloma.