Science.gov

Sample records for agonist attenuates bone

  1. Mas-related G-protein-coupled receptor c agonist bovine adrenal medulla 8-22 attenuates bone cancer pain in mice

    PubMed Central

    Sun, Yu-E; Lu, Cui-E; Lei, Yishan; Liu, Yue; Ma, Zhengliang; Gu, Xiaoping

    2015-01-01

    Objectives: The aim of this study is to investigate the effects of Mas-related G-protein-coupled receptor C (MrgC) agonist bovine adrenal medulla 8-22 (BAM8-22) on bone cancer pain and mirror-image pain. Methods: Bone cancer pain was induced by intramedullary injection of NC2472 fibrosarcoma cells in the mice. BAM8-22 and/or anti-MrgC antibody were injected intrathecally at day 14 after bone cancer induction and their effects on pain behaviors were detected. The pain behaviours were assessed by the number of spontaneous foot lifts and paw withdrawal mechanical threshold (PWMT) tests. MrgC expression was detected using western blot analysis and immunofluorescence assay. Results: There were increased bone cancer pain and mirror-image pain in the tumor-bearing mice while not in the sham-treated mice. BAM8-22 attenuated bone cancer pain in mice dose dependently with the highest effects at 2 hr after BAM8-22 administration, and anti-MrgC antibody reversed the effects of BAM8-22. However, intrathecal administration of BAM8-22 did not affect the mirror-image pain. Furthermore, BAM8-22 stimulated the expression of MrgC in the spinal dorsal horn. Conclusions: MrgC agonist BAM8-22 could attenuate bone cancer pain in mice. This study may provide a novel strategy for the treatment of bone cancer pain. PMID:26884930

  2. Activation of spinal MrgC-Gi-NR2B-nNOS signaling pathway by Mas oncogene-related gene C receptor agonist bovine adrenal medulla 8-22 attenuates bone cancer pain in mice

    PubMed Central

    Sun, Yu’e; Zhang, Juan; Lei, Yishan; Lu, Cui’e; Hou, Bailing; Ma, Zhengliang; Gu, Xiaoping

    2016-01-01

    Objectives: In the present study, we investigate the effects of Mas oncogene-related gene (Mrg) C receptors (MrgC) on the expression and activation of spinal Gi protein, N-methyl-D-aspartate receptor subunit 2B (NR2B), and neuronal nitric oxide synthase (nNOS) in mouse model of bone cancer pain. Methods: The number of spontaneous foot lift (NSF) and paw withdrawal mechanical threshold (PWMT) were measured after inoculation of tumor cells and intrathecal injection of MrgC agonist bovine adrenal medulla 8-22 (BAM8-22) or MrgC antagonist anti-MrgC for 14 days after operation. Expression of spinal MrgC, Gi protein, NR2B and nNOS and their phosphorylated forms after inoculation was examined by immunohistochemistry and Western blotting. Double labeling was used to identify the co-localization of NR2B or nNOS with MrgC in spinal cord dorsal horn (SCDH) neurons. The effects of intrathecal injection of BAM8-22 or anti-MrgC on nociceptive behaviors and the corresponding expression of spinal MrgC, Gi protein, NR2B and nNOS were also investigated. Results: The expression of spinal MrgC, Gi protein, NR2B, and nNOS was higher in tumor-bearing mice in comparison to sham mice or normal mice. Intrathecal injection of MrgC agonist BAM8-22 significantly alleviated bone cancer pain, up-regulated MrgC and Gi protein expression, and down-regulated the expression of spinal p-NR2B, t-nNOS and p-nNOS in SCDH on day 14 after operation, whereas administration of anti-MrgC produced the opposite effect. Meanwhile, MrgC-like immunoreactivity (IR) co-localizes with NR2B-IR or nNOS-IR in SCDH neurons. Conclusions: The present study demonstrates that MrgC-activated spinal Gi-NR2B-nNOS signaling pathway plays important roles in the development of bone cancer pain. These findings may provide a novel strategy for the treatment of bone cancer pain. PMID:27158400

  3. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine. PMID:25379267

  4. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  5. Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse.

    PubMed

    Swift, Joshua M; Swift, Sibyl N; Allen, Matthew R; Bloomfield, Susan A

    2014-01-01

    The sympathetic nervous system (SNS) plays an important role in mediating bone remodeling. However, the exact role that beta-1 adrenergic receptors (beta1AR) have in this process has not been elucidated. We have previously demonstrated the ability of dobutamine (DOB), primarily a beta1AR agonist, to inhibit reductions in cancellous bone formation and mitigate disuse-induced loss of bone mass. The purpose of this study was to characterize the independent and combined effects of DOB and hindlimb unloading (HU) on cancellous bone microarchitecture, tissue-level bone cell activity, and osteocyte apoptosis. Male Sprague-Dawley rats, aged 6-mos, were assigned to either normal cage activity (CC) or HU (n = 18/group) for 28 days. Animals were administered either daily DOB (4 mg/kg BW/d) or an equal volume of saline (VEH) (n = 9/gp). Unloading resulted in significantly lower distal femur cancellous BV/TV (-33%), Tb.Th (-11%), and Tb.N (-25%) compared to ambulatory controls (CC-VEH). DOB treatment during HU attenuated these changes in cancellous bone microarchitecture, resulting in greater BV/TV (+29%), Tb.Th (+7%), and Tb.N (+21%) vs. HU-VEH. Distal femur cancellous vBMD (+11%) and total BMC (+8%) were significantly greater in DOB- vs. VEH-treated unloaded rats. Administration of DOB during HU resulted in significantly greater osteoid surface (+158%) and osteoblast surface (+110%) vs. HU-VEH group. Furthermore, Oc.S/BS was significantly greater in HU-DOB (+55%) vs. CC-DOB group. DOB treatment during unloading fully restored bone formation, resulting in significantly greater bone formation rate (+200%) than in HU-VEH rats. HU resulted in an increased percentage of apoptotic cancellous osteocytes (+85%), reduced osteocyte number (-16%), lower percentage of occupied osteocytic lacunae (-30%) as compared to CC-VEH, these parameters were all normalized with DOB treatment. Altogether, these data indicate that beta1AR agonist treatment during disuse mitigates negative

  6. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

    PubMed Central

    Ho, Peggy P.; Steinman, Lawrence

    2016-01-01

    Bile acids are ligands for the nuclear hormone receptor, farnesoid X receptor (FXR). The bile acid–FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, bile acid–FXR regulation has been reported to play an integral role in both hepatic and intestinal inflammation, and in atherosclerosis. In this study, we found that FXR knockout mice had more disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Obeticholic acid (6α-ethyl-chenodeoxycholic acid, 6-ECDCA), a synthetic FXR agonist, is an orally available drug that is currently in clinical trials for the treatment of inflammatory diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis. When we treated mice exhibiting established EAE with 6-ECDCA, or the natural FXR ligand chenodeoxycholic acid (CDCA), clinical disease was ameliorated by (i) suppressing lymphocyte activation and proinflammatory cytokine production; (ii) reducing CD4+ T cells and CD19+ B cell populations and their expression of negative checkpoint regulators programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and B and T lymphocyte attenuator (BTLA); (iii) increasing CD8+ T cells and PD1, PDl-1, and BTLA expression; and (iv) reducing VLA-4 expression in both the T- and B-cell populations. Moreover, adoptive transfer of 6-ECDCA– or CDCA-treated donor cells failed to transfer disease in naive recipients. Thus, we show that FXR functions as a negative regulator in neuroinflammation and we highlight that FXR agonists represent a potential previously unidentified therapy for MS. PMID:26811456

  7. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    SciTech Connect

    Hasegawa-Moriyama, Maiko; Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  8. NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use

    PubMed Central

    McCaffrey, Gwen; Thompson, Michelle L.; Majuta, Lisa; Fealk, Michelle N.; Chartier, Stephane; Longo, Geraldine; Mantyh, Patrick W.

    2014-01-01

    Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and non-malignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in bone cancer patients. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40-70% depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight. PMID:25287160

  9. Alpha-7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress and brain injury in mice with ischemic stroke and bone fracture

    PubMed Central

    Han, Zhenying; Li, Li; Wang, Liang; Degos, Vincent; Maze, Mervyn; Su, Hua

    2014-01-01

    Bone fracture at the acute stage of stroke exacerbates stroke injury by increasing neuroinflammation. We hypothesize that activation of α-7 nicotinic acetylcholine (α-7 nAchR) agonist attenuates neuroinflammation and oxidative stress, and reduces brain injury in mice with bone fracture and stroke. Permanent middle cerebral artery occlusion (pMCAO) was performed in C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0.8 mg/kg PHA568487 (PHA, α-7 nAchR-specific agonist), 6 mg/kg Methyllycaconitine (MLA, α-7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Behavior was tested 3 days after pMCAO. Neuronal injury, CD68+, M1 (pro-inflammatory) and M2 (anti-inflammatory) microglia/macrophages, phosphorylated p65 component of NF-kb in microglia/macrophages, oxidative and anti-oxidant gene expression were quantified. Compared to saline-treated mice, PHA-treated mice performed better in behavioral tests, had fewer apoptotic neurons (NeuN+TUNEL+), fewer CD68+ and M1 macrophages, and more M2 macrophages. PHA increased anti-oxidant gene expression and decreased oxidative stress and phosphorylation of NF-κb p65. MLA had the opposite effects. Our data indicate that α-7 nAchR agonist treatment reduces neuroinflammation and oxidative stress, which are associated with reduced brain injury in mice with ischemic stroke plus tibia fracture. PMID:25040630

  10. Adenosine A(3) receptor agonist acts as a homeostatic regulator of bone marrow hematopoiesis.

    PubMed

    Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Holá, Jirina; Vacek, Antonín; Streitová, Denisa

    2007-07-01

    The present study was performed to define the optimum conditions of the stimulatory action of the adenosine A(3) receptor agonist, N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), on bone marrow hematopoiesis in mice. Effects of 2-day treatment with IB-MECA given at single doses of 200nmol/kg twice daily were investigated in normal mice and in mice whose femoral bone marrow cells were either depleted or regenerating after pretreatment with the cytotoxic drug 5-fluorouracil. Morphological criteria were used to determine the proliferation state of the granulocytic and erythroid cell systems. Significant negative correlation between the control proliferation state and the increase of cell proliferation after IB-MECA treatment irrespective of the cell lineage investigated was found. The results suggest the homeostatic character of the induced stimulatory effects and the need to respect the functional state of the target tissue when investigating effects of adenosine receptor agonists under in vivo conditions.

  11. β2-Adrenergic agonists attenuate organic dust-induced lung inflammation.

    PubMed

    Romberger, Debra J; Heires, Art J; Nordgren, Tara M; Poole, Jill A; Toews, Myron L; West, William W; Wyatt, Todd A

    2016-07-01

    Agricultural dust exposure results in significant lung inflammation, and individuals working in concentrated animal feeding operations (CAFOs) are at risk for chronic airway inflammatory diseases. Exposure of bronchial epithelial cells to aqueous extracts of hog CAFO dusts (HDE) leads to inflammatory cytokine production that is driven by protein kinase C (PKC) activation. cAMP-dependent protein kinase (PKA)-activating agents can inhibit PKC activation in epithelial cells, leading to reduced inflammatory cytokine production following HDE exposure. β2-Adrenergic receptor agonists (β2-agonists) activate PKA, and we hypothesized that β2-agonists would beneficially impact HDE-induced adverse airway inflammatory consequences. Bronchial epithelial cells were cultured with the short-acting β2-agonist salbutamol or the long-acting β2-agonist salmeterol prior to stimulation with HDE. β2-Agonist treatment significantly increased PKA activation and significantly decreased HDE-stimulated IL-6 and IL-8 production in a concentration- and time-dependent manner. Salbutamol treatment significantly reduced HDE-induced intracellular adhesion molecule-1 expression and neutrophil adhesion to epithelial cells. Using an established intranasal inhalation exposure model, we found that salbutamol pretreatment reduced airway neutrophil influx and IL-6, TNF-α, CXCL1, and CXCL2 release in bronchoalveolar lavage fluid following a one-time exposure to HDE. Likewise, when mice were pretreated daily with salbutamol prior to HDE exposure for 3 wk, HDE-induced neutrophil influx and inflammatory mediator production were also reduced. The severity of HDE-induced lung pathology in mice repetitively exposed to HDE for 3 wk was also decreased with daily salbutamol pretreatment. Together, these results support the need for future clinical investigations to evaluate the utility of β2-agonist therapies in the treatment of airway inflammation associated with CAFO dust exposure. PMID:27190062

  12. Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: interactive effects

    PubMed Central

    Fischer, Bradford D.; Ward, Sara J.; Henry, Fredrick E.; Dykstra, Linda A.

    2009-01-01

    CB1 cannabinoid (CB1) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB1/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB1 receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (zmix) with predicted additive potency (zadd). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (zadd = zmix), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (zadd > zmix). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations. PMID:19699755

  13. Experimental study of bone formation around a titanium rod with beta-tricalcium phosphate and prostaglandin E2 receptor agonists.

    PubMed

    Masuzawa, Michinaga; Beppu, Moroe; Ishii, Shoji; Oyake, Yuichiro; Aoki, Haruhito; Takagi, Masayuki

    2005-05-01

    beta-Tricalcium phosphate (beta-TCP) is an excellent bone-filling material that is completely absorbed by the body and replaced by autologous bone. Unfortunately, its mechanical strength is low, rendering its application at loaded regions difficult. The purpose of this study is to evaluate the histological and mechanical effects of single and combined use of beta-TCP and EP4 agonist on bone formation around a titanium rod. beta-TCP was loaded into the femoral bone marrow from the distal end of the femur, where the titanium implants were inserted, and the animals received twice-daily subcutaneous injections of EP4 agonist. Group I received the rod only and was designated the control group; group II received EP4 agonist only; group III received beta-TCP only; and group IV received both beta-TCP and EP4 agonist. Examination of decalcified specimens revealed favorable bone formation in all treatment groups compared with that in group I, with the most active bone formation seen in group IV. Mechanical evaluation revealed significant differences in maximum pull-out force compared with group I at weeks 4 and 8. There were no differences between groups II and III at either week 4 or 8, but the values seen in group IV at weeks 4 and 8 were significantly higher compared with the other groups. Combined use of beta-TCP and EP4 agonist is expected to compensate for bone defects resulting from revision total joint arthroplasty and to achieve stability at an early stage. PMID:15928895

  14. Oral administration of soluble guanylate cyclase agonists to rats results in osteoclastic bone resorption and remodeling with new bone formation in the appendicular and axial skeleton.

    PubMed

    Homer, Bruce L; Morton, Daniel; Bagi, Cedo M; Warneke, James A; Andresen, Catharine J; Whiteley, Laurence O; Morris, Dale L; Tones, Michael A

    2015-04-01

    Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.

  15. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

    SciTech Connect

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

  16. Accuracy of CT-Based Attenuation Correction in PET/CT Bone Imaging

    PubMed Central

    Abella, Monica; Alessio, Adam M.; Mankoff, David A.; MacDonald, Lawrence R.; Vaquero, Juan Jose; Desco, Manuel; Kinahan, Paul E.

    2012-01-01

    We evaluate the accuracy of scaling CT images for attenuation correction of PET data measured for bone. While the standard tri-linear approach has been well-tested for soft tissues, the impact of CT-based attenuation correction on the accuracy of tracer uptake in bone has not been reported in detail. We measured the accuracy of attenuation coefficients of bovine femur segments and patient data using a tri-linear method applied to CT images obtained at different kVp settings. Attenuation values at 511 keV obtained with a 68Ga/68Ge transmission scan were used as a reference standard. The impact of inaccurate attenuation images on PET standardized uptake values (SUVs) was then evaluated using simulated emission images and emission images from five patients with elevated levels of FDG uptake in bone at disease sites. The CT-based linear attenuation images of the bovine femur segments underestimated the true values by 2.9±0.3% for cancellous bone regardless of kVp. For compact bone the underestimation ranged from 1.3% at 140 kVp to 14.1% at 80 kVp. In the patient scans at 140 kVp the underestimation was approximately 2% averaged over all bony regions. The sensitivity analysis indicated that errors in PET SUVs in bone are approximately proportional to errors in the estimated attenuation coefficients for the same regions. The variability in SUV bias also increased approximately linearly with the error in linear attenuation coefficients. These results suggest that bias in bone uptake SUVs of PET tracers range from 2.4% to 5.9% when using CT scans at 140 and 120 kVp for attenuation correction. Lower kVp scans have the potential for considerably more error in dense bone. This bias is present in any PET tracer with bone uptake but may be clinically insignificant for many imaging tasks. However, errors from CT-based attenuation correction methods should be carefully evaluated if quantitation of tracer uptake in bone is important. PMID:22481547

  17. Accuracy of CT-based attenuation correction in PET/CT bone imaging.

    PubMed

    Abella, Monica; Alessio, Adam M; Mankoff, David A; MacDonald, Lawrence R; Vaquero, Juan Jose; Desco, Manuel; Kinahan, Paul E

    2012-05-01

    We evaluate the accuracy of scaling CT images for attenuation correction of PET data measured for bone. While the standard tri-linear approach has been well tested for soft tissues, the impact of CT-based attenuation correction on the accuracy of tracer uptake in bone has not been reported in detail. We measured the accuracy of attenuation coefficients of bovine femur segments and patient data using a tri-linear method applied to CT images obtained at different kVp settings. Attenuation values at 511 keV obtained with a (68)Ga/(68)Ge transmission scan were used as a reference standard. The impact of inaccurate attenuation images on PET standardized uptake values (SUVs) was then evaluated using simulated emission images and emission images from five patients with elevated levels of FDG uptake in bone at disease sites. The CT-based linear attenuation images of the bovine femur segments underestimated the true values by 2.9 ± 0.3% for cancellous bone regardless of kVp. For compact bone the underestimation ranged from 1.3% at 140 kVp to 14.1% at 80 kVp. In the patient scans at 140 kVp the underestimation was approximately 2% averaged over all bony regions. The sensitivity analysis indicated that errors in PET SUVs in bone are approximately proportional to errors in the estimated attenuation coefficients for the same regions. The variability in SUV bias also increased approximately linearly with the error in linear attenuation coefficients. These results suggest that bias in bone uptake SUVs of PET tracers ranges from 2.4% to 5.9% when using CT scans at 140 and 120 kVp for attenuation correction. Lower kVp scans have the potential for considerably more error in dense bone. This bias is present in any PET tracer with bone uptake but may be clinically insignificant for many imaging tasks. However, errors from CT-based attenuation correction methods should be carefully evaluated if quantitation of tracer uptake in bone is important.

  18. Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus.

    PubMed

    Ha, Tae-Young; Kim, Young-Seok; Kim, Chun Hwa; Choi, Hyo-Sun; Yang, Jin; Park, Soo Hyun; Kim, Dae Hoon; Rhee, Jae-Keol

    2014-05-01

    In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic β-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in β-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster β-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic β-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.

  19. The Extravehicular Suit Impact Load Attenuation Study for Use in Astronaut Bone Fracture Prediction

    NASA Technical Reports Server (NTRS)

    Lewandowski, Beth E.; Gilkey, Kelly M.; Sulkowski, Christina M.; Samorezov, Sergey; Myers, Jerry G.

    2011-01-01

    The NASA Integrated Medical Model (IMM) assesses the risk, including likelihood and impact of occurrence, of all credible in-flight medical conditions. Fracture of the proximal femur is a traumatic injury that would likely result in loss of mission if it were to happen during spaceflight. The low gravity exposure causes decreases in bone mineral density which heightens the concern. Researchers at the NASA Glenn Research Center have quantified bone fracture probability during spaceflight with a probabilistic model. It was assumed that a pressurized extravehicular activity (EVA) suit would attenuate load during a fall, but no supporting data was available. The suit impact load attenuation study was performed to collect analogous data. METHODS: A pressurized EVA suit analog test bed was used to study how the offset, defined as the gap between the suit and the astronaut s body, impact load magnitude and suit operating pressure affects the attenuation of impact load. The attenuation data was incorporated into the probabilistic model of bone fracture as a function of these factors, replacing a load attenuation value based on commercial hip protectors. RESULTS: Load attenuation was more dependent on offset than on pressurization or load magnitude, especially at small offsets. Load attenuation factors for offsets between 0.1 - 1.5 cm were 0.69 +/- 0.15, 0.49 +/- 0.22 and 0.35 +/- 0.18 for mean impact forces of 4827, 6400 and 8467 N, respectively. Load attenuation factors for offsets of 2.8 - 5.3 cm were 0.93 +/- 0.2, 0.94 +/- 0.1 and 0.84 +/- 0.5, for the same mean impact forces. Reductions were observed in the 95th percentile confidence interval of the bone fracture probability predictions. CONCLUSIONS: The reduction in uncertainty and improved confidence in bone fracture predictions increased the fidelity and credibility of the fracture risk model and its benefit to mission design and operational decisions.

  20. Phase velocity and attenuation predictions of waves in cancellous bone using an iterative effective medium approximation.

    PubMed

    Potsika, Vassiliki T; Protopappas, Vasilios C; Vavva, Maria G; Polyzos, Demosthenes; Fotiadis, Dimitrios I

    2013-01-01

    The quantitative determination of wave dispersion and attenuation in bone is an open research area as the factors responsible for ultrasound absorption and scattering in composite biological tissues have not been completely explained. In this study, we use the iterative effective medium approximation (IEMA) proposed in [1] so as to calculate phase velocity and attenuation in media with properties similar to those of cancellous bones. Calculations are performed for a frequency range of 0.4-0.8 MHz and for different inclusions' volume concentrations and sizes. Our numerical results are compared with previous experimental findings so as to assess the effectiveness of IEMA. It was made clear that attenuation and phase velocity estimations could provide supplementary information for cancellous bone characterization. PMID:24111396

  1. The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain

    PubMed Central

    Uhelski, Megan L.; Cain, David M.; Harding-Rose, Catherine; Simone, Donald A.

    2013-01-01

    Pain from cancer can be severe, difficult to treat, and greatly diminishes patients’ quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. In this model, implantation of fibrosarcoma cells into and around the calcaneous bone produces mechanical and thermal hyperalgesia in mice. C-fiber nociceptors in tumor-bearing mice develop spontaneous ongoing activity and sensitization to thermal stimuli. However, it is unclear whether sensitization of nociceptors to mechanical stimuli underlies the mechanical hyperalgesia seen in tumor-bearing mice. We therefore examined responses of C-fiber nociceptors to suprathreshold mechanical stimuli in tumor-bearing mice and found they did not differ from those of C-nociceptors in control mice. Thus, sensitization of C-fiber nociceptors to mechanical stimulation does not appear to underlie tumor-evoked mechanical hyperalgesia in this murine model of bone cancer pain. We also examined the effect of the non-selective cannabinoid receptor agonist, WIN 55, 212-2, on spontaneous activity and responses evoked by mechanical stimuli of C-fiber nociceptors innervating the tumor-bearing paw. Selective CB1 and CB2 antagonists were administered to determine the contribution of each receptor subtype to the effects of WIN 55,212-2. Intraplantar administration of WIN 55,212-2 attenuated spontaneous discharge and responses evoked by mechanical stimulation of C-fiber nociceptors. These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C-fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide

  2. Yeast-incorporated gallium attenuates glucocorticoid-induced bone loss in rats by inhibition of bone resorption.

    PubMed

    Ren, Zhaozhou; Yang, Liqing; Xue, Feng; Meng, Qingjie; Wang, Kejia; Wu, Xian; Ji, Chao; Jiang, Teng; Liu, Da; Zhou, Long; Zhang, Jing; Fu, Qin

    2013-06-01

    Glucocorticoids (GC) are potent anti-inflammatory agents and widely used for the treatment of many immune-mediated and inflammatory diseases, whereas GC-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and significantly increases the patients' morbidity and mortality. GIOP is characterized as diminished osteogenesis and accelerated bone resorption. Yeast-incorporated gallium (YG) as an organic compound not only reduces elements-associated toxicity, but also maintains its therapeutic effect on improving bone loss or promoting fracture healing in ovariectomized female rats. The aim of this study was to examine whether YG could prevent GC-induced bone loss. Five-month-old male Sprague-Dawley rats were randomly divided into three groups (n = 6): two groups were administered dexamethasone (0.1 mg/kg/day) or vehicle (PBS) subcutaneously for 5 weeks; one other group was received dexamethasone subcutaneously and YG (120 μg/kg/day) orally. Trabecular bone microarchitectural parameters, bone mineral density (BMD), bone strength, body weight, and serum biochemical markers of bone resorption and formation were examined. Compared to the GC alone group, treatment with YG not only prevented microarchitectural deterioration of trabecular bone volume relative to tissue volume, trabecular number, and trabecular separation, but also significantly improved BMD, mechanical strength, and body weight in GC-treated rats. Moreover, YG decreased tartrate-resistant acid phosphatase 5b level but failed to change alkaline phosphatase level in GC-treated rats. This is the first study to show that YG prominently attenuates bone loss and microarchitectural deterioration and inhibits the increased bone resorption in GIOP. It implies that YG might be an alternative therapy for prevention of GC-induced bone loss in humans.

  3. The Galanin Receptor Agonist, Galnon, Attenuates Cocaine-Induced Reinstatement and Dopamine Overflow in the Frontal Cortex

    PubMed Central

    Ogbonmwan, Yvonne E.; Sciolino, Natale R.; Groves-Chapman, Jessica L.; Freeman, Kimberly G.; Schroeder, Jason P.; Edwards, Gaylen L.; Holmes, Philip V.; Weinshenker, David

    2014-01-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement, and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels, or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex. PMID:25053279

  4. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

    PubMed

    Ogbonmwan, Yvonne E; Sciolino, Natale R; Groves-Chapman, Jessica L; Freeman, Kimberly G; Schroeder, Jason P; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2015-07-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex. PMID:25053279

  5. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

    PubMed

    Ogbonmwan, Yvonne E; Sciolino, Natale R; Groves-Chapman, Jessica L; Freeman, Kimberly G; Schroeder, Jason P; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2015-07-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex.

  6. Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists

    PubMed Central

    Fan, Jiabing; Im, Choong Sung; Guo, Mian; Cui, Zhong-Kai; Fartash, Armita; Kim, Soyon; Patel, Nikhil; Bezouglaia, Olga; Wu, Benjamin M.; Wang, Cun-Yu

    2016-01-01

    Although adipose-derived stem cells (ASCs) are an attractive cell source for bone tissue engineering, direct use of ASCs alone has had limited success in the treatment of large bone defects. Although bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors to promote osteogenic differentiation of ASCs, their clinical applications require supraphysiological dosage, leading to high medical burden and adverse side effects. In the present study, we demonstrated an alternative approach that can effectively complement the BMP activity to maximize the osteogenesis of ASCs without exogenous application of BMPs by regulating levels of antagonists and agonists to BMP signaling. Treatment of ASCs with the amiloride derivative phenamil, a positive regulator of BMP signaling, combined with gene manipulation to suppress the BMP antagonist noggin, significantly enhanced osteogenic differentiation of ASCs through increased BMP–Smad signaling in vitro. Furthermore, the combination approach of noggin suppression and phenamil stimulation enhanced the BMP signaling and bone repair in a mouse calvarial defect model by adding noggin knockdown ASCs to apatite-coated poly(lactic-coglycolic acid) scaffolds loaded with phenamil. These results suggest novel complementary osteoinductive strategies that could maximize activity of the BMP pathway in ASC bone repair while reducing potential adverse effects of current BMP-based therapeutics. Significance Although stem cell-based tissue engineering strategy offers a promising alternative to repair damaged bone, direct use of stem cells alone is not adequate for challenging healing environments such as in large bone defects. This study demonstrates a novel strategy to maximize bone formation pathways in osteogenic differentiation of mesenchymal stem cells and functional bone formation by combining gene manipulation with a small molecule activator toward osteogenesis. The findings indicate promising stem cell

  7. VTX-1463, a novel TLR-8 agonist, attenuates nasal congestion after ragweed challenge in sensitized beagle dogs.

    PubMed

    Royer, Christopher M; Rudolph, Karin; Dietsch, Gregory N; Hershberg, Robert M; Barrett, Edward G

    2016-03-01

    VTX-1463 is a selective toll-like receptor (TLR) 8 agonist that activates a subset of innate immune cells to produce a unique cytokine profile. Delivery of VTX-1463 via nasal spray may modulate the nasal response in allergic rhinitis. The aim of this study was to determine the effects of VTX-1463 on the nasal response in a dog model of allergic rhinitis. Ragweed (RW)-sensitized dogs were pretreated with increasing doses of VTX-1463 1 day prior to RW challenge or with two doses (4 or 8 days and 1 day prior to RW). Changes in nasal cavity volume (NV) were determined by acoustic rhinometry and nasal lavage fluid was assessed for histamine, lipid mediators, and cellular infiltrates at sequential times following RW challenge. VTX-1463 pretreatment significantly preserved NV during the acute response to RW challenge for all doses tested. The area under the curve (AUC) for NV over the 1.5 h assessment period in RW challenged vehicle controls averaged 51.5% (SEM: ±2.12%) of the baseline NV over all studies. A single 100 µg dose of VTX-1463 given 1 day prior to RW yielded an AUC for NV of 69.3% (±6.59%) of baseline, while a 1000 µg dose administered twice (8 days and 1 day prior to RW) resulted in an AUC for NV of 85.4% (±4.74%, P < 0.05) of baseline. For a single 1000 µg VTX-1463 dose 1 day prior to RW, multiple mediators produced by mast cells, including histamine, PGE2, PGD2, and cysteinyl LTs, were significantly reduced relative to the vehicle control. The selective TLR8 agonist, VTX-1463, preserved NV in a dose-dependent manner in the acute phase of a nasal allergic response. The therapeutic effect appears to result from attenuated mast cell mediator release. Modulating the local cytokine response via TLR8 agonism appears to have a therapeutic effect on the acute allergic nasal response. PMID:27042301

  8. Protein malnutrition attenuates bone anabolic response to PTH in female rats.

    PubMed

    Ammann, P; Zacchetti, G; Gasser, J A; Lavet, C; Rizzoli, R

    2015-02-01

    PTH is indicated for the treatment of severe osteoporosis. Elderly osteoporotic patients frequently suffer from protein malnutrition, which may contribute to bone loss. It is unknown whether this malnutrition may affect the response to PTH. Therefore, the aim of the present study was to assess whether an isocaloric low-protein (LP) diet may influence the bone anabolic response to intermittent PTH in 6-month-old female rats. Six-month-old female rats were either pair fed an isocaloric LP diet (2.5% casein) or a normal-protein (NP) diet (15% casein) for 2 weeks. The rats continued on their respective diet while being treated with 5- or 40-μg/kg recombinant human PTH amino-terminal fragment 1-34 (PTH-[1-34]) daily, or with vehicle for 4 weeks. At the end of this period, areal bone mineral density, bone mineral content, microstructure, and bone strength in axial compression of proximal tibia or 3-point bending for midshaft tibia tests were measured. Blood was collected for the determination of IGF-I and osteocalcin. After 4 weeks of PTH-(1-34), the dose-dependent increase of proximal tibia bone mineral density, trabecular microstructure variables, and bone strength was attenuated in rats fed a LP diet as compared with rats on a NP intake. At the level of midshaft tibia cortical bone, PTH-(1-34) exerted an anabolic effect only in the NP but not in the LP diet group. Protein malnutrition was associated with lower IGF-I levels. Protein malnutrition attenuates the bone anabolic effects of PTH-(1-34) in rats. These results suggest that a sufficient protein intake should be recommended for osteoporotic patients undergoing PTH therapy.

  9. The nonlinear transition period of broadband ultrasound attenuation as bone density varies.

    PubMed

    Serpe, L; Rho, J Y

    1996-07-01

    The purpose of this study was to determine whether a transition period occurs between cortical and cancellous bone in the relationship between ultrasound parameters [broadband ultrasound attenuation (BUA) and ultrasonic velocity] and density. Twenty-two cancellous bone discs wee obtained from proximal bovine tibiae. Also included were three samples of human vertebral cancellous bone from an elderly female and four samples of bovine cortical bone. Ultrasonic velocity did not show any transition period as density varied from cancellous to cortical bone. Ultrasonic velocity exhibited a definite linear dependence on density over the entire range examined. However, BUA has shown a transition period as density varied. Although BUA increased linearly with density for a low density cancellous bone tested (below 0.64 g cm-3), the dependence of BUA on density is nonlinear with a downwardly inflected parabola shape when covering a wide density range (0.130-0.913 g cm-3) of cancellous bone. When one includes cortical bone, the parabola tends to level off in a slow exponential decay. This nonlinear dependence may help to understand the characteristics of BUA measurement. PMID:8809627

  10. Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

    PubMed

    Lambert, C S; Philpot, R M; Engberg, M E; Johns, B E; Wecker, L

    2015-09-15

    Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle.

  11. A dopamine receptor d2-type agonist attenuates the ability of stress to alter sleep in mice.

    PubMed

    Jefferson, F; Ehlen, J C; Williams, N S; Montemarano, J J; Paul, K N

    2014-11-01

    Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between PRL secretion and REM sleep after restraint stress to determine whether: 1) the ability of stress to increase REM sleep is PRL-dependent, and 2) fluctuating PRL levels underlie sex differences in sleep responses to stress. Because dopamine D2 receptors in the pituitary gland are the primary regulator of PRL secretion, D2 receptor agonist, 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea (cabergoline), was used to attenuate PRL levels in mice before 1 hour of restraint stress. Mice were implanted with electroencephalographic/electromyographic recording electrodes and received an ip injection of either 0.3-mg/kg cabergoline or vehicle before a control procedure of 1 hour of sleep deprivation by gentle handling during the light phase. Six days after the control procedure, mice received cabergoline or vehicle 15 minutes before 1 hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on PRL and that sex differences in REM sleep amount may be driven by PRL.

  12. Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

    PubMed

    Lambert, C S; Philpot, R M; Engberg, M E; Johns, B E; Wecker, L

    2015-09-15

    Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle. PMID:26049061

  13. Determining attenuation properties of interfering fast and slow ultrasonic waves in cancellous bone

    PubMed Central

    Nelson, Amber M.; Hoffman, Joseph J.; Anderson, Christian C.; Holland, Mark R.; Nagatani, Yoshiki; Mizuno, Katsunori; Matsukawa, Mami; Miller, James G.

    2011-01-01

    Previous studies have shown that interference between fast waves and slow waves can lead to observed negative dispersion in cancellous bone. In this study, the effects of overlapping fast and slow waves on measurements of the apparent attenuation as a function of propagation distance are investigated along with methods of analysis used to determine the attenuation properties. Two methods are applied to simulated data that were generated based on experimentally acquired signals taken from a bovine specimen. The first method uses a time-domain approach that was dictated by constraints imposed by the partial overlap of fast and slow waves. The second method uses a frequency-domain log-spectral subtraction technique on the separated fast and slow waves. Applying the time-domain analysis to the broadband data yields apparent attenuation behavior that is larger in the early stages of propagation and decreases as the wave travels deeper. In contrast, performing frequency-domain analysis on the separated fast waves and slow waves results in attenuation coefficients that are independent of propagation distance. Results suggest that features arising from the analysis of overlapping two-mode data may represent an alternate explanation for the previously reported apparent dependence on propagation distance of the attenuation coefficient of cancellous bone. PMID:21973378

  14. Determining attenuation properties of interfering fast and slow ultrasonic waves in cancellous bone.

    PubMed

    Nelson, Amber M; Hoffman, Joseph J; Anderson, Christian C; Holland, Mark R; Nagatani, Yoshiki; Mizuno, Katsunori; Matsukawa, Mami; Miller, James G

    2011-10-01

    Previous studies have shown that interference between fast waves and slow waves can lead to observed negative dispersion in cancellous bone. In this study, the effects of overlapping fast and slow waves on measurements of the apparent attenuation as a function of propagation distance are investigated along with methods of analysis used to determine the attenuation properties. Two methods are applied to simulated data that were generated based on experimentally acquired signals taken from a bovine specimen. The first method uses a time-domain approach that was dictated by constraints imposed by the partial overlap of fast and slow waves. The second method uses a frequency-domain log-spectral subtraction technique on the separated fast and slow waves. Applying the time-domain analysis to the broadband data yields apparent attenuation behavior that is larger in the early stages of propagation and decreases as the wave travels deeper. In contrast, performing frequency-domain analysis on the separated fast waves and slow waves results in attenuation coefficients that are independent of propagation distance. Results suggest that features arising from the analysis of overlapping two-mode data may represent an alternate explanation for the previously reported apparent dependence on propagation distance of the attenuation coefficient of cancellous bone.

  15. Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists.

    PubMed

    Kuo, Dong-Yih

    2006-07-01

    1. Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. 2. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. 3. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. 4. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0-6 h in both groups of rats. 5. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. 6. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration.

  16. Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists

    PubMed Central

    Kuo, Dong-Yih

    2006-01-01

    Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0–6 h in both groups of rats. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration. PMID:16702993

  17. Hearing protection: surpassing the limits to attenuation imposed by the bone-conduction pathways.

    PubMed

    Berger, Elliott H; Kieper, Ronald W; Gauger, Dan

    2003-10-01

    With louder and louder weapon systems being developed and military personnel being exposed to steady noise levels approaching and sometimes exceeding 150 dB, a growing interest in greater amounts of hearing protection is evident. When the need for communications is included in the equation, the situation is even more extreme. New initiatives are underway to design improved hearing protection, including active noise reduction (ANR) earplugs and perhaps even active cancellation of head-borne vibration. With that in mind it may be useful to explore the limits to attenuation, and whether they can be approached with existing technology. Data on the noise reduction achievable with high-attenuation foam earplugs, as a function of insertion depth, will be reported. Previous studies will be reviewed that provide indications of the bone-conduction (BC) limits to attenuation that, in terms of mean values, range from 40 to 60 dB across the frequencies from 125 Hz to 8 kHz. Additionally, new research on the effects of a flight helmet on the BC limits, as well as the potential attenuation from deeply inserted passive foam earplugs, worn with passive earmuffs, or with active-noise reduction (ANR) earmuffs, will be examined. The data demonstrate that gains in attenuation exceeding 10 dB above the head-not-covered limits can be achieved if the head is effectively shielded from acoustical stimulation.

  18. Hearing protection: Surpassing the limits to attenuation imposed by the bone-conduction pathways

    NASA Astrophysics Data System (ADS)

    Berger, Elliott H.; Kieper, Ronald W.; Gauger, Dan

    2003-10-01

    With louder and louder weapon systems being developed and military personnel being exposed to steady noise levels approaching and sometimes exceeding 150 dB, a growing interest in greater amounts of hearing protection is evident. When the need for communications is included in the equation, the situation is even more extreme. New initiatives are underway to design improved hearing protection, including active noise reduction (ANR) earplugs and perhaps even active cancellation of head-borne vibration. With that in mind it may be useful to explore the limits to attenuation, and whether they can be approached with existing technology. Data on the noise reduction achievable with high-attenuation foam earplugs, as a function of insertion depth, will be reported. Previous studies will be reviewed that provide indications of the bone-conduction (BC) limits to attenuation that, in terms of mean values, range from 40 to 60 dB across the frequencies from 125 Hz to 8 kHz. Additionally, new research on the effects of a flight helmet on the BC limits, as well as the potential attenuation from deeply inserted passive foam earplugs, worn with passive earmuffs, or with active-noise reduction (ANR) earmuffs, will be examined. The data demonstrate that gains in attenuation exceeding 10 dB above the head-not-covered limits can be achieved if the head is effectively shielded from acoustical stimulation.

  19. PPARγ antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function

    PubMed Central

    Sato, Kazuya; Feng, Xingmin; Chen, Jichun; Li, Jungang; Muranski, Pawel; Desierto, Marie J.; Keyvanfar, Keyvan; Malide, Daniela; Kajigaya, Sachiko; Young, Neal S.

    2016-01-01

    Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically “fatless” mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation. PMID:26589913

  20. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain.

    PubMed

    Ghilardi, Joseph R; Röhrich, Heidi; Lindsay, Theodore H; Sevcik, Molly A; Schwei, Matthew J; Kubota, Kazufumi; Halvorson, Kyle G; Poblete, Jeannie; Chaplan, Sandra R; Dubin, Adrienne E; Carruthers, Nicholas I; Swanson, Devin; Kuskowski, Michael; Flores, Christopher M; Julius, David; Mantyh, Patrick W

    2005-03-23

    Cancer colonization of bone leads to the activation of osteoclasts, thereby producing local tissue acidosis and bone resorption. This process may contribute to the generation of both ongoing and movement-evoked pain, resulting from the activation of sensory neurons that detect noxious stimuli (nociceptors). The capsaicin receptor TRPV1 (transient receptor potential vanilloid subtype 1) is a cation channel expressed by nociceptors that detects multiple pain-producing stimuli, including noxious heat and extracellular protons, raising the possibility that it is an important mediator of bone cancer pain via its capacity to detect osteoclast- and tumor-mediated tissue acidosis. Here, we show that TRPV1 is present on sensory neuron fibers that innervate the mouse femur and that, in an in vivo model of bone cancer pain, acute or chronic administration of a TRPV1 antagonist or disruption of the TRPV1 gene results in a significant attenuation of both ongoing and movement-evoked nocifensive behaviors. Administration of the antagonist had similar efficacy in reducing early, moderate, and severe pain-related responses, suggesting that TRPV1 may be a novel target for pharmacological treatment of chronic pain states associated with bone cancer metastasis.

  1. Alpha 2A adrenergic receptor agonist, guanfacine, attenuates cocaine-related impairments of inhibitory response control and working memory in animal models

    PubMed Central

    Terry, Alvin V.; Callahan, Patrick M.; Schade, Rosann; Kille, Nancy J.; Plagenhoef, Marc

    2014-01-01

    There is considerable evidence that centrally acting α2A adrenergic receptor agonists can attenuate impairments in executive function that result from dysfunction of the prefrontal cortex. Such positive effects resulted in the recent approval by the United States Food and Drug Administration (FDA) of the α2A agonists clonidine and guanfacine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but also suggest that they could have beneficial effects in substance abuse disorders and other neuropsychiatric conditions. The purpose of this study was to evaluate guanfacine for its ability to attenuate behavioral alterations associated with acute cocaine exposure in rats trained to perform a task of sustained attention, the five choice serial reaction time task (5C-SRTT) and monkeys trained to perform a task of working/short term memory, the delayed match to sample task (DMTS). In the rodent 5C-SRTT acute intraperitoneal (i.p.) administration of cocaine (3.5–15.0 mg/kg) did not affect accuracy, but was associated with dose-dependent increases in premature responses and timeout responses. Guanfacine (0.1–1.0 mg/kg i.p.) dose-dependently decreased premature responses and timeout responses associated with cocaine and it attenuated similar deficits in inhibitory response control observed in a variable ITI version of the 5C-SRTT. In the DMTS task in monkeys, acute intramuscular (i.m.) administration of cocaine (4.0 mg/kg) was associated with impairments in accuracy at long delay intervals, an effect that was attenuated by guanfacine (0.4 mg/kg). These animal studies suggest that guanfacine may have therapeutic potential for treating impairments of executive function that are associated with the abuse of cocaine. PMID:25242808

  2. Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl-Induced Hypertension in Female Rats.

    PubMed

    Dai, Shu-Yan; Zhang, Yu-Ping; Peng, Wei; Shen, Ying; He, Jing-Jing

    2016-01-01

    The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R) attenuates deoxycorticosterone acetate (DOCA)/NaCl-induced hypertension in intact and ovariectomized (OVX) female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines.

  3. Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl-Induced Hypertension in Female Rats

    PubMed Central

    Dai, Shu-Yan; Zhang, Yu-Ping; Peng, Wei; Shen, Ying; He, Jing-Jing

    2016-01-01

    The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R) attenuates deoxycorticosterone acetate (DOCA)/NaCl-induced hypertension in intact and ovariectomized (OVX) female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines. PMID:26783414

  4. Attenuated Human Bone Morphogenetic Protein-2–Mediated Bone Regeneration in a Rat Model of Composite Bone and Muscle Injury

    PubMed Central

    Li, Mon-Tzu A.; Uhrig, Brent A.; Boerckel, Joel David; Huebsch, Nathaniel; Lundgren, Taran L.; Warren, Gordon L.; Guldberg, Robert E.

    2013-01-01

    Extremity injuries involving large bone defects with concomitant severe muscle damage are a significant clinical challenge often requiring multiple treatment procedures and possible amputation. Even if limb salvage is achieved, patients are typically left with severe short- and long-term disabilities. Current preclinical animal models do not adequately mimic the severity, complexity, and loss of limb function characteristic of these composite injuries. The objectives of this study were to establish a composite injury model that combines a critically sized segmental bone defect with an adjacent volumetric muscle loss injury, and then use this model to quantitatively assess human bone morphogenetic protein-2 (rhBMP-2)–mediated tissue regeneration and restoration of limb function. Surgeries were performed on rats in three experimental groups: muscle injury (8-mm-diameter full-thickness defect in the quadriceps), bone injury (8-mm nonhealing defect in the femur), or composite injury combining the bone and muscle defects. Bone defects were treated with 2 μg of rhBMP-2 delivered in the pregelled alginate injected into a cylindrical perforated nanofiber mesh. Bone regeneration was quantitatively assessed using microcomputed tomography, and limb function was assessed using gait analysis and muscle strength measurements. At 12 weeks postsurgery, treated bone defects without volumetric muscle loss were consistently bridged. In contrast, the volume and mechanical strength of regenerated bone were attenuated by 45% and 58%, respectively, in the identically treated composite injury group. At the same time point, normalized muscle strength was reduced by 51% in the composite injury group compared to either single injury group. At 2 weeks, the gait function was impaired in all injury groups compared to baseline with the composite injury group displaying the greatest functional deficit. We conclude that sustained delivery of rhBMP-2 at a dose sufficient to induce bridging of

  5. Kramers-Kronig analysis of attenuation and dispersion in trabecular bone.

    PubMed

    Waters, Kendall R; Hoffmeister, Brent K

    2005-12-01

    A restricted-bandwidth form of the Kramers-Kronig dispersion relations is applied to in vitro measurements of ultrasonic attenuation and dispersion properties of trabecular bone specimens from bovine tibia. The Kramers-Kronig analysis utilizes only experimentally measured properties and avoids extrapolation of ultrasonic properties beyond the known bandwidth. Compensation for the portions of the Kramers-Kronig integrals over the unknown bandwidth is partially achieved by the method of subtractions, where a subtraction frequency acts as an adjustable parameter. Good agreement is found between experimentally measured and Kramers-Kronig reconstructed dispersions. The restricted-bandwidth approach improves upon other forms of the Kramers-Kronig relations and may provide further insight into how ultrasound interacts with trabecular bone.

  6. Mas-Related Gene (Mrg) C Activation Attenuates Bone Cancer Pain via Modulating Gi and NR2B

    PubMed Central

    Lu, Cui’e; Lei, Yishan; Ma, Zhengliang; Gu, Xiaoping

    2016-01-01

    Objective This study is to investigate the role of Mas-related gene (Mrg) C in the pathogenesis and treatment of bone cancer pain (BCP). Methods BCP mouse model was established by osteosarcoma cell inoculation. Pain-related behaviors were assessed with the spontaneous lifting behavior test and mechanical allodynia test. Expression levels of MrgC, Gi, and NR2B in the spinal cord were detected with Western blot analysis and immunohistochemistry. Results Pain-related behavior tests showed significantly increased spontaneous flinches (NSF) and decreased paw withdrawal mechanical threshold (PWMT) in mouse models of BCP. Western blot analysis showed that, compared with the control group and before modeling, all the expression levels of MrgC, Gi, and NR2B in the spinal cord of BCP mice were dramatically elevated, which were especially increased at day 7 after operation and thereafter, in a time-dependent manner. Moreover, the treatment of MrgC agonist BAM8-22 significantly up-regulated Gi and down-regulated NR2B expression levels, in the spinal cord of BCP mice, in a time-dependent manner. On the other hand, anti-MrgC significantly down-regulated Gi expression, while dramatically up-regulated NR2B expression, in the BCP mice. Similar results were obtained from the immunohistochemical detection. Importantly, BAM8-22 significantly attenuated the nociceptive behaviors in the BCP mice. Conclusion Our results indicated the MrgC-mediated Gi and NR2B expression alterations in the BCP mice, which might contribute to the pain hypersensitivity. These findings may provide a novel strategy for the treatment of BCP in clinic. PMID:27152740

  7. High dose compressive loads attenuate bone mineral loss in humans with spinal cord injury

    PubMed Central

    Dudley-Javoroski, S.; Saha, P. K.; Liang, G.; Li, C.; Gao, Z.

    2012-01-01

    Summary People with spinal cord injury (SCI) lose bone and muscle integrity after their injury. Early doses of stress, applied through electrically induced muscle contractions, preserved bone density at high-risk sites. Appropriately prescribed stress early after the injury may be an important consideration to prevent bone loss after SCI. Introduction Skeletal muscle force can deliver high compressive loads to bones of people with spinal cord injury (SCI). The effective osteogenic dose of load for the distal femur, a chief site of fracture, is unknown. The purpose of this study is to compare three doses of bone compressive loads at the distal femur in individuals with complete SCI who receive a novel stand training intervention. Methods Seven participants performed unilateral quadriceps stimulation in supported stance [150% body weight (BW) compressive load—“High Dose” while opposite leg received 40% BW—“Low Dose”]. Five participants stood passively without applying quadriceps electrical stimulation to either leg (40% BW load—“Low Dose”). Fifteen participants performed no standing (0% BW load—“Untrained”) and 14 individuals without SCI provided normative data. Participants underwent bone mineral density (BMD) assessment between one and six times over a 3-year training protocol. Results BMD for the High Dose group significantly exceeded BMD for both the Low Dose and the Untrained groups (p<0.05). No significant difference existed between the Low Dose and Untrained groups (p>0.05), indicating that BMD for participants performing passive stance did not differ from individuals who performed no standing. High-resolution CT imaging of one High Dose participant revealed 86% higher BMD and 67% higher trabecular width in the High Dose limb. Conclusion Over 3 years of training, 150% BW compressive load in upright stance significantly attenuated BMD decline when compared to passive standing or to no standing. High-resolution CT indicated that

  8. Prevention of bone demineralization by calcium supplementation in precocious puberty during gonadotropin-releasing hormone agonist treatment.

    PubMed

    Antoniazzi, F; Bertoldo, F; Lauriola, S; Sirpresi, S; Gasperi, E; Zamboni, G; Tatò, L

    1999-06-01

    We have previously demonstrated a negative impact on peak bone mass in girls with precocious puberty treated with GnRH agonist (GnRHa). Several studies have shown that a high calcium intake positively influences bone mass in prepubertal girls and leads to a higher peak bone mass. The aim of this study was to evaluate the effect of calcium supplementation in girls with precocious puberty during GnRHa treatment. Forty girls affected by true central precocious puberty and treated with the GnRHa triptorelin were studied for 2 yr. After diagnosis, the patients were randomly assigned to three groups: group A, treated only with GnRHa; group B, treated for 12 months solely with GnRHa and then supplemented with calcium gluconolactate/carbonate (1 g calcium/day in two doses) for 12 months; and group C, treated from the beginning with combined GnRHa and calcium. Bone mineral density (BMD) at the lumbar spine was measured by dual energy x-ray absorptiometry at the beginning of the study and after 12 and 24 months and was expressed as the calculated true volumetric density (BMDv) in milligrams per cm3. Group A showed a decrease in absolute BMDv levels, in SD score for chronological age (CA), and even more in SD score for bone age (BA). Group B showed the same behavior during the first year, but this trend was reversed in the second year, when calcium supplementation was added to GnRHa treatment. Group C showed an increase in absolute BMDv levels and in SD score for CA and BA. BMDv variations (expressed as absolute values, SD score for CA, and SD score for BA) became statistically significant at 24 months between groups C and A (P = 0.036, P = 0.032, and P = 0.025, respectively). The behavior of the lumbar spine BMDv in the three groups is consistent with a positive effect of calcium supplementation during GnRHa treatment. In calcium-supplemented patients, the normal process of bone mass accretion at puberty is preserved despite GnRHa treatment. Therefore, the reduction in BMD

  9. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone

    PubMed Central

    Cui, Zhuang; Crane, Janet; Xie, Hui; Jin, Xin; Zhen, Gehua; Li, Changjun; Xie, Liang; Wang, Long; Bian, Qin; Qiu, Tao; Wan, Mei; Xie, Min; Ding, Sheng; Yu, Bin; Cao, Xu

    2016-01-01

    Objectives Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA

  10. Fractal dimension predicts broadband ultrasound attenuation in stereolithography models of cancellous bone

    NASA Astrophysics Data System (ADS)

    Langton, C. M.; Whitehead, M. A.; Haire, T. J.; Hodgskinson, R.

    1998-02-01

    There has been considerable debate on the relative dependence of broadband ultrasound attenuation (nBUA, ) upon the density and structure of cancellous bone. A nonlinear relationship between nBUA and porosity has recently been demonstrated using stereolithography models, indicating a high structural dependence for nBUA. We report here on the measurement of trabecular perimeter and fractal dimension on the two-dimensional images used to create the stereolithography models. Adjusted coefficients of determination with nBUA were 94.4% and 98.4% for trabecular perimeter and fractal dimension respectively. The feature of fractal dimension representing both the porosity and connectivity of a given structure is most exciting. Further work is required to determine the relationship between broadband ultrasound attenuation and fractal dimension in complex three-dimensional cancellous bone structures.

  11. Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes.

    PubMed Central

    Yu, JingJia; Wang, Xiaojing; Liu, Dongmei; Zhao, Lin; Sun, Lihao; Zhao, Hongyan; Tao, Bei; Liu, Jianmin

    2015-01-01

    Recently, a number of studies have demonstrated the potential beneficial role for novel anti-diabetic GLP-1 receptor agonists (GLP-1RAs) in the skeleton metabolism in diabetic rodents and patients. In this study, we evaluated the impacts of the synthetic GLP-1RA Liraglutide on bone mass and quality in osteoporotic rats induced by ovariectomy (OVX) but without diabetes, as well as its effect on the adipogenic and osteoblastogenic differentiation of bone marrow stromal cells (BMSCs). Three months after sham surgery or bilateral OVX, eighteen 5-month old female Wistar rats were randomly divided into three groups to receive the following treatments for 2 months: (1) Sham + normal saline; (2) OVX + normal saline; and (3) OVX + Liraglutide (0.6 mg/day). As revealed by micro-CT analysis, Liraglutide improved trabecular volume, thickness and number, increased BMD, and reduced trabecular spacing in the femurs in OVX rats; similar results were observed in the lumbar vertebrae of OVX rats treated with Liraglutide. Following in vitro treatment of rat and human BMSCs with 10 nM Liraglutide, there was a significant increase in the mRNA expression of osteoblast-specific transcriptional factor Runx2 and the osteoblast markers alkaline phosphatase (ALP) and collagen α1 (Col-1), but a significant decrease in peroxisome proliferator-activated receptor γ (PPARγ). In conclusion, our results indicate that the anti-diabetic drug Liraglutide can exert a bone protective effect even in non-diabetic osteoporotic OVX rats. This protective effect is likely attributable to the impact of Liraglutide on the lineage fate determination of BMSCs. PMID:26177280

  12. Atrial natriuretic peptide attenuates agonist-induced pulmonary edema in mice with targeted disruption of the gene for natriuretic peptide receptor-A

    PubMed Central

    Tsai, Shu-Whei; Green, Sabrina; Grinnell, Katie L.; Machan, Jason T.; Harrington, Elizabeth O.

    2013-01-01

    Atrial natriuretic peptide (ANP) inhibits agonist-induced pulmonary edema formation, but the signaling pathway responsible is not well defined. To investigate the role of the particulate guanylate cyclase-linked receptor, natriuretic peptide receptor-A (NPR-A), we measured acute lung injury responses in intact mice and pulmonary microvascular endothelial cells (PMVEC) with normal and disrupted expression of NPR-A. NPR-A wild-type (NPR-A+/+), heterozygous (NPR-A+/−), and knockout (NPR-A−/−) mice were anesthetized and treated with thrombin receptor agonist peptide (TRAP) or lipopolysaccharide (LPS). Lung injury was assessed by lung wet-to-dry (W/D) weight and by protein and cell concentration of bronchoalveolar lavage (BAL) fluid. No difference in pulmonary edema formation was seen between NPR-A genotypes under baseline conditions. TRAP and LPS increased lung W/D weight and BAL fluid cell counts more in NPR-A−/− mice than in NPR-A+/− or NPR-A+/+ mice, but no genotype-related differences were seen in TRAP-induced increases in bloodless lung W/D weight or LPS-induced increases in BAL protein concentration. Pretreatment with ANP infusion completely blocked TRAP-induced increases in lung W/D weight and blunted LPS-induced increases in BAL cell counts and protein concentration in both NPR-A−/− and NPR-A+/+ mice. Thrombin decreased transmembrane electrical resistance in monolayers of PMVECs in vitro, and this effect was attenuated by ANP in PMVECs isolated from both genotypes. Administration of the NPR-C-specific ligand, cANF, also blocked TRAP-induced increases in lung W/D weight and LPS-induced increases in BAL cell count and protein concentration in NPR-A+/+ and NPR-A−/− mice. We conclude that ANP is capable of attenuating agonist-induced lung edema in the absence of NPR-A. The protective effect of ANP on agonist-induced lung injury and pulmonary barrier function may be mediated by NPR-C. PMID:23195629

  13. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia.

    PubMed

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to d-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. PMID:23954466

  14. Validation of model-based pelvis bone segmentation from MR images for PET/MR attenuation correction

    NASA Astrophysics Data System (ADS)

    Renisch, S.; Blaffert, T.; Tang, J.; Hu, Z.

    2012-02-01

    With the recent introduction of combined Magnetic Resonance Imaging (MRI) / Positron Emission Tomography (PET) systems, the generation of attenuation maps for PET based on MR images gained substantial attention. One approach for this problem is the segmentation of structures on the MR images with subsequent filling of the segments with respective attenuation values. Structures of particular interest for the segmentation are the pelvis bones, since those are among the most heavily absorbing structures for many applications, and they can serve at the same time as valuable landmarks for further structure identification. In this work the model-based segmentation of the pelvis bones on gradient-echo MR images is investigated. A processing chain for the detection and segmentation of the pelvic bones is introduced, and the results are evaluated using CT-generated "ground truth" data. The results indicate that a model based segmentation of the pelvis bone is feasible with moderate requirements to the pre- and postprocessing steps of the segmentation.

  15. Treatment with recombinant lubricin attenuates osteoarthritis by positive feedback loop between articular cartilage and subchondral bone in ovariectomized rats.

    PubMed

    Cui, Zhuang; Xu, Changpeng; Li, Xue; Song, Jinqi; Yu, Bin

    2015-05-01

    Osteoarthritis (OA) is a most commonly multifactorial degenerative joint disease along with the aging population, particularly in postmenopausal women. During the onset of OA, articular cartilage and subchondral bone act in concert as a functional unit. This present study is to investigate the effects of early or late treatment with recombinant lubricin on the onset of osteoarthritis (OA) in ovariectomized (OVX) rats. We found that both early and late recombinant lubricin treatments attenuated the onset of OA by positive feedback loop between articular cartilage and subchondral bone, although late treatment contributed to a lesser effect compared with early treatment. Specifically, treatment with recombinant lubricin protected articular cartilage from degeneration, demonstrated by lower proteoglycan loss, lower OARSI scores, less calcification cartilage zone and reduced immunostaining for collagen X (Col X) and matrix metalloproteinase (MMP-13) but increased the expression of lubricin, in comparison with vehicle-treated OVX rat group. Further, chondroprotective effects of lubricin normalized bone remodeling in subchondral bone underneath. It's suggested that treatment with recombinant lubricin inhibited the elevation of TRAP and Osterix positive cells in OVX rats and led to the normalization of subchondral bone microarchitectures with the suppression of subsidence of bone volume ratio (BV/TV) and trabecular thickness (Tb.Th) and the increase of trabecular separation (Tb.Sp) in vehicle-treated OVX rats. What's more, the normalization of subchondral bone in turn attenuated the articular cartilage erosion by inhibiting vascular invasion from subchondral bone to calcified cartilage zone, exemplified by inhibiting the elevation of CD31 positive cells in calcified cartilage and angiography in subchondral bone. Together, these results shed light that both early and late recombinant lubricin treatments attenuate the onset of OA by balancing the interplay between articular

  16. Treatment with recombinant lubricin attenuates osteoarthritis by positive feedback loop between articular cartilage and subchondral bone in ovariectomized rats.

    PubMed

    Cui, Zhuang; Xu, Changpeng; Li, Xue; Song, Jinqi; Yu, Bin

    2015-05-01

    Osteoarthritis (OA) is a most commonly multifactorial degenerative joint disease along with the aging population, particularly in postmenopausal women. During the onset of OA, articular cartilage and subchondral bone act in concert as a functional unit. This present study is to investigate the effects of early or late treatment with recombinant lubricin on the onset of osteoarthritis (OA) in ovariectomized (OVX) rats. We found that both early and late recombinant lubricin treatments attenuated the onset of OA by positive feedback loop between articular cartilage and subchondral bone, although late treatment contributed to a lesser effect compared with early treatment. Specifically, treatment with recombinant lubricin protected articular cartilage from degeneration, demonstrated by lower proteoglycan loss, lower OARSI scores, less calcification cartilage zone and reduced immunostaining for collagen X (Col X) and matrix metalloproteinase (MMP-13) but increased the expression of lubricin, in comparison with vehicle-treated OVX rat group. Further, chondroprotective effects of lubricin normalized bone remodeling in subchondral bone underneath. It's suggested that treatment with recombinant lubricin inhibited the elevation of TRAP and Osterix positive cells in OVX rats and led to the normalization of subchondral bone microarchitectures with the suppression of subsidence of bone volume ratio (BV/TV) and trabecular thickness (Tb.Th) and the increase of trabecular separation (Tb.Sp) in vehicle-treated OVX rats. What's more, the normalization of subchondral bone in turn attenuated the articular cartilage erosion by inhibiting vascular invasion from subchondral bone to calcified cartilage zone, exemplified by inhibiting the elevation of CD31 positive cells in calcified cartilage and angiography in subchondral bone. Together, these results shed light that both early and late recombinant lubricin treatments attenuate the onset of OA by balancing the interplay between articular

  17. Administration of the nicotinic acetylcholine receptor agonists ABT-089 and ABT-107 attenuates the reinstatement of nicotine-seeking behavior in rats.

    PubMed

    Lee, Alycia M; Arreola, Adrian C; Kimmey, Blake A; Schmidt, Heath D

    2014-11-01

    Current smoking cessation pharmacotherapies have modest efficacy, and most smokers relapse within the first few days after a quit attempt. Nicotine withdrawal-induced craving and cognitive impairments predict smoking relapse during abstinence and suggest that cognitive-enhancing drugs may prevent relapse. ABT-089 and ABT-107 are subtype-selective nAChR agonists that improve cognitive performance in laboratory animals. However, there are no studies examining the effects of ABT-089 and ABT-107 on nicotine self-administration and the reinstatement of nicotine-seeking behavior, an animal model of relapse in human smokers. The goal of the present study was to determine the effects of the α4β2*/α6β2* nAChR agonist ABT-089 and the α7 nAChR agonist ABT-107 on nicotine taking and seeking in rats. The effects of acute ABT-089 and ABT-107 pretreatment on nicotine self-administration and reinstatement were tested in male Sprague Dawley rats. Parallel studies of ABT-089 and ABT-107 on sucrose self-administration and reinstatement were tested in separate groups of rats to determine if the effects of these drug treatments generalized to other reinforced behaviors. Nicotine and sucrose self-administration behaviors were not altered following acute administration of ABT-089 (0, 0.12, 1.2 and 12.0mg/kg) or ABT-107 (0, 0.03 and 0.3mg/kg). In contrast, both ABT-089 and ABT-107 pretreatment dose-dependently attenuated nicotine reinstatement. These effects were reinforcer-specific as no effects of ABT-089 or ABT-107 pretreatment on sucrose seeking were noted. Taken together, these findings suggest that ABT-089 and ABT-107 do not affect nicotine consumption, but may reduce the likelihood that a smoking lapse will lead to relapse.

  18. Prostaglandins and muscarinic agonists induce cyclic AMP attenuation by two distinct mechanisms in the pregnant-rat myometrium. Interaction between cyclic AMP and Ca2+ signals.

    PubMed Central

    Goureau, O; Tanfin, Z; Harbon, S

    1990-01-01

    In pregnant-rat myometrium (day 21 of gestation), isoprenaline-induced cyclic AMP accumulation, resulting from receptor-mediated activation of adenylate cyclase, was negatively regulated by prostaglandins [PGE2, PGF2 alpha; EC50 (concn. giving 50% of maximal response) = 2 nM] and by the muscarinic agonist carbachol (EC50 = 2 microM). PG-induced inhibition was prevented by pertussis-toxin treatment, supporting the idea that it was mediated by the inhibitory G-protein Gi through the inhibitory pathway of the adenylate cyclase. Both isoprenaline-induced stimulation and PG-evoked inhibition of cyclic AMP were insensitive to Ca2+ depletion. By contrast, carbachol-evoked attenuation of cyclic AMP accumulation was dependent on Ca2+ and was insensitive to pertussis toxin. The inhibitory effect of carbachol was mimicked by ionomycin. Indirect evidence was thus provided for the enhancement of cyclic AMP degradation by a Ca2(+)-dependent phosphodiesterase activity in the muscarinic-mediated effect. The attenuation of cyclic AMP elicited by carbachol coincided with carbachol-stimulated inositol phosphate (InsP3, InsP2 and InsP) generation, which displayed an almost identical EC50 (3 microM) and was similarly unaffected by pertussis toxin. Both carbachol effects were reproduced by oxotremorine, whereas pilocarpine (a partial muscarinic agonist) failed to induce any decrease in cyclic AMP accumulation and concurrently was unable to stimulate the generation of inositol phosphates. These data support our proposal for a carbachol-mediated enhancement of a Ca2(+)-dependent phosphodiesterase activity, compatible with the rises in Ca2+ associated with muscarinic-induced increased generation of inositol phosphates. They further illustrate that a cross-talk between the two major transmembrane signalling systems contributed to an ultimate decrease in cyclic AMP in the pregnant-rat myometrium near term. PMID:1700899

  19. The 5-HT(1A) receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain.

    PubMed

    Deseure, Kristof; Koek, Wouter; Colpaert, Francis C; Adriaensen, Hugo

    2002-12-01

    The effects of acute intraperitoneal injections of the 5-HT(1A) receptor agonists F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone] and F 13714 [3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone] were studied in comparison with those of baclofen and morphine on responsiveness to von Frey hair stimulation after chronic constriction injury to the rat's infraorbital nerve (IoN-CCI). Following IoN-CCI, an ipsilateral hyperresponsiveness developed that remained stable in control rats throughout the period of drug testing. F 13640, F 13714, baclofen and morphine dose-dependently decreased the hyperresponsiveness; normalization of the response occurred at doses 0.63, 0.04, 5 and 10 mg/kg, respectively. Confirming earlier data, baclofen's effects further validate IoN-CCI as a model of trigeminal neuralgia. The effects of F 13640 and F 13714 are initial evidence that 5-HT(1A) receptor agonists produce profound analgesia in the IoN-CCI model. The present data extend recent evidence that high-efficacy 5-HT(1A) receptor activation constitutes a new mechanism of central analgesia the spectrum of which may also encompass trigeminal neuropathic pain. PMID:12450569

  20. The glucagon‐like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents

    PubMed Central

    Vallöf, Daniel; Maccioni, Paola; Colombo, Giancarlo; Mandrapa, Minja; Jörnulf, Julia Winsa; Egecioglu, Emil; Engel, Jörgen A.

    2015-01-01

    Abstract The incretin hormone, glucagon‐like peptide 1 (GLP‐1), regulates gastric emptying, glucose‐dependent stimulation of insulin secretion and glucagon release, and GLP‐1 analogs are therefore approved for treatment of type II diabetes. GLP‐1 receptors are expressed in reward‐related areas such as the ventral tegmental area and nucleus accumbens, and GLP‐1 was recently shown to regulate several alcohol‐mediated behaviors as well as amphetamine‐induced, cocaine‐induced and nicotine‐induced reward. The present series of experiments were undertaken to investigate the effect of the GLP‐1 receptor agonist, liraglutide, on several alcohol‐related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well‐documented effects of alcohol on the mesolimbic dopamine system, namely alcohol‐induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self‐administration of alcohol in selectively bred Sardinian alcohol‐preferring rats. Collectively, these data suggest that GLP‐1 receptor agonists could be tested for treatment of alcohol dependence in humans. PMID:26303264

  1. Norisoboldine, an Anti-Arthritis Alkaloid Isolated from Radix Linderae, Attenuates Osteoclast Differentiation and Inflammatory Bone Erosion in an Aryl Hydrocarbon Receptor-Dependent Manner.

    PubMed

    Wei, Zhi-feng; Lv, Qi; Xia, Ying; Yue, Meng-fan; Shi, Can; Xia, Yu-feng; Chou, Gui-xin; Wang, Zheng-tao; Dai, Yue

    2015-01-01

    Norisoboldine (NOR), the primary isoquinoline alkaloid constituent of the root of Lindera aggregata, has previously been demonstrated to attenuate osteoclast (OC) differentiation. Accumulative evidence has shown that aryl hydrocarbon receptor (AhR) plays an important role in regulating the differentiation of various cells, and multiple isoquinoline alkaloids can modulate AhR. In the present study, we explored the role of NOR in the AhR signaling pathway. These data showed that the combination of AhR antagonist resveratrol (Res) or α-naphthoflavone (α-NF) nearly reversed the inhibition of OC differentiation through NOR. NOR could stably bind to AhR, up-regulate the nuclear translocation of AhR, and enhance the accumulation of the AhR-ARNT complex, AhR-mediated reporter gene activity and CYP1A1 expression in RAW 264.7 cells, suggesting that NOR might be an agonist of AhR. Moreover, NOR inhibited the nuclear translocation of NF-κB-p65, resulting in the evident accumulation of the AhR-NF-κB-p65 complex, which could be markedly inhibited through either Res or α-NF. Although NOR only slightly affected the expression of HIF-1α, NOR markedly reduced VEGF mRNA expression and ARNT-HIF-1α complex accumulation. In vivo studies indicated that NOR decreased the number of OCs and ameliorated the bone erosion in the joints of rats with collagen-induced arthritis, accompanied by the up-regulation of CYP1A1 and the down-regulation of VEGF mRNA expression in the synovium of rats. A combination of α-NF nearly completely reversed the effects of NOR. In conclusion, NOR attenuated OC differentiation and bone erosion through the activation of AhR and the subsequent inhibition of both NF-κB and HIF pathways.

  2. Bone mass at final height in precocious puberty after gonadotropin-releasing hormone agonist with and without calcium supplementation.

    PubMed

    Antoniazzi, Franco; Zamboni, Giorgio; Bertoldo, Francesco; Lauriola, Silvana; Mengarda, Fabio; Pietrobelli, Angelo; Tatò, Luciano

    2003-03-01

    The aim of our longitudinal study was to evaluate bone mass in girls affected by central precocious puberty (CPP) that have reached final height, treated with GnRH agonist triptorelin (GnRHa), with or without calcium supplementation. We studied 48 Caucasian females affected by CPP (age at diagnosis, 7.19 +/- 0.96 yr), randomly assigned to two groups: group A (n = 21) treated with GnRHa and group B (n = 27) treated with GnRHa plus calcium gluconolactate and carbonate (1 g calcium/day in two doses) for at least 2 yr. Auxological parameters (standing height, weight, body mass index) and bone mineral density (BMD) at the lumbar spine [L2-L4, anteroposterior (AP)-BMD; lateral BMD; volumetric (v)BMD)] by dual-energy x-ray absorptiometry were evaluated at the beginning [chronological age (CA), 7.29 +/- 0.91 yr; bone age (BA), 8.80 +/- 1.24 yr] and end of treatment (CA, 11.27 +/- 0.97 yr; BA, 12.35 +/- 0.43 yr) and at final height (CA, 16.17 +/- 1.9 yr; BA, 16.93 +/- 0.98 yr, in each case >15 yr). Total bone mineral content, total BMD, and fat percentage were evaluated at the end of the study period using dual-energy x-ray absorptiometry. Final height was significantly higher than predicted height at diagnosis (159.9 +/- 6.3 cm vs. 152.9 +/- 9.6 cm; P < 0.05). Body mass index and fat percentage were not statistically different from control values. Densitometric values at final evaluation in groups A and B together were lower than in controls, but the differences were not statistically significant. The vBMD was significantly higher in group B than in group A at the end of treatment period (0.213 +/- 0.022 g/cm(3) vs. 0.192 +/- 0.021 g/cm(3); P < 0.01) and at final evaluation (0.246 +/- 0.023 g/cm(3) vs. 0.227 +/- 0.024 g/cm(3); P < 0.05). The percentage change (Delta%) between the start and end of treatment period in AP-BMD and vBMD was significantly higher in group B than in group A (Delta% AP-BMD: 20.36% +/- 1.10% vs. 16.16% +/- 1.90%, P < 0.01; Delta% vBMD: 19.08% +/- 3

  3. CCR2 elimination in mice results in larger and stronger tibial bones but bone loss is not attenuated following ovariectomy or muscle denervation.

    PubMed

    Mader, Tara L; Novotny, Susan A; Lin, Angela S; Guldberg, Robert E; Lowe, Dawn A; Warren, Gordon L

    2014-11-01

    Bone loss due to age and disuse contributes to osteoporosis and increases fracture risk. It has been hypothesized that such bone loss can be attenuated by modulation of the C-C chemokine receptor 2 (CCR2) and/or its ligands. The objectives of this study were to examine the effects of genetic elimination of CCR2 on cortical and trabecular bones in the mouse tibia and how bone loss was impacted following disuse and estrogen loss. Female CCR2 knockout (CCR2(-/-)) and wildtype mice underwent ovariectomy (OVX) or denervation of musculature adjacent to the tibia (DEN) to induce bone loss. Cortical and trabecular structural properties as well as mechanical properties (i.e., strength) of tibial bones were measured. Compared to wildtype mice, CCR2(-/-) mice had tibiae that were up to 9% larger and stronger; these differences could be explained mainly by the 17% greater body mass (P < 0.001) of CCR2(-/-) mice. The majority of the tibia's structural and functional responses to OVX and DEN were similar regardless of the lack or presence of CCR2, indicating that CCR2 is not protective against bone loss per se. These findings indicate that while CCR2(-/-) mice do have larger and stronger bones than do wildtype mice, there is minimal evidence that CCR2 elimination provides protection against bone loss during disuse and estrogen loss.

  4. Continuous MR bone density measurement using water- and fat-suppressed projection imaging (WASPI) for PET attenuation correction in PET-MR.

    PubMed

    Huang, C; Ouyang, J; Reese, T G; Wu, Y; El Fakhri, G; Ackerman, J L

    2015-10-21

    Due to the lack of signal from solid bone in normal MR sequences for the purpose of MR-based attenuation correction, investigators have proposed using the ultrashort echo time (UTE) pulse sequence, which yields signal from bone. However, the UTE-based segmentation approach might not fully capture the intra- and inter-subject bone density variation, which will inevitably lead to bias in reconstructed PET images. In this work, we investigated using the water- and fat-suppressed proton projection imaging (WASPI) sequence to obtain accurate and continuous attenuation for bones. This approach is capable of accounting for intra- and inter-subject bone attenuation variations. Using data acquired from a phantom, we have found that that attenuation correction based on the WASPI sequence is more accurate and precise when compared to either conventional MR attenuation correction or UTE-based segmentation approaches.

  5. Continuous MR bone density measurement using water- and fat-suppressed projection imaging (WASPI) for PET attenuation correction in PET-MR

    NASA Astrophysics Data System (ADS)

    Huang, C.; Ouyang, J.; Reese, T. G.; Wu, Y.; El Fakhri, G.; Ackerman, J. L.

    2015-10-01

    Due to the lack of signal from solid bone in normal MR sequences for the purpose of MR-based attenuation correction, investigators have proposed using the ultrashort echo time (UTE) pulse sequence, which yields signal from bone. However, the UTE-based segmentation approach might not fully capture the intra- and inter-subject bone density variation, which will inevitably lead to bias in reconstructed PET images. In this work, we investigated using the water- and fat-suppressed proton projection imaging (WASPI) sequence to obtain accurate and continuous attenuation for bones. This approach is capable of accounting for intra- and inter-subject bone attenuation variations. Using data acquired from a phantom, we have found that that attenuation correction based on the WASPI sequence is more accurate and precise when compared to either conventional MR attenuation correction or UTE-based segmentation approaches.

  6. Selective Non-Steroidal Glucocorticoid Receptor Agonists Attenuate Inflammation but Do Not Impair Intestinal Epithelial Cell Restitution In Vitro

    PubMed Central

    Reuter, Kerstin C.; Loitsch, Stefan M.; Dignass, Axel U.; Steinhilber, Dieter; Stein, Jürgen

    2012-01-01

    Introduction Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile. Methods The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis. Results Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348. Conclusion Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing

  7. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists' treatment: a meta-analysis of randomized controlled trials.

    PubMed

    Su, Bin; Sheng, Hui; Zhang, Manna; Bu, Le; Yang, Peng; Li, Liang; Li, Fei; Sheng, Chunjun; Han, Yuqi; Qu, Shen; Wang, Jiying

    2015-02-01

    Traditional anti-diabetic drugs may have negative or positive effects on risk of bone fractures. Yet the relationship between the new class glucagon-like peptide-1 receptor agonists (GLP-1 RA) and risk of bone fractures has not been established. We performed a meta-analysis including randomized controlled trials (RCT) to study the risk of bone fractures associated with liraglutide or exenatide, compared to placebo or other active drugs. We searched MEDLINE, EMBASE, and clinical trial registration websites for published or unpublished RCTs comparing the effects of liraglutide or exenatide with comparators. Only studies with disclosed bone fracture data were included. Separate pooled analysis was performed for liraglutide or exenatide, respectively, by calculating Mantel-Haenszel odds ratio (MH-OR). 16 RCTs were identified including a total of 11,206 patients. Liraglutide treatment was associated with a significant reduced risk of incident bone fractures (MH-OR=0.38, 95% CI 0.17-0.87); however, exenatide treatment was associated with an elevated risk of incident bone fractures (MH-OR=2.09, 95% CI 1.03-4.21). Publication bias and heterogeneity between studies were not observed. Our study demonstrated a divergent risk of bone fractures associated with different GLP-1 RA treatments. The current findings need to be confirmed by future well-designed prospective or RCT studies.

  8. The alpha(2)-adrenoceptor agonist dexmedetomidine suppresses memory formation only at doses attenuating the perception of sensory input.

    PubMed

    van Oostrom, Hugo; Stienen, Peter J; Doornenbal, Arie; Hellebrekers, Ludo J

    2010-03-10

    It was investigated whether continuous rate infusion of the alpha(2)-adrenoceptor agonist dexmedetomidine can suppress memory formation by mechanisms other than reducing perception of sensory input in a fear-conditioning paradigm. Different groups of rats infused with either saline or dexmedetomidine (2.0, 4.0 or 10.0microg/kg bolus, followed by 2.0, 4.0 or 10.0microg/kg/h continuous rate infusion respectively), were subjected to a somatosensory-evoked potential (SEP) fear-conditioning paradigm. This paradigm combined the pairing of an innoxious conditioned stimulus (CS) and a noxious unconditioned stimulus (US), of which the latter was used to generate the SEPs (training phase).The following day, the perception of the US during the training phase was assessed by presenting the CS only and subsequently scoring the resulting duration of freezing behaviour (testing phase). Freezing behaviour was reduced only in those groups which demonstrated reduced SEPs. Based on these findings, it is concluded that dexmedetomidine suppresses memory formation only at doses reducing central nervous system activity in response to sensory input.

  9. Retinoic acid receptor agonist Am80 inhibits CXCL2 production from microglial BV-2 cells via attenuation of NF-κB signaling.

    PubMed

    Takaoka, Yuichiro; Takahashi, Moeka; Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Shudo, Koichi; Katsuki, Hiroshi

    2016-09-01

    Accumulating lines of evidence suggest that retinoic acid receptor agonists such as Am80 exerts anti-inflammatory actions in the central nervous system, although detailed mechanisms of the action remain largely unknown. Our previous findings suggest that Am80 provides therapeutic effect on intracerebral hemorrhage in mice via suppression of expression of chemokine (C-X-C motif) ligand 2 (CXCL2). Here we investigated the mechanisms of inhibitory action of Am80 on expression of CXCL2 and other pro-inflammatory factors in microglial BV-2 cells. Pretreatment with Am80 markedly suppressed lipopolysaccharide (LPS)-induced expression of CXCL2 mRNA and release of CXCL2 protein. Am80 had no effect on LPS-induced activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. On the other hand, Am80 prevented LPS-induced nuclear translocation of p65 subunit of NF-κB complex. In addition, total expression levels of p65 and IκBα proteins, as well as of mRNAs encoding p65 and IκBα, were lowered by Am80. Dependence of CXCL2 expression on NF-κB was confirmed by the effect of an NF-κB inhibitor caffeic acid phenethyl ester that abolished LPS-induced CXCL2 expression. Caffeic acid phenethyl ester also abolished LPS-induced expression of inducible nitric oxide synthase, interleukin-1β and tumor necrosis factor α, which may be relevant to the inhibitory effect of Am80 on expression of these pro-inflammatory factors. We additionally found that Am80 attenuated LPS-induced up-regulation of CD14, a co-receptor for Toll-like receptor 4 (TLR4). These results suggest that inhibitory effect on TLR4 signaling mediated by NF-κB pathway underlies the anti-inflammatory action of retinoic acid receptor agonists in microglia. PMID:27351827

  10. Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10{sup −/−} mice by attenuating the activation of T cells and promoting their apoptosis

    SciTech Connect

    Singh, Udai P.; Singh, Narendra P.; Singh, Balwan; Price, Robert L.; Nagarkatti, Mitzi; Nagarkatti, Prakash S.

    2012-01-15

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10{sup −/−} mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10{sup −/−} mice. After JWH-133 treatment, the percentage of CD4{sup +} T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-γ expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. -- Highlights: ► JWH-133, a cannnabinoid receptor-2 agonist ameliorates experimental colitis. ► JWH-133 suppressed inflammation and

  11. Measurement of the normalized broadband ultrasound attenuation in trabecular bone by using a bidirectional transverse transmission technique

    NASA Astrophysics Data System (ADS)

    Lee, Kang Il

    2015-01-01

    A new method for measuring the normalized broadband ultrasound attenuation (nBUA) in trabecular bone by using a bidirectional transverse transmission technique was proposed and validated with measurements obtained by using the conventional transverse transmission technique. There was no significant difference between the nBUA measurements obtained for 14 bovine femoral trabecular bone samples by using the bidirectional and the conventional transverse transmission techniques. The nBUA measured by using the two transverse transmission techniques showed strong positive correlations of r = 0.87 to 0.88 with the apparent bone density, consistent with the behavior in human trabecular bone invitro. We expect that the new method can be usefully applied for improved accuracy and precision in clinical measurements.

  12. Propranolol, a β-adrenergic antagonist, attenuates the decrease in trabecular bone mass in high calorie diet fed growing mice.

    PubMed

    Baek, Kyunghwa; Hwang, Hyo Rin; Park, Hyun-Jung; Kwon, Arang; Qadir, Abdul S; Baek, Jeong-Hwa

    2014-09-01

    We investigated the effects of high calorie and low calorie diets on skeletal integrity, and whether β-adrenergic blockade (BB) attenuates bone loss induced by dietary calorie alteration. Male 6-week-old C57BL/6 mice were assigned to either an ad-lib fed control diet (CON), a high calorie diet (HIGH), or a low calorie diet (LOW) group. In each diet group, mice were treated with either vehicle (VEH) or propranolol, a β-adrenergic antagonist. Over 12-weeks, β-blockade mitigated body weight and fat mass increases induced by the high calorie diet. Femoral trabecular bone mineral density and the expression levels of osteogenic marker genes in bone marrow cells were reduced in HIGHVEH and LOWVEH mice, and BB significantly attenuated this decline only in HIGH mice. In summary, the magnitude of bone loss induced by low calorie diet was greater than that caused by high calorie diet in growing mice, and β-blockade mitigated high calorie diet-induced bone loss.

  13. An NMDA antagonist (LY 235959) attenuates abstinence-induced withdrawal of planarians following acute exposure to a cannabinoid agonist (WIN 55212-2).

    PubMed

    Rawls, Scott M; Gomez, Teresa; Raffa, Robert B

    2007-03-01

    The mechanisms that facilitate the development and expression of cannabinoid physical dependence in humans and other mammals are poorly understood. The present experiments used a planarian model to provide evidence that pharmacological antagonism of NMDA receptors significantly attenuates the development of cannabinoid physical dependence. Abstinence-induced withdrawal from the cannabinoid agonist WIN 55212-2 (10 microM) was manifested as a significant (P<0.05) decrease in the rate of planarian spontaneous locomotor velocity (pLMV) when WIN 55212-2 (10 microM)-exposed planarians were placed into drug-free water. No change in pLMV occurred when WIN 55212-2 (10 microM)-exposed planarians were placed into water containing WIN 55212-2 (10 microM). WIN 55212-2 (10 microM)-exposed planarians placed into water containing LY 235959 (1 or 10 microM) did not display withdrawal (no significant difference, P>0.05, in pLMV). In addition, withdrawal was not observed (no significant difference, P>0.05, in pLMV) in planarians that were co-exposed to a solution containing WIN 55212-2 (10 microM) and LY 235959 (10 microM). The present results reveal that NMDA receptor activation mediates the development of cannabinoid physical dependence and the expression of cannabinoid withdrawal in planarians.

  14. A nitric oxide synthase inhibitor (L-NAME) attenuates abstinence-induced withdrawal from both cocaine and a cannabinoid agonist (WIN 55212-2) in Planaria.

    PubMed

    Rawls, Scott M; Rodriguez, Tonatiu; Baron, David A; Raffa, Robert B

    2006-07-12

    We previously reported that planarians (Dugesia dorotocephala) that have been exposed to cocaine for 1 h undergo abstinence-induced withdrawal when placed into cocaine-free, but not cocaine-containing, water. We now report that planarians also display dose-related abstinence-induced withdrawal following exposure to the synthetic cannabinoid agonist WIN 55212-2, but not its inactive enantiomer (WIN 55212-3). The withdrawal from WIN 55212-2 was manifested as a significant (P < 0.05) decrease in the rate of planarian spontaneous locomotor activity over a 5-min observation period, using a recently designed metric (pLMV). We also report that withdrawal from cocaine (80 microM) or WIN 55212-2 (10 microM) was attenuated by the selective inhibitor of nitric oxide synthesis L-NAME (L-nitro-arginine methyl ester), which had no effect of its own on pLMV. These results suggest a common NO-dependent pathway of withdrawal from cocaine and WIN 55212-2 in Planaria.

  15. Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer.

    PubMed

    Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane; Tsai, James; Burton, Elizabeth A; Habets, Gaston; Lin, Paul S; West, Brian L; Mantyh, Patrick W

    2015-09-01

    Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here, we explored whether PLX3397, a high-affinity small molecular antagonist that binds to and inhibits phosphorylation of colony-stimulating factor-1 receptor, the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3, can reduce CIBP. These 3 targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells. Preliminary experiments show that PLX3397 attenuated inflammatory pain after formalin injection into the hind paw of the rat. As there is an inflammatory component in CIBP, involving macrophages and osteoclasts, the effect of PLX3397 was explored in a prostate model of CIBP where skeletal pain, cancer cell proliferation, tumor metastasis, and bone remodeling could be monitored in the same animal. Administration of PLX3397 was initiated on day 14 after prostate cancer cell injection when the tumor was well established, and tumor-induced bone remodeling was first evident. Over the next 6 weeks, sustained administration of PLX3397 attenuated CIBP behaviors by approximately 50% and was equally efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. Developing a better understanding of potential effects that analgesic therapies have on the tumor itself may allow the development of therapies that not only better control the pain but also positively impact disease progression and overall survival in patients with bone cancer.

  16. Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer.

    PubMed

    Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane; Tsai, James; Burton, Elizabeth A; Habets, Gaston; Lin, Paul S; West, Brian L; Mantyh, Patrick W

    2015-09-01

    Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here, we explored whether PLX3397, a high-affinity small molecular antagonist that binds to and inhibits phosphorylation of colony-stimulating factor-1 receptor, the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3, can reduce CIBP. These 3 targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells. Preliminary experiments show that PLX3397 attenuated inflammatory pain after formalin injection into the hind paw of the rat. As there is an inflammatory component in CIBP, involving macrophages and osteoclasts, the effect of PLX3397 was explored in a prostate model of CIBP where skeletal pain, cancer cell proliferation, tumor metastasis, and bone remodeling could be monitored in the same animal. Administration of PLX3397 was initiated on day 14 after prostate cancer cell injection when the tumor was well established, and tumor-induced bone remodeling was first evident. Over the next 6 weeks, sustained administration of PLX3397 attenuated CIBP behaviors by approximately 50% and was equally efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. Developing a better understanding of potential effects that analgesic therapies have on the tumor itself may allow the development of therapies that not only better control the pain but also positively impact disease progression and overall survival in patients with bone cancer. PMID:25993548

  17. PPARα agonist fenofibrate attenuates TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway

    SciTech Connect

    Wang, Weirong; Lin, Qinqin; Lin, Rong; Zhang, Jiye; Ren, Feng; Zhang, Jianfeng; Ji, Meixi; Li, Yanxiang

    2013-06-10

    The ligand-activated transcription factor peroxisome proliferator-activated receptor-α (PPARα) participates in the regulation of cellular inflammation. More recent studies indicated that sirtuin1 (SIRT1), a NAD{sup +}-dependent deacetylase, regulates the inflammatory response in adipocytes. However, whether the role of PPARα in inflammation is mediated by SIRT1 remains unclear. In this study, we aimed to determine the effect of PPARα agonist fenofibrate on the expressions of SIRT1 and pro-inflammatory cytokine CD40 and underlying mechanisms in 3T3-L1 adipocytes. We found that fenofibrate inhibited CD40 expression and up-regulated SIRT1 expression in tumor necrosis factor-α (TNF-α)-stimulated adipocytes, and these effects of fenofibrate were reversed by PPARα antagonist GW6471. Moreover, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or knockdown of SIRT1 could attenuate the effect of fenofibrate on TNF-α-induced CD40 expression in adipocytes. Importantly, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression in adipocytes. Further study found that fenofibrate decreased the expression of acetylated-NF-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated adipocytes, and the effect of fenofibrate was abolished by SIRT1 inhibition. In addition, fenofibrate up-regulated SIRT1 expression through AMPK in TNF-α-stimulated adipocytes. Taken together, these findings indicate that PPARα agonist fenofibrate inhibits TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway. -- Highlights: • Fenofibrate up-regulates SIRT1 expression in TNF-α-stimulated adipocytes. • Fenofibrate inhibits CD40 expression through SIRT1 in adipocytes. • The effects of fenofibrate on CD40 and SIRT1 expressions are dependent on PPARα. • Fenofibrate inhibits CD40 expression via SIRT1-dependent deacetylation of NF-κB. • Fenofibrate increases SIRT1 expression through PPARα and AMPK in adipocytes.

  18. Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor.

    PubMed

    Majuta, Lisa A; Longo, Geraldine; Fealk, Michelle N; McCaffrey, Gwen; Mantyh, Patrick W

    2015-01-01

    The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain-related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti-nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains.

  19. Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

    PubMed Central

    Majuta, Lisa A.; Longo, Geraldine; Fealk, Michelle N.; McCaffrey, Gwen; Mantyh, Patrick W.

    2015-01-01

    The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain–related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti–nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains. PMID:25599311

  20. Stimulus-response coupling in monocytes infected with Leishmania. Attenuation of calcium transients is related to defective agonist-induced accumulation of inositol phosphates.

    PubMed

    Olivier, M; Baimbridge, K G; Reiner, N E

    1992-02-15

    Mononuclear phagocytes infected with Leishmania have been shown to have defective responses to extracellular stimuli. To investigate the potential relationship of these findings to alterations in calcium-dependent signaling pathways, the regulation of [Ca2+]i concentrations was examined in human peripheral blood monocytes infected with amastigotes of Leishmania donovani. Measurements of [Ca2+]i in fura-2-loaded monocytes were made at the single cell level by microfluorimetry. In normal monocytes, resting [Ca2+]i was 56 +/- 2 nM (mean +/- SEM). In contrast, in monocytes infected with Leishmania there was an approximately twofold increase in basal [Ca2+]i (122 +/- 5 nM, p less than 0.01 vs control). Treatment of cells with pertussis toxin before infection did not abrogate infection-induced increases in basal [Ca2+]i, suggesting that this effect was not mediated via the activation of a G protein coupled to phospholipase C. However, elevated resting [Ca2+]i did correlate with increased rates of 45Ca2+ uptake by infected monocytes. As expected, in response to treatment with 10(-7) M FMLP, control monocytes showed rapid net increases in [Ca2+]i of 303 +/- 19 nM. In contrast, net transients of [Ca2+]i in infected monocytes in response to FMLP were attenuated to only 137 +/- 9 nM (p less than 0.01 vs control). This result was not related to excess buffering of [Ca2+]i in infected cells as both control and infected monocytes showed equivalent transients of [Ca2+]i in response to the calcium ionophore A23187. Rather, inhibition of agonist-induced calcium release in infected cells appeared related to defective generation of second messenger because compared to control cells labeled with myo-[2-3H]inositol, little accumulation of inositol 1,4,5-trisphosphate was detected in infected monocytes. Attenuation of inositol phosphate accumulation and calcium release in response to chemotactic peptide correlated with decreased FMLP-induced superoxide and hydrogen peroxide production

  1. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic analysis of regenerated bone

    NASA Astrophysics Data System (ADS)

    Benetti, Carolina; Kazarain, Sergei G.; Alves, Marco A. V.; Blay, Alberto; Correa, Luciana; Zezell, Denise M.

    2014-03-01

    The cutting of bone is routinely required in medical procedures, especially in dental applications. In such cases, bone regeneration and new bone quality can determine the success of the treatment. This study investigated the main spectral differences of undamaged and healed bone using the ATR-FTIR spectroscopy technique. Three rabbits were submitted to a surgical procedure; a small piece of bone (3x3 mm2) was removed from both sides of their jaws using a high speed drill. After 15 days, the rabbits were euthanized and the jaws were removed. A bone slice was cut from each side of the jaw containing regions of undamaged and newly formed bone, resulting in six samples which were polished for spectroscopic comparison. The samples were analyzed by FTIR spectroscopy using a diamond ATR accessory. Spectral characteristics were compared and particular attention was paid to the proportion of phosphate to amide I bands and the width of the phosphate band. The results show that the ratio of phosphate to amide I is smaller in new bone tissue than in the undamaged bone, indicating a higher organic content in the newly formed bone. The analysis of the width of the phosphate band suggests a crystallinity difference between both tissues, since the width was higher in the new bone than in the natural bone. These results suggest that the differences observed in bone aging processes by FTIR spectroscopic can be applied to the study of healing processes.

  2. Putative Dopamine Agonist (KB220Z) Attenuates Lucid Nightmares in PTSD Patients: Role of Enhanced Brain Reward Functional Connectivity and Homeostasis Redeeming Joy

    PubMed Central

    McLaughlin, Thomas; Blum, Kenneth; Oscar-Berman, Marlene; Febo, Marcelo; Agan, Gozde; Fratantonio, James L.; Simpatico, Thomas; Gold, Mark S.

    2015-01-01

    Background Lucid dreams are frequently pleasant and training techniques have been developed to teach dreamers to induce them. In addition, the induction of lucid dreams has also been used as a way to ameliorate nightmares. On the other hand, lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. In the latter conditions, lucid dreams can assume an unpleasant and frequently terrifying character. Case Presentations We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. In the first case study, a 51-year-old, obese woman, diagnosed with PTSD and depression, had attempted suicide and experienced terrifying lucid nightmares linked to sexual/physical abuse from early childhood by family members including her alcoholic father. Her vivid “bad dreams” remained refractory in spite of 6 months of treatment with Dialectical Behavioral Therapy (DBT) and standard pharmaceutical agents which included prazosin, clonidie and Adderall. The second 39-year-old PTSD woman patient had also suffered from lucid nightmares. Results The medication visit notes reveal changes in the frequency, intensity and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient’s regimen. The patient reported her first experience of an extended period of happy dreams. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter. Conclusions These cases are discussed with reference to the known effects of KB220Z including enhanced dopamine homeostasis and functional connectivity of brain reward circuitry in rodents and humans. Their understanding awaits intensive investigation involving large-population, double-blinded studies. PMID:26132915

  3. Icariin attenuates titanium-particle inhibition of bone formation by activating the Wnt/β-catenin signaling pathway in vivo and in vitro

    PubMed Central

    Wang, Junhua; Tao, Yunxia; Ping, Zichuan; Zhang, Wen; Hu, Xuanyang; Wang, Yijun; Wang, Liangliang; Shi, Jiawei; Wu, Xiexing; Yang, Huilin; Xu, Yaozeng; Geng, Dechun

    2016-01-01

    Wear-debris-induced periprosthetic osteolysis (PIO) is a common clinical condition following total joint arthroplasty, which can cause implant instability and failure. The host response to wear debris promotes bone resorption and impairs bone formation. We previously demonstrated that icariin suppressed wear-debris-induced osteoclastogenesis and attenuated particle-induced osteolysis in vivo. Whether icariin promotes bone formation in a wear-debris-induced osteolytic site remains unclear. Here, we demonstrated that icariin significantly attenuated titanium-particle inhibition of osteogenic differentiation of mesenchymal stem cells (MSCs). Additionally, icariin increased bone mass and decreased bone loss in titanium-particle-induced osteolytic sites. Mechanistically, icariin inhibited decreased β-catenin stability induced by titanium particles in vivo and in vitro. To confirm icariin mediated its bone-protective effects via the Wnt/β-catenin signaling pathway, we demonstrated that ICG-001, a selective Wnt/β-catenin inhibitor, attenuated the effects of icariin on MSC mineralization in vitro and bone formation in vivo. Therefore, icariin could induce osteogenic differentiation of MSCs and promote new bone formation at a titanium-particle-induced osteolytic site via activation of the Wnt/β-catenin signaling pathway. These results further support the protective effects of icariin on particle-induced bone loss and provide novel mechanistic insights into the recognized bone-anabolic effects of icariin and an evidence-based rationale for its use in PIO treatment. PMID:27029606

  4. Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis

    PubMed Central

    Dong, Yonghui; Liu, Hui; Zhang, Xuejun; Xu, Fei; Qin, Liang; Cheng, Peng; Huang, Hui; Guo, Fengjing; Yang, Qing; Chen, Anmin

    2016-01-01

    Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA) mice models were prepared by transecting the anterior cruciate ligament (ACLT), or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS) or AMD3100 (an inhibitor of CXCR4) and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT). Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I) were quantified by ELISA. Bone marrow mononuclear cells (BMMCs) were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP), cathepsin K (CK), and matrix metalloproteinase (MMP)-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage degeneration in

  5. Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis.

    PubMed

    Dong, Yonghui; Liu, Hui; Zhang, Xuejun; Xu, Fei; Qin, Liang; Cheng, Peng; Huang, Hui; Guo, Fengjing; Yang, Qing; Chen, Anmin

    2016-01-01

    Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA) mice models were prepared by transecting the anterior cruciate ligament (ACLT), or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS) or AMD3100 (an inhibitor of CXCR4) and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT). Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I) were quantified by ELISA. Bone marrow mononuclear cells (BMMCs) were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP), cathepsin K (CK), and matrix metalloproteinase (MMP)-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage degeneration in

  6. Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice

    PubMed Central

    Watari, Kosuke; Shibata, Tomohiro; Nabeshima, Hiroshi; Shinoda, Ai; Fukunaga, Yuichi; Kawahara, Akihiko; Karasuyama, Kazuyuki; Fukushi, Jun-ichi; Iwamoto, Yukihide; Kuwano, Michihiko; Ono, Mayumi

    2016-01-01

    N-myc downstream regulated gene 1 (NDRG1) is a responsible gene for a hereditary motor and sensory neuropathy-Lom (Charcot–Marie–Tooth disease type 4D). This is the first study aiming to assess the contribution of NDRG1 to differentiation of macrophage lineage cells, which has important implications for bone remodeling and inflammatory angiogenesis. Ndrg1 knockout (KO) mice exhibited abnormal curvature of the spine, high trabecular bone mass, and reduced number of osteoclasts. We observed that serum levels of macrophage colony-stimulating factor (M-CSF) and macrophage-related cytokines were markedly decreased in KO mice. Differentiation of bone marrow (BM) cells into osteoclasts, M1/M2-type macrophages and dendritic cells was all impaired. Furthermore, KO mice also showed reduced tumor growth and angiogenesis by cancer cells, accompanied by decreased infiltration of tumor-associated macrophages. The transfer of BM-derived macrophages from KO mice into BM-eradicated wild type (WT) mice induced much less tumor angiogenesis than observed in WT mice. Angiogenesis in corneas in response to inflammatory stimuli was also suppressed with decreased infiltration of macrophages. Taken together, these results indicate that NDRG1 deficiency attenuates the differentiation of macrophage lineage cells, suppressing bone remodeling and inflammatory angiogenesis. This study strongly suggests the crucial role of NDRG1 in differentiation process for macrophages. PMID:26778110

  7. Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice.

    PubMed

    Ishiguro, Susumu; Yoshimura, Kiyoshi; Tsunedomi, Ryouichi; Oka, Masaaki; Takao, Sonshin; Inui, Makoto; Kawabata, Atsushi; Wall, Terrahn; Magafa, Vassiliki; Cordopatis, Paul; Tzakos, Andreas G; Tamura, Masaaki

    2015-01-01

    We have recently discovered the potential involvement of angiotensin II type 2 receptor (AT2R) signaling in pancreatic cancer using AT2R deficient mice. To examine the involvement of AT2R expression in human PDAC, expressions of AT2R as well as the major angiotensin II receptor (type 1 receptor, AT1R) in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using surgically dissected human PDAC specimens. In immunohistochemical analysis, relatively strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, whereas moderate AT2R expression was detected in 78.5% of PDAC specimens and 100% of normal area of the pancreas. AT1R, but not AT2R, mRNA levels were significantly higher in the PDAC area than in the normal pancreas. AT2R mRNA levels showed a negative correlation trend with overall survival. In cell cultures, treatment with a novel AT2R agonist significantly attenuated both murine and human PDAC cell growth with negligible cytotoxicity in normal epithelial cells. In a mouse study, administrations of the AT2R agonist in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in syngeneic mice. The AT2R agonist treatment induced apoptosis primarily in tumor cells but not in stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development and pinpoint that the novel AT2R agonist could serve as an effective therapeutic for PDAC treatment.

  8. Green tea polyphenols attenuate deterioration of bone microarchitecture in female rats with systemic chronic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: Our previous study demonstrated that green tea polyphenols (GTP) benefit bone health in female rats with chronic inflammation, because of GTP’s antioxidant capacity. The current study further evaluates whether GTP can restore bone microstructure along with related mechanism in rats wit...

  9. Correction of quantification errors in pelvic and spinal lesions caused by ignoring higher photon attenuation of bone in [{sup 18}F]NaF PET/MR

    SciTech Connect

    Schramm, Georg Maus, Jens; Hofheinz, Frank; Petr, Jan; Lougovski, Alexandr; Beuthien-Baumann, Bettina; Oehme, Liane; Platzek, Ivan; Hoff, Jörg van den

    2015-11-15

    Purpose: MR-based attenuation correction (MRAC) in routine clinical whole-body positron emission tomography and magnetic resonance imaging (PET/MRI) is based on tissue type segmentation. Due to lack of MR signal in cortical bone and the varying signal of spongeous bone, standard whole-body segmentation-based MRAC ignores the higher attenuation of bone compared to the one of soft tissue (MRAC{sub nobone}). The authors aim to quantify and reduce the bias introduced by MRAC{sub nobone} in the standard uptake value (SUV) of spinal and pelvic lesions in 20 PET/MRI examinations with [{sup 18}F]NaF. Methods: The authors reconstructed 20 PET/MR [{sup 18}F]NaF patient data sets acquired with a Philips Ingenuity TF PET/MRI. The PET raw data were reconstructed with two different attenuation images. First, the authors used the vendor-provided MRAC algorithm that ignores the higher attenuation of bone to reconstruct PET{sub nobone}. Second, the authors used a threshold-based algorithm developed in their group to automatically segment bone structures in the [{sup 18}F]NaF PET images. Subsequently, an attenuation coefficient of 0.11 cm{sup −1} was assigned to the segmented bone regions in the MRI-based attenuation image (MRAC{sub bone}) which was used to reconstruct PET{sub bone}. The automatic bone segmentation algorithm was validated in six PET/CT [{sup 18}F]NaF examinations. Relative SUV{sub mean} and SUV{sub max} differences between PET{sub bone} and PET{sub nobone} of 8 pelvic and 41 spinal lesions, and of other regions such as lung, liver, and bladder, were calculated. By varying the assigned bone attenuation coefficient from 0.11 to 0.13 cm{sup −1}, the authors investigated its influence on the reconstructed SUVs of the lesions. Results: The comparison of [{sup 18}F]NaF-based and CT-based bone segmentation in the six PET/CT patients showed a Dice similarity of 0.7 with a true positive rate of 0.72 and a false discovery rate of 0.33. The [{sup 18}F]NaF-based bone

  10. Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway

    PubMed Central

    Dou, C; Ding, N; Xing, J; Zhao, C; Kang, F; Hou, T; Quan, H; Chen, Y; Dai, Q; Luo, F; Xu, J; Dong, S

    2016-01-01

    Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss. PMID:27031959

  11. Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway.

    PubMed

    Dou, C; Ding, N; Xing, J; Zhao, C; Kang, F; Hou, T; Quan, H; Chen, Y; Dai, Q; Luo, F; Xu, J; Dong, S

    2016-01-01

    Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss. PMID:27031959

  12. Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43.

    PubMed

    Chung, Dong Jin; Castro, Charlles H M; Watkins, Marcus; Stains, Joseph P; Chung, Min Young; Szejnfeld, Vera Lucia; Willecke, Klaus; Theis, Martin; Civitelli, Roberto

    2006-10-15

    Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the alpha1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43-/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43-/fl mice, with Cx43-/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43-/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

  13. Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARgamma agonist pioglitazone.

    PubMed

    Artunc, Ferruh; Sandulache, Diana; Nasir, Omaima; Boini, Krishna M; Friedrich, Björn; Beier, Norbert; Dicks, Edith; Pötzsch, Sven; Klingel, Karin; Amann, Kerstin; Blazer-Yost, Bonnie L; Scholz, Wolfgang; Risler, Teut; Kuhl, Dietmar; Lang, Florian

    2008-05-01

    PPARgamma-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARgamma-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARgamma agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na+ channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARgamma agonists. To test this hypothesis, food containing the PPARgamma agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1-/-, n=12) and their wild-type littermates (sgk1+/+), n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1+/+ mice. The treatment increased body weight significantly in both, sgk1+/+ mice (+2.2+/-0.3 g) and sgk-/- mice (+1.3+/-0.2 g), and decreased hematocrit significantly in sgk1+/+ mice (-6.5+/-1.0%) and sgk1-/- mice (-3.1+/-0.6%). Both effects were significantly (p<0.05) more pronounced in sgk1+/+ mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1+/+ mice (from 50.9+/-3.9 to 63.7+/-2.5 microl/g bw) but not in sgk-/- mice (from 46.8+/-3.8 to 48.3+/-5.2 microl/g bw). Pioglitazone decreased aldosterone plasma levels and blood pressure and increased leptin plasma levels in both genotypes. We conclude that SGK1 contributes to but does not fully account for the volume retention during treatment with the PPARgamma agonist pioglitazone. PMID:18172605

  14. VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth.

    PubMed

    O'Donnell, Rebekah K; Falcon, Beverly; Hanson, Jeff; Goldstein, Whitney E; Perruzzi, Carole; Rafii, Shahin; Aird, William C; Benjamin, Laura E

    2016-02-01

    Antiangiogenesis-based cancer therapies, specifically those targeting the VEGF-A/VEGFR2 pathway, have been approved for subsets of solid tumors. However, these therapies result in an increase in hematologic adverse events. We surmised that both the bone marrow vasculature and VEGF receptor-positive hematopoietic cells could be impacted by VEGF pathway-targeted therapies. We used a mouse model of spontaneous breast cancer to decipher the mechanism by which VEGF pathway inhibition alters hematopoiesis. Tumor-bearing animals, while exhibiting increased angiogenesis at the primary tumor site, showed signs of shrinkage in the sinusoidal bone marrow vasculature accompanied by an increase in the hematopoietic stem cell-containing Lin-cKit(+)Sca1(+) (LKS) progenitor population. Therapeutic intervention by targeting VEGF-A, VEGFR2, and VEGFR3 inhibited tumor growth, consistent with observed alterations in the primary tumor vascular bed. These treatments also displayed systemic effects, including reversal of the tumor-induced shrinkage of sinusoidal vessels and altered population balance of hematopoietic stem cells in the bone marrow, manifested by the restoration of sinusoidal vessel morphology and hematopoietic homeostasis. These data indicate that tumor cells exert an aberrant systemic effect on the bone marrow microenvironment and VEGF-A/VEGFR targeting restores bone marrow function.

  15. Effects of phase cancellation and receiver aperture size on broadband ultrasonic attenuation for trabecular bone in vitro.

    PubMed

    Cheng, Jiqi; Serra-Hsu, Frederick; Tian, Yuan; Lin, Wei; Qin, Yi-Xian

    2011-12-01

    Phase cancellation in ultrasound due to large receiver size has been proposed as a contributing factor to the inaccuracy of estimating broadband ultrasound attenuation (BUA), which is used to characterize bone quality. Transducers with aperture size ranging from 2 to 5 mm have been used in previous attempts to study the effect of phase cancellation. However, these receivers themselves are susceptible to phase cancellation because aperture size is close to one center wavelength (about 3 mm at 500 KHz in water). This study uses an ultra small receiver (aperture size: 0.2 mm) in conjunction with a newly developed two-dimensional (2-D) synthetic array system to investigate the effects of phase cancellation and receiver aperture size on BUA estimations of bone tissue. In vitro ultrasound measurements were conducted on 54 trabecular bone samples (harvested from sheep femurs) in a confocal configuration with a focused transmitter and synthesized focused receivers of different aperture sizes. Phase sensitive (PS) and phase insensitive (PI) detections were performed. The results show that phase cancellation does have a significant effect on BUA. The normalized BUA (nBUA) with PS is 8.1% higher than PI nBUA while PI BUA is well correlated with PS BUA. Receiver aperture size also influences the BUA reading for both PI and PS detection and smaller receiver aperture tends to result in higher BUA readings. The results also indicate that the receiver aperture size used in the confocal configuration with PI detection should at least equal the aperture of the transmitter to capture most of the energy redistributed by the interference and diffraction from the trabecular bone.

  16. Levo-Tetrahydropalmatine Attenuates Bone Cancer Pain by Inhibiting Microglial Cells Activation

    PubMed Central

    Zhang, Mao-yin; Liu, Yue-peng; Zhang, Lian-yi; Yue, Dong-mei; Qi, Dun-yi; Liu, Gong-jian; Liu, Su

    2015-01-01

    Objective. The present study is to investigate the analgesic roles of L-THP in rats with bone cancer pain caused by tumor cell implantation (TCI). Methods. Thermal hyperalgesia and mechanical allodynia were measured at different time points before and after operation. L-THP (20, 40, and 60 mg/kg) were administrated intragastrically at early phase of postoperation (before pain appearance) and later phase of postoperation (after pain appearance), respectively. The concentrations of TNF-α, IL-1β, and IL-18 in spinal cord were measured by enzyme-linked immunosorbent assay. Western blot was used to test the activation of astrocytes and microglial cells in spinal cord after TCI treatment. Results. TCI treatment induced significant thermal hyperalgesia and mechanical allodynia. Administration of L-THP at high doses significantly prevented and/or reversed bone cancer-related pain behaviors. Besides, TCI-induced activation of microglial cells and the increased levels of TNF-α and IL-18 were inhibited by L-THP administration. However, L-THP failed to affect TCI-induced astrocytes activation and IL-1β increase. Conclusion. This study suggests the possible clinical utility of L-THP in the treatment of bone cancer pain. The analgesic effects of L-THP on bone cancer pain maybe underlying the inhibition of microglial cells activation and proinflammatory cytokines increase. PMID:26819501

  17. Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth In Vivo

    PubMed Central

    Buijs, Jeroen T.; van der Horst, Geertje; Cheung, Henry; van der Mark, Maaike; van Bloois, Louis; Rizzo, Larissa Y.; Lammers, Twan; Pelger, Rob C.; Storm, Gert; van der Pluijm, Gabri; Metselaar, Josbert M.

    2015-01-01

    Background The inflammatory tumor microenvironment, and more specifically the tumor‐associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which ‐ combined with the prolonged circulation kinetics of liposomes ‐ leads to efficient tumor localization of these drug carriers, via the so‐called enhanced permeability and retention (EPR) ‐effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor‐bearing Balb‐c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free‐ and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well‐tolerated at clinically‐relevant dosages that display potent anti‐tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation. Prostate 75: 815–824, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc. PMID:25663076

  18. A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol

    PubMed Central

    Langley, Ruth E.; Kynaston, Howard G.; Alhasso, Abdulla A.; Duong, Trinh; Paez, Edgar M.; Jovic, Gordana; Scrase, Christopher D.; Robertson, Andrew; Cafferty, Fay; Welland, Andrew; Carpenter, Robin; Honeyfield, Lesley; Abel, Richard L.; Stone, Michael; Parmar, Mahesh K.B.; Abel, Paul D.

    2016-01-01

    Background Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. Objective To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). Design, setting, and participants Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. Interventions LHRHa as per local practice, OP (FemSeven 100 μg/24 h patches). Outcome measurements and statistical analysis The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. Results and limitations A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001). Conclusions Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. Patient summary This study found that prostate cancer patients treated with transdermal oestradiol

  19. Effects of adenosine A(3) receptor agonist on bone marrow granulocytic system in 5-fluorouracil-treated mice.

    PubMed

    Hofer, Michal; Pospísil, Milan; Vacek, Antonín; Holá, Jirina; Znojil, Vladimír; Weiterová, Lenka; Streitová, Denisa

    2006-05-24

    The purpose of the experiments reported was to investigate effects of N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a selective adenosine A(3) receptor agonist, on the granulocytic system in femoral marrow of mice depleted by the cytotoxic drug 5-fluorouracil. In the phase of the highest cell depletion IB-MECA was injected i.p. at single doses of 200 nmol/kg given either once or twice daily in 2- and 4-day regimens starting on day 1 after 5-fluorouracil administration; the effects were evaluated on days 3 and 5, respectively. The general effect of IB-MECA in all these experiments was an enhancement of the counts of morphologically recognizable proliferative granulocytic cells, interpreted as evidence of the differentiation of committed progenitor cells. A more expressive effect was observed after IB-MECA injected twice daily. It was found that the induction of the strong differentiation pressures by IB-MECA given twice daily shortly after 5-fluorouracil treatment can be counterproductive due to the preponderance of differentiaton processes over the proliferation control. In additional experiments, it has been shown that the use of the 2-day administration of IB-MECA given twice daily in the recovery phase, i.e., on days 5 and 6 after 5-fluorouracil administration, does not induce stimulatory effects. Thus, the dosing and timing of IB-MECA treatment determines its effectivity in stimulating granulopoiesis under conditions of myelosuppression.

  20. Sesamol attenuates genotoxicity in bone marrow cells of whole-body γ-irradiated mice.

    PubMed

    Kumar, Arun; Selvan, Tamizh G; Tripathi, Akanchha M; Choudhary, Sandeep; Khan, Shahanshah; Adhikari, Jawahar S; Chaudhury, Nabo K

    2015-09-01

    Ionising radiation causes free radical-mediated damage in cellular DNA. This damage is manifested as chromosomal aberrations and micronuclei (MN) in proliferating cells. Sesamol, present in sesame seeds, has the potential to scavenge free radicals; therefore, it can reduce radiation-induced cytogenetic damage in cells. The aim of this study was to investigate the radioprotective potential of sesamol in bone marrow cells of mice and related haematopoietic system against radiation-induced genotoxicity. A comparative study with melatonin was designed for assessing the radioprotective potential of sesamol. C57BL/6 mice were administered intraperitoneally with either sesamol or melatonin (10 and 20mg/kg body weight) 30 min prior to 2-Gy whole-body irradiation (WBI) and sacrificed after 24h. Total chromosomal aberrations (TCA), MN and cell cycle analyses were performed using bone marrow cells. The comet assay was performed on bone marrow cells, splenocytes and lymphocytes. Blood was drawn to study haematological parameters. Prophylactic doses of sesamol (10 and 20mg/kg) in irradiated mice reduced TCA and micronucleated polychromatic erythrocyte frequency in bone marrow cells by 57% and 50%, respectively, in comparison with radiation-only groups. Sesamol-reduced radiation-induced apoptosis and facilitated cell proliferation. In the comet assay, sesamol (20mg/kg) treatment reduced radiation-induced comets (% DNA in tail) compared with radiation only (P < 0.05). Sesamol also increased granulocyte populations in peripheral blood similar to melatonin. Overall, the radioprotective efficacy of sesamol was found to be similar to that of melatonin. Sesamol treatment also showed recovery of relative spleen weight at 24h of WBI. The results strongly suggest the radioprotective efficacy of sesamol in the haematopoietic system of mice. PMID:25863274

  1. Increasing 2-arachidonoyl glycerol signaling in the periphery attenuates mechanical hyperalgesia in a model of bone cancer pain

    PubMed Central

    Khasabova, Iryna A.; Chandiramani, Anisha; Harding-Rose, Catherine; Simone, Donald A.; Seybold, Virginia S.

    2011-01-01

    Metastatic and primary bone cancers are usually accompanied by severe pain that is difficult to manage. In light of the adverse side effects of opioids, manipulation of the endocannabinoid system may provide an effective alternative for the treatment of cancer pain. The present study determined that a local, peripheral increase in the endocannabinoid 2-arachidonoylglycgerol (2-AG) reduced mechanical hyperalgesia evoked by the growth of a fibrosarcoma tumor in and around the calcaneous bone. Intraplantar (ipl) injection of 2-AG attenuated hyperalgesia (ED50 of 8.2 μg) by activation of peripheral CB2 but not CB1 receptors and had an efficacy comparable to that of morphine. JZL184 (10 μg, ipl.), an inhibitor of 2-AG degradation, increased the local level of 2AG and mimicked the antihyperalgesic effect of 2-AG, also through a CB2 receptor-dependent mechanism. These effects were accompanied by an increase in CB2 receptor protein in plantar skin of the tumor-bearing paw as well as an increase in the level of 2AG. In naïve mice, intraplantar administration of the CB2 receptor antagonist AM630 did not alter responses to mechanical stimuli demonstrating that peripheral CB2 receptor tone does not modulate mechanical sensitivity. These data extend our previous findings with anandamide in the same model and suggest that the peripheral endocannabinoid system is a promising target for the management of cancer pain. PMID:21440630

  2. Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist.

    PubMed

    Goncalves, Maria B; Clarke, Earl; Hobbs, Carl; Malmqvist, Tony; Deacon, Robert; Jack, Julian; Corcoran, Jonathan P T

    2013-04-01

    The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.

  3. Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist

    PubMed Central

    Goncalves, Maria B; Clarke, Earl; Hobbs, Carl; Malmqvist, Tony; Deacon, Robert; Jack, Julian; Corcoran, Jonathan P T

    2013-01-01

    The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD. PMID:23379615

  4. Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes.

    PubMed

    Massaro, Marika; Scoditti, Egeria; Pellegrino, Mariangela; Carluccio, Maria Annunziata; Calabriso, Nadia; Wabitsch, Martin; Storelli, Carlo; Wright, Matthew; De Caterina, Raffaele

    2016-05-01

    Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)α and γ, combining in a single molecule the metabolic and inflammatory-regulatory properties of α and γ agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPARα/γ agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPARα or γ fenofibrate or rosiglitazone, respectively, for 24h before stimulation with TNF-α. Aleglitazar, at concentrations as low as 10nmol/L, providing the half-maximal transcriptional activation of both PPARα and PPARγ, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-α-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-α-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPARα and γ agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPARα and γ agonism, but with no evidence of synergism. PMID:26976796

  5. Resveratrol attenuates ovariectomy-induced hypertension and bone loss in stroke-prone spontaneously hypertensive rats.

    PubMed

    Mizutani, K; Ikeda, K; Kawai, Y; Yamori, Y

    2000-04-01

    We examined the effect of resveratrol (3,4',5-trihydroxy stilbene), a phenolic compound found in the skins of most grapes, on blood pressure and bone loss in ovariectomized (OVX), stroke-prone spontaneously hypertensive rats (SHRSP). Nineteen-week-old female SHRSP were divided into a sham-ovariectomized (sham) group fed a control diet and two OVX groups fed either a control diet (OVX-Cont) or a diet supplemented with resveratrol (5 mg/kg per d; OVX-Resv). Ovariectomy induced significant increases in systolic blood pressure (SBP). Resveratrol lowered the SBP by 15%) by the third week of administration, and this effect was maintained throughout the study. Resveratrol treatment also significantly enhanced endothelium-dependent vascular relaxation in response to acetylcholine (ACh) in OVX rats. Finally, femur breaking energies measured for the resveratrol-treated (OVX-Resv) group were significantly higher than those of the resveratrol-untreated (OVX-Cont) group. While no significant differences in calcium, magnesium and phosphorus content were found between the femurs of OVX-Cont and OVX-Resv rats, the femur hydroxyproline content in the OVX-Resv group was significantly higher than of the OVX-Cont group. We conclude that, in OVX-SHRSP, resveratrol acts by a similar mechanism to mammalian estrogens, lowering blood pressure by increasing dilatory responses to ACh. The present study also demonstrated that resveratrol was able to prevent ovariectomy-induced decreases in femoral bone strength.

  6. AKP-11 - A Novel S1P1 Agonist with Favorable Safety Profile Attenuates Experimental Autoimmune Encephalomyelitis in Rat Model of Multiple Sclerosis

    PubMed Central

    Samuvel, Devadoss J.; Saxena, Nishant; Dhindsa, Jasdeep S.; Singh, Avtar K.; Gill, Gurmit S.; Grobelny, Damian W.; Singh, Inderjit

    2015-01-01

    Sphingosine-1-phosphate receptor 1 (S1P1) mediated regulation of lymphocyte egress from lymphoid organs is recognized as the mechanism of FTY720 (Fingolimod, Gilenya) efficacy in relapsing-remitting forms of multiple sclerosis (RRMS). In this study we describe a novel S1P1 agonist AKP-11, next generation of S1P1 agonist, with immunomodulatory activities in cell culture model and for therapeutic efficacy against an animal model of MS, i.e. experimental autoimmune encephalomyelitis (EAE) but without the adverse effects observed with FTY720. Like FTY720, AKP-11 bound to S1P1 is internalized and activates intracellular AKT and ERKs cellular signaling pathways. In contrast to FTY720, AKP-11 mediated S1P1 downregulation is independent of sphingosine kinase activity indicating it to be a direct agonist of S1P1. The S1P1 loss and inhibition of lymphocyte egress by FTY720 leads to lymphopenia. In comparison with FTY720, oral administration of AKP-11 caused milder and reversible lymphopenia while providing a similar degree of therapeutic efficacy in the EAE animal model. Consistent with the observed reversible lymphopenia with AKP-11, the S1P1 recycled back to cell membrane in AKP-11 treated cells following its withdrawal, but not with withdrawal of FTY720. Accordingly, a smaller degree of ubiquitination and proteolysis of S1P1 was observed in AKP-11 treated cells as compared to FTY720. Consistent with previous observations, FTY720 treatment is associated with adverse effects of bradycardia and lung vascular leaks in rodents, whereas AKP-11 treatment had undetectable effects on bradycardia and reduced lung vascular leaks as compared to FTY720. Taken together, the data documents that AKP-11 treatment cause milder and reversible lymphopenia with milder adverse effects while maintaining therapeutic efficacy similar to that observed with FTY720, thus indicating therapeutic potential of AKP-11 for treatment of MS and related autoimmune disorders. PMID:26513477

  7. Intrathecal administration of a gap junction decoupler, an inhibitor of Na(+)-K(+)-2Cl(-) cotransporter 1, or a GABA(A) receptor agonist attenuates mechanical pain hypersensitivity induced by REM sleep deprivation in the rat.

    PubMed

    Wei, Hong; Hao, Bin; Huang, Jin-Lu; Ma, Ai-Niu; Li, Xin-Yan; Wang, Yong-Xiang; Pertovaara, Antti

    2010-12-01

    We studied the hypothesis that some of the spinal mechanisms that are involved in neuropathic hypersensitivity play a role in hypersensitivity induced by REM sleep deprivation (REMSD). Rats with a chronic intrathecal (i.t.) catheter had REMSD of 48h duration that induced hypersensitivity to mechanical stimulation. After REMSD, the animals were treated i.t. with carbenoxolone (a gap junction decoupler), bumetanide (a blocker of Na(+)-K(+)-2Cl(-) cotransporter 1 or NKCC1), muscimol (a GABA(A) receptor agonist), or pretreated intraperitoneally with minocycline (an inhibitor of microglia activation). Previously, all these treatments attenuated neuropathic hypersensitivity. Following REMSD, carbenoxolone, bumetanide and muscimol had a strong antihypersensitivity effect, whereas pretreatment with minocycline failed to prevent development of hypersensitivity. The results suggest that among spinal pain facilitatory mechanisms that are common to REMSD and neuropathy are NKCC1 blocker- and gap junction decoupler-reversible mechanisms. Moreover, there is a net pain inhibitory effect by spinal administration of an exogenous GABA(A) receptor agonist following REMSD as shown earlier in neuropathy. In contrast, activation of spinal microglia may not be as important for the development of hypersensitivity induced by REMSD as following nerve injury.

  8. Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

    PubMed Central

    Song, Zhen-peng; Xiong, Bing-rui; Guan, Xue-hai; Cao, Fei; Manyande, Anne; Zhou, Ya-qun; Zheng, Hua; Tian, Yu-ke

    2016-01-01

    Aim: To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. Methods: A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro. Results: BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus. Conclusion: Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes. PMID:27157092

  9. Bone Marrow Stem/Progenitor Cells Attenuate the Inflammatory Milieu Following Substitution Urethroplasty

    PubMed Central

    Liu, Joceline S.; Bury, Matthew I.; Fuller, Natalie J.; Sturm, Renea M.; Ahmad, Nida; Sharma, Arun K.

    2016-01-01

    Substitution urethroplasty for the treatment of male stricture disease is often accompanied by subsequent tissue fibrosis and secondary stricture formation. Patients with pre-existing morbidities are often at increased risk of urethral stricture recurrence brought upon in-part by delayed vascularization accompanied by overactive inflammatory responses following surgery. Within the context of this study, we demonstrate the functional utility of a cell/scaffold composite graft comprised of human bone marrow-derived mesenchymal stem cells (MSC) combined with CD34+ hematopoietic stem/progenitor cells (HSPC) to modulate inflammation and wound healing in a rodent model of substitution urethroplasty. Composite grafts demonstrated potent anti-inflammatory effects with regards to tissue macrophage and neutrophil density following urethral tissue analyses. This was accompanied by a significant reduction in pro-inflammatory cytokines TNFα and IL-1β and further resulted in an earlier transition to tissue remodeling and maturation with a shift in collagen type III to I. Grafted animals demonstrated a progressive maturation and increase in vessel size compared to control animals. Overall, MSC/CD34+ HSPC composite grafts reduce inflammation, enhance an earlier transition to wound remodeling and maturation concurrently increasing neovascularization in the periurethral tissue. We demonstrate the feasibility and efficacy of a stem cell-seeded synthetic graft in a rodent substitution urethroplasty model. PMID:27762304

  10. Infusion of Bone Marrow Mesenchymal Stem Cells Attenuates Experimental Severe Acute Pancreatitis in Rats

    PubMed Central

    Huang, Dandan; Gao, Jun; Gong, Yanfang; Wu, Hongyu; Xu, Aifang

    2016-01-01

    Background & Aims. Severe acute pancreatitis (SAP) remains a high-mortality disease. Bone marrow (BM) mesenchymal stem cells (MSCs) have been demonstrated to have plasticity of transdifferentiation and to have immunomodulatory functions. In the present study, we assessed the roles of MSCs in SAP and the therapeutic effects of MSC on SAP after transplantation. Methods. A pancreatitis rat model was induced by the injection of taurocholic acid (TCA) into the pancreatic duct. After isolation and characterization of MSC from BM, MSC transplantation was conducted 24 hrs after SAP induction by tail vein injection. The survival rate was observed and MSCs were traced after transplantation. The expression of TNF-α and IL-1β mRNA in the transplantation group was also analyzed. Results. The survival rate of the transplantation group was significantly higher compared to the control group (p < 0.05). Infused MSCs were detected in the pancreas and BM 3 days after transplantation. The expression of TNF-α and IL-1β mRNA in the transplantation group was significantly lower than in the control group in both the pancreas and the lungs (p < 0.05). Conclusions. MSC transplantation could improve the prognosis of SAP rats. Engrafted MSCs have the capacity of homing, migration, and planting during the treatment of SAP. PMID:27721836

  11. Reactive Bone Marrow Stromal Cells Attenuate Systemic Inflammation via sTNFR1

    PubMed Central

    Yagi, Hiroshi; Soto-Gutierrez, Alejandro; Navarro-Alvarez, Nalu; Nahmias, Yaakov; Goldwasser, Yoni; Kitagawa, Yuko; Tilles, Arno W; Tompkins, Ronald G; Parekkadan, Biju; Yarmush, Martin L

    2010-01-01

    Excessive systemic inflammation following trauma, sepsis, or burn could lead to distant organ damage. The transplantation of bone marrow stromal cells or mesenchymal stem cells (MSCs) has been reported to be an effective treatment for several immune disorders by modulating the inflammatory response to injury. We hypothesized that MSCs can dynamically secrete systemic factors that can neutralize the activity of inflammatory cytokines. In this study, we showed that cocultured MSCs are able to decrease nuclear factor κ-B (NFκB) activation in target epithelial cells incubated in inflammatory serum conditions. Proteomic screening revealed a responsive secretion of soluble tumor necrosis factor (TNF) receptor 1 (sTNFR1) when MSCs were exposed to lipopolysaccharide (LPS)-stimulated rat serum. The responsive effect was eliminated when NFκB activation was blocked in MSCs. Intramuscular transplantation of MSCs in LPS-endotoxic rats decreased a panel of inflammatory cytokines and inflammatory infiltration of macrophages and neutrophils in lung, kidney, and liver when compared to controls. These results suggest that improvements of inflammatory responses in animal models after local transplantation of MSCs are at least, in part, explained by the NFκB-dependent secretion of sTNFR1 by MSCs. PMID:20664529

  12. Green Tea Modulates Cytokine Expression in the Periodontium and Attenuates Alveolar Bone Resorption in Type 1 Diabetic Rats

    PubMed Central

    Gennaro, Gabriela; Claudino, Marcela; Cestari, Tania Mary; Ceolin, Daniele; Germino, Patrícia; Garlet, Gustavo Pompermaier; de Assis, Gerson Francisco

    2015-01-01

    Diabetes mellitus comprises a heterogeneous group of disorders with the main feature of hyperglycemia. Chronic hyperglycemia increases the severity of periodontal disease via an exacerbated inflammatory response, activated by advanced glycation end products and their receptor, RAGE. Therefore, anti-inflammatory agents represent potential inhibitors of this pathological interaction. In particular, green tea has been shown to possess anti-inflammatory properties mediated by its polyphenol content. Objectives: This study investigated the mechanisms by which green tea attenuates the spontaneous onset of diabetes-induced periodontitis. Methods: Diabetes was induced in rats via a single intraperitoneal injection of streptozotocin (STZ). Diabetic and control animals were divided into water-treated and green tea-treated subgroups and were analyzed at 15, 30, 60 and 90 days after diabetes induction. Immunohistochemistry was performed to quantitatively evaluate tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), interleukin-10 (IL-10) and runt-related transcription factor 2 (RUNX-2) expression in serial sections of each hemimaxilla. Morphometric measurements of the distance from the cementum-enamel junction (CEJ) of the superior distal root of the first molar to the alveolar bone crest (ABC) were performed to assess bone loss. Results: Diabetes resulted in significant bone loss and alterations in the number of cells that stained positive for inflammatory mediators. In the diabetic rats treated with green tea, we observed a decreased number of cells expressing RANKL and TNF-α compared with that observed in the diabetic rats treated with water. Additionally, green tea increased the numbers of cells that stained positive for OPG, RUNX-2 and IL-10 in the diabetic rats. Conclusion: Green tea intake reduces expression of the pro-inflammatory cytokine TNF-α and the osteoclastogenic mediator RANKL to normal levels

  13. Attenuation of Hepatic Graft-versus-host Disease in Allogeneic Recipients of MyD88-deficient Donor Bone Marrow

    PubMed Central

    Lim, Ji-Young; Lee, Young-Kwan; Lee, Sung-Eun; Ju, Ji-Min; Park, Gyeongsin; Choi, Eun Young

    2015-01-01

    Acute graft-versus-host-disease (GVHD) is characterized by selective damage to the liver, the skin, and the gastrointestinal tract. Following allogeneic hematopoietic stem cell transplantation, donor bone marrow (BM) cells repopulate the immune system of the recipient. We previously demonstrated that the acute intestinal GVHD (iGVHD) mortality rate was higher in MyD88-deficient BM recipients than that in the control BM recipients. In the present study, the role of MyD88 (expressed by donor BM) in the pathophysiology of hepatic GVHD (hGVHD) was examined. Unlike iGVHD, transplantation with MyD88-deficient T-cell depleted (TCD) BM attenuated hGVHD severity and was associated with low infiltration of T cells into the liver of the recipients. Moreover, GVHD hosts, transplanted with MyD88-deficient TCD BM, exhibited markedly reduced expansion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) in the liver. Adoptive injection of the MDSC from wild type mice, but not MyD88-deficient mice, enhanced hepatic T cell infiltration in the MyD88-deficient TCD BM recipients. Pre-treatment of BM donors with LPS increased MDSC levels in the liver of allogeneic wild type BM recipients. In conclusion, hGVHD and iGVHD may occur through various mechanisms based on the presence of MyD88 in the non-T cell compartment of the allograft. PMID:26140044

  14. Unfractionated bone marrow cells attenuate paraquat-induced glomerular injury and acute renal failure by modulating the inflammatory response

    PubMed Central

    Gu, Sing-Yi; Yeh, Ti-Yen; Lin, Shih-Yi; Peng, Fu-Chuo

    2016-01-01

    The aim of this study was to evaluate the efficacy of unfractionated bone marrow cells (BMCs) in attenuating acute kidney injury (AKI) induced by paraquat (PQ) in a mouse model. PQ (55 mg/kg BW) was intraperitoneally injected into C57BL/6 female mice to induce AKI, including renal function failure, glomerular damage and renal tubule injury. Glomerular podocytes were the first target damaged by PQ, which led to glomerular injury. Upon immunofluorescence staining, podocytes depletion was validated and accompanied by increased urinary podocin levels, measured on days 1 and 6. A total of 5.4 × 106 BMCs obtained from the same strain of male mice were injected into AKI mice through the tail vein at 3, 24, and 48 hours after PQ administration. As a result, renal function increased, tubular and glomerular injury were ameliorated, podocytes loss improved, and recipient mortality decreased. In addition, BMCs co-treatment decreased the extent of neutrophil infiltration and modulated the inflammatory response by shifting from pro-inflammatory Th1 to an anti-inflammatory Th2 profile, where IL-1β, TNF-α, IL-6 and IFN-γ levels declined and IL-10 and IL-4 levels increased. The present study provides a platform to investigate PQ-induced AKI and repeated BMCs injection represents an efficient therapeutic strategy. PMID:26988026

  15. The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats.

    PubMed

    Borner, Tito; Loi, Laura; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2016-07-01

    The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia. PMID:27147616

  16. The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats.

    PubMed

    Borner, Tito; Loi, Laura; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2016-07-01

    The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia.

  17. k-space sampling optimization for ultrashort TE imaging of cortical bone: Applications in radiation therapy planning and MR-based PET attenuation correction

    SciTech Connect

    Hu, Lingzhi E-mail: raymond.muzic@case.edu; Traughber, Melanie; Su, Kuan-Hao; Pereira, Gisele C.; Grover, Anu; Traughber, Bryan; Muzic, Raymond F. Jr. E-mail: raymond.muzic@case.edu

    2014-10-15

    Purpose: The ultrashort echo-time (UTE) sequence is a promising MR pulse sequence for imaging cortical bone which is otherwise difficult to image using conventional MR sequences and also poses strong attenuation for photons in radiation therapy and PET imaging. The authors report here a systematic characterization of cortical bone signal decay and a scanning time optimization strategy for the UTE sequence through k-space undersampling, which can result in up to a 75% reduction in acquisition time. Using the undersampled UTE imaging sequence, the authors also attempted to quantitatively investigate the MR properties of cortical bone in healthy volunteers, thus demonstrating the feasibility of using such a technique for generating bone-enhanced images which can be used for radiation therapy planning and attenuation correction with PET/MR. Methods: An angularly undersampled, radially encoded UTE sequence was used for scanning the brains of healthy volunteers. Quantitative MR characterization of tissue properties, including water fraction and R2{sup ∗} = 1/T2{sup ∗}, was performed by analyzing the UTE images acquired at multiple echo times. The impact of different sampling rates was evaluated through systematic comparison of the MR image quality, bone-enhanced image quality, image noise, water fraction, and R2{sup ∗} of cortical bone. Results: A reduced angular sampling rate of the UTE trajectory achieves acquisition durations in proportion to the sampling rate and in as short as 25% of the time required for full sampling using a standard Cartesian acquisition, while preserving unique MR contrast within the skull at the cost of a minimal increase in noise level. The R2{sup ∗} of human skull was measured as 0.2–0.3 ms{sup −1} depending on the specific region, which is more than ten times greater than the R2{sup ∗} of soft tissue. The water fraction in human skull was measured to be 60%–80%, which is significantly less than the >90% water fraction in

  18. [Administration of bone marrow mesenchymal stem cells attenuates inflammation of rats with sepsis].

    PubMed

    Hao, Yufang; Geng, Lixia

    2016-09-01

    Objective To investigate the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) in rats with sepsis. Methods Forty-eight Wistar rats were divided into blank group, sham group, model group and treatment group. Sepsis model was made using cecum ligation and puncture (CLP). BMSCs were extracted and cultured to the third generation. The rats in the treatment group received BMSCs through a tail vein and the rats in the model group received an equivalent dose of PBS. The survival rate was recorded in each group 72 hours after operation. Pathological changes of lung tissues were observed by HE staining. The mRNA levels of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), fork head box protein 3 (Foxp3), CC chemokine ligand 2 (CCL2) were tested by quantitative real-time fluorescence PCR. The serum levels of IL-6, IL-17 and TNF-α proteins were detected by ELISA. Results In both blank group and sham group, the survival rate and histological changes of the lungs showed normal; no bacteria were found growing in rats' blood culture; IL-6, IL-17, TNF-α, CCL2, Foxp3 mRNA and IL-6, IL-17, TNF-α protein levels had no significant differences. In the model group, the survival rate of rats was obviously lower than that of the sham group; the pathological changes of the lungs were significant; any amount of enterobacteria were seen growing in rats' blood culture; IL-6, IL-17, TNF-α, CCL2 mRNA and protein expression levels were apparently higher than those of sham group, while Foxp3 mRNA expression level was obviously lower than that of sham group. In the treatment group, the survival rate was significantly higher than that of the model group; the pathological changes of the lung tissues were evidently eased; IL-6, IL-17, TNF-α, CCL2 mRNA and protein expression levels significantly decreased compared with the model group, while Foxp3 mRNA expression level significantly increased compared with the model group. Conclusion BMSCs injection increases the

  19. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI.

    PubMed

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D; Hill-Smith, Tiffany E; Berg, Alexandra R; Lucki, Irwin; Mikkelsen, Jens D; Coyle, Joseph T

    2014-02-01

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation.

  20. The blocking of uPAR suppresses lipopolysaccharide‐induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway

    PubMed Central

    Ishisaki, Akira; Miyashita, Mei; Matsuo, Osamu

    2016-01-01

    Abstract Introduction Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, cause the bone destruction by promotion of the differentiation of monocyte/macrophage lineage cells into mature osteoclasts (OCs) with active bone‐resorbing character. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of urokinase plasminogen activator receptor (uPAR) in the bone destruction caused by chronic inflammation. Methods We investigated that the effect of uPAR on inflammatory OC formation induced by lipopolysaccharide (LPS) in inflammatory diseases. Results We found that the LPS more weakly induced OC formation and the resultant bone loss in uPAR‐deficient mice than in wild‐type mice. Additionally, we demonstrated that uPAR significantly potentiated LPS‐induced OC formation of RAW264.7 mouse monocyte/macrophage linage cells in integrin β3/Akt‐dependent manner. Moreover, we showed that the blocking of uPAR function by the administration of anti‐uPAR neutralizing antibody significantly attenuated the LPS‐induced OC formation and the resultant bone loss in mice. Conclusions These results strongly suggest that uPAR negatively regulates the LPS‐induced inflammatory OC formation and the resultant bone loss mediated through the integrin β3/Akt pathway. Our findings partly clarify the molecular mechanisms underlying bone destruction caused by chronic inflammatory diseases, and would benefit research on identifying antibody therapy for the treatment of these diseases.

  1. The blocking of uPAR suppresses lipopolysaccharide‐induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway

    PubMed Central

    Ishisaki, Akira; Miyashita, Mei; Matsuo, Osamu

    2016-01-01

    Abstract Introduction Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, cause the bone destruction by promotion of the differentiation of monocyte/macrophage lineage cells into mature osteoclasts (OCs) with active bone‐resorbing character. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of urokinase plasminogen activator receptor (uPAR) in the bone destruction caused by chronic inflammation. Methods We investigated that the effect of uPAR on inflammatory OC formation induced by lipopolysaccharide (LPS) in inflammatory diseases. Results We found that the LPS more weakly induced OC formation and the resultant bone loss in uPAR‐deficient mice than in wild‐type mice. Additionally, we demonstrated that uPAR significantly potentiated LPS‐induced OC formation of RAW264.7 mouse monocyte/macrophage linage cells in integrin β3/Akt‐dependent manner. Moreover, we showed that the blocking of uPAR function by the administration of anti‐uPAR neutralizing antibody significantly attenuated the LPS‐induced OC formation and the resultant bone loss in mice. Conclusions These results strongly suggest that uPAR negatively regulates the LPS‐induced inflammatory OC formation and the resultant bone loss mediated through the integrin β3/Akt pathway. Our findings partly clarify the molecular mechanisms underlying bone destruction caused by chronic inflammatory diseases, and would benefit research on identifying antibody therapy for the treatment of these diseases. PMID:27621816

  2. The D1 dopamine receptor agonist, SKF83959, attenuates hydrogen peroxide-induced injury in RGC-5 cells involving the extracellular signal-regulated kinase/p38 pathways

    PubMed Central

    Li, Guang-Yu; Li, Ting; Fan, Bin; Zheng, Yong-Chen

    2012-01-01

    Purpose Oxidative stress is widely implicated in the death of retinal ganglion cells associated with various optic neuropathies. Agonists of the dopamine D1 receptor have recently been found to be potentially neuroprotective against oxidative stress–induced injury. The goal of this study was to investigate whether SKF83959, a next-generation high-affinity D1 receptor agonist, could protect retinal ganglion cell 5 (RGC-5) cells from H2O2-induced damage and the molecular mechanism involved. Methods We examined expression of the D1 receptor in RGC-5 cells with reverse-transcription–PCR and immunoblotting and assessed neuroprotection using propidium iodide staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, we monitored the activation and involvement of members of mitogen-activated protein kinase family, extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase, with western blot and specific inhibitors. Results We found that the D1 receptor was expressed in RGC-5 cells, but the sequence analysis suggested this cell line is from mouse and not rat origin. SKF83959 exhibited a remarkable neuroprotective effect on H2O2-damaged RGC-5 cells, which was blocked by the specific D1 receptor antagonist, SCH23390. ERK and p38 were activated by SKF83959, and pretreatment with their inhibitors U0126 and SB203580, respectively, significantly blunted the SKF83959-induced cytoprotection. However, the specific c-Jun NH2-terminal kinase inhibitor, SP600125, had no effect on the SKF83959-induced protection. Conclusions We conclude that SKF83959 attenuates hydrogen peroxide–induced injury in RGC-5 cells via a mechanism involving activation of the ERK and p38 pathways and the D1 receptor is a potential molecular target for developing neuroprotective drugs. PMID:23233790

  3. The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice.

    PubMed

    Al Mansouri, Shamma; Ojha, Shreesh; Al Maamari, Elyazia; Al Ameri, Mouza; Nurulain, Syed M; Bahi, Amine

    2014-09-01

    Several recent studies have suggested that brain CB2 cannabinoid receptors play a major role in alcohol reward. In fact, the implication of cannabinoid neurotransmission in the reinforcing effects of ethanol (EtOH) is becoming increasingly evident. The CB2 receptor agonist, β-caryophyllene (BCP) was used to investigate the role of the CB2 receptors in mediating alcohol intake and ethanol-induced conditioned place preference (EtOH-CPP) and sensitivity in mice. The effect of BCP on alcohol intake was evaluated using the standard two-bottle choice drinking method. The mice were presented with increasing EtOH concentrations and its consumption was measured daily. Consumption of saccharin and quinine solutions was measured following the EtOH preference tests. Finally, the effect of BCP on alcohol reward and sensitivity was tested using an unbiased EtOH-CPP and loss of righting-reflex (LORR) procedures, respectively. BCP dose-dependently decreased alcohol consumption and preference. Additionally, BCP-injected mice did not show any difference from vehicle mice in total fluid intake in a 24-hour paradigm nor in their intake of graded concentrations of saccharin or quinine, suggesting that the CB2 receptor activation did not alter taste function. More importantly, BCP inhibited EtOH-CPP acquisition and exacerbated LORR duration. Interestingly, these effects were abrogated when mice were pre-injected with a selective CB2 receptor antagonist, AM630. Overall, the CB2 receptor system appears to be involved in alcohol dependence and sensitivity and may represent a potential pharmacological target for the treatment of alcoholism.

  4. Rosiglitazone, a Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, Attenuates Inflammation Via NF-κB Inhibition in Lipopolysaccharide-Induced Peritonitis.

    PubMed

    Zhang, Yun-Fang; Zou, Xun-Liang; Wu, Jun; Yu, Xue-Qing; Yang, Xiao

    2015-12-01

    We assessed the anti-inflammatory effect of peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, in a lipopolysaccharide (LPS)-induced peritonitis rat model. LPS was intraperitoneally injected into rats to establish peritonitis model. Male Sprague-Dawley (SD) rats were assigned to normal saline (the solvent of LPS), LPS, rosiglitazone plus LPS, and rosiglitazone alone. A simple peritoneal equilibrium test was performed with 20 ml 4.25 % peritoneal dialysis fluid. We measured the leukocyte count in dialysate and ultrafiltration volume. Peritoneal membrane histochemical staining was performed, and peritoneal thickness was assessed. CD40 and intercellular adhesion molecule-1 messenger RNA (ICAM-1 mRNA) levels in rat visceral peritoneum were detected by reverse transcription (RT)-PCR. IL-6 in rat peritoneal dialysis effluent was measured using enzyme-linked immunosorbent assay. The phosphorylation of NF-κB-p65 and IκBα was analyzed by Western blot. LPS administration resulted in increased peritoneal thickness and decreased ultrafiltration volume. Rosiglitazone pretreatment significantly decreased peritoneal thickness. In addition to CD40 and ICAM-1 mRNA expression, the IL-6, p-p65, and p-IκBα protein expressions were enhanced in LPS-administered animals. Rosiglitazone pretreatment significantly decreased ICAM-1 mRNA upregulation, secretion of IL-6 protein, and phosphorylation of NF-κB-p65 and IκBα without decreasing CD40 mRNA expression. Rosiglitazone has a protective effect in peritonitis, simultaneously decreasing NF-κB phosphorylation, suggesting that NF-κB signaling pathway mediated peritoneal inflammation induced by LPS. PPAR-γ might be considered a potential therapeutic target against peritonitis.

  5. MO-G-17A-03: MR-Based Cortical Bone Segmentation for PET Attenuation Correction with a Non-UTE 3D Fast GRE Sequence

    SciTech Connect

    Ai, H; Pan, T; Hwang, K

    2014-06-15

    Purpose: To determine the feasibility of identifying cortical bone on MR images with a short-TE 3D fast-GRE sequence for attenuation correction of PET data in PET/MR. Methods: A water-fat-bone phantom was constructed with two pieces of beef shank. MR scans were performed on a 3T MR scanner (GE Discovery™ MR750). A 3D GRE sequence was first employed to measure the level of residual signal in cortical bone (TE{sub 1}/TE{sub 2}/TE{sub 3}=2.2/4.4/6.6ms, TR=20ms, flip angle=25°). For cortical bone segmentation, a 3D fast-GRE sequence (TE/TR=0.7/1.9ms, acquisition voxel size=2.5×2.5×3mm{sup 3}) was implemented along with a 3D Dixon sequence (TE{sub 1}/TE{sub 2}/TR=1.2/2.3/4.0ms, acquisition voxel size=1.25×1.25×3mm{sup 3}) for water/fat imaging. Flip angle (10°), acquisition bandwidth (250kHz), FOV (480×480×144mm{sup 3}) and reconstructed voxel size (0.94×0.94×1.5mm{sup 3}) were kept the same for both sequences. Soft tissue and fat tissue were first segmented on the reconstructed water/fat image. A tissue mask was created by combining the segmented water/fat masks, which was then applied on the fast-GRE image (MRFGRE). A second mask was created to remove the Gibbs artifacts present in regions in close vicinity to the phantom. MRFGRE data was smoothed with a 3D anisotropic diffusion filter for noise reduction, after which cortical bone and air was separated using a threshold determined from the histogram. Results: There is signal in the cortical bone region in the 3D GRE images, indicating the possibility of separating cortical bone and air based on signal intensity from short-TE MR image. The acquisition time for the 3D fast-GRE sequence was 17s, which can be reduced to less than 10s with parallel imaging. The attenuation image created from water-fat-bone segmentation is visually similar compared to reference CT. Conclusion: Cortical bone and air can be separated based on intensity in MR image with a short-TE 3D fast-GRE sequence. Further research is required

  6. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (PAI-1-/-) on bone structure in mice bearing Lewis lung carcinoma (LLC) in lungs. Reduction in bone volume fraction (BV/TV) by 22% and 21%, trabecular number (Tb.N) by 8% and 4% and bone mineral de...

  7. Bone

    NASA Astrophysics Data System (ADS)

    Helmberger, Thomas K.; Hoffmann, Ralf-Thorsten

    The typical clinical signs in bone tumours are pain, destruction and destabilization, immobilization, neurologic deficits, and finally functional impairment. Primary malignant bone tumours are a rare entity, accounting for about 0.2% of all malignancies. Also benign primary bone tumours are in total rare and mostly asymptomatic. The most common symptomatic benign bone tumour is osteoid osteoma with an incidence of 1:2000.

  8. The selective mGluR5 agonist CHPG attenuates SO2-induced oxidative stress and inflammation through TSG-6/NF-κB pathway in BV2 microglial cells.

    PubMed

    Qiu, Jun-Ling; Zhu, Wen-Li; Lu, Yu-Jie; Bai, Zheng-Fa; Liu, Zhi-Gang; Zhao, Pei; Sun, Chao; Zhang, Ya-Bin; Li, Hua; Liu, Wei

    2015-01-01

    Sulfur dioxide (SO2) is a common air pollutant and can cause harmful insults on neurons. Microglial activation has been implicated in the signaling cascades that contribute to neuronal cell death in various neurological disorders. In the present study, we found that SO2 derivatives decreased cell viability via inducing oxidative stress, inflammatory responses and apoptotic cell death in BV2 microglial cells. Pretreatment with (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, significantly attenuated the SO2-induced cytotoxicity, which was fully prevented by the mGluR5 antagonist MPEP. CHPG increased the expression of TNF-α stimulated gene/protein 6 (TSG-6), but decreased the activation of nuclear factor-κB (NF-κB) after SO2 derivatives treatment in BV2 cells. In addition, knockdown of TSG-6 expression by specific targeted short interfering RNA (siRNA) partially reversed the protection induced by CHPG. Therefore, our findings reveal a mechanistic basis for exploring the association between SO2 exposure and neurological disorders, and also for opening up therapeutic approaches of ameliorating neuronal injury resulting from exposure in atmospheric polluting environment.

  9. Laser Doppler flowmetry for bone blood flow measurements: helium-neon laser light attenuation and depth of perfusion assessment.

    PubMed

    Nötzli, H P; Swiontkowski, M F; Thaxter, S T; Carpenter, G K; Wyatt, R

    1989-01-01

    Laser Doppler flowmetry (LDF) has been successfully used in clinical and experimental settings to evaluate bone perfusion but unanswered questions regarding its capabilities and limitations still remain. This study was undertaken to determine absorption of He-Ne laser light (632.8 nm) and maximum depth for flow assessment (threshold thickness) under optimal conditions in bone. Light transmittance in bovine bone samples of femora and tibia was measured after each step of grinding and depth of penetration calculated. The threshold thickness was obtained by placing the same samples in a flow chamber where a solution of 2% latex circulated beneath; flow was detected by a laser Doppler probe resting on top of the sample. The results showed a significantly higher depth of penetration for trabecular than for cortical bone. A regression analysis showed a high correlation between the inorganic fraction of the bone and the depth of penetration. The maximum depth at which the laser Doppler probe can evaluate flow in bone conditions was found to be 2.9 +/- 0.2 mm in cortical bone, 3.5 +/- 0.3 mm in bone covered by 1 mm cartilage and 3.5 +/- 0.2 mm in trabecular bone. The study showed the limitations of LDF in bone and their correlations to various bone properties.

  10. Decibel attenuation of pulsed electromagnetic field (PEMF) in blood and cortical bone determined experimentally and from the theory of ohmic losses.

    PubMed

    Zborowski, Maciej; Kligman, Boris; Midura, Ronald J; Wolfman, Alan; Patterson, Thomas E; Ibiwoye, Michael; Grabiner, Mark

    2006-06-01

    We studied the PEMF power attenuation in tissues representative of clinical applications (blood and cortical bone) to determine the amount of power available for PEMF purported biological effects. The experimental system consisted of a pair of nearly circular, parallel and coaxial coils separated by a distance of one coil diameter. The power attenuation was measured using a small search coil connected to a digital oscilloscope. The coils were powered by a voltage switch operating at two different frequencies (3.8 and 63 kHz) producing bursts of pulses (numbering 21 and 1619) and triggered at two different frequencies (1.5 and 15 Hz, respectively). The tissue samples were placed inside the coils so as to expose them to either transverse electric field (at the center of coils) or the transverse magnetic field (at the coil wire). The cylindrical coil geometry yielded closed-form expressions for power attenuation based on magnetic diffusion equation and ohmic losses due to bulk tissue magnetic permeability and electrical conductivity. The measured power attenuation at these PEMF frequencies of not more than one decibel (1 dB) was well explained by the theory for the 3.8 kHz but less so for the 63 kHz frequency PEMF. The results provide important insights regarding physical mechanism of weak PEMF power dissipation in tissues.

  11. Whole-Body PET/MR Imaging: Quantitative Evaluation of a Novel Model-Based MR Attenuation Correction Method Including Bone

    PubMed Central

    Paulus, Daniel H.; Quick, Harald H.; Geppert, Christian; Fenchel, Matthias; Zhan, Yiqiang; Hermosillo, Gerardo; Faul, David; Boada, Fernando; Friedman, Kent P.; Koesters, Thomas

    2016-01-01

    In routine whole-body PET/MR hybrid imaging, attenuation correction (AC) is usually performed by segmentation methods based on a Dixon MR sequence providing up to 4 different tissue classes. Because of the lack of bone information with the Dixon-based MR sequence, bone is currently considered as soft tissue. Thus, the aim of this study was to evaluate a novel model-based AC method that considers bone in whole-body PET/MR imaging. Methods The new method (“Model”) is based on a regular 4-compartment segmentation from a Dixon sequence (“Dixon”). Bone information is added using a model-based bone segmentation algorithm, which includes a set of prealigned MR image and bone mask pairs for each major body bone individually. Model was quantitatively evaluated on 20 patients who underwent whole-body PET/MR imaging. As a standard of reference, CT-based μ-maps were generated for each patient individually by nonrigid registration to the MR images based on PET/CT data. This step allowed for a quantitative comparison of all μ-maps based on a single PET emission raw dataset of the PET/MR system. Volumes of interest were drawn on normal tissue, soft-tissue lesions, and bone lesions; standardized uptake values were quantitatively compared. Results In soft-tissue regions with background uptake, the average bias of SUVs in background volumes of interest was 2.4% ± 2.5% and 2.7% ± 2.7% for Dixon and Model, respectively, compared with CT-based AC. For bony tissue, the −25.5% ± 7.9% underestimation observed with Dixon was reduced to −4.9% ± 6.7% with Model. In bone lesions, the average underestimation was −7.4% ± 5.3% and −2.9% ± 5.8% for Dixon and Model, respectively. For soft-tissue lesions, the biases were 5.1% ± 5.1% for Dixon and 5.2% ± 5.2% for Model. Conclusion The novel MR-based AC method for whole-body PET/MR imaging, combining Dixon-based soft-tissue segmentation and model-based bone estimation, improves PET quantification in whole-body hybrid PET

  12. Orchidectomy-induced alterations in volumetric bone density, cortical porosity and strength of femur are attenuated by dietary conjugated linoleic acid in aged guinea pigs.

    PubMed

    DeGuire, Jason R; Mak, Ivy L; Lavery, Paula; Agellon, Sherry; Wykes, Linda J; Weiler, Hope A

    2015-04-01

    Age-related osteoporosis and sarcopenia are ascribed in part to reductions in anabolic hormones. Dietary conjugated linoleic acid (CLA) improves lean and bone mass, but its impact during androgen deficiency is not known. This study tested if CLA would attenuate the effects of orchidectomy (ORX)-induced losses of bone and lean tissue. Male guinea pigs (n=40; 70-72 weeks), were randomized into four groups: (1) SHAM+Control diet, (2) SHAM+CLA diet, (3) ORX+Control diet, (4) ORX+CLA diet. Baseline blood sampling and dual-energy X-ray absorptiometry (DXA) scans were conducted, followed by surgery 4 days later with the test diets started 7 days after baseline sampling. Serial blood sampling and DXA scans were repeated 2, 4, 8 and 16 weeks on the test diets. Body composition and areal BMD (aBMD) of whole body, lumbar spine, femur and tibia were measured using DXA. At week 16, muscle protein fractional synthesis rate (FSR), volumetric BMD (vBMD), microarchitecture and bone strength were assessed. Body weight declined after SHAM and ORX surgery, with slower recovery in the ORX group. Dietary CLA did not affect weight or lean mass, but attenuated gains in fat mass. Lean mass was stable in SHAM and reduced in ORX by 2 weeks with whole body and femur bone mineral content (BMC) reduced by 4 weeks; CLA did not alter BMC. By week 16 ORX groups had lower free testosterone and myofibrillar FSR, yet higher cortisol, osteocalcin and ionized calcium with no alterations due to CLA. ORX+Control had higher prostaglandin E2 (PGE2) and total alkaline phosphatase compared to SHAM+Control whereas ORX+CLA were not different from SHAM groups. Femur metaphyseal vBMD was reduced in ORX+CTRL with the reduction attenuated by CLA. Femur cortical thickness (Ct.Th.) and biomechanical strength were reduced and cortical porosity (Ct.Po.) elevated by ORX and attenuated by CLA. This androgen deficient model with a sarcopenic-osteoporotic phenotype similar to aging men responded to dietary CLA with

  13. Dried Plum Protects From Radiation-Induced Bone Loss by Attenuating Pro-Osteoclastic and Oxidative Stress Responses

    NASA Technical Reports Server (NTRS)

    Globus, Ruth

    2015-01-01

    Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of

  14. Xenotransplantation of Bone Marrow-Derived Human Mesenchymal Stem Cell Sheets Attenuates Left Ventricular Remodeling in a Porcine Ischemic Cardiomyopathy Model

    PubMed Central

    Kawamura, Masashi; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Toda, Koichi; Daimon, Takashi; Shimizu, Tatsuya; Okano, Teruo

    2015-01-01

    Introduction: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the most promising cell sources for cell therapy to treat heart failure. The cell sheet technique has allowed transplantation of a large number of cells and enhanced the efficacy of cell therapy. We hypothesized that the transplantation of MSC sheets may be a feasible, safe, and effective treatment for ischemic cardiomyopathy (ICM). Methods and Results: Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105 and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1×108 MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on the left anterior descending coronary artery without any procedural-related complications (MSC group=6: sheet transplantation; sham group=6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter electrocardiogram (ECG) in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, left ventricular (LV) remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the von Willebrand factor showed that the vascular density in the infarct border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct border area of the MSC group was significantly greater than that of the sham group, as measured by real-time polymerase chain reaction. Conclusions: Bone marrow-derived MSC sheets improved cardiac function and attenuated LV remodeling in ICM without

  15. St. John's Wort (Hypericum perforatum) stimulates human osteoblastic MG-63 cell proliferation and attenuates trabecular bone loss induced by ovariectomy

    PubMed Central

    You, Mi-kyoung; Kim, Du-Woon; Jeong, Kyu-Shik; Bang, Mi-Ae; Kim, Hwan-Seon; Rhuy, Jin

    2015-01-01

    BACKGROUND/OBJECFTIVES The effect of St. John's Wort extract (SJW) on MG-63 cell proliferation and trabecular bone loss induced by ovariectomy was examined. MATERIALS/METHODS Proliferation, expression of estrogen receptor (ER) α and ER β, and gene expressions of osteoprotegerin (OPG), osteocalcin (OC) and alkaline phosphatase (ALP) were examined in MG-63 cells treated with or without SJW. Ovariectomized rats were treated with SJW at the dose of 100 or 200 mg/kg/day, β-estradiol-3-benzoate (E2), or vehicle only (OVX-C), and sham operated rats were treated with vehicle only (Sham-C). Serum ALP and C-telopeptide (CTX), and femoral trabecular bone loss were examined. RESULTS SJW increased MG-63 cell proliferation and expression of ER α and ER β, and positive effect was shown on gene expressions of ALP, OC and OPG. SJW also showed estrogen like effect on bone associated with slowing down in trabecular bone loss. Histopathology by H&E showed rats treated with SJW displayed denser structure in metaphyseal region of distal femur compared with rats in OVX-C. SJW was shown to reduce serum CTX in OVX rats. CONCLUSION The present study provides new insight in preventing estrogen deficiency induced bone loss of SJW and possibility for its application in bone health supplement. PMID:26425274

  16. Inhibition of spinal UCHL1 attenuates pain facilitation in a cancer-induced bone pain model by inhibiting ubiquitin and glial activation.

    PubMed

    Cheng, Wei; Chen, Yuan-Li; Wu, Liang; Miao, Bei; Yin, Qin; Wang, Jin-Feng; Fu, Zhi-Jian

    2016-01-01

    The present study examined alterations of spinal ubiquitin C-terminal hydrolase L1 (UCHL1), ubiquitin expression and glial activation in the cancer-induced bone pain rats. Furthermore, whether inhibition of spinal UCHL1 could alleviate cancer-induced bone pain was observed. The CIBP model was established by intrathecal Walker 256 mammary gland carcinoma cells in SD rats. The rats of CIBP developed significant pain facilitation in the Von Frey test. Double immunofluorescence analyses revealed that in the spines of CIBP rats, ubiquitin co-localized with NeuN, Iba-1 or GFAP; UCHL1 and NeuN were co-expressed and UCHL1 also co-localized with ubiquitin. The CIBP model induced up-regulation of ubiquitin and UCHL1 in the spines, as well as glial activation. Inhibition of spinal UCHL1 attenuated pain facilitation by down-regulation of ubiquitin expression and glial activation. in the CIBP rats. Our data suggests that UCHL1/ubiquitin distributed and increased in the spines of CIBP rats, that glial activation also increased in the CIBP model and that inhibition of spinal UCHL1 may be an effective method to alleviate cancer-induced bone pain. PMID:27508024

  17. Changes in the linear attenuation coefficient of canine appendicular bone following intravenous infusion of strontium lactate, measured using gamma-ray computed tomography.

    PubMed

    Overton, T R; Snyder, R E; Hangartner, T N; Girgis, S; Audette, R J; Secord, D C

    1992-04-01

    Changes in the average linear attenuation coefficient (LAC) within a fixed measurement volume in the proximal end of the dog tibia, which contains trabecular bone and associated soft tissues (the trabecular bone "space"), were monitored continuously using gamma-ray computed tomography (gamma-CT) prior to, during, and following intravenous infusion of strontium (Sr) lactate. An infusion of 1.3-4.7 g of Sr over a period of 110-160 minutes into 20-kg dogs resulted, within 6-8 hours, in an increase of 0.019-0.045 cm-1 (P less than 0.002) in the LAC. Calibration of the gamma-CT system showed that 0.44 mg/cm3 of Sr produced a change of 0.01 cm-1 in the LAC. Using this conversion factor, the Sr concentration in the trabecular bone space resulting from infusion, as measured by flame atomic absorption spectroscopy, agreed with that predicted by the change observed in the LAC. Sr present in the serum and urine was consistent with the changes observed in the LAC over the study period. Control dogs infused with mineral-free solutions showed no change in LAC. Calcium equivalents required to give the changes observed in the LAC using Sr indicate that variations in skeletal turnover in man can be monitored in the peripheral skeleton using gamma-CT. PMID:1571847

  18. Inhibition of spinal UCHL1 attenuates pain facilitation in a cancer-induced bone pain model by inhibiting ubiquitin and glial activation

    PubMed Central

    Cheng, Wei; Chen, Yuan-Li; Wu, Liang; Miao, Bei; Yin, Qin; Wang, Jin-Feng; Fu, Zhi-Jian

    2016-01-01

    The present study examined alterations of spinal ubiquitin C-terminal hydrolase L1 (UCHL1), ubiquitin expression and glial activation in the cancer-induced bone pain rats. Furthermore, whether inhibition of spinal UCHL1 could alleviate cancer-induced bone pain was observed. The CIBP model was established by intrathecal Walker 256 mammary gland carcinoma cells in SD rats. The rats of CIBP developed significant pain facilitation in the Von Frey test. Double immunofluorescence analyses revealed that in the spines of CIBP rats, ubiquitin co-localized with NeuN, Iba-1 or GFAP; UCHL1 and NeuN were co-expressed and UCHL1 also co-localized with ubiquitin. The CIBP model induced up-regulation of ubiquitin and UCHL1 in the spines, as well as glial activation. Inhibition of spinal UCHL1 attenuated pain facilitation by down-regulation of ubiquitin expression and glial activation. in the CIBP rats. Our data suggests that UCHL1/ubiquitin distributed and increased in the spines of CIBP rats, that glial activation also increased in the CIBP model and that inhibition of spinal UCHL1 may be an effective method to alleviate cancer-induced bone pain. PMID:27508024

  19. Aqueous extract of pomegranate seed attenuates glucocorticoid-induced bone loss and hypercalciuria in mice: A comparative study with alendronate.

    PubMed

    Zhang, Yan; Shao, Jin; Wang, Zhi; Yang, Tieyi; Liu, Shuyi; Liu, Yue; Fan, Xinbing; Ye, Weiguang

    2016-08-01

    The present study was performed in order to examine bone loss and calcium homeostasis in mice with glucocorticoid (GC)-induced osteoporosis (GIOP) following treatment with the aqueous extract of pomegranate seed (AE-PS). In addition, a comparative study with alendronate was performed. Biomarkers in the serum and the urine were measured. The tibias, kidney and duodenum were removed in order to measure the levels of bone calcium, protein expression as well as to perform histomorphological analysis of the bone. GC treatment facilitated the induction of hypercalciuria in the mice, and the AE-PS‑treated mice exhibited a greater increase in serum calcium and a decrease in urine calcium. The AE-PS reversed the deleterious effects on the trabecular bone induced by DXM and stimulated bone remodeling, including an increase in bone calcium and alkaline phosphatase‑b (ALP-b) and a decrease in a the critical bone resorption markers C-terminal telopeptide of type I collagen (CTX) and tartrate‑resistant acid phosphatase-5b (TRAP-5b). Hematoxylin and eosin (H&E) staining revealed the increased disconnections and separation between the growth plate and the trabecular bone network as well as the reduction in the trabecular bone mass of the primary and secondary spongiosa throughout the proximal metaphysis of the tibia in the DXM group. Moreover, the decreased protein expression of transient receptor potential vanilloid (TRPV)5, TRPV6 and calbindin‑D9k (CaBP‑9k) was reversed by the AE-PS or alendronate supplementation in the kidneys and the duodenum as well as plasma membrane Ca2+‑ATPase1 (PMCA1) expression in the kidneys of mice with GIOP. There was no marked difference in pharmacological effectiveness between alendronate and the AE-PS. Taken together, these findings suggest that the AE-PS may be an alternative therapy suitable for use in the management of secondary osteoporosis. PMID:27278225

  20. A calcium-collagen chelate dietary supplement attenuates bone loss in postmenopausal women with osteopenia: a randomized controlled trial.

    PubMed

    Elam, Marcus L; Johnson, Sarah A; Hooshmand, Shirin; Feresin, Rafaela G; Payton, Mark E; Gu, Jennifer; Arjmandi, Bahram H

    2015-03-01

    Menopause leads to an increased risk for osteoporosis in women. Although drug therapies exist, increasing numbers of people prefer alternative therapies such as dietary supplements, for example, calcium, vitamin D, and collagen hydrolysates for the prevention and treatment of osteoporosis. We have previously shown that a 3-month intervention using a calcium-collagen chelate (CC) dietary supplement was efficacious in improving bone mineral density (BMD) and blood biomarkers of bone turnover in osteopenic postmenopausal women. This study reports the long-term efficacy of CC in reducing bone loss in postmenopausal women with osteopenia. Thirty-nine women were randomly assigned to one of two groups: 5 g of CC containing 500 mg of elemental calcium and 200 IU vitamin D (1,25-dihydroxyvitamin D3) or control (500 mg of calcium and 200 IU vitamin D) daily for 12 months. Total body, lumbar, and hip BMD were evaluated at baseline, 6 and 12 months using dual-energy X-ray absorptiometry. Blood was collected at baseline, 6 and 12 months to assess levels of blood biomarkers of bone turnover. Intent-to-treat (ITT) analysis was performed using repeated measures analysis of variance pairwise comparisons and multivariate analysis to assess time and group interactions. The loss of whole body BMD in women taking CC was substantially lower than that of the control group at 12 months in those who completed the study and the ITT analysis, respectively (CC: -1.33% and -0.33% vs. control: -3.75% and -2.17%; P=.026, P=.035). The CC group had significantly reduced levels of sclerostin and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) (P<.05), and higher bone-specific alkaline phosphatase/TRAP5b ratio (P<.05) than control at 6 months. These results support the use of CC in reducing bone loss in osteopenic postmenopausal women.

  1. Bone marrow mesenchymal stem cells attenuate 2,5-hexanedione-induced neuronal apoptosis through a NGF/AKT-dependent pathway

    PubMed Central

    Wang, Qingshan; Sun, Guohua; Gao, Chenxue; Feng, Lina; Zhang, Yan; Hao, Jie; Zuo, Enjun; Zhang, Cong; Li, Shuangyue; Piao, Fengyuan

    2016-01-01

    Growing evidence suggests that the increased neuronal apoptosis is involved in n-hexane-induced neuropathy. We have recently reported that bone marrow-mesenchymal stem cells-derived conditioned medium (BMSC-CM) attenuated 2,5-hexanedione (HD, the active metabolite of n-hexane)-induced apoptosis in PC12 cells. Here, we explored the anti-apoptotic efficacy of BMSC in vivo. HD-treated rats received BMSC by tail vein injection 5 weeks after HD intoxication. We found that in grafted rats, BMSC significantly attenuated HD-induced neuronal apoptosis in the spinal cord, which was associated with elevation of nerve growth factor (NGF). Neutralization of NGF in BMSC-CM blocked the protection against HD-induced apoptosis in VSC4.1 cells, suggesting that NGF is essential for BMSC-afforded anti-apoptosis. Mechanistically, we found that the decreased activation of Akt induced by HD was significantly recovered in the spinal cord by BMSC and in VSC4.1 cells by BMSC-CM in a TrkA-dependent manner, leading to dissociation of Bad/Bcl-xL complex in mitochondria and release of anti-apoptotic Bcl-xL. The importance of Akt was further corroborated by showing the reduced anti-apoptotic potency of BMSC in HD-intoxicated VSC4.1 cells in the presence of Akt inhibitor, MK-2206. Thus, our findings show that BMSC attenuated HD-induced neuronal apoptosis in vivo through a NGF/Akt-dependent manner, providing a novel solution against n-hexane-induced neurotoxicity. PMID:27703213

  2. Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17β-estradiol

    PubMed Central

    Di Gregorio, Gina B.; Yamamoto, Matsuo; Ali, A. Afshan; Abe, Etsuko; Roberson, Paula; Manolagas, Stavros C.; Jilka, Robert L.

    2001-01-01

    In agreement with evidence that estrogens slow the rate of bone remodeling by suppressing the production of both osteoclasts and osteoblasts, loss of estrogens leads to an increase in the number of osteoclast as well as early osteoblast progenitors (CFU-osteoblasts; CFU-OBs) in the murine bone marrow. Here we show that CFU-OBs are early transit-amplifying progenitors, i.e., dividing cells capable of limited self-renewal, and that 17β-estradiol acts in vivo and in vitro to attenuate their self-renewal by approximately 50%. Consistent with a direct receptor–mediated action of estrogens on early mesenchymal cell progenitors, anti–estrogen receptor-α (anti-ERα) Ab’s stain a small number of marrow cells that exhibit characteristics of primitive undifferentiated cells, including a high nucleus/cytoplasm ratio and lack of lineage-specific biochemical markers; the effect of 17β-estradiol on CFU-OB self-renewal is absent in mice lacking ERα. Because both osteoblasts and the stromal/osteoblastic cells that are required for osteoclast development are derived from CFU-OBs, suppression of the self-renewal of this common progenitor may represent a key mechanism of the anti-remodeling effects of estrogens. PMID:11285299

  3. β-Glucans (Saccharomyces cereviseae) Reduce Glucose Levels and Attenuate Alveolar Bone Loss in Diabetic Rats with Periodontal Disease

    PubMed Central

    2015-01-01

    The objective of this study was to assess the effects of oral ingestion of β-glucans isolated from Saccharomyces cereviseae on the metabolic profile, expression of gingival inflammatory markers and amount of alveolar bone loss in diabetic rats with periodontal disease. Diabetes mellitus was induced in 48 Wistar rats by intraperitoneal injection of streptozotocin (80 mg/kg). After confirming the diabetes diagnosis, the animals were treated with β-glucans (by gavage) for 28 days. On the 14th day of this period, periodontal disease was induced using a ligature protocol. β-glucans reduced the amount of alveolar bone loss in animals with periodontal disease in both the diabetic and non-diabetic groups (p < 0.05). β-glucans reduced blood glucose, cholesterol and triacylglycerol levels in diabetic animals, both with and without periodontal disease (p < 0.05). Furthermore, treatment with β-glucans reduced the expression of cyclooxygenase-2 and receptor activator of nuclear factor kappa-B ligand and increased osteoprotegerin expression in animals with diabetes and periodontal disease (p < 0.05). It was concluded that treatment with β-glucans has beneficial metabolic and periodontal effects in diabetic rats with periodontal disease. PMID:26291983

  4. Soy milk and dairy consumption is independently associated with ultrasound attenuation of the heel bone among postmenopausal women: the Adventist Health Study-2.

    PubMed

    Matthews, Vichuda Lousuebsakul; Knutsen, Synnove F; Beeson, W Lawrence; Fraser, Gary E

    2011-10-01

    Soy milk has become a popular substitute for dairy milk with important health claims. We hypothesized that soy milk, based on its nutrient composition, is comparable to dairy products and, therefore, beneficial for bone health. To test this hypothesis, we examined the benefit of soy milk and dairy products intake on bone health using broadband ultrasound attenuation of the calcaneus. Postmenopausal white women (n = 337) who had completed a lifestyle and dietary questionnaire at enrollment into the Adventist Health Study-2 had their calcaneal broadband ultrasound attenuation measured 2 years later. The association between osteoporosis (defined as a T-score <-1.8) and some dietary factors (soy milk, dairy) and selected lifestyle factors was assessed using logistic regression. In a multivariable model adjusted for demographics, hormone use, and other dietary factors, osteoporosis was positively associated with age (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.06-1.12) and inversely associated with body mass index (OR = 0.91; 95% CI, 0.86-0.97) and current estrogen use (OR = 0.27; 95% CI, 0.13-0.56). Compared with women who did not drink soy milk, women drinking soy milk once a day or more had 56% lower odds of osteoporosis (OR = 0.44; 95% CI, 0.20-0.98; P(trend) = .04). Women whose dairy intake was once a day or more had a 62% reduction in the likelihood of having osteoporosis (OR = 0.38; 95% CI, 0.17-0.86; P(trend) = .02) compared with women whose dairy intake was less than twice a week. Among individual dairy products, only cheese showed an independent and significant protection (OR = 0.28; 95% CI, 0.12-0.66; P(trend) = .004) for women eating cheese more than once per week vs those who ate cheese less than once a week. We concluded that osteoporosis is inversely associated with soy milk intake to a similar degree as dairy intake after accounting for age, body mass index, and estrogen use.

  5. Downregulation of PI3Kcb utilizing adenovirus-mediated transfer of siRNA attenuates bone cancer pain.

    PubMed

    Huang, Huan-Jun; Zhang, Mei

    2014-01-01

    Phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in intracellular signal transduction pathways involved in chronic pain states. PI3K is implicated in pathomechanisms of enhanced synaptic strength, such as wind-up and central sensitization in the spinal dorsal horn. The PI3Kcb gene encoding the class 1A PI3K catalytic subunit p110beta is one of the most important molecular of the P13K signaling pathway. Here, we used small interfering RNA (siRNA) targeted to PI3Kcb by adenovirus-mediated transfer, to determine whether inhibition of PI3Kcb was a potential therapeutic target for bone cancer pain (BCP). In this study, treatment of BCP model in rats with PI3Kcb-specific siRNA resulted in inhibited pain-related behavior. Depletion of PI3Kcb decreased the protein levels of spinal PI3Kcb and phospho-Akt (P-Akt)-downstream targets of PI3K. Knockdown of PI3Kcb by siRNA also induced decreased expression of GFAP and OX42, suggesting that the upregulation of spinal PI3Kcb may increase glia excitability, at least in part by regulating glia message. Our findings suggest that siRNA-mediated gene silencing of PI3Kcb may be a useful therapeutic strategy for BCP. PMID:25550861

  6. Autologous bone marrow mononuclear cells therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury

    PubMed Central

    Bedi, Supinder S.; Walker, Peter A.; Shah, Shinil K.; Jimenez, Fernando; Thomas, Chelsea P.; Smith, Philippa; Hetz, Robert A.; Xue, Hasen; Pati, Shibani; Dash, Pramod K.; Cox, Charles S.

    2014-01-01

    Background Autologous bone marrow-derived mononuclear cells (AMNC) have shown therapeutic promise for central nervous system insults such as stroke and traumatic brain injury (TBI). We hypothesized that intravenous injection of AMNC provides neuroprotection which leads to cognitive improvement after TBI. Methods A controlled cortical impact (CCI) rodent traumatic brain injury (TBI) model was used to examine blood-brain barrier permeability (BBB), neuronal and glial apoptosis and cognitive behavior. Two groups of rats underwent CCI with (CCI-Autologous) or without AMNC treatment (CCI-Alone), consisting of 2 million AMNC/kilogram body weight harvested from the tibia and intravenously injected 72 hr after injury. CCI-Alone animals underwent sham harvests and received vehicle injections. Results 96 hr after injury, AMNC significantly reduced the BBB permeability in injured animals, and there was an increase in apoptosis of pro-inflammatory activated microglia in the ipsilateral hippocampus. At 4 weeks after injury, we examined changes in spatial memory after TBI due to AMNC treatment. There was a significant improvement in probe testing of CCI-Autologous group in comparison to CCI-Alone in the Morris Water Maze paradigm. Conclusions Our data demonstrate that the intravenous injection of AMNC after TBI leads to neuroprotection by preserving early BBB integrity and increasing activated microglial apoptosis. In addition, AMNC also improves cognitive function. PMID:23928737

  7. Calpain inhibitor attenuates ER stress-induced apoptosis in injured spinal cord after bone mesenchymal stem cells transplantation.

    PubMed

    Wang, Chao; Shi, Dongling; Song, Xinghui; Chen, Yingying; Wang, Linlin; Zhang, Xiaoming

    2016-07-01

    Bone marrow mesenchymal stem cells (BMSCs) therapy for tissue repair is limited by low survival of cells transplanted in the recipient sites after spinal cord injury (SCI). Here, we investigated the effects of a calpain inhibitor (MDL28170) on BMSCs survival by a rat model of spinal cord injury in vitro and in vivo. Conditioned medium from hypoxia injured VSC4.1 motor neurons (Hypoxia-CM) were collected to mimic the micro-environment of injured spinal cord. Tunicamycin was also applied to induce endoplasmic reticulum (ER) stress in BMSCs. The CCK-8 assay, LDH leakage assay and flow cytometer assay demonstrated that MDL28170 could enhance BMSCs survival in response to Hypoxia-CM and tunicamycin. Moreover, MDL28170 significantly enhanced GFP-positive BMSCs survival in vivo after transplantation into the contused spinal cord of SCI rats. The protective effects of MDL28170 on BMSCs survival may inhibit the activation of calpain and the downstream ER stress-induced apoptosis. The present results suggested for the first time that MDL28170 with BMSCs transplant helped to rescue cells in injured spinal cord by modulating the ER stress-induced apoptosis. The calpain inhibitor, MDL28170 may have the promising new strategies for promoting the survival of transplanted BMSCs on cell-based regenerative medicine.

  8. Downregulation of PI3Kcb utilizing adenovirus-mediated transfer of siRNA attenuates bone cancer pain

    PubMed Central

    Huang, Huan-Jun; Zhang, Mei

    2014-01-01

    Phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in intracellular signal transduction pathways involved in chronic pain states. PI3K is implicated in pathomechanisms of enhanced synaptic strength, such as wind-up and central sensitization in the spinal dorsal horn. The PI3Kcb gene encoding the class 1A PI3K catalytic subunit p110beta is one of the most important molecular of the P13K signaling pathway. Here, we used small interfering RNA (siRNA) targeted to PI3Kcb by adenovirus-mediated transfer, to determine whether inhibition of PI3Kcb was a potential therapeutic target for bone cancer pain (BCP). In this study, treatment of BCP model in rats with PI3Kcb-specific siRNA resulted in inhibited pain-related behavior. Depletion of PI3Kcb decreased the protein levels of spinal PI3Kcb and phospho-Akt (P-Akt)-downstream targets of PI3K. Knockdown of PI3Kcb by siRNA also induced decreased expression of GFAP and OX42, suggesting that the upregulation of spinal PI3Kcb may increase glia excitability, at least in part by regulating glia message. Our findings suggest that siRNA-mediated gene silencing of PI3Kcb may be a useful therapeutic strategy for BCP. PMID:25550861

  9. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

    Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.

  10. The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment.

    PubMed

    Björkman, Lena; Mårtensson, Jonas; Winther, Malene; Gabl, Michael; Holdfeldt, André; Uhrbom, Martin; Bylund, Johan; Højgaard Hansen, Anders; Pandey, Sunil K; Ulven, Trond; Forsman, Huamei; Dahlgren, Claes

    2016-10-15

    Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, and we here characterize the neutrophil responses induced by one such agonist (Cmp1) and one antagonist (CATPB). Cmp1 triggered an increase in the cytosolic concentration of Ca(2+), and the neutrophils were then desensitized to Cmp1 and to acetate, a naturally occurring FFA2R agonist. The antagonist CATPB selectively inhibited responses induced by Cmp1 or acetate. The activated FFA2R induced superoxide anion secretion at a low level in naive blood neutrophils. This response was largely increased by tumor necrosis factor alpha (TNF-α) in a process associated with a recruitment of easily mobilizable granules, but neutrophils recruited to an aseptic inflammation in vivo were nonresponding. Superoxide production induced by Cmp1 was increased in latrunculin A-treated neutrophils, but no reactivation of desensitized FFA2R was induced by this drug, suggesting that the cytoskeleton is not directly involved in terminating the response. The functional and regulatory differences between the receptors that recognize short-chain fatty acids and formylated peptides, respectively, imply different roles of these receptors in the orchestration of inflammation and confirm the usefulness of a selective FFA2R agonist and antagonist as tools for the exploration of the precise role of the FFA2R. PMID:27503855

  11. Controllable attenuators

    NASA Astrophysics Data System (ADS)

    Krylov, G. M.; Khoniak, E. I.; Tynynyka, A. N.; Iliushenko, V. N.; Sikolenko, S. F.

    Methods for the synthesis of controllable attenuators and their implementations are examined. In particular, attention is given to the general properties of controllable attenuators, control elements, types of controllable attenuators and methods of their analysis, and synthesis of the control characteristic of attenuators. The discussion also covers the efficiency of attenuator control, the use of transmission line segments in wide-band controllable attenuators, and attenuators with a discretely controlled transmission coefficient.

  12. Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells Protect against Experimental Colitis via Attenuating Colon Inflammation, Oxidative Stress and Apoptosis

    PubMed Central

    Fan, Heng; Tang, Qing; Shou, Zhe-Xing; Zuo, Dong-Mei; Zou, Zhou; Xu, Meng; Chen, Qian-Yun; Peng, Ying; Deng, Shuang-Jiao; Liu, Yu-Jin

    2015-01-01

    The administration of bone mesenchymal stem cells (BMSCs) could reverse experimental colitis, and the predominant mechanism in tissue repair seems to be related to their paracrine activity. BMSCs derived extracellular vesicles (BMSC-EVs), including mcirovesicles and exosomes, containing diverse proteins, mRNAs and micro-RNAs, mediating various biological functions, might be a main paracrine mechanism for stem cell to injured cell communication. We aimed to investigate the potential alleviating effects of BMSC-EVs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Intravenous injection of BMSC-EVs attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI) and histological colonic damage. In inflammation response, the BMSC-EVs treatment significantly reduced both the mRNA and protein levels of nuclear factor kappaBp65 (NF-κBp65), tumor necrosis factor-alpha (TNF-α), induciblenitric oxidesynthase (iNOS) and cyclooxygenase-2 (COX-2) in injured colon. Additionally, the BMSC-EVs injection resulted in a markedly decrease in interleukin-1β (IL-1β) and an increase in interleukin-10 (IL-10) expression. Therapeutic effect of BMSC-EVs associated with suppression of oxidative perturbations was manifested by a decrease in the activity of myeloperoxidase (MPO) and Malondialdehyde (MDA), as well as an increase in superoxide dismutase (SOD) and glutathione (GSH). BMSC-EVs also suppressed the apoptosis via reducing the cleavage of caspase-3, caspase-8 and caspase-9 in colitis rats. Data obtained indicated that the beneficial effects of BMSC-EVs were due to the down regulation of pro-inflammatory cytokines levels, inhibition of NF-κBp65 signal transduction pathways, modulation of anti-oxidant/ oxidant balance, and moderation of the occurrence of apoptosis. PMID:26469068

  13. Dose-attenuated radioimmunotherapy with tositumomab and iodine 131 tositumomab in patients with recurrent non-Hodgkin's lymphoma (NHL) and extensive bone marrow involvement.

    PubMed

    Mones, Jodi V; Coleman, Morton; Kostakoglu, Lale; Furman, Richard R; Chadburn, Amy; Shore, Tsiporah B; Muss, Daniel; Stewart, Patricia; Kroll, Stewart; Vallabhajosula, Shankar; Goldsmith, Stanley J; Leonard, John P

    2007-02-01

    Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor >25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of >25% and platelet count of >or=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count <500 cells/mm3 or platelets <25,000/mm3 for >17 days, or absolute neutrophil count <750/mm3 or platelets <50,000/mm3 for >24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with >25% BMI has acceptable toxicity and can result in lymphoma responses.

  14. Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress.

    PubMed

    He, Jieqiong; Wang, Chao; Sun, Yunpeng; Lu, Bo; Cui, Jinjin; Dong, Nana; Zhang, Maomao; Liu, Youbing; Yu, Bo

    2016-04-01

    Exendin-4 (ex-4) is a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist which exerts beneficial effects on glycemic control and promotes cell viability. In the present study, we investigated the anti-apoptotic effects of ex-4, as well as the potential mechanisms responsible for these effects in rat bone marrow-derived mesenchymal stem cells (BM-MSCs) under conditions of oxygen, glucose and serum deprivation (OGD). The apoptosis of the MSCs was induced by subjecting the cells to OGD conditions for 4 h and was detected by Annexin V/PI and Hoechst 33258 staining. The MSCs were pre-conditioned with ex-4 for 12 h prior to being subjected to OGD conditions, and the expression levels of an apoptotic marker (cleaved caspase-3), endoplasmic reticulum (ER) stress markers [phosphorylated (p-)protein kinase RNA-like endoplasmic reticulum kinase (PERK), PERK, binding immunoglobulin protein (BIP), activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP)], as well as those of a survival marker (Bcl-2) were measured by western blot analysis. Furthermore, the mRNA levels of ATF-4 and CHOP were determined by RT-qPCR. ELISA was used to examine the activity of intracellular cAMP. Moreover, the GLP-1R antagonist, exendin9-39 (ex9-39), the protein kinase A (PKA) inhibitor, H89, and small interfering RNA (siRNA) targeting rat ATF-4 and CHOP were co-incubated with the MSCs. The apoptotic rate was markedly diminished following pre-conditioning with ex-4 in a dose‑dependent manner (P<0.05). The ER stress markers, p-PERK, BIP, ATF-4 and CHOP, were upregulated in the cells subjected to OGD conditions. Ex-4 pre-conditioning significantly decreased the mRNA and protein levels of ATF-4 and CHOP (P<0.05), and increased the activity of intracellular cAMP (P<0.05). Furthermore, the anti-apoptotic effects of ex-4 were almost reversed by treatment with either H89 or ex9-39 (P<0.05); transfection with siRNA-CHOP significantly reduced the apoptotic rate of the MSCs

  15. Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress

    PubMed Central

    HE, JIEQIONG; WANG, CHAO; SUN, YUNPENG; LU, BO; CUI, JINJIN; DONG, NANA; ZHANG, MAOMAO; LIU, YOUBING; YU, BO

    2016-01-01

    Exendin-4 (ex-4) is a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist which exerts beneficial effects on glycemic control and promotes cell viability. In the present study, we investigated the anti-apoptotic effects of ex-4, as well as the potential mechanisms responsible for these effects in rat bone marrow-derived mesenchymal stem cells (BM-MSCs) under conditions of oxygen, glucose and serum deprivation (OGD). The apoptosis of the MSCs was induced by subjecting the cells to OGD conditions for 4 h and was detected by Annexin V/PI and Hoechst 33258 staining. The MSCs were pre-conditioned with ex-4 for 12 h prior to being subjected to OGD conditions, and the expression levels of an apoptotic marker (cleaved caspase-3), endoplasmic reticulum (ER) stress markers [phosphorylated (p-)protein kinase RNA-like endoplasmic reticulum kinase (PERK), PERK, binding immunoglobulin protein (BIP), activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP)], as well as those of a survival marker (Bcl-2) were measured by western blot analysis. Furthermore, the mRNA levels of ATF-4 and CHOP were determined by RT-qPCR. ELISA was used to examine the activity of intracellular cAMP. Moreover, the GLP-1R antagonist, exendin9-39 (ex9-39), the protein kinase A (PKA) inhibitor, H89, and small interfering RNA (siRNA) targeting rat ATF-4 and CHOP were co-incubated with the MSCs. The apoptotic rate was markedly diminished following pre-conditioning with ex-4 in a dose-dependent manner (P<0.05). The ER stress markers, p-PERK, BIP, ATF-4 and CHOP, were upregulated in the cells subjected to OGD conditions. Ex-4 pre-conditioning significantly decreased the mRNA and protein levels of ATF-4 and CHOP (P<0.05), and increased the activity of intracellular cAMP (P<0.05). Furthermore, the anti-apoptotic effects of ex-4 were almost reversed by treatment with either H89 or ex9-39 (P<0.05); transfection with siRNA-CHOP significantly reduced the apoptotic rate of the MSCs and

  16. Peripheral cannabinoid receptor, CB2, regulates bone mass

    PubMed Central

    Ofek, Orr; Karsak, Meliha; Leclerc, Nathalie; Fogel, Meirav; Frenkel, Baruch; Wright, Karen; Tam, Joseph; Attar-Namdar, Malka; Kram, Vardit; Shohami, Esther; Mechoulam, Raphael; Zimmer, Andreas; Bab, Itai

    2006-01-01

    The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2–/– phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-κB ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries. PMID:16407142

  17. siRNA-mediated downregulation of GluN2B in the rostral anterior cingulate cortex attenuates mechanical allodynia and thermal hyperalgesia in a rat model of pain associated with bone cancer

    PubMed Central

    XU, YONGGUANG; WANG, GONGMING; ZOU, XULI; YANG, ZAIQI; WANG, QIN; FENG, HAO; ZHANG, MENGYUAN

    2016-01-01

    It has previously been suggested that the upregulation of GluN2B-containing N-methyl D-aspartate receptors (GluN2B) within the rostral anterior cingulate cortex (rACC) may contribute to the development of chronic pain. The present study used a rat model of bone cancer pain in order to investigate whether lentiviral-mediated delivery of small interfering RNAs targeting GluN2B (LV-GluN2B) could attenuate pain associated with bone cancer, by selectively decreasing GluN2B expression within the rACC. Sprague Dawley rats were inoculated with osteosarcoma cells into the intramedullary space of the right tibia in order to induce persistent bone cancer-associated pain. Intra-rACC administration of the lentiviral siRNA was performed in the tumor bearing rats; and reverse transcription-quantitative polymerase chain reaction and western blotting were performed in order to detect the expression levels of GluN2B. Pain behavior changes were evaluated via paw withdrawal threshold and latency determinations. Marked and region-selective decreases in the mRNA and protein expression levels of GluN2B were detected in the rACC following the intra-rACC administration of LV-GluN2B. Furthermore, the rats also exhibited pain behavior changes corresponding to the decreased levels of GluN2B. By post-operative day 14, inoculation of osteosarcoma cells had significantly enhanced mechanical allodynia and thermal hyperalgesia in the rats, which were subsequently attenuated by the intra-rACC administration of LV-GluN2B. Notably, the paw withdrawal threshold and latency of the tumor-bearing rats had recovered to normal levels, by day 14 post-administration. The results of the present study suggest that GluN2B within the rACC may be a potential target for RNA interference therapy for the treatment of pain associated with bone cancer. Furthermore, the lentiviral vector delivery strategy may be a promising novel approach for the treatment of bone cancer pain. PMID:26889244

  18. A two-year history of high bone loading physical activity attenuates ethnic differences in bone strength and geometry in pre-/early pubertal children from a low-middle income country.

    PubMed

    Meiring, Rebecca M; Avidon, Ingrid; Norris, Shane A; McVeigh, Joanne A

    2013-12-01

    We examined the interplay between ethnicity and weight-bearing physical activity on the content and volumetric properties of bone in a pre- to early pubertal South African Black and White population. Sixty six children [Black boys, 10.4 (1.4)yrs, n=15; Black girls, 10.1 (1.2)yrs, n=27; White boys, 10.1 (1.1)yrs, n=7; White girls, 9.6 (1.3)yrs, n=17] reported on all their physical activities over the past two years in an interviewer administered physical activity questionnaire (PAQ). All participants underwent a whole body and site-specific DXA scan and we also assessed bone structure and estimated bone strength with pQCT. Children were classified as being either high or low bone loaders based on the cohort's median peak bone strain score estimated from the PAQ. In the low bone loading group, Black children had greater femoral neck bone mineral content (BMC) (2.9 (0.08)g) than White children (2.4 (0.11)g; p=0.05). There were no ethnic differences in the high bone loaders for femoral neck BMC. At the cortical site, the Black low bone loaders had a greater radius area (97.3 (1.3) vs 88.8 (2.6)mm(2); p=0.05) and a greater tibia total area (475.5 (8.7) vs. 397.3 (14.0)mm(2); p=0.001) and strength (1633.7 (60.1) vs. 1271.8 (98.6)mm(3); p=0.04) compared to the White low bone loaders. These measures were not different between the Black low and high bone loaders or between the Black and White high bone loaders. In conclusion, the present study shows that there may be ethnic and physical activity associations in the bone health of Black and White pre-pubertal children and further prospective studies are required to determine the possible ethnic specific response to mechanical loading.

  19. Consumption of onion juice modulates oxidative stress and attenuates the risk of bone disorders in middle-aged and post-menopausal healthy subjects.

    PubMed

    Law, Yat-Yin; Chiu, Hui-Fang; Lee, Hui-Hsin; Shen, You-Cheng; Venkatakrishnan, Kamesh; Wang, Chin-Kun

    2016-02-01

    Osteoporosis is a chronic inflammatory condition that is characterized by the loss of bone mineral density (BMD). The current study was undertaken to evaluate the impact of onion juice intake on the bone mineral density (BMD) and bone loss in corroboration with antioxidant effects in human (in vivo) as well as inhibitory effects on the differentiation of osteoclasts in the cell line (in vitro). For in vitro studies, the RAW 264.7 (osteoclast progenitor) cells were used to examine the anti-osteoclastogenic effect of onion. In the case of in vivo studies, twenty-four subjects were divided into two groups and advised to intake 100 mL of onion juice or placebo for 8 weeks. Anthropometric measurements and blood samples were collected at the initial, 2(nd), 6(th), 8(th) and 10(th) week. The result of in vitro studies indicated that onion extract would effectively inhibit the osteoclastogenesis and its differentiation. Significant changes in the levels of alkaline phosphatase (ALP), free radicals, total antioxidant capacity (TEAC) and various antioxidants were observed in onion administered subjects. The BMD of three postmenopausal women was also found to be mildly improved on supplementation with onion juice. Onion juice consumption showed a positive modulatory effect on the bone loss and BMD by improving antioxidant activities and thus can be recommended for treating various bone-related disorders, especially osteoporosis. PMID:26686359

  20. Consumption of onion juice modulates oxidative stress and attenuates the risk of bone disorders in middle-aged and post-menopausal healthy subjects.

    PubMed

    Law, Yat-Yin; Chiu, Hui-Fang; Lee, Hui-Hsin; Shen, You-Cheng; Venkatakrishnan, Kamesh; Wang, Chin-Kun

    2016-02-01

    Osteoporosis is a chronic inflammatory condition that is characterized by the loss of bone mineral density (BMD). The current study was undertaken to evaluate the impact of onion juice intake on the bone mineral density (BMD) and bone loss in corroboration with antioxidant effects in human (in vivo) as well as inhibitory effects on the differentiation of osteoclasts in the cell line (in vitro). For in vitro studies, the RAW 264.7 (osteoclast progenitor) cells were used to examine the anti-osteoclastogenic effect of onion. In the case of in vivo studies, twenty-four subjects were divided into two groups and advised to intake 100 mL of onion juice or placebo for 8 weeks. Anthropometric measurements and blood samples were collected at the initial, 2(nd), 6(th), 8(th) and 10(th) week. The result of in vitro studies indicated that onion extract would effectively inhibit the osteoclastogenesis and its differentiation. Significant changes in the levels of alkaline phosphatase (ALP), free radicals, total antioxidant capacity (TEAC) and various antioxidants were observed in onion administered subjects. The BMD of three postmenopausal women was also found to be mildly improved on supplementation with onion juice. Onion juice consumption showed a positive modulatory effect on the bone loss and BMD by improving antioxidant activities and thus can be recommended for treating various bone-related disorders, especially osteoporosis.

  1. Interleukin-1 and tumor necrosis factor antagonists attenuate ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis.

    PubMed

    Perrien, Daniel S; Brown, Elizabeth C; Fletcher, Terry W; Irby, David J; Aronson, James; Gao, Guan G; Skinner, Robert A; Hogue, William R; Feige, Ulrich; Suva, Larry J; Ronis, Martin J J; Badger, Thomas M; Lumpkin, Charles K

    2002-12-01

    Chronic ethanol exposure inhibits rapid bone formation during distraction osteogenesis (DO; fracture and limb lengthening) and decreases volumetric bone mineral density (BMD) in a model of intragastric dietary infusion [total enteral nutrition (TEN)] in the rat. The hypothesis tested herein was that overexpression of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha mediates these deleterious effects of ethanol on the rat skeleton. Two studies (study 1, female rats; study 2, male rats) were performed to test the potential protective effects of the IL-1 and TNF antagonists: IL-1 receptor antagonist (IL-1ra) and 30-kDa polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1). All rats were infused with a liquid diet +/- ethanol (EtOH) and underwent tibial fractures and DO. During distraction, the animals received a combination of IL-1ra (1.8-2.0 mg/kg/day) and sTNFR1 (2.0 mg/kg/2 days) or vehicle. A comparison of distracted tibial histological sections demonstrated 1) significant antagonist-related increases in bone column formation over the EtOH controls (studies 1 and 2), and 2) restoration of new bone equivalent to that of the TEN controls (study 2). In contrast, examination of intact proximal tibial metaphyses by peripheral quantitative computerized tomography revealed decreases in volumetric BMD of both EtOH control and EtOH antagonist groups (study 2). These results demonstrate that short-term systemic administration of IL-1 and TNF antagonists together protect rapid bone formation during DO from the deleterious effects of chronic ethanol but are ineffective in regard to intact bone homeostasis.

  2. Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7.

    PubMed

    Gan, Ke; Xu, Lingxiao; Feng, Xiaoke; Zhang, Qiande; Wang, Fang; Zhang, Miaojia; Tan, Wenfeng

    2015-02-01

    Recently, the traditional Chinese medicine Tripterygium wilfordii Hook f (TwHF) of the Celastraceae family has attracted increasing attention for its potential therapeutic application in patients with rheumatoid arthritis (RA). It is well accepted that TwHF exerts the antirheumatic activity and mainly depends on its potent anti-inflammatory property. To further explore the therapeutic potential of the well-defined TwHF-derived single compound - celastrol in RA, we study the therapeutic efficacy of celastrol on bone erosion in collagen-induced arthritis (CIA) mice and delineate its effects on osteoclast differentiation and functions in RANKL-induced osteoclast precursors RAW264.7 cell line. In CIA mice, daily injection of celastrol (beginning on day 28 after arthritis induction) markedly suppressed arthritis, and reduced bone damage in the joints as demonstrated by histology and bone micro-computed tomography (CT). The effects were accompanied by reductions of osteoclast cells in joints, serum tartrate-resistant acid phosphatase (TRAP) 5b, and expression of osteoclastic genes (Trap, Ctsk, Ctr, Mmp-9) and transcriptional factors (c-Fos, c-Jun and NFATc1). When RAW264.7 cells were treated with RANKL, celastrol inhibited the formation of TRAP+ multinucleated cells and the bone-resorbing activity in dose-dependent manners. Furthermore, celastrol reduced the RANKL-induced expression of osteoclastic genes and transcriptional factors, as well as phosphorylation of NF-kB and mitogen-activated protein kinases (MAPK). These findings show that celastrol could directly inhibit osteoclast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction.

  3. Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus.

    PubMed

    Elshikha, Ahmed S; Lu, Yuanqing; Chen, Mong-Jen; Akbar, Mohammad; Zeumer, Leilani; Ritter, Andrea; Elghamry, Hanaa; Mahdi, Mahmoud A; Morel, Laurence; Song, Sihong

    2016-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans. PMID:27232337

  4. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  5. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  6. The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

    PubMed Central

    Movérare-Skrtic, Sofia; Börjesson, Anna E.; Farman, Helen H.; Sjögren, Klara; Windahl, Sara H.; Lagerquist, Marie K.; Andersson, Annica; Stubelius, Alexandra; Carlsten, Hans; Gustafsson, Jan-Åke; Ohlsson, Claes

    2014-01-01

    The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. It was recently demonstrated that the ER antagonist ICI 182,780 (ICI) acts as an ER agonist in uterus of mice with mutations in the ERα AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ERα AF-2 (ERαAF-20) were treated with ICI, estradiol, or vehicle for 3 wk. Estradiol increased the trabecular and cortical bone mass as well as the uterine weight, whereas it reduced fat mass, thymus weight, and the growth plate height in wild-type but not in ERαAF-20 mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERαAF-20 mice. It acted as an ERα agonist on trabecular bone mass and uterine weight, whereas no effect was seen on cortical bone mass, fat mass, or thymus weight. Surprisingly, a pronounced inverse agonistic activity was seen on the growth plate height, resulting in enhanced longitudinal bone growth. In conclusion, ICI uses ERα AF-1 in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist. PMID:24395795

  7. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  8. Bone Grafts

    MedlinePlus

    A bone graft transplants bone tissue. Surgeons use bone grafts to repair and rebuild diseased bones in your hips, knees, ... fractures or cancers. Once your body accepts the bone graft, it provides a framework for growth of new, ...

  9. Bone Diseases

    MedlinePlus

    ... avoid smoking and drinking too much alcohol. Bone diseases can make bones easy to break. Different kinds ... break Osteogenesis imperfecta makes your bones brittle Paget's disease of bone makes them weak Bones can also ...

  10. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  11. A direct measurement of skull attenuation for quantitative SPECT

    SciTech Connect

    Turkington, T.G.; Gilland, D.R.; Jaszczak, R.J.; Greer, K.L.; Coleman, R.E. . Dept. of Radiology); Smith, M.F. . Dept. of Biomedical Engineering)

    1993-08-01

    The attenuation of 140 keV photons was measured in three empty skulls by placing a [sup 99m]Tc line source inside each one and acquiring projection data. These projections were compared to projections of the line source alone to determine the transmission through each point in the skull surrounding the line source. The effective skull thickness was calculated for each point using an assumed dense bone attenuation coefficient. The relative attenuation for this thickness of bone was compared to that of an equivalent amount of soft tissue to evaluate the increased attenuation of photons in brain SPECT relative to a uniform soft tissue approximation. For the skull regions surrounding most of the brain, the effective bone thickness varied considerably, but was generally less than 6 mm, resulting in a relative attenuation increases of less than 6%.

  12. Diabetes and bone health.

    PubMed

    Antonopoulou, Marianna; Bahtiyar, Gül; Banerji, Mary Ann; Sacerdote, Alan S

    2013-11-01

    The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti-diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population. PMID:23628280

  13. Potent agonists of a hematopoietic stem cell cytokine receptor, c-Mpl.

    PubMed

    Tarasova, Anna; Haylock, David N; Meagher, Laurence; Be, Cheang Ly; White, Jacinta; Nilsson, Susan K; Andrade, Jessica; Cartledge, Kellie; Winkler, David A

    2013-05-01

    Several growth factors feature prominently in the control of hematopoiesis. Thrombopoietin, a class I hematopoietic cytokine, plays critical roles in regulating hematopoietic stem cell numbers and also stimulates the production and differentiation of megakaryocytes, the bone marrow cells that ultimately produce platelets. Thrombopoietin interacts with the c-Mpl cell-surface receptor. Recently, several peptide and small-molecule agonists and antagonists of c-Mpl have been reported. We conducted a bioinformatics and molecular modeling study aimed at understanding the agonist activities of peptides that bind to c-Mpl, and developed new potent peptide agonists with low nanomolar activity. These agonists also show very high activity in human CD34(+) primary cell cultures, and doubled the mean blood platelet counts when injected into mice.

  14. Activation of CXCL10/CXCR3 signaling attenuates morphine analgesia: involvement of Gi protein.

    PubMed

    Ye, Dawei; Bu, Huilian; Guo, Genhua; Shu, Bin; Wang, Wei; Guan, Xuehai; Yang, Hui; Tian, Xuebi; Xiang, Hongbing; Gao, Feng

    2014-08-01

    Morphine is a potent agonist of μ-opioid receptor and is widely used to relieve severe pain, including cancer pain. Some chemokines, for example, CX3CL1 and CCL2, participate in the regulation of opioid santinociception. In our previous study, we found overexpression of chemokine CXCL10/CXCR3 in spinal cord participated in the development of cancer-induced bone pain, so we supposed that CXCL10 may have influence in morphine analgesia in cancer pain relief. In this study, we found that a single dose of morphine could transiently increase the expression of CXCL10 in spinal cord. Blocking the function of CXCL10 enhanced morphine antinociception in cancer-induced bone pain rats. However, overexpression of CXCL10 induced acute algesia and decreased the analgesic effect of morphine in normal mice. The algesic effect of CXCL10 was blocked by inhibition of CXCR3 and Gi protein. These results suggested that CXCL10 in spinal cord serves as a novel negative regulator of morphine analgesia and provided evidence that activation of CXCL10/CXCR3 in spinal cord may attenuate antinociceptive potency of morphine in cancer pain relief.

  15. Attenuation of diacylglycerol second messengers

    SciTech Connect

    Bishop, W.R.; Ganong, B.R.; Bell, R.M.

    1986-05-01

    Diacylglycerol(DAG) derived from phosphatidylinositol activates protein kinase C in agonist-stimulated cells. At least two pathways may contribute to the attenuation of the DAG signal: (1) phosphorylation to phosphatidic acid(PA) by DAG kinase(DGK), and (2) deacylation by DAG and monoacylglycerol lipases. A number of DAG analogs were tested as substrates and inhibitors of partially purified pig brain DGK. Two analogs were potent inhibitors in vitro, 1-monooleoylglycerol(MOG,K/sub I/ = 91 ..mu..M) and diotanoylethyleneglycol (diC/sub 8/EG, K/sub I/ = 58 ..mu..M). These compounds were tested in human platelets. DiC/sub 8/EG inhibited (70 - 100%) (/sup 32/P/sub i/) incorporation into PA in thrombin-stimulated platelets. Under these conditions the DAG signal was somewhat long-lived but was still metabolized, presumably by the lipase pathway. MOG treatment elevated DAG levels up to 4-fold in unstimulated platelets. The DAG formed was in a pool where it did not activate protein kinase C. Thrombin-stimulation of MOG-treated platelets resulted in DAG levels 10-fold higher than control platelets. This appears to be due to the inability of these platelets to metabolize agonist-linked DAG via the lipase pathway. The development of specific inhibitors of DAG kinase and DAG lipase, in conjunction with mass quantification of DAG levels as used here, will provide further insights into the regulation of DAG second messengers.

  16. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  17. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways.

  18. DC attenuation meter

    DOEpatents

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  19. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

    PubMed Central

    Wang, Hong; Sethi, Gautam; Loke, Weng-Keong; Sim, Meng-Kwoon

    2015-01-01

    ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely

  20. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  1. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  2. Effects of oxytocin on serotonin 1B agonist-induced autism-like behavior in mice.

    PubMed

    Lawson, Sarah K; Gray, Andrew C; Woehrle, Nancy S

    2016-11-01

    Social impairments in autism remain poorly understood and without approved pharmacotherapies. Novel animals models are needed to elucidate mechanisms and evaluate novel treatments for the social deficits in autism. Recently, serotonin 1B receptor (5-HT1B) agonist challenge in mice was shown to induce autism-like behaviors including perseveration, reduced prepulse inhibition, and delayed alternation deficits. However, the effects of 5-HT1B agonists on autism-related social behaviors in mice remain unknown. Here, we examine the effects of 5-HT1B agonist challenge on sociability and preference for social novelty in mice. We also examine the effects of 5-HT1B agonist treatment on average rearing duration, a putative rodent measure of non-selective attention. Non-selective attention is an associated feature of autism that is also not well understood. We show that 5-HT1B receptor activation reduces sociability, preference for social novelty, and rearing in mice. In addition, we examine the ability of oxytocin, an off-label treatment for the social impairments in autism, to reverse 5-HT1B agonist-induced social and attention deficits in mice. We show that oxytocin restores social novelty preference in mice treated with a 5-HT1B agonist. We also show that oxytocin attenuates 5-HT1B agonist-induced sociability and rearing deficits in mice. Our results suggest that 5-HT1B agonist challenge provides a useful pharmacological mouse model for aspects of autism, and implicate 5-HT1B in autism social and attention deficits. Moreover, our findings suggest that oxytocin may treat the social deficits in autism through a mechanism involving 5-HT1B.

  3. Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse

    PubMed Central

    Di Rocco, Agnese; Uchibe, Kenta; Larmour, Colleen; Berger, Rebecca; Liu, Min; Barton, Elisabeth R.; Iwamoto, Masahiro

    2016-01-01

    Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor γ (RARγ) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RARγ agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification lesion, suggesting that RARγ agonist may oppose skeletal muscle damage. To test this hypothesis, we generated a critical defect in the tibialis anterior muscle of 7-week-old mice with a cautery, treated them with RARγ agonist or vehicle corn oil, and examined the effects of RARγ agonist on muscle repair. The muscle defects were partially repaired with newly regenerating muscle cells, but also filled with adipose and fibrous scar tissue in both RARγ-treated and control groups. The fibrous or adipose area was smaller in RARγ agonist–treated mice than in the control. In addition, muscle repair was remarkably delayed in RARγ-null mice in both critical defect and cardiotoxin injury models. Furthermore, we found a rapid increase in retinoid signaling in lacerated muscle, as monitored by retinoid signaling reporter mice. Together, our results indicate that endogenous RARγ signaling is involved in muscle repair and that selective RARγ agonists may be beneficial to promote repair in various types of muscle injuries. PMID:26205250

  4. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  5. Pressure surge attenuator

    DOEpatents

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  6. Living Bones, Strong Bones

    NASA Video Gallery

    In this classroom activity, engineering, nutrition, and physical activity collide when students design and build a healthy bone model of a space explorer which is strong enough to withstand increas...

  7. Bone Tumor

    MedlinePlus

    ... most common types of primary bone cancer are: • Multiple myeloma. Multiple myeloma is the most common primary bone cancer. It ... Any bone can be affected by this cancer. Multiple myeloma affects approximately six people per 100,000 each ...

  8. Bone Cancer

    MedlinePlus

    Cancer that starts in a bone is uncommon. Cancer that has spread to the bone from another ... more common. There are three types of bone cancer: Osteosarcoma - occurs most often between ages 10 and ...

  9. Tracer attenuation in groundwater

    NASA Astrophysics Data System (ADS)

    Cvetkovic, Vladimir

    2011-12-01

    The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

  10. Imaging characteristics of bone graft materials.

    PubMed

    Beaman, Francesca D; Bancroft, Laura W; Peterson, Jeffrey J; Kransdorf, Mark J; Menke, David M; DeOrio, James K

    2006-01-01

    Bone graft materials are widely used in reconstructive orthopedic procedures to promote new bone formation and bone healing, provide a substrate and scaffolding for development of bone structure, and function as a means for direct antibiotic delivery. Bone graft materials include autografts, allografts, and synthetic substitutes. An autograft (from the patient's own bone) supplies both bone volume and osteogenic cells capable of new bone formation. The imaging appearance of an autograft depends on its type, composition, and age. Autografts often appear as osseous fragments at radiography. At computed tomography (CT), autografts appear similar to the adjacent cortical bone. At magnetic resonance (MR) imaging, however, autografts have a variable appearance as a consequence of the viable marrow inside them, a feature not present in other graft materials. An allograft (from cadaveric bone) has an appearance similar to that of cortical bone on radiographs and CT images. An allograft in the form of bone chips or morsels does not show those features on radiographs and CT images, but instead appears as a conglomerate with medium to high opacity and attenuation within the bone defect. In the immediate postoperative period, allografts appear hypointense on both T1- and T2-weighted MR images. Hematopoietic tissue replaces the normal fatty marrow in the later phases of graft incorporation. Synthetic bone substitutes are much more variable in imaging appearance. As the use of bone allografts and synthetic substitutes increases, familiarity with postoperative imaging features is essential for differentiation between grafts and residual or recurrent disease.

  11. Ultrasonic Evaluation of Deeply Located Trabecular Bones - Preliminary Results

    NASA Astrophysics Data System (ADS)

    Cieślik, Lucyna; Litniewski, Jerzy

    The analysis of ultrasonic signals scattered by soft tissues have been successfully applied for their characterization. Similarly, the trabecular bone backscattered signal contains information about the properties of the bone structure. Therefore scattering-based ultrasonic technique potentially enables the assessment of microstructure characteristics of a bone. The femoral neck fracture often occurs in the course of osteoporosis and can lead to severe complications. Therefore assessment of femoral bone microstructure and condition is important and essential for the diagnosis and treatment monitoring. As far most of the trabecular bone investigations have been performed in vitro. The only in vivo measurements were carried out in transmission and mostly concerned estimation of the attenuation in heel bone. We have built the ultrasonic scanner that could be useful in acquiring the RF (Radio Frequency) echoes backscattered by the trabecular bone in vivo. Moreover, the bone scanner provides data not only from heel bone but from deeply located bones as well (e.g. femoral bone). It can be also used for easily accessible bones like heel bone or breastbone. In this case a gel-pad is applied to assure focusing of ultrasound in trabecular bone (approximately 10 mm beneath the cortical bone). This study presents preliminary results of the attenuating properties evaluation of trabecular bone from the ultrasonic echoes backscattered by heel bone and femoral neck.

  12. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  13. Bone and bone turnover.

    PubMed

    Crofton, Patricia M

    2009-01-01

    Children with cancer are exposed to multiple influences that may adversely affect bone health. Some treatments have direct deleterious effects on bone whilst others may have indirect effects mediated through various endocrine abnormalities. Most clinical outcome studies have concentrated on survivors of acute lymphoblastic leukaemia (ALL). There is now good evidence that earlier treatment protocols that included cranial irradiation with doses of 24 Gy or greater may result in growth hormone deficiency and low bone mineral density (BMD) in the lumbar spine and femoral neck. Under current protocols, BMD decreases during intensive chemotherapy and fracture risk increases. Although total body BMD may eventually return to normal after completion of chemotherapy, lumbar spine trabecular BMD may remain low for many years. The implications for long-term fracture risk are unknown. Risk factors for low BMD include high dose methotrexate, higher cumulative doses of glucocorticoids, male gender and low physical activity. BMD outcome in non-ALL childhood cancers has been less well studied but there is evidence that survivors of childhood brain or bone tumours, and survivors of bone marrow transplants for childhood malignancy, all have a high risk of long-term osteopenia. Long-term follow-up is required, with appropriate treatment of any endocrine abnormalities identified.

  14. Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis*

    PubMed Central

    Sophocleous, Antonia; Marino, Silvia; Logan, John G.; Mollat, Patrick; Ralston, Stuart H.; Idris, Aymen I.

    2015-01-01

    The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing. PMID:26195631

  15. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency.

  16. Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats.

    PubMed

    McKay, N J; Daniels, D

    2013-10-01

    Glucagon-like peptide-1 (GLP-1) plays an important role in energy homeostasis. Injections of GLP-1 receptor (GLP-1R) agonists suppress food intake, and endogenous GLP-1 is released when nutrients enter the gut. There is also growing evidence that the GLP-1 system is involved in the regulation of body fluid homeostasis. GLP-1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP-1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP-1R agonists liraglutide (0.05 μg) and exendin-4 (0.05 μg) on water and saline intake, as stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD-PR). Each agonist suppressed AngII-induced water intake; however, only exendin-4 suppressed saline intake. WD-PR-induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD-PR found a reliable effect of the agonists on burst number. Furthermore, exendin-4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP-1R activation is not selective to water intake, is a function of post-ingestive feedback, and is not secondary to visceral malaise.

  17. Using Micro-CT Derived Bone Microarchitecture to Analyze Bone Stiffness - A Case Study on Osteoporosis Rat Bone.

    PubMed

    Wu, Yuchin; Adeeb, Samer; Doschak, Michael R

    2015-01-01

    Micro-computed tomography (Micro-CT) images can be used to quantitatively represent bone geometry through a range of computed attenuation-based parameters. Nonetheless, those parameters remain indirect indices of bone microarchitectural strength and require further computational tools to interpret bone structural stiffness and potential for mechanical failure. Finite element analysis (FEA) can be applied to measure trabecular bone stiffness and potentially predict the location of structural failure in preclinical animal models of osteoporosis, although that procedure from image segmentation of Micro-CT derived bone geometry to FEA is often challenging and computationally expensive, resulting in failure of the model to build. Notably, the selection of resolution and threshold for bone segmentation are key steps that greatly affect computational complexity and validity. In the following study, we evaluated an approach whereby Micro-CT derived grayscale attenuation and segmentation data guided the selection of trabecular bone for analysis by FEA. We further correlated those FEA results to both two- and three-dimensional bone microarchitecture from sham and ovariectomized (OVX) rats (n = 10/group). A virtual cylinder of vertebral trabecular bone 40% in length from the caudal side was selected for FEA, because Micro-CT based image analysis indicated the largest differences in microarchitecture between the two groups resided there. Bone stiffness was calculated using FEA and statistically correlated with the three-dimensional values of bone volume/tissue volume, bone mineral density, fractal dimension, trabecular separation, and trabecular bone pattern factor. Our method simplified the process for the assessment of trabecular bone stiffness by FEA from Micro-CT images and highlighted the importance of bone microarchitecture in conferring significantly increased bone quality capable of resisting failure due to increased mechanical loading. PMID:26042089

  18. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  19. Locomotion induced by ventral tegmental microinjections of a nicotinic agonist.

    PubMed

    Museo, E; Wise, R A

    1990-03-01

    Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

  20. Neuropeptide FF receptors as novel targets for limbic seizure attenuation.

    PubMed

    Portelli, Jeanelle; Meurs, Alfred; Bihel, Frederic; Hammoud, Hassan; Schmitt, Martine; De Kock, Joery; Utard, Valerie; Humbert, Jean-Paul; Bertin, Isabelle; Buffel, Ine; Coppens, Jessica; Tourwe, Dirk; Maes, Veronique; De Prins, An; Vanhaecke, Tamara; Massie, Ann; Balasubramaniam, Ambikaipakan; Boon, Paul; Bourguignon, Jean-Jacques; Simonin, Frederic; Smolders, Ilse

    2015-08-01

    Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures. PMID:25963417

  1. Neuropeptide FF receptors as novel targets for limbic seizure attenuation.

    PubMed

    Portelli, Jeanelle; Meurs, Alfred; Bihel, Frederic; Hammoud, Hassan; Schmitt, Martine; De Kock, Joery; Utard, Valerie; Humbert, Jean-Paul; Bertin, Isabelle; Buffel, Ine; Coppens, Jessica; Tourwe, Dirk; Maes, Veronique; De Prins, An; Vanhaecke, Tamara; Massie, Ann; Balasubramaniam, Ambikaipakan; Boon, Paul; Bourguignon, Jean-Jacques; Simonin, Frederic; Smolders, Ilse

    2015-08-01

    Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures.

  2. Bone scanning.

    PubMed

    Greenfield, L D; Bennett, L R

    1975-03-01

    Scanning is based on the uptake of a nuclide by the crystal lattice of bone and is related to bone blood flow. Cancer cells do not take up the tracer. Normally, the scan visualizes the highly vascular bones. Scans are useful and are indicated in metastatic bone disease, primary bone tumors, hematologic malignancies and some non-neoplastic diseases. The scan is more sensitive than x-ray in the detection of malignant diseases of the skeleton. PMID:1054210

  3. Variable laser attenuator

    DOEpatents

    Foltyn, S.R.

    1987-05-29

    The disclosure relates to low loss, high power variable attenuators comprising one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength. 9 figs.

  4. Variable laser attenuator

    DOEpatents

    Foltyn, Stephen R.

    1988-01-01

    The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

  5. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  6. A high-fat diet increases IL-1, IL-6, and TNF-α production by increasing NF-κB and attenuating PPAR-γ expression in bone marrow mesenchymal stem cells.

    PubMed

    Cortez, Mayara; Carmo, Luciana Simão; Rogero, Marcelo Macedo; Borelli, Primavera; Fock, Ricardo Ambrósio

    2013-04-01

    It is well established that a high-fat diet (HFD) can lead to overweight and ultimately to obesity, as well as promoting low-grade chronic inflammation associated with increased levels of such mediators as TNF-α, IL-1, and IL-6. Bone marrow mesenchymal stem cells (MSCs), which are involved in hematopoietic niches and microenvironments, can be affected by these cytokines, resulting in induction of NF-κB and inhibition of PPAR-γ. Because this phenomenon could ultimately lead to suppression of bone marrow adipogenesis, we set out to investigate the effect of an HFD on the expression of PPAR-γ and NF-κB, as well as the production of IL-1, IL-6, and TNF-α in MSCs. Two-month-old male Wistar rats were fed a HFD diet and evaluated by means of leukograms and myelograms along with blood total cholesterol, triglyceride, and C-reactive protein levels. MSCs were isolated, and PPAR-γ and NF-κB were quantified, as well as IL-1, IL-6, and TNF-α production. Animals that were fed a HFD showed higher levels of blood total cholesterol, triglycerides, and C-reactive protein with leukocytosis and bone marrow hyperplasia. MSCs from HFD animals showed increased production of IL-1, IL-6, and TNF-α and increased NF-κB and reduced PPAR-γ expression. Therefore, ingestion of an HFD induces alterations in MSCs that may influence modulation of hematopoiesis.

  7. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  8. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  9. Low Bone Density

    MedlinePlus

    ... Density Exam/Testing › Low Bone Density Low Bone Density Low bone density is when your bone density ... people with normal bone density. Detecting Low Bone Density A bone density test will determine whether you ...

  10. Bone Fracture Exacerbates Murine Ischemic Cerebral Injury

    PubMed Central

    Degos, Vincent; Maze, Mervyn; Vacas, Susana; Hirsch, Jan; Guo, Yi; Shen, Fanxia; Jun, Kristine; van Rooijen, Nico; Gressens, Pierre; Young, William L.; Su, Hua

    2014-01-01

    Background Bone fracture increases alarmins and pro-inflammatory cytokines in the blood, and provokes macrophage infiltration and pro-inflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome, the impact of bone fracture on stroke outcome is unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response. Methods Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n=10), infarct volume, neuronal death, and macrophages/microglia-infiltration (n=6–7) were analyzed three days after. Results We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere±SD: 30±7% vs. 12±3%, n=6, P<0.001) more severe neurobehavioral dysfunction, and more macrophages/microglia in the peri-infarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction. Conclusions These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke. PMID:23438676

  11. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  12. PPAR Agonists and Cardiovascular Disease in Diabetes.

    PubMed

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  13. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  14. Melatonin attenuates Leishmania (L.) amazonensis infection by modulating arginine metabolism.

    PubMed

    Laranjeira-Silva, Maria Fernanda; Zampieri, Ricardo A; Muxel, Sandra M; Floeter-Winter, Lucile Maria; Markus, Regina P

    2015-11-01

    Acute inflammatory responses induced by bacteria or fungi block nocturnal melatonin synthesis by rodent pineal glands. Here, we show Leishmania infection does not impair daily melatonin rhythm in hamsters. Remarkably, the attenuated parasite burden and lesion progression in hamsters infected at nighttime was impaired by blockage of melatonin receptors with luzindole, whereas melatonin treatment during the light phase attenuated Leishmania infection. In vitro studies corroborated in vivo observations. Melatonin treatment reduced macrophage expression of Cat-2b, Cat1, and ArgI, genes involved in arginine uptake and polyamine synthesis. Indeed, melatonin reduced macrophage arginine uptake by 40%. Putrescine supplementation reverted the attenuation of infectivity by melatonin indicating that its effect was due to the arrest of parasite replication. This study shows that the Leishmania/host interaction varies in a circadian manner according to nocturnal melatonin pineal synthesis. Our results provide new data regarding Leishmania infectiveness and show new approaches for applying agonists of melatonin receptors in Leishmaniasis therapy.

  15. Bone tumor

    MedlinePlus

    ... physical exam. Tests that may be done include: Alkaline phosphatase blood level Bone biopsy Bone scan Chest x- ... may also be ordered to monitor the disease: Alkaline phosphatase isoenzyme Blood calcium level Parathyroid hormone Blood phosphorus ...

  16. Bone Markers

    MedlinePlus

    ... Alkaline Phosphatase; Osteocalcin; P1NP; Procollagen Type 1 N-Terminal Propeptide Formal name: Biochemical Markers of Bone Remodeling ... tests for evaluating bone turnover: C-telopeptide (C-terminal telopeptide of type 1 collagen (CTx)) – a marker ...

  17. Bone Infections

    MedlinePlus

    ... of the body, bones can get infected. The infections are usually bacterial, but can also be fungal. ... bloodstream. People who are at risk for bone infections include those with diabetes, poor circulation, or recent ...

  18. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists

    SciTech Connect

    Zhang Songwen Liu Qiangyuan; Wang Juan; Harnish, Douglas C.

    2009-02-06

    C-reactive protein (CRP), a human acute-phase protein, is a risk factor for future cardiovascular events and exerts direct pro-inflammatory and pro-atherogenic properties. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. In this study, we report that two synthetic FXR agonists, WAY-362450 and GW4064, suppressed interleukin-6-induced CRP expression in human Hep3B hepatoma cells. Knockdown of FXR by short interfering RNA attenuated the inhibitory effect of the FXR agonists and also increased the ability of interleukin-6 to induce CRP production. Furthermore, treatment of wild type C57BL/6 mice with the FXR agonist, WAY-362450, attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, whereas no effect was observed in FXR knockout mice. These data provide new evidence for direct anti-inflammatory properties of FXR.

  19. Effects of Estrogen Receptor Agonists on Regulation of the Inflammatory Response in Astrocytes from Young Adult and Middle-Aged Female Rats

    PubMed Central

    Lewis, Danielle K; Johnson, Adam B.; Stohlgren, Shannon; Simpson, Ashley; Sohrabji, Farida

    2008-01-01

    Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examined the effects of ERα- and ERβ-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17β-estradiol (ERα/ERβ agonist), HPTE (ERα agonist/ERβ antagonist) and DPN (ERβ agonist) led to attenuation of IL-1β, TNFα, and MMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ERα agonist) attenuated IL-1β (but not TNFα or MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work determined that 17β-estradiol was unable to attenuate the LPS-induced increase in IL-1β in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1β was not attenuated by pre-treatment with 17β-estradiol, PPT or HPTE. Interestingly, the ERβ agonist, DPN significantly decreased IL-1β following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compounds which bind ERβ are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use. PMID:18328572

  20. Modulation of agonist binding to human dopamine receptor subtypes by L-prolyl-L-leucyl-glycinamide and a peptidomimetic analog.

    PubMed

    Verma, Vaneeta; Mann, Amandeep; Costain, Willard; Pontoriero, Giuseppe; Castellano, Jessica M; Skoblenick, Kevin; Gupta, Suresh K; Pristupa, Zdenek; Niznik, Hyman B; Johnson, Rodney L; Nair, Venugopalan D; Mishra, Ram K

    2005-12-01

    The present study was undertaken to investigate the role of the hypothalamic tripeptide L-prolyl-L-leucyl-glycinamide (PLG) and its conformationally constrained analog 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) in modulating agonist binding to human dopamine (DA) receptor subtypes using human neuroblastoma SH-SY5Y cells stably transfected with respective cDNAs. Both PLG and PAOPA enhanced agonist [3H]N-propylnorapomorphine (NPA) and [3H]quinpirole binding in a dose-dependent manner to the DA D2L,D2S, and D4 receptors. However, agonist binding to the D1 and D3 receptors and antagonist binding to the D2L receptors by PLG were not significantly affected. Scatchard analysis of [3H]NPA binding to membranes in the presence of PLG revealed a significant increase in affinity of the agonist binding sites for the D2L, D2S, and D4 receptors. Analysis of agonist/antagonist competition curves revealed that PLG and PAOPA increased the population and affinity of the high-affinity form of the D2L receptor and attenuated guanosine 5'-(beta,gamma-imido)-triphosphate-induced inhibition of high-affinity agonist binding sites for the DA D2L receptor. Furthermore, direct NPA binding with D2L cell membranes pretreated with suramin, a compound that can uncouple receptor/G protein complexes, and incubated with and without DA showed that both PLG and PAOPA had only increased agonist binding in membranes pretreated with both suramin and DA, suggesting that PLG requires the D2L receptor/G protein complex to increase agonist binding. These results suggest that PLG possibly modulates DA D2S, D2L, and D4 receptors in an allosteric manner and that the coupling of D2 receptors to the G protein is essential for this modulation to occur. PMID:16126839

  1. Landing gear noise attenuation

    NASA Technical Reports Server (NTRS)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  2. RADIO FREQUENCY ATTENUATOR

    DOEpatents

    Giordano, S.

    1963-11-12

    A high peak power level r-f attenuator that is readily and easily insertable along a coaxial cable having an inner conductor and an outer annular conductor without breaking the ends thereof is presented. Spaced first and second flares in the outer conductor face each other with a slidable cylindrical outer conductor portion therebetween. Dielectric means, such as water, contact the cable between the flares to attenuate the radio-frequency energy received thereby. The cylindrical outer conductor portion is slidable to adjust the voltage standing wave ratio to a low level, and one of the flares is slidable to adjust the attenuation level. An integral dielectric container is also provided. (AFC)

  3. Compensation for non-uniform attenuation in SPECT brain imaging

    SciTech Connect

    Glick, S.J.; King, M.A.; Pan, T.S.

    1994-05-01

    Photon attenuation is a major limitation in performing quantitative SPECT brain imaging. A number of methods have been proposed for compensation of attenuation in regions of the body that can be modelled as a uniform attenuator. The magnitude of the errors introduced into reconstructed brain images by assuming the head to be a uniform attenuator are uncertain (the skull, sinus cavities and head holder all have different attenuation properties than brain tissue). Brain imaging is unique in that the radioisotope, for the most part, is taken up within a uniform attenuation medium (i.e., brain tissue) which is surrounded by bone (i.e., the skull) of a different density. Using this observation, Bellini`s method for attenuation compensation (which is an exact solution to the exponential Radon transform) has been modified to account for the different attenuation properties of the skull. To test this modified Bellini method, a simple mathematical phantom was designed to model the brain and a skull of varying thickness less than 7.5 mm. To model brain imaging with Tc-99m HMPAO, the attenuation coefficient of the brain tissue and skull were set to 0.15 cm{sup -1} and 0.22 cm{sup -1} respectively. A ray-driven projector which accounted for non-uniform attenuation was used to simulate projection data from 128 views. The detector response and scatter were not simulated. It was observed that reconstructions processed with uniform attenuation compensation (i.e., where it was assumed that the brain tissue and the skull had the same attenuation coefficient) provided errors of 6-20%, whereas those processed with the non-uniform Bellini algorithm were biased by only 0-5%.

  4. Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

    PubMed

    Codd, Ellen E; Baker, Judith; Brandt, Michael R; Bryant, Stewart; Cai, Chaozhong; Carson, John R; Chevalier, Kristen M; Colburn, Raymond W; Coogan, Timothy P; Dax, Scott L; Decorte, Bart; Kemmerer, Michael; Legrand, Edmund K; Lenhard, James M; Leone, Angelique M; Lin, Ling; Mabus, John R; McDonnell, Mark E; McMillian, Michael K; McNally, James J; Stone, Dennis J; Wang, Charles Y; Zhang, Sui-Po; Flores, Christopher M

    2010-10-01

    The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.

  5. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants

    PubMed Central

    Willis, Daniel N.; Liu, Boyi; Ha, Michael A.; Jordt, Sven-Eric; Morris, John B.

    2011-01-01

    Menthol, the cooling agent in peppermint, is added to almost all commercially available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacological actions affecting smoking behavior. Using plethysmography, we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concentration (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concentrations sufficient for activation of sensory TRP channels. These experiments demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities.— Willis, D. N., Liu, B., Ha, M. A., Jordt, S.-E., Morris, J. B. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. PMID:21903934

  6. The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses isolation rearing-induced abnormal behaviors in mice.

    PubMed

    Ago, Yukio; Araki, Ryota; Yano, Koji; Kawasaki, Toshiyuki; Chaki, Shigeyuki; Nakazato, Atsuro; Onoe, Hirotaka; Hashimoto, Hitoshi; Baba, Akemichi; Takuma, Kazuhiro; Matsuda, Toshio

    2012-01-01

    Isolation-induced abnormal behaviors are useful animal models for assessing potential anti-psychotic drugs. This study examined the effect of MGS0028, a selective metabotropic glutamate 2/3 receptor agonist, on abnormal behaviors such as hyperactivity, aggression, and deficits of prepulse inhibition in isolation-reared mice. MGS0028 attenuated hyperactivity and aggressive behaviors in isolation-reared mice. The agonist also reversed isolation rearing-induced deficits of prepulse inhibition. On the other hand, MGS0028 did not affect locomotor activity and prepulse inhibition in group-reared mice. These results suggest that the metabotropic glutamate 2/3 receptor agonist, MGS0028, is a potential compound for the treatment of psychiatric disorders.

  7. Protein intake and bone health.

    PubMed

    Bonjour, Jean-Philippe

    2011-03-01

    Adequate nutrition plays an important role in the development and maintenance of bone structures resistant to usual mechanical stresses. In addition to calcium in the presence of an adequate supply of vitamin D, dietary proteins represent key nutrients for bone health and thereby function in the prevention of osteoporosis. Several studies point to a positive effect of high protein intake on bone mineral density or content. This fact is associated with a significant reduction in hip fracture incidence, as recorded in a large prospective study carried out in a homogeneous cohort of postmenopausal women. Low protein intake (< 0.8 g/kg body weight/day) is often observed in patients with hip fractures and an intervention study indicates that following orthopedic management, protein supplementation attenuates post-fracture bone loss, tends to increase muscle strength, and reduces medical complications and rehabilitation hospital stay. There is no evidence that high protein intake per se would be detrimental for bone mass and strength. Nevertheless, it appears reasonable to avoid very high protein diets (i. e. more than 2.0 g/kg body weight/day) when associated with low calcium intake (i. e. less than 600 mg/day). In the elderly, taking into account the attenuated anabolic response to dietary protein with ageing, there is concern that the current dietary protein recommended allowance (RDA), as set at 0.8 g/kg body weight/day, might be too low for the primary and secondary prevention of fragility fractures. PMID:22139564

  8. Stimulation of Wnt/beta-Catenin Signaling Pathway with Wnt Agonist Reduces Organ Injury after Hemorrhagic Shock

    PubMed Central

    Kuncewitch, Michael; Yang, Weng-Lang; Jacob, Asha; Khader, Adam; Giangola, Matthew; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

    2014-01-01

    Background Hemorrhagic shock is a leading cause of morbidity and mortality in surgery and trauma patients. Despite a large number of preclinical trials conducted to develop therapeutic strategies against hemorrhagic shock, there is still an unmet need exist for effective therapy for hemorrhage victims. Wnt/β-catenin signaling controls developmental processes and cellular regeneration owing to its central role in cell survival and proliferation. We therefore hypothesized that the activation of Wnt signaling reduces systemic injury caused by hemorrhagic shock. Methods Adult male Sprague-Dawley rats underwent hemorrhagic shock by controlled bleeding of the femoral artery to maintain a mean arterial pressure (MAP) of 30 mmHg for 90 min, followed by resuscitation with crystalloid equal to two times the shed blood volume. After resuscitation, animals were infused with Wnt agonist (5 mg/kg) or Vehicle (20% DMSO in saline). Blood and tissue samples were collected 6 h after resuscitation for analysis. Results Hemorrhagic shock increased serum levels of AST, lactate, and LDH. Treatment with Wnt agonist significantly reduced these levels by 40%, 36%, and 77%, respectively. Wnt agonist also decreased BUN and creatinine by 34% and 56%, respectively. Treatment reduced lung myeloperoxidase activity and IL-6 mRNA by 55% and 68% respectively and, significantly improved lung histology. Wnt agonist treatment increased Bcl-2 protein to Sham values and decreased cleaved caspase-3 by 46% indicating attenuation of hemorrhage-induced apoptosis in the lungs. Hemorrhage resulted in significant reductions of β-catenin protein levels in the lungs as well as down-regulation of a Wnt target gene, Cyclin-D1, while Wnt agonist treatment preserved these levels. Conclusions The administration of Wnt agonist attenuated hemorrhage-induced organ injury, inflammation and apoptosis. This was correlated with preservation of the Wnt signaling pathway. Thus, Wnt/β-catenin activation could be protective

  9. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  10. A study of stress-free living bone and its application to space flight

    NASA Technical Reports Server (NTRS)

    Leblanc, A.; Spira, M.

    1983-01-01

    Observations of animals and human subjects in weightless space flight (Skylab and COSMOS) document altered bone metabolism. Bone metabolism is affected by a number of local and systemic factors. The calcification and growth of transplanted bone is independent of local muscle, nervous, and mechanical forces; therefore, transplanted bone would provide data on the role of local vs. systematic factors. Bone metabolism in living transplanted bone, devoid of stress, was investigated as a possible tool for the investigation of countermeasures against disuse bone loss. An animal model using Sprague-Dawley rats was developed for transplantation of femur bone tissue on a nutrient vascular pedicel. The long term course of these implants was assessed through the measure of regional and total bone mineral, blood flow, and methylene diphosphonate (MDP) uptake. Clomid, an estrogen agonist/antagonist, was shown to protect bone from disuse loss of minerals by retarding trabecular and cortical resorption.

  11. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2

    PubMed Central

    Mediero, Aránzazu; Wilder, Tuere; Perez-Aso, Miguel; Cronstein, Bruce N.

    2015-01-01

    Promoting bone regeneration and repair of bone defects is a need that has not been well met to date. We have previously found that adenosine, acting via A2A receptors (A2AR) promotes wound healing and inhibits inflammatory osteolysis and hypothesized that A2AR might be a novel target to promote bone regeneration. Therefore, we determined whether direct A2AR stimulation or increasing endogenous adenosine concentrations via purine transport blockade with dipyridamole regulates bone formation. We determined whether coverage of a 3 mm trephine defect in a mouse skull with a collagen scaffold soaked in saline, bone morphogenetic protein-2 (BMP-2; 200 ng), 1 μM CGS21680 (A2AR agonist, EC50 = 160 nM), or 1 μM dipyridamole (EC50 = 32 nM) promoted bone regeneration. Microcomputed tomography examination demonstrated that CGS21680 and dipyridamole markedly enhanced bone regeneration as well as BMP-2 8 wk after surgery (60 ± 2%, 79 ± 2%, and 75 ± 1% bone regeneration, respectively, vs. 32 ± 2% in control, P < 0.001). Blockade by a selective A2AR antagonist (ZM241385, 1 μM) or deletion of A2AR abrogated the effect of CGS21680 and dipyridamole on bone regeneration. Both CGS21680 and dipyridamole treatment increased alkaline phosphatase-positive osteoblasts and diminished tartrate resistance acid phosphatase-positive osteoclasts in the defects. In vivo imaging with a fluorescent dye for new bone formation revealed a strong fluorescent signal in treated animals that was equivalent to BMP-2. In conclusion, stimulation of A2AR by specific agonists or by increasing endogenous adenosine levels stimulates new bone formation as well as BMP-2 and represents a novel approach to stimulating bone regeneration.—Mediero, A., Wilder, T., Perez-Aso, M., Cronstein, B. N. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2. PMID:25573752

  12. [Bone diseases].

    PubMed

    Uebelhart, Brigitte; Rizzoli, René

    2016-01-13

    Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw.

  13. Phytoestrogens and bone.

    PubMed

    Anderson, J J; Garner, S C

    1998-12-01

    Practically all plant foods contain small amounts of the diverse phytoestrogen molecules that have the potential to improve health. Phytoestrogens, especially the soy-derived isoflavones, are receiving great scrutiny as food supplements for the purposes of both enhancing the health of tissues and preventing several common diseases, such as cardiovascular diseases, cancers of reproductive tissues and osteoporosis. Investigations of isoflavones, in particular, have recently become more prominent because of their oestrogenic activities. These actions may be as either partial oestrogen agonists or anti-oestrogens (inhibitors of natural oestrogen activity). For example, the isoflavones of soy, mainly genistein and daidzein, have been shown by at least three different laboratories to conserve bone in ovariectomized rodent models, and they probably have similar conservatory effects in higher mammalian species. Nevertheless, the only positive effects of phytoestrogens on bone observed so far in post-menopausal women have been small and limited to the lumbar vertebrae. Additional information on human studies currently in progress is needed before the efficacy of these preparations in human subjects is known.

  14. Contractile effect of TRPA1 receptor agonists in the isolated mouse intestine.

    PubMed

    Penuelas, Angelica; Tashima, Kimihito; Tsuchiya, Shizuko; Matsumoto, Kenjiro; Nakamura, Tomonori; Horie, Syunji; Yano, Shingo

    2007-12-01

    TRPA1 is a member of the transient receptor potential (TRP) channel family expressed in sensory neurons. The present study focused on the effects of TRPA1 activation on contractile responses in isolated mouse intestine preparations. The jejunum, ileum, and proximal and distal colon were surgically isolated from male ddY mice. Intestinal motility was recorded as changes in isotonic tension. TRPA1, TRPM8, and TRPV1 expressions were examined by reverse transcription-polymerase chain reaction (RT-PCR). A TRPA1 agonist allyl isothiocyanate (AITC) dose-dependently induced contractions in the proximal and distal colon, whereas in the jejunum and ileum, even 100 muM AITC caused very little contraction. Likewise, a TRPA1 and TRPM8 agonist icilin, a TRPA1 agonist allicin, and a TRPV1 agonist capsaicin induced contractions in the colon. However, a TRPM8 agonist menthol induced long-lasting relaxation in the colon. Repeated exposure to AITC produced desensitization of its own contraction in the colon. Moreover, contractions induced by AITC generate cross-desensitization with icilin and capsaicin. Tetrodotoxin completely abolished AITC-induced contractions in the colon, whereas atropine significantly attenuated AITC-induced contractions in the distal colon, but not in the proximal colon. Menthol-induced relaxation in the colon was not inhibited by tetrodotoxin and atropine. RT-PCR analysis revealed the expression of TRPA1 and TRPV1, but not TRPM8, throughout the mouse intestine. These results suggest that TRPA1, but not TRPM8, are functionally expressed in the enteric nervous system throughout the mouse intestine on neurons that may also co-express TRPV1, yet the contractile responses to TRPA1 activation differ depending on their location along the intestine.

  15. Planetary Ices Attenuation Properties

    NASA Astrophysics Data System (ADS)

    McCarthy, Christine; Castillo-Rogez, Julie C.

    In this chapter, we review the topic of energy dissipation in the context of icy satellites experiencing tidal forcing. We describe the physics of mechanical dissipation, also known as attenuation, in polycrystalline ice and discuss the history of laboratory methods used to measure and understand it. Because many factors - such as microstructure, composition and defect state - can influence rheological behavior, we review what is known about the mechanisms responsible for attenuation in ice and what can be inferred from the properties of rocks, metals and ceramics. Since attenuation measured in the laboratory must be carefully scaled to geologic time and to planetary conditions in order to provide realistic extrapolation, we discuss various mechanical models that have been used, with varying degrees of success, to describe attenuation as a function of forcing frequency and temperature. We review the literature in which these models have been used to describe dissipation in the moons of Jupiter and Saturn. Finally, we address gaps in our present knowledge of planetary ice attenuation and provide suggestions for future inquiry.

  16. Generation of attenuation map for MR-based attenuation correction of PET data in the head area employing 3D short echo time MR imaging

    NASA Astrophysics Data System (ADS)

    Khateri, Parisa; Salighe Rad, Hamidreza; Fathi, Anahita; Ay, Mohammad Reza

    2013-02-01

    Attenuation correction is a crucial step to get accurate quantification of Positron Emission Tomography (PET) data. An attenuation map to provide attenuation coefficients at 511 keV can be generated using Magnetic Resonance Images (MRI). One of the main steps involved in MR-based attenuation correction (MRAC) of PET data is to separate bone from air. Low signal intensity of bone in conventional MRI makes it difficult to separate bone from air in the head area, while their attenuation coefficients are very different. In literature, several groups proposed ultrashort echo-time (UTE) sequences to differentiate bone from air [4,5,7], because these sequences are capable of imaging tissues with short T2* relaxation time, such as cortical bone; however, they are difficult to use, expensive and time-consuming. Employing short echo-time (STE) MRI in combination with long echo-time (LTE) MRI, and along with high performance image processing algorithms is a good substitute for UTE-based PET attenuation correction; they are widely available, easy to use, inexpensive and much faster than UTE pulse sequences. In this work, we propose the use of STE sequences along with LTE ones, as well as a dedicated image processing method to differentiate bone from air cavities in the head area by creating contrast between the tissues. Attenuation coefficients at 511 kev, relying on literature [5], will then be assigned to the voxels. Acquisition was performed on a clinical 3T Tim Trio scanner (Siemens Medical Solution, Erlangen, Germany), employing a dual echo sequence. To achieve an optimized protocol with the best result for discrimination of bone and air, two types of acquisitions were performed, with and without fat suppression; the acquisition parameters were as follows: TE=1.21/5 ms, TR=5/17, FA=30, and TE=1.12/3.16 ms, TR=5/5, FA=12 for non-fat-suppressed and fat-suppressed protocol, respectively. Contrast enhancement and tissue segmentation were applied as processing steps, to

  17. Gonadotropin-releasing hormone agonists in the treatment of girls with central precocious puberty.

    PubMed

    Breyer, P; Haider, A; Pescovitz, O H

    1993-09-01

    The onset of puberty before the age of 8 years in a girl is considered precocious. A child who presents with premature sexual development requires a thorough history, physical examination, and appropriate laboratory evaluation. Making the correct diagnosis is crucial to the selection of the appropriate form of therapy and management. Generally, CPP is the result of premature activation of the hypothalamic-pituitary-gonadal axis and can be successfully managed with long-acting GnRH agonists. In addition, GnRH analogue therapy has been shown to be safe, effective, and reversible. Treatment has resulted in a delay in the progression of secondary sexual development, normalization of the growth velocity, slowing of the rate of bone maturation, and an increase in the predicted final adult height. The GnRH agonists are ineffective in the therapy of gonadotropin-independent precocious puberty.

  18. Vortex attenuation flight experiments

    NASA Technical Reports Server (NTRS)

    Barber, M. R.; Hastings, E. C., Jr.; Champine, R. A.; Tymczyszyn, J. J.

    1977-01-01

    Flight tests evaluating the effects of altered span loading, turbulence ingestion, combinations of mass and turbulence ingestion, and combinations of altered span loading turbulance ingestion on trailed wake vortex attenuation were conducted. Span loadings were altered in flight by varying the deflections of the inboard and outboard flaps on a B-747 aircraft. Turbulence ingestion was achieved in flight by mounting splines on a C-54G aircraft. Mass and turbulence ingestion was achieved in flight by varying the thrust on the B-747 aircraft. Combinations of altered span loading and turbulence ingestion were achieved in flight by installing a spoiler on a CV-990 aircraft and by deflecting the existing spoilers on a B-747 aircraft. The characteristics of the attenuated and unattenuated vortexes were determined by probing them with smaller aircraft. Acceptable separation distances for encounters with the attenuated and unattenuated vortexes are presented.

  19. Radiofrequency attenuator and method

    SciTech Connect

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-01-20

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  20. Radiofrequency attenuator and method

    DOEpatents

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-11-10

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3 C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  1. Identification of Selective ERRγ Inverse Agonists.

    PubMed

    Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin

    2016-01-12

    GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  2. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  3. Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway

    PubMed Central

    Ma, Zhi-Gang; Lv, Xiao-Dan; Zhan, Ling-Ling; Chen, Lan; Zou, Qi-Yuan; Xiang, Ji-Qiao; Qin, Jiao-Li; Zhang, Wei-Wei; Zeng, Zhao-Jing; Jin, Hui; Jiang, Hai-Xing; Lv, Xiao-Ping

    2016-01-01

    AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) with human urokinase-type plasminogen activator (uPA) on liver fibrosis, and to investigate the mechanism of gene therapy. METHODS: BMSCs transfected with adenovirus-mediated human urokinase plasminogen activator (Ad-uPA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson’s staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and mRNA expression levels. RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type III were markedly decreased, whereas the levels of serum albumin were increased by uPA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while uPA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area (16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment (12.38% ± 2.27%) and was further reduced by uPA-BMSCs treatment (8.31% ± 1.21%). Both protein and mRNA expression of β-catenin, Wnt4 and Wnt5a was down-regulated in liver tissues following uPA gene modified BMSCs treatment when compared with the model animals. CONCLUSION: Transplantation of uPA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with uPA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt

  4. Bone marrow-derived mesenchymal stem cells attenuate acute liver injury and regulate the expression of fibrinogen-like-protein 1 and signal transducer and activator of transcription 3.

    PubMed

    Zou, Zhuolin; Cai, Yijing; Chen, Yi; Chen, Si; Liu, Liyuan; Shen, Zhonghai; Zhang, Sainan; Xu, Lanman; Chen, Yongping

    2015-08-01

    In recent years, bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to exert extensive therapeutic effects on acute liver injury; however, the underlying mechanisms of these effects have remained to be elucidated. The present study focused on the potential anti-apoptotic and pro-regenerative effects of BMSCs in D-galactosamine (D-Gal) and lipopolysaccharide (LPS)-induced acute liver injury in rats. An experimental rat acute liver injury model was established by intraperitoneal injection of D-Gal (400 mg/kg) and LPS (80 μg/kg). BMSCs and an identical volume of saline were administered via the caudal vein 2 h after the D-Gal and LPS challenge. Subsequently, the serum samples were collected to detect the levels of alanine aminotransferase and aspartate aminotransferase. Hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay and immunohistochemical staining were performed to determine apoptosis, regeneration and histological changes of liver sections. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the protein and mRNA expression levels of fibrinogen-like-protein 1 (FGL1), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), STAT3 and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) in liver tissue samples. The results indicated that intravenous transplantation of BMSCs significantly decreased the levels of alanine aminotransferase and aspartate aminotransferase, and reduced hepatocellular necrosis and inflammatory cell infiltration. Additionally, a terminal deoxynucleotidyl transferase-mediated nick-end labeling assay and immunohistochemical staining revealed that BMSC treatment reduced hepatocyte apoptosis and enhanced liver regeneration. Furthermore, Bcl-2 expression was increased, whilst the protein expression of Bax was reduced. The expression of FGL1 and p-STAT3 were elevated concurrently with the

  5. FXR agonist activity of conformationally constrained analogs of GW 4064

    SciTech Connect

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  6. FXR agonist activity of conformationally constrained analogs of GW 4064.

    PubMed

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

    2009-08-15

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  7. Talking Bones.

    ERIC Educational Resources Information Center

    Johnson, Jaclyn; Kassing, Sharon

    2002-01-01

    Describes cooperation with the Saint Louis Zoo to provide opportunities for elementary school students to learn about bones, how animals move, what they eat, and how much they grow. Uses biofacts which include bones, skulls, and other parts to make the laboratory a hands-on experience for students. (YDS)

  8. Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Chandraratna, Roshantha As; Noelle, Randolph J; Nowak, Elizabeth C

    2016-01-01

    Retinoid x receptors (RXRs) are master regulators that control cell growth, differentiation, and survival and form heterodimers with many other family members. Here we show that treatment with the RXR agonist IRX4204 enhances the differentiation of CD4(+) T cells into inducible regulatory T cells (iTreg) and suppresses the development of T helper (Th) 17 cells in vitro. Furthermore in a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)), treatment with IRX4204 profoundly attenuates both active and Th17-mediated passive disease. In the periphery, treatment with IRX4204 is associated with decreased numbers of CD4(+) T cells that produce pro-inflammatory cytokines. In addition, CD4(+) T cells express decreased levels of Ki-67 and increased expression of CTLA-4. Our findings demonstrate IRX4204 treatment during EAE results in immune modulation and profound attenuation of disease severity. PMID:27158387

  9. Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimmune encephalomyelitis

    PubMed Central

    Chandraratna, Roshantha AS; Noelle, Randolph J; Nowak, Elizabeth C

    2016-01-01

    Retinoid x receptors (RXRs) are master regulators that control cell growth, differentiation, and survival and form heterodimers with many other family members. Here we show that treatment with the RXR agonist IRX4204 enhances the differentiation of CD4+ T cells into inducible regulatory T cells (iTreg) and suppresses the development of T helper (Th) 17 cells in vitro. Furthermore in a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)), treatment with IRX4204 profoundly attenuates both active and Th17-mediated passive disease. In the periphery, treatment with IRX4204 is associated with decreased numbers of CD4+ T cells that produce pro-inflammatory cytokines. In addition, CD4+ T cells express decreased levels of Ki-67 and increased expression of CTLA-4. Our findings demonstrate IRX4204 treatment during EAE results in immune modulation and profound attenuation of disease severity. PMID:27158387

  10. Exercise Regulation of Marrow Fat in the Setting of PPARγ Agonist Treatment in Female C57BL/6 Mice.

    PubMed

    Styner, Maya; Pagnotti, Gabriel M; Galior, Kornelia; Wu, Xin; Thompson, William R; Uzer, Gunes; Sen, Buer; Xie, Zhihui; Horowitz, Mark C; Styner, Martin A; Rubin, Clinton; Rubin, Janet

    2015-08-01

    The contribution of marrow adipose tissue (MAT) to skeletal fragility is poorly understood. Peroxisome proliferator-activated receptor (PPAR)γ agonists, associated with increased fractures in diabetic patients, increase MAT. Here, we asked whether exercise could limit the MAT accrual and increase bone formation in the setting of PPARγ agonist treatment. Eight-week-old female C57BL/6 mice were treated with 20-mg/kg · d rosiglitazone (Rosi) and compared with control (CTL) animals. Exercise groups ran 12 km/d when provided access to running wheels (CTL exercise [CTL-E], Rosi-E). After 6 weeks, femoral MAT (volume of lipid binder osmium) and tibial bone morphology were assessed by microcomputer tomography. Rosi was associated with 40% higher femur MAT volume compared with CTL (P < .0001). Exercise suppressed MAT volume by half in CTL-E mice compared with CTL (P < .01) and 19% in Rosi-E compared with Rosi (P < .0001). Rosi treatment increased fat markers perilipin and fatty acid synthase mRNA by 4-fold (P < .01). Exercise was associated with increased uncoupling protein 1 mRNA expression in both CTL-E and Rosi-E groups (P < .05), suggestive of increased brown fat. Rosi increased cortical porosity (P < .0001) but did not significantly impact trabecular or cortical bone quantity. Importantly, exercise induction of trabecular bone volume was not prevented by Rosi (CTL-E 21% > CTL, P < .05; Rosi-E 26% > Rosi, P < .01). In summary, despite the Rosi induction of MAT extending well into the femoral diaphysis, exercise was able to significantly suppress MAT volume and induce bone formation. Our results suggest that the impact of PPARγ agonists on bone and marrow health can be partially mitigated by exercise. PMID:26052898

  11. Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice.

    PubMed

    Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

    2015-01-01

    Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo.

  12. Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice

    PubMed Central

    Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M.W.; Miyaura, Chisato; Inada, Masaki

    2015-01-01

    Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo. PMID:26155460

  13. PPARα agonist, fenofibrate, ameliorates age-related renal injury.

    PubMed

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Kim, Hyung Wook; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-08-01

    The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney. PMID:27130813

  14. Tritium Attenuation by Distillation

    SciTech Connect

    Wittman, N.E.

    2001-07-31

    The objective of this study was to determine how a 100 Area distillation system could be used to reduce to a satisfactory low value the tritium content of the dilute moderator produced in the 100 Area stills, and whether such a tritium attenuator would have sufficient capacity to process all this material before it is sent to the 400 Area for reprocessing.

  15. Leptin regulates bone formation via the sympathetic nervous system

    NASA Technical Reports Server (NTRS)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

  16. [Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists].

    PubMed

    Jouzeau, Jean-Yves; Moulin, David; Koufany, Meriem; Sebillaud, Sylvie; Bianchi, Arnaud; Netter, Patrick

    2008-01-01

    Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or

  17. PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

    SciTech Connect

    Milton, Flora Aparecida; Cvoro, Aleksandra; Amato, Angelica A.; Sieglaff, Douglas H.; Filgueira, Carly S.; Arumanayagam, Anithachristy Sigamani; Caro Alves de Lima, Maria do; Rocha Pitta, Ivan; Assis Rocha Neves, Francisco de; Webb, Paul

    2015-08-28

    Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation.

  18. Metastatic Bone Disease

    MedlinePlus

    ... Bone Disease cont. Page ( 4 ) MBD vs. Primary Bone Cancer The diagnosis of metastatic bone disease should not ... from an unknown primary carcinoma or a primary bone cancer (sarcoma). For example, if an area of bone ...

  19. Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension.

    PubMed

    García-Álvarez, Ana; Pereda, Daniel; García-Lunar, Inés; Sanz-Rosa, David; Fernández-Jiménez, Rodrigo; García-Prieto, Jaime; Nuño-Ayala, Mario; Sierra, Federico; Santiago, Evelyn; Sandoval, Elena; Campelos, Paula; Agüero, Jaume; Pizarro, Gonzalo; Peinado, Víctor I; Fernández-Friera, Leticia; García-Ruiz, José M; Barberá, Joan A; Castellá, Manuel; Sabaté, Manel; Fuster, Valentín; Ibañez, Borja

    2016-07-01

    Beta-3 adrenergic receptor (β3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of β3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of β3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of β3AR mRNA and the vasodilator response of β3AR agonists in pulmonary arteries. Single intravenous administration of the β3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different β3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. +1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. +1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in β3AR agonists-treated pigs. β3AR was expressed in human pulmonary arteries and β3AR agonists produced vasodilatation. β3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.

  20. Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats

    PubMed Central

    Morani, Aashish S.; Kivell, Bronwyn; Prisinzano, Thomas E.; Schenk, Susan

    2011-01-01

    Our previous work indicated that pretreatment with the selective kappa opioid receptor (KOPr) agonist, U69593, attenuated the ability of priming injections of cocaine to reinstate extinguished cocaine-seeking behavior. The present study expanded these initial tests to include other traditional KOPr agonists, U50488H, spiradoline (SPR), and salvinorin A (Sal A), an active constituent of the plant Salvia divinorum. Following acquisition and stabilization of cocaine self-administration, cocaine-produced drug-seeking was measured. This test was conducted in a single day and comprised an initial phase of self-administration, followed by a phase of extinguished responding. The final phase examined reinstatement of extinguished cocaine self-administration followed by a priming injection of cocaine (20.0 mg/kg, intraperitoneal (I.P.)) in combination with the various KOPr agonists. Cocaine-induced drug-seeking was attenuated by pretreatment with U69593 (0.3 mg/kg, subcutaneous (S.C.)), U50488H (30.0 mg/kg, I.P.), SPR (1.0, 3.0 mg/kg, I.P.) and Sal A (0.3, 1.0 mg/kg, I.P.). Sal A (0.3, 1.0 mg/kg, I.P.) had no effect on operant responding to obtain sucrose reinforcement or on cocaine induced hyperactivity. These findings show that Sal A, like other traditional KOPr agonists attenuates cocaine-induced drug seeking behavior. PMID:19747933

  1. Consequences of Daily Administered Parathyroid Hormone on Myeloma Growth, Bone Disease, and Molecular Profiling of Whole Myelomatous Bone

    PubMed Central

    Pennisi, Angela; Ling, Wen; Li, Xin; Khan, Sharmin; Wang, Yuping; Barlogie, Bart; Shaughnessy, John D.; Yaccoby, Shmuel

    2010-01-01

    Background Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates. Methodology/Principal Findings We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro. Conclusions/Significance We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption

  2. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone.

    PubMed

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang

    2016-09-01

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects. PMID:27369072

  3. Nicotinic agonists modulate basal forebrain control of cortical cerebral blood flow in anesthetized rats.

    PubMed

    Linville, D G; Williams, S; Raszkiewicz, J L; Arneric, S P

    1993-10-01

    Previous studies have indicated that electrical microstimulation of the cholinergic (basal forebrain, BF) elicits profound increases in cortical cerebral blood flow (CBF) that are selectively attenuated by nicotinic receptor antagonists. This study sought to determine whether nicotinic receptor agonists such as (-)-nicotine, and related agents, can enhance the increases in CBF elicited by electrical stimulation of the BF of urethane-anesthetized rats. The magnitude of cortical CBF responses, measured by laser-Doppler flowmetry, increased progressively with higher frequencies (range = 6.25-50 Hz) to a maximum of 248% of control. (-)-Nicotine and (-)-lobeline each further enhanced the responses to BF stimulation, with (-)-nicotine having the most potent effect (up to 350%). (+)-Nicotine and (-)-cotinine were without effect, suggesting stereoselectivity and that the effects were not mediated by the major metabolite of (-)-nicotine. In contrast, (-)-cystisine, another nicotinic receptor agonist, modestly inhibited the BF-elicited increase in CBF suggesting nicotinic receptor subtype selectivity in mediating the response. Arecoline, a potent muscarinic agonist, was without effect suggesting that muscarinic mechanisms are not involved in the mediation of this response. None of the nicotinic agents had overt effects on heart rate or blood pressure in the dose ranges examined. In experiments targeting the site of action of the nicotinically mediated enhancement, (-)-nicotine microinjections into the BF elicited profound increases in cortical CBF, whereas similar injections into the cerebral cortex were without effect suggesting that nicotine receptors mediating CBF increases are localized to the BF.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8229773

  4. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    PubMed

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  5. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  6. Stimulation of a Gs-like G protein in the osteoclast inhibits bone resorption but enhances tartrate-resistant acid phosphatase secretion.

    PubMed

    Moonga, B S; Pazianas, M; Alam, A S; Shankar, V S; Huang, C L; Zaidi, M

    1993-01-29

    Previous studies have demonstrated that G-protein agonists induce quiescence (Q effect) or retraction (R effect) in isolated osteoclasts. We now report the functional effects of such agonists on osteoclastic bone resorption and enzyme release. Exposure of osteoclasts to tetrafluoro-aluminate anions (AlF4-), a universal G protein stimulator, resulted in a marked concentration-dependent inhibition of bone resorption. This was associated with a dramatic increase in the secretion of the osteoclast-specific enzyme, tartrate-resistant acid phosphatase (TRAP). Cholera toxin, a Gs stimulator and a selective Q effect agonist, similarly abolished bone resorption and enhanced TRAP secretion. In contrast, pertussis toxin, a Gi inhibitor and a selective R effect agonist, inhibited bone resorption significantly, but slightly reduced enzyme release. The results suggest an involvement of a Gs-like G protein in TRAP secretion from the osteoclast, possibly through a cyclic AMP-dependent mechanism.

  7. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  8. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  9. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits.

  10. Monitored natural attenuation.

    PubMed

    Jørgensen, Kirsten S; Salminen, Jani M; Björklöf, Katarina

    2010-01-01

    Monitored natural attenuation (MNA) is an in situ remediation technology that relies on naturally occurring and demonstrable processes in soil and groundwater which reduce the mass and concentration of the contaminants. Natural attenuation (NA) involves both aerobic and anaerobic degradation of the contaminants due to the fact that oxygen is used up near the core of the contaminant plume. The aerobic and anaerobic microbial processes can be assessed by microbial activity measurements and molecular biology methods in combination with chemical analyses. The sampling and knowledge on the site conditions are of major importance for the linkage of the results obtained to the conditions in situ. Rates obtained from activity measurements can, with certain limitations, be used in modeling of the fate of contaminants whereas most molecular methods mainly give qualitative information on the microbial community and gene abundances. However, molecular biology methods are fast and describe the in situ communities and avoid the biases inherent to activity assays requiring laboratory incubations.

  11. Fluid dynamic bowtie attenuators

    NASA Astrophysics Data System (ADS)

    Szczykutowicz, Timothy P.; Hermus, James

    2015-03-01

    Fluence field modulated CT allows for improvements in image quality and dose reduction. To date, only 1-D modulators have been proposed, the extension to 2-D modulation is difficult with solid-metal attenuation-based modulators. This work proposes to use liquids and gas to attenuate the x-ray beam which can be arrayed allowing for 2-D fluence modulation. The thickness of liquid and the pressure for a given path length of gas were determined that provided the same attenuation as 30 cm of soft tissue at 80, 100, 120, and 140 kV. Gaseous Xenon and liquid Iodine, Zinc Chloride, and Cerium Chloride were studied. Additionally, we performed some proof-of-concept experiments in which (1) a single cell of liquid was connected to a reservoir which allowed the liquid thickness to be modulated and (2) a 96 cell array was constructed in which the liquid thickness in each cell was adjusted manually. Liquid thickness varied as a function of kV and chemical composition, with Zinc Chloride allowing for the smallest thickness; 1.8, 2.25, 3, and 3.6 cm compensated for 30 cm of soft tissue at 80, 100, 120, and 140 kV respectively. The 96 cell Iodine attenuator allowed for a reduction in both dynamic range to the detector and scatter to primary ratio. Successful modulation of a single cell was performed at 0, 90, and 130 degrees using a simple piston/actuator. The thickness of liquids and the Xenon gas pressure seem logistically implementable within the constraints of CBCT and diagnostic CT systems.

  12. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants.

    PubMed

    Willis, Daniel N; Liu, Boyi; Ha, Michael A; Jordt, Sven-Eric; Morris, John B

    2011-12-01

    Menthol, the cooling agent in peppermint, is added to almost all commercially available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacological actions affecting smoking behavior. Using plethysmography, we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concentration (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concentrations sufficient for activation of sensory TRP channels. These experiments demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities. PMID:21903934

  13. Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity.

    PubMed

    Gupta, Achla; Gomes, Ivone; Bobeck, Erin N; Fakira, Amanda K; Massaro, Nicholas P; Sharma, Indrajeet; Cavé, Adrien; Hamm, Heidi E; Parello, Joseph; Devi, Lakshmi A

    2016-05-24

    Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10- to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects. PMID:27162327

  14. TLR3 and TLR9 Agonists Improve Postexposure Vaccination Efficacy of Live Smallpox Vaccines

    PubMed Central

    Israely, Tomer; Erez, Noam; Politi, Boaz; Waner, Trevor; Lustig, Shlomo; Paran, Nir

    2014-01-01

    Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV), a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C) even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs) were less protective than the TLR3 agonist poly(I:C). We show that activation of type 1 IFN by poly(I:C) and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination. PMID:25350003

  15. Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death.

    PubMed

    Smith, Joshua A; Das, Arabinda; Butler, Jonathan T; Ray, Swapan K; Banik, Naren L

    2011-09-01

    Inflammation is an important pathogenic mechanism in many neurodegenerative disorders. Activated microglia play a pivotal role in releasing pro-inflammatory factors including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) for inducing inflammation. While microglia mediated inflammation is essential in maintaining CNS homeostasis, chronic inflammation results in activation of proteases for cell death. Here, we examined the effect of PPT (estrogen receptor α agonist), DPN (estrogen receptor β agonist), and estrogen on rat primary microglia following exposure to lipopolysaccharide (LPS). Exposure of microglia to LPS (200 ng/ml) for 24 h induced cell death. After LPS toxicity for 15 min, microglia were treated with 25 nM PPT, 25 nM DPN, or 100 nM estrogen that prevented cell death by attenuating the release of IL-1α, IL-1β, TNF-α, and COX-2. Treatment of cells with 100 nM fulvestrant (estrogen receptor antagonist) prior to addition of PPT, DPN, or estrogen significantly decreased their ability to prevent cell death, indicating involvement of estrogen receptor (ER) in providing PPT, DPN, or estrogen mediated cytoprotection. Reverse transcriptase polymerase chain reaction (RT-PCR) analyses showed alterations in mRNA expression of Bax, Bcl-2, calpain, and calpastatin during apoptosis. We also examined mRNA expression of ERβ and ERα following exposure of microglia to LPS and subsequent treatment with PPT, DPN, or estrogen. We found that estrogen or estrogen receptor agonists upregulated expression of ERs. Overall, results indicate that estrogen receptor agonist or estrogen uses a receptor mediated pathway to protect microglia from LPS toxicity.

  16. Eomesodermin is required for antitumor immunity mediated by 4-1BB-agonist immunotherapy

    PubMed Central

    Song, Chang; Sadashivaiah, Kavitha; Furusawa, Aki; Davila, Eduardo; Tamada, Koji; Banerjee, Arnob

    2014-01-01

    CD8+ T cells in progressing tumors frequently fail to mount an effective antitumor response often in association with the expression of inhibitory receptors, including programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (Lag3). Using a lymphoma tumor model, we demonstrate that tumor-infiltrating CD8+ T cells from growing tumors co-express inhibitory receptors and co-stimulatory receptors, including 4-1BB (TNFRSF9) as well as high levels of 2 transcription factors, Eomesodermin (Eomes) and T-bet (Tbx21), critical determinants of CD8+ T cell fate. Immunotherapy with an agonistic anti-4–1-BB antibody altered the ratio of Eomes to T-bet expression in tumor-infiltrating CD8+ T cells by increasing Eomes and decreasing T-bet expression. 4-1BB-agonist immunotherapy was also associated with downregulated expression of the inhibitory receptors PD-1 and Lag3 on tumor-infiltrating CD8+ T cells, a molecular phenotype associated with subsequent attenuation of tumor growth. Furthermore, 4-1BB-agonist immunotherapy failed to effect tumor progression in mice with Eomes deficient T cells. However, upon resumption of tumor growth, tumor-infiltrating CD8+ T cells from treated animals continued to express high levels of Eomes as well as elevated levels of the inhibitory receptors PD-1 and Lag3. Our data suggest that tumor-infiltrating CD8+ T cells are poised between activation and inhibition as dictated by expression of both co-stimulatory receptors and inhibitory receptors and demonstrate that T cell expression of Eomes is necessary, but not sufficient, for efficacious 4-1BB-agonist-mediated immunotherapy. PMID:24790793

  17. TLR3 and TLR9 agonists improve postexposure vaccination efficacy of live smallpox vaccines.

    PubMed

    Israely, Tomer; Melamed, Sharon; Achdout, Hagit; Erez, Noam; Politi, Boaz; Waner, Trevor; Lustig, Shlomo; Paran, Nir

    2014-01-01

    Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV), a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C) even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs) were less protective than the TLR3 agonist poly(I:C). We show that activation of type 1 IFN by poly(I:C) and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination.

  18. Control algorithms for dynamic attenuators

    SciTech Connect

    Hsieh, Scott S.; Pelc, Norbert J.

    2014-06-15

    Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not requirea priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

  19. Therapeutic use of gonadotropin-releasing hormone agonists in polycystic ovarian syndrome.

    PubMed

    Markussis, V; Goni, M H; Tolis, G

    1993-05-28

    Polycystic ovarian syndrome is a heterogeneous disorder characterized by abnormal function of the hypothalamic-pituitary-gonadal axis, excessive production of androgens, aberrant intermediary metabolism, and structural changes in ovarian morphology. Long-term administration of the GnRH agonistic analogues brings about pituitary gonadotroph down-regulation after an initial period of stimulation of FSH/LH release. The resulting decrease in LH output and ovarian androgen production exerts beneficial effects on the clinical and biochemical parameters of the PCO syndrome. Ovarian volume and stroma usually decrease, but the results of treatment are not permanent, since relapse of the syndrome is usually observed a few months after cessation of the agonist. There are no serious side effects, and a small decrease in bone mineral content is recovered after discontinuation of the treatment. Possible indications for this regime include patients with very large ovaries and resistant hyperandrogenemia. On the other hand, the use of GnRH agonists in the preparation of PCOS patients for ovulation induction is already established.

  20. Agonist antibody that induces human malignant cells to kill one another

    PubMed Central

    Yea, Kyungmoo; Zhang, Hongkai; Xie, Jia; Jones, Teresa M.; Lin, Chih-Wei; Francesconi, Walter; Berton, Fulvia; Fallahi, Mohammad; Sauer, Karsten; Lerner, Richard A.

    2015-01-01

    An attractive, but as yet generally unrealized, approach to cancer therapy concerns discovering agents that change the state of differentiation of the cancer cells. Recently, we discovered a phenomenon that we call “receptor pleiotropism” in which agonist antibodies against known receptors induce cell fates that are very different from those induced by the natural agonist to the same receptor. Here, we show that one can take advantage of this phenomenon to convert acute myeloblastic leukemic cells into natural killer cells. Upon induction with the antibody, these leukemic cells enter into a differentiation cascade in which as many as 80% of the starting leukemic cells can be differentiated. The antibody-induced killer cells make large amounts of perforin, IFN-γ, and granzyme B and attack and kill other members of the leukemic cell population. Importantly, induction of killer cells is confined to transformed cells, in that normal bone marrow cells are not induced to form killer cells. Thus, it seems possible to use agonist antibodies to change the differentiation state of cancer cells into those that attack and kill other members of the malignant clone from which they originate. PMID:26487683

  1. Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

    PubMed Central

    Simpson-Haidaris, P. J.; Pollock, S. J.; Ramon, S.; Guo, N.; Woeller, C. F.; Feldon, S. E.; Phipps, R. P.

    2010-01-01

    The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-γ agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARγ agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARγ agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARγ and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow. PMID:20204067

  2. Ultrasonic attenuation in pearlitic steel.

    PubMed

    Du, Hualong; Turner, Joseph A

    2014-03-01

    Expressions for the attenuation coefficients of longitudinal and transverse ultrasonic waves are developed for steel with pearlitic microstructure. This type of lamellar duplex microstructure influences attenuation because of the lamellar spacing. In addition, longitudinal attenuation measurements were conducted using an unfocused transducer with 10 MHz central frequency on the cross section of a quenched railroad wheel sample. The dependence of longitudinal attenuation on the pearlite microstructure is observed from the changes of longitudinal attenuation from the quenched tread surface to deeper locations. The results show that the attenuation value is lowest and relatively constant within the quench depth, then increases linearly. The experimental results demonstrate a reasonable agreement with results from the theoretical model. Ultrasonic attenuation provides an important non-destructive method to evaluate duplex microstructure within grains which can be implemented for quality control in conjunction with other manufacturing processes.

  3. Bone marrow transplant

    MedlinePlus

    Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; Umbilical ...

  4. Successful Improvement of Metabolic Disorders, Including Osteopenia, by a Dopamine Agonist in a Male Patient with Macro-Prolactinoma

    PubMed Central

    Takeno, Ayumu; Yamamoto, Masahiro; Okazaki, Kyoko; Yamaguchi, Toru; Toshitsugu, Sugimoto

    2016-01-01

    Patient: Male, 43 Final Diagnosis: Prolactinoma Symptoms: — Medication: — Clinical Procedure: Treatments by a dopamine agonist Specialty: Endocrinology and Metabolic Objective: Unknown ethiology Background: Bone metabolic disorders in patients with prolactinoma have not been fully characterized. The case presented herein illustrates potential causal associations between prolactinoma and osteopenia, with a reversal of the disorder by treatment with a dopamine agonist. Case Report: A 43-year-old male with macro-prolactinoma [PRL 7770 ng/mL] was referred to our hospital. He suffered was overweight [body mass index (BMI) 29.4 kg/m2] and had impaired glucose tolerance, hypertriglyceridemia, and osteopenia. The patient was administered cabergoline, a dopamine D2 receptor agonist, and the dose was gradually increased up to 9 mg/week over the period of 1 year. One year later, the patient’s serum PRL levels decreased to within the normal range (19.1 ng/mL), and his pituitary tumor mass decreased to 1/4 of its initial size. His weight, dyslipidemia, and impaired glucose tolerance improved within 1 year. A marked increase in the bone mineral density (BMD) at the second to fourth lumbar spine (from 0.801 g/cm2 to 0.870 g/cm2, +8.6%) and at the femoral neck (from 0.785 g/cm2 to 0.864 g/cm2, +10.1%) were observed despite the presence of unresolved hypogonadism. Conclusions: Treatments with dopamine agonists represent a beneficial strategy for patients with prolactinoma accompanied with bone loss, in addition to their established efficacy in shrinkage of the size of pituitary tumors, normalization of PRL levels, and improvement of metabolic disorders. PMID:26971354

  5. Ultrasound attenuation as a quantitative measure of fracture healing

    NASA Astrophysics Data System (ADS)

    Gheduzzi, Sabina; Humphrey, Victor F.; Dodd, Simon P.; Cunningham, James L.; Miles, Anthony W.

    2004-10-01

    The monitoring of fracture healing still relies upon the judgment of callus formation and on the manual assessment of the stiffness of the fracture. A diagnostic tool capable of quantitatively measuring healing progression of a fracture would allow the fine-tuning of the treatment regime. Ultrasound attenuation measurements were adopted as a possible method of assessing the healing process in human long bones. The method involves exciting ultrasonic waves at 200 kHz in the bone and measuring the reradiation along the bone and across the fracture zone. Seven cadaveric femora were tested in vitro in intact form and after creating a transverse fracture by sawing through the cortex. The effects of five different fracture types were investigated. A partial fracture, corresponding to a 50% cut through the cortex, a closed fracture, and fractures of widths varying between 1, 2, and 4 mm were investigated. The introduction of a fracture was found to produce a dramatic effect on the amplitude of the signal. Ultrasound attenuation was found to be sensitive to the presence of a fracture, even when the fracture was well reduced. It would therefore appear feasible to adopt attenuation across a fracture as a quantitative measurement of fracture healing.

  6. Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression.

    PubMed

    Girer, Nathaniel G; Murray, Iain A; Omiecinski, Curtis J; Perdew, Gary H

    2016-07-15

    The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor α (PPARα), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist-activated AHR impairs PPARα-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARα-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling. PMID:27226639

  7. Digitally Controlled Beam Attenuator

    NASA Astrophysics Data System (ADS)

    Peppler, W. W.; Kudva, B.; Dobbins, J. T.; Lee, C. S.; Van Lysel, M. S.; Hasegawa, B. H.; Mistretta, C. A.

    1982-12-01

    In digital fluorographic techniques the video camera must accommodate a wide dynamic range due to the large variation in the subject thickness within the field of view. Typically exposure factors and the optical aperture are selected such that the maximum video signal is obtained in the most transmissive region of the subject. Consequently, it has been shown that the signal-to-noise ratio is severely reduced in the dark regions. We have developed a prototype digital beam attenuator (DBA) which will alleviate this and some related problems in digital fluorography. The prototype DBA consists of a 6x6 array of pistons which are individually controlled. A membrane containing an attenuating solu-tion of (CeC13) in water and the piston matrix are placed between the x-ray tube and the subject. Under digital control the pistons are moved into the attenuating material in order to adjust the beam intensity over each of the 36 cells. The DBA control unit which digitizes the image during patient positioning will direct the pistons under hydraulic control to produce a uniform x-ray field exiting the subject. The pistons were designed to produce very little structural background in the image. In subtraction studies any structure would be cancelled. For non-subtraction studies such as cine-cardiology we are considering higher cell densities (eg. 64x64). Due to the narrow range of transmission provided by the DBA, in such studies ultra-high contrast films could be used to produce a high resolution quasi-subtraction display. Additional benefits of the DBA are: 1) reduced dose to the bright image areas when the dark areas are properly exposed. 2) improved scatter and glare to primary ratios, leading to improved contrast in the dark areas.

  8. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    SciTech Connect

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  9. [Bone transplant].

    PubMed

    San Julián, M; Valentí, A

    2006-01-01

    We describe the methodology of the Bone and Soft Tissue Bank, from extraction and storage until use. Since the year 1986, with the creation of the Bone Bank in the University Clinic of Navarra, more than 3,000 grafts have been used for very different types of surgery. Bone grafts can be classified into cortical and spongy; the former are principally used in surgery to save tumour patients, in large post-traumatic reconstructions and in replacement surgery where there are massive bone defects and a structural support is required. The spongy grafts are the most used due to their numerous indications; they are especially useful in filling cavities that require a significant quantity of graft when the autograft is insufficient, or as a complement. They are also of special help in treating fractures when there is bone loss and in the treatment of delays in consolidation and pseudoarthrosis in little vascularized and atrophic zones. They are also used in prosthetic surgery against the presence of cavity type defects. Allografts of soft tissues are specially recognised in multiple ligament injuries that require reconstructions. Nowadays, the most utilised are those employed in surgery of the anterior cruciate ligament although they can be used for filling any ligament or tendon defect. The principal difficulties of the cortical allografts are in the consolidation of the ends with the bone itself and in tumour surgery, given that these are patients immunodepressed by the treatment, the incidence of infection is increased with respect to spongy grafts and soft tissues, which is irrelevant. In short, the increasingly widespread use of allografts is an essential therapeutic weapon in orthopaedic surgery and traumatology. It must be used by expert hands.

  10. [Bone transplant].

    PubMed

    San Julián, M; Valentí, A

    2006-01-01

    We describe the methodology of the Bone and Soft Tissue Bank, from extraction and storage until use. Since the year 1986, with the creation of the Bone Bank in the University Clinic of Navarra, more than 3,000 grafts have been used for very different types of surgery. Bone grafts can be classified into cortical and spongy; the former are principally used in surgery to save tumour patients, in large post-traumatic reconstructions and in replacement surgery where there are massive bone defects and a structural support is required. The spongy grafts are the most used due to their numerous indications; they are especially useful in filling cavities that require a significant quantity of graft when the autograft is insufficient, or as a complement. They are also of special help in treating fractures when there is bone loss and in the treatment of delays in consolidation and pseudoarthrosis in little vascularized and atrophic zones. They are also used in prosthetic surgery against the presence of cavity type defects. Allografts of soft tissues are specially recognised in multiple ligament injuries that require reconstructions. Nowadays, the most utilised are those employed in surgery of the anterior cruciate ligament although they can be used for filling any ligament or tendon defect. The principal difficulties of the cortical allografts are in the consolidation of the ends with the bone itself and in tumour surgery, given that these are patients immunodepressed by the treatment, the incidence of infection is increased with respect to spongy grafts and soft tissues, which is irrelevant. In short, the increasingly widespread use of allografts is an essential therapeutic weapon in orthopaedic surgery and traumatology. It must be used by expert hands. PMID:16998521

  11. Agonist-Directed Desensitization of the β2-Adrenergic Receptor

    PubMed Central

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

    2011-01-01

    The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

  12. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  13. Bone Marrow Transplantation

    MedlinePlus

    Bone marrow is the spongy tissue inside some of your bones, such as your hip and thigh bones. ... platelets, which help the blood to clot. A bone marrow transplant is a procedure that replaces a person's ...

  14. Genetics of Bone Density

    MedlinePlus

    ... study linked 32 novel genetic regions to bone mineral density. The findings may help researchers understand why ... or treating osteoporosis. Bones are made of a mineral and protein scaffold filled with bone cells. Bone ...

  15. Bone biopsy (image)

    MedlinePlus

    A bone biopsy is performed by making a small incision into the skin. A biopsy needle retrieves a sample of bone and it ... examination. The most common reasons for bone lesion biopsy are to distinguish between benign and malignant bone ...

  16. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  17. Deregulation of bone forming cells in bone diseases and anabolic effects of strontium-containing agents and biomaterials.

    PubMed

    Tan, Shuang; Zhang, Binbin; Zhu, Xiaomei; Ao, Ping; Guo, Huajie; Yi, Weihong; Zhou, Guang-Qian

    2014-01-01

    Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium effects on bone has led to its expected application in a variety of biomaterial scaffolds used in tissue engineering strategies aiming at bone repairing and regeneration. While summarizing the recent progress in these respects, this review also proposes the new approaches such as systems biology in order to reveal new insights in the pathology of osteoporosis as well as possible discovery of new therapies. PMID:24800251

  18. Deregulation of Bone Forming Cells in Bone Diseases and Anabolic Effects of Strontium-Containing Agents and Biomaterials

    PubMed Central

    Tan, Shuang; Zhang, Binbin; Zhu, Xiaomei; Ao, Ping; Guo, Huajie; Yi, Weihong; Zhou, Guang-Qian

    2014-01-01

    Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium effects on bone has led to its expected application in a variety of biomaterial scaffolds used in tissue engineering strategies aiming at bone repairing and regeneration. While summarizing the recent progress in these respects, this review also proposes the new approaches such as systems biology in order to reveal new insights in the pathology of osteoporosis as well as possible discovery of new therapies. PMID:24800251

  19. Deregulation of bone forming cells in bone diseases and anabolic effects of strontium-containing agents and biomaterials.

    PubMed

    Tan, Shuang; Zhang, Binbin; Zhu, Xiaomei; Ao, Ping; Guo, Huajie; Yi, Weihong; Zhou, Guang-Qian

    2014-01-01

    Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium effects on bone has led to its expected application in a variety of biomaterial scaffolds used in tissue engineering strategies aiming at bone repairing and regeneration. While summarizing the recent progress in these respects, this review also proposes the new approaches such as systems biology in order to reveal new insights in the pathology of osteoporosis as well as possible discovery of new therapies.

  20. Neuroprotective action of group I metabotropic glutamate receptor agonists against oxygen-glucose deprivation-induced neuronal death.

    PubMed

    Kalda, A; Kaasik, A; Vassiljev, V; Pokk, P; Zharkovsky, A

    2000-01-24

    The metabotropic glutamate receptor (mGluR) non-selective agonist (1S,3R)-1-aminocycloheptane-trans-1,3-dicarboxylic acid [(1S, 3R)ACPD] and group I selective receptor agonist 3, 5-dihydrophenylglycine (DHPG) effectively attenuated oxygen-glucose deprivation (OGD)-induced death of the cultured cerebellar granule cells. Furthermore, (1S,3R)ACPD (100 microM) reduced the number of apoptotic cells. Antiapoptotic action of (1S,3R)ACPD was prevented by the group I selective antagonist (RS)-1-aminoindan-1, 5-dicarboxylic acid (AIDA, 100 microM) and protein kinase C (PKC) inhibitor bisindolylmaleimide (BMI, 1 microM).

  1. β-Arrestin-Selective G Protein-Coupled Receptor Agonists Engender Unique Biological Efficacy in Vivo

    PubMed Central

    Gesty-Palmer, Diane; Yuan, Ling; Martin, Bronwen; Wood, William H.; Lee, Mi-Hye; Janech, Michael G.; Tsoi, Lam C.; Zheng, W. Jim; Maudsley, Stuart

    2013-01-01

    Biased G protein-coupled receptor agonists are orthosteric ligands that possess pathway-selective efficacy, activating or inhibiting only a subset of the signaling repertoire of their cognate receptors. In vitro, d-Trp12,Tyr34-bPTH(7–34) [bPTH(7–34)], a biased agonist for the type 1 PTH receptor, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, both bPTH(7–34) and the conventional agonist hPTH(1–34) stimulate anabolic bone formation. To understand how two PTH receptor ligands with markedly different in vitro efficacy could elicit similar in vivo responses, we analyzed transcriptional profiles from calvarial bone of mice treated for 8 wk with vehicle, bPTH(7–34) or hPTH(1–34). Treatment of wild-type mice with bPTH(7–34) primarily affected pathways that promote expansion of the osteoblast pool, notably cell cycle regulation, cell survival, and migration. These responses were absent in β-arrestin2-null mice, identifying them as downstream targets of β-arrestin2-mediated signaling. In contrast, hPTH(1–34) primarily affected pathways classically associated with enhanced bone formation, including collagen synthesis and matrix mineralization. hPTH(1–34) actions were less dependent on β-arrestin2, as might be expected of a ligand capable of G protein activation. In vitro, bPTH(7–34) slowed the rate of preosteoblast proliferation, enhanced osteoblast survival when exposed to an apoptotic stimulus, and stimulated cell migration in wild-type, but not β-arrestin2-null, calvarial osteoblasts. These results suggest that bPTH(7–34) and hPTH(1–34) affect bone mass in vivo through predominantly separate genomic mechanisms created by largely distinct receptor-signaling networks and demonstrate that functional selectivity can be exploited to change the quality of G protein-coupled receptor efficacy. PMID:23315939

  2. BONE BANKS

    PubMed Central

    de Alencar, Paulo Gilberto Cimbalista; Vieira, Inácio Facó Ventura

    2015-01-01

    Bone banks are necessary for providing biological material for a series of orthopedic procedures. The growing need for musculoskeletal tissues for transplantation has been due to the development of new surgical techniques, and this has led to a situation in which a variety of hospital services have been willing to have their own source of tissue for transplantation. To increase the safety of transplanted tissues, standards for bone bank operation have been imposed by the government, which has limited the number of authorized institutions. The good performance in a bone bank depends on strict control over all stages, including: formation of well-trained harvesting teams; donor selection; conducting various tests on the tissues obtained; and strict control over the processing techniques used. Combination of these factors enables greater scope of use and numbers of recipient patients, while the incidence of tissue contamination becomes statistically insignificant, and there is traceability between donors and recipients. This paper describes technical considerations relating to how a bone bank functions, the use of grafts and orthopedic applications, the ethical issues and the main obstacles encountered. PMID:27026958

  3. Ultrasonic Attenuation in Zircaloy-4

    SciTech Connect

    Gomez, M.P.; Banchik, A.D.; Lopez Pumarega, M.I.; Ruzzante, J.E.

    2005-04-09

    In this work the relationship between Zircaloy-4 grain size and ultrasonic attenuation behavior was studied for longitudinal waves in the frequency range of 10-90 MHz. The attenuation was analyzed as a function of frequency for samples with different mechanical and heat treatments having recrystallized and Widmanstatten structures with different grain size. The attenuation behavior was analyzed by different scattering models, depending on grain size, wavelength and frequency.

  4. Chopping-Wheel Optical Attenuator

    NASA Technical Reports Server (NTRS)

    Leviton, Douglas B.

    1988-01-01

    Star-shaped rotating chopping wheel provides adjustable time-averaged attenuation of narrow beam of light without changing length of optical path or spectral distribution of light. Duty cycle or attenuation factor of chopped beam controlled by adjusting radius at which beam intersects wheel. Attenuation factor independent of wavelength. Useful in systems in which chopping frequency above frequency-response limits of photodetectors receiving chopped light. Used in systems using synchronous detection with lock-in amplifiers.

  5. Bone acquisition during adolescence in athletes.

    PubMed

    Markou, Kostas B; Theodoropoulou, Anastasia; Tsekouras, Athanasios; Vagenakis, Apostolos G; Georgopoulos, Neoklis A

    2010-09-01

    Bone mass (BM) and skeletal size are similar in prepubertal girls and boys and double between the onset of puberty and early adult life. Sex steroids are responsible for the maturation in human skeleton, as well as for the sexual dimorphism, observed after the onset of puberty. Physical activity in childhood is critical for maximizing bone growth and thus for preventing osteoporosis during older age. Therefore, it constitutes the most effective prevention strategy available. In athletes, high-impact loading activities have been shown to improve BM, whereas in sports requiring a lean somatotype (therefore leading to a negative energy balance), the delay in skeletal maturation and pubertal development predisposes athletes to osteopenia and osteoporosis. Although the early onset of training, the continuous intensive exercise and its long duration attenuate bone acquisition, the excess mechanical load to which these athletes are exposed from a young age exerts beneficial effects on bone formation that lead to a positive net-effect on BM.

  6. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

    Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K.; Sica, Gabriel L.; Corsino, Patrick E.; Zhou, Jia; Ding, Chunyong; White, Mark A.; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2014-01-01

    Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here, we employed the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite. Three compounds, small molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumor growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anti-cancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

  7. Effects of cod bone gelatin on bone metabolism and bone microarchitecture in ovariectomized rats.

    PubMed

    Han, XiaoLong; Xu, YaJun; Wang, JunBo; Pei, XinRong; Yang, RuiYue; Li, Ning; Li, Yong

    2009-05-01

    Several animal studies have showed that gelatin may be effective for minimizing bone loss in OVX rats with established osteopenia. To gain insight into how cod bone gelatin administration affects bone loss after ovariectomy, studies were carried out focusing on bone quality and the molecular mechanisms. Eighty-four female rats were ovariectomized, 12 sham-operated, divided into six groups of 12 each and treated one week after ovariectomy either with vehicle or cod bone gelatin (0.375, 0.75, 1.5, 3, 6 mg/kg body weight) for 90 days. Bone densitometry, microCT analysis, real-time PCR analysis and biochemical analysis were used at the end of the study. After 90 days, BMD of proximal tibia and femoral neck decreased in OVX rats, whereas the loss of BMD in those regions was prevented at 3 g/kg (P<0.05). However, the BMD of midshaft femurs showed no significant differences. BV/TV, Tb.N. and Tb.Th. in the 3 g/kg group were, respectively, 30.4% (P<0.05), 145.5% (P<0.05) and 81.5% (P<0.05) higher than in the OVX group. A significant decrease was detected in urine CTX, NTX and DPD, suggesting decreased bone resorption. Treatment with 3 g/kg and 6 g/kg cod bone gelatin attenuated the increase in serum IL-1beta, IL-6 and TNF-alpha observed in the OVX group. Real-time PCR showed significantly decreased levels of mRNA expression for RANKL at the dosage of 6 g/kg and the RANKL/OPG mRNA ratio in the 3 g/kg and 6 g/kg group significantly decreased compared to the OVX group (P<0.05). In conclusion, our data confirmed that the cod bone gelatin treatment at 3 g/kg is effective in the prevention of estrogen deficient bone loss by modulating the expression of RANKL and OPG and suppressing the release of proinflammatory cytokines.

  8. Natural attenuation of contaminated soils.

    PubMed

    Mulligan, Catherine N; Yong, Raymond N

    2004-06-01

    Natural attenuation is increasing in use as a low cost means of remediating contaminated soil and groundwater. Modelling of contaminant migration plays a key role in evaluating natural attenuation as a remediation option and in ensuring that there will be no adverse impact on humans and the environment. During natural attenuation, the contamination must be characterized thoroughly and monitored through the process. In this paper, attenuation mechanisms for both organic and inorganic contaminants, use of models and protocols, role of monitoring and field case studies will be reviewed.

  9. Effects of the Trace Amine Associated Receptor 1 Agonist RO5263397 on Abuse-Related Behavioral Indices of Methamphetamine in Rats

    PubMed Central

    Jing, Li; Zhang, Yanan

    2015-01-01

    Background: Methamphetamine is a major drug of abuse with no effective pharmacotherapy available. Trace amine associated receptor 1 is implicated in cocaine addiction and represents a potential therapeutic target. However, the effects of trace amine associated receptor 1 agonists on addiction-related behavioral effects of methamphetamine are unknown. Methods: This study examined the effects of a trace amine associated receptor 1 agonist RO5263397 on methamphetamine-induced behavioral sensitization, methamphetamine self-administration, cue- and methamphetamine-induced reinstatement of drug seeking, and cue-induced reinstatement of sucrose-seeking behaviors in rats. Male Sprague-Dawley rats were used to examine the effects of methamphetamine alone and in combination with the trace amine associated receptor 1 agonist RO5263397 (3.2–10mg/kg). Results: RO5263397 dose-dependently attenuated the expression of behavioral sensitization to methamphetamine, reduced methamphetamine self-administration, and decreased both cue- and a priming dose of methamphetamine-induced reinstatement of drug-seeking behaviors. However, RO5263397 did not alter cue-induced reinstatement of sucrose-seeking behavior. Conclusions: Taken together, trace amine associated receptor 1 agonists attenuate some abuse-related behavioral effects of methamphetamine, strongly suggesting that drugs activating trace amine associated receptor 1 may be potentially useful for the treatment of methamphetamine addiction and warrant further studies. PMID:25522401

  10. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    PubMed Central

    Meng, Jingru; Ma, Xue; Wang, Ning; Jia, Min; Bi, Long; Wang, Yunying; Li, Mingkai; Zhang, Huinan; Xue, Xiaoyan; Hou, Zheng; Zhou, Ying; Yu, Zhibin; He, Gonghao; Luo, Xiaoxing

    2016-01-01

    Summary Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs), but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis. PMID:26947974

  11. Glucocorticoids, bone and energy metabolism.

    PubMed

    Cooper, Mark S; Seibel, Markus J; Zhou, Hong

    2016-01-01

    Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated with serious clinical features including altered body composition and the development of insulin resistance, impaired glucose tolerance and diabetes. It had been assumed that these adverse effects were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are mediated through bone. This article is part of a Special Issue entitled Bone and diabetes. PMID:26051468

  12. Growth Attenuation Therapy.

    PubMed

    Kerruish, Nikki

    2016-01-01

    The "Ashley treatment" has provoked much debate and remains ethically controversial. Given that more children are being referred for such treatment, there remains a need to provide advice to clinicians and ethics committees regarding how to respond to such requests. This article contends that there is one particularly important gap in the existing literature about growth attenuation therapy (GAT) (one aspect of the Ashley treatment): the views of parents of children with profound cognitive impairment (PCI) remain significantly underrepresented. The article attempts to redress this balance by analyzing published accounts both from parents of children who have received GAT and from parents who oppose treatment. Using these accounts, important points are illuminated regarding how parents characterize benefits and harms, and their responsibilities as surrogate decisionmakers. This analysis could contribute to decisionmaking about future requests for GAT and might also have wider relevance to healthcare decisionmaking for children with PCI. PMID:26788948

  13. Fiber optic attenuator

    NASA Technical Reports Server (NTRS)

    Buzzetti, Mike F. (Inventor)

    1994-01-01

    A fiber optic attenuator of the invention is a mandrel structure through which a bundle of optical fibers is wrapped around in a complete circle. The mandrel structure includes a flexible cylindrical sheath through which the bundle passes. A set screw on the mandrel structure impacts one side of the sheath against two posts on the opposite side of the sheath. By rotating the screw, the sheath is deformed to extend partially between the two posts, bending the fiber optic bundle to a small radius controlled by rotating the set screw. Bending the fiber optic bundle to a small radius causes light in each optical fiber to be lost in the cladding, the amount depending upon the radius about which the bundle is bent.

  14. Cannabinoid Receptor 1 Mediates Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury.

    PubMed

    Wang, Lin; Yang, Le; Tian, Lei; Mai, Ping; Jia, Shuangshuang; Yang, Lin; Li, Liying

    2017-01-01

    Cannabinoid receptors (CBs) have been implicated in the pathogenesis of various liver diseases, including liver fibrosis. Our previous studies have demonstrated that after liver injury, mouse bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to the injured liver and differentiate to myofibroblasts, contributing to hepatic fibrogenesis. However, the role of CBs in the homing of BMSCs in liver injury is yet unclear. In this study, we found that both CB1 and CB2 were expressed in BMSCs. Migration assays were performed by transwell chambers. CB1 agonist ACEA promoted the migration of BMSCs, but CB2 agonist JWH133 had no effect. Pharmacological or genetic ablation of CB1 reduced ACEA-induced migration, whereas CB2 did not. Moreover, activation of CB1 increased active GTP-bound Rac1, RhoA, and Cdc42 protein levels. The elevated GTP-bound Rac1 and RhoA protein levels were decreased by CB1 antagonist AM281 treatment, but not Cdc42. In addition, ACEA-induced migration was suppressed by NSC23766 (Rac1 inhibitor) or C3 transferase (RhoA inhibitor), whereas MLS-573151 (Cdc42 inhibitor) had no effect. Consistent with these data, Rac1 or RhoA knock-down significantly blocked CB1-mediated migration. Meanwhile, CB1-mediated migration was associated with cytoskeletal remodeling. In vivo, administration of CB1 antagonist AM281 markedly inhibited the recruitment of BMSCs to the injured liver using fluorescence-activated cell sorting. Furthermore, blockade of CB1 significantly attenuated liver fibrosis. In conclusion, our results suggest that CB1 plays a crucial role in liver fibrosis through mediating the homing of BMSCs to damaged liver, which may provide new insight into the pathogenesis and treatment of liver fibrosis. J. Cell. Physiol. 232: 110-121, 2017. © 2016 Wiley Periodicals, Inc.

  15. Bone image segmentation.

    PubMed

    Liu, Z Q; Liew, H L; Clement, J G; Thomas, C D

    1999-05-01

    Characteristics of microscopic structures in bone cross sections carry essential clues in age determination in forensic science and in the study of age-related bone developments and bone diseases. Analysis of bone cross sections represents a major area of research in bone biology. However, traditional approaches in bone biology have relied primarily on manual processes with very limited number of bone samples. As a consequence, it is difficult to reach reliable and consistent conclusions. In this paper we present an image processing system that uses microstructural and relational knowledge present in the bone cross section for bone image segmentation. This system automates the bone image analysis process and is able to produce reliable results based on quantitative measurements from a large number of bone images. As a result, using large databases of bone images to study the correlation between bone structural features and age-related bone developments becomes feasible.

  16. Suicide Risk: Amplifiers and Attenuators.

    ERIC Educational Resources Information Center

    Plutchik, Robert; Van Praag, Herman M.

    1994-01-01

    Attempts to integrate findings on correlates of suicide and violent risk in terms of a theory called a two-stage model of countervailing forces, which assumes that the strength of aggressive impulses is modified by amplifiers and attenuators. The vectorial interaction of amplifiers and attenuators creates an unstable equilibrium making prediction…

  17. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  18. GLP-1 agonist treatment: implications for diabetic retinopathy screening.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Hariman, Christian; Walker, Adrian B; Varughese, George I

    2011-12-01

    Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. PMID:21906831

  19. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  20. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K(+), and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs.

  1. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K, and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs. PMID:27110632

  2. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K(+), and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs. PMID:26567724

  3. Cadmium content of human cancellous bone

    SciTech Connect

    Knuuttila, M.; Lappalainen, R.; Olkkonen, H.; Lammi, S.; Albava, E.M.

    1982-09-01

    The cadmium content of human cancellous bone was related to age, sex, bone loss, physical properties, and elemental composition. Bone specimens from the anterior iliac crest were collected from 88 cadavers with a normal mineral status, and from 50 cadavers which had bone loss from chronic diseases and immobilization. The element concentrations were analyzed using atomic absorption spectrophotometry. Bone fluoride levels were determined with the ion specific electrode, the mineral density with the gamma ray attenuation method, and the compressive strength with a strain transducer. The data were analyzed using multiple linear regression analysis. The mean cadmium content of 0.22 +/- 0.16 ..mu..g/g dry weight (+/- SD) in the samples did not change with age and its content was slightly greater in males than in females. Furthermore, no statistically significant relationship was found in cadmium content to bone loss changes or to the calcium content of bone. The cadmium content had a high statistically significant positive correlation with the strontium and nickel content.

  4. Cadmium content of human cancellous bone.

    PubMed

    Knuuttila, M; Lappalainen, R; Olkkonen, H; Lammi, S; Alhava, E M

    1982-01-01

    The cadmium content of human cancellous bone was related to age, sex, bone loss, physical properties, and elemental composition. Bone specimens from the anterior iliac crest were collected from 889 cadavers with a normal mineral status, and from 50 cadavers which had bone loss from chronic diseases and immobilization. The element concentrations were analyzed using atomic absorption spectrophotometry. Bone fluoride levels ere determined with the ion specific electrode, the mineral density with the gamma ray attenuation method, and the compressive strength with a strain transducer. The data were analyzed using multiple linear regression analysis. The mean cadmium content of 0.22 +/- 9.16 micrograms/g dry weight (+/- SD) in the samples did not change with age and its content was slightly greater in males than in females. Furthermore, no statistically significant relation was found in cadmium content to bone loss changes or to the calcium content of bone. The cadmium content had a high statistically significant positive correlation with the strontium and nickel content. PMID:7138079

  5. Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

    PubMed

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin G; Eggert, Tobias; Hawk, Nga; Kleiner, David E; Korangy, Firouzeh; Greten, Tim F

    2015-05-01

    Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

  6. Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

    PubMed

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin G; Eggert, Tobias; Hawk, Nga; Kleiner, David E; Korangy, Firouzeh; Greten, Tim F

    2015-05-01

    Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC.

  7. Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models.

    PubMed

    Vincenzi, Fabrizio; Targa, Martina; Corciulo, Carmen; Tabrizi, Mojgan Aghazadeh; Merighi, Stefania; Gessi, Stefania; Saponaro, Giulia; Baraldi, Pier Giovanni; Borea, Pier Andrea; Varani, Katia

    2013-06-01

    Cannabinoid CB(2) receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB(2)agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB(2) agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB(2) compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB(2) receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB(2) receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB(1)-mediated central side effects.

  8. Supplementation with green tea polyphenols improves bone microstructure and quality in aged, orchidectomized rats.

    PubMed

    Shen, Chwan-Li; Cao, Jay J; Dagda, Raul Y; Tenner, Thomas E; Chyu, Ming-Chien; Yeh, James K

    2011-06-01

    Recent studies show that green tea polyphenols (GTPs) attenuate bone loss and microstructure deterioration in ovariectomized aged female rats, a model of postmenopausal osteoporosis. This study evaluated the efficacy of GTPs at mitigating bone loss and microstructure deterioration along with related mechanisms in androgen-deficient aged rats, a model of male osteoporosis. A 2 (sham vs. orchidectomy) × 2 (no GTP and 0.5% GTP in drinking water) factorial design was studied for 16 weeks using 40 aged male rats. An additional 10 rats (baseline group) were killed at the beginning of study to provide baseline parameters. There was no difference in femoral mineral density between baseline and the sham only group. Orchidectomy suppressed serum testosterone and tartrate-resistant acid phosphatase concentrations, liver glutathione peroxidase activity, bone mineral density, and bone strength. Orchidectomy also decreased trabecular bone volume, number, and thickness in the distal femur and proximal tibia and bone-formation rate in trabecular bone of proximal tibia but increased serum osteocalcin concentrations and bone-formation rates in the endocortical tibial shaft. GTP supplementation resulted in increased serum osteocalcin concentrations, bone mineral density, and trabecular volume, number, and strength of femur; increased trabecular volume and thickness and bone formation in both the proximal tibia and periosteal tibial shaft; decreased eroded surface in the proximal tibia and endocortical tibial shaft; and increased liver glutathione peroxidase activity. We conclude that GTP supplementation attenuates trabecular and cortical bone loss through increasing bone formation while suppressing bone resorption due to its antioxidant capacity.

  9. Effects of a7nAChR agonist on the tissue estrogen receptor expression of castrated rats

    PubMed Central

    Ma, Feng; Gong, Fan; Lv, Jinhan; Gao, Jun; Ma, Jingzu

    2015-01-01

    Osteoporosis is one common disease in postmenopausal women due to depressed estrogen level. It has been known that inflammatory factors are involved in osteoporosis pathogenesis. One regulator of inflammatory cascade reaction, a7-nicotinic acetylcholine receptor (a7nAChR), therefore, may exert certain role in osteoporosis. This study thus investigated this question on an osteoporosis rat model after castration. Rats were firstly castrated to induce osteoporosis, and then received a7nAChR agonist (PNU-282987), diethylstilbestrol or saline via intraperitoneal injection. After 6 or 12 weeks, bone samples were collected for counting osteoblast number, bone density and estrogen receptor (ERα and ERβ) expression, in addition to the serum laboratory of inflammatory factors. Bone density, osteoclast number, ERα and ERβ expression level were significantly depressed in model group, and were remarkable potentiated in the drug treatment group (P<0.05). The levels of BGP and PTH in drug treatment group were decreased compared to diethylstilbestrol group, while E2 and IGF-1 showed up-regulation. Agonist of a7nAChR can up-regulate estrogen receptor expression and may prevent the occurrence and development of osteoporosis. PMID:26722551

  10. Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.

    PubMed

    García-Morales, Victoria; Montero, Fernando; Moreno-López, Bernardo

    2015-05-01

    Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination.

  11. Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.

    PubMed

    García-Morales, Victoria; Montero, Fernando; Moreno-López, Bernardo

    2015-05-01

    Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination. PMID:25595101

  12. Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

    SciTech Connect

    Engber, T.M.; Susel, Z.; Kuo, S.; Chase, T.N. )

    1990-12-01

    The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.

  13. Thermogenesis and mitochondrial GDP binding with age in response to the novel agonist CGP-12177A.

    PubMed

    Scarpace, P J; Matheny, M; Borst, S E

    1992-02-01

    The ability to regulate body temperature diminishes with age in both humans and rodents. To investigate whether attenuation of sympathetically activated thermogenesis in brown adipose tissue (BAT) may account for the loss of thermoregulation with age, we assessed O2 consumption and body temperature in response to norepinephrine and the specific BAT beta-adrenergic agonist CGP-12177A in 6-, 18-, and 24-mo-old rats. In addition, the effects of this agonist on interscapular BAT mitochondrial GDP binding in young and senescent rats were determined. CGP-12177A rapidly induced an elevation in O2 consumption, which peaked at 25 min, followed by a decline over 4 h. The peak increase in O2 consumption over baseline and the cumulative 4-h response were decreased with age [P less than 0.02, analysis of variance (ANOVA)]. CGP-12177A induced an increase in body temperature that paralleled but appropriately lagged behind the increase in O2 consumption and that was decreased with age (P less than 0.02, ANOVA). The norepinephrine-induced increase in O2 consumption was also reduced with age but was not paralleled by a change in body temperature and was associated with a four- to fivefold increase in physical activity. In young rats CGP-12177A increased the number of available BAT mitochondrial GDP binding sites at 20 and 60 min post-injection, but in senescent rats GCP-12177A was unable to increase GDP binding. These data indicate that CGP-12177A is a novel agonist for BAT thermogenesis. With age there is a reduced capacity for thermogenesis that involves a failure to increase GDP binding, either due to a diminished amount of uncoupling protein with age or a failure to unmask reserve GDP binding sites.

  14. Bone growth and turnover in progesterone receptor knockout mice.

    SciTech Connect

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jaime C.; Waters, Katrina M.; Lydon, John P.; O'Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    2008-05-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bones of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.

  15. PPAR-{gamma} agonist protects against intestinal injury during necrotizing enterocolitis

    SciTech Connect

    Baregamian, Naira; Mourot, Joshua M.; Ballard, Amie R.; Evers, B. Mark; Chung, Dai H.

    2009-02-06

    Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-{gamma} in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-{gamma} agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-{gamma} expression and activation of NF-{kappa}B in small intestine. Pretreatment with PPAR-{gamma} agonist, 15d-PGJ{sub 2}, attenuated intestinal NF-{kappa}B response and I/R-induced gut injury. Activation of PPAR-{gamma} demonstrated a protective effect on small bowel during I/R-induced gut injury.

  16. Novel Retinoic Acid Receptor Alpha Agonists for Treatment of Kidney Disease

    PubMed Central

    Liu, Ruijie; Li, Zhengzhe; Chen, Yibang; Evans, Todd; Chuang, Peter; Das, Bhaskar; He, John Cijiang

    2011-01-01

    Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN. PMID:22125642

  17. Novel retinoic acid receptor alpha agonists for treatment of kidney disease.

    PubMed

    Zhong, Yifei; Wu, Yingwei; Liu, Ruijie; Li, Zhengzhe; Chen, Yibang; Evans, Todd; Chuang, Peter; Das, Bhaskar; He, John Cijiang

    2011-01-01

    Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.

  18. β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

    PubMed Central

    Chiarella, Sergio E.; Soberanes, Saul; Urich, Daniela; Morales-Nebreda, Luisa; Nigdelioglu, Recep; Green, David; Young, James B.; Gonzalez, Angel; Rosario, Carmen; Misharin, Alexander V.; Ghio, Andrew J.; Wunderink, Richard G.; Donnelly, Helen K.; Radigan, Kathryn A.; Perlman, Harris; Chandel, Navdeep S.; Budinger, G.R. Scott; Mutlu, Gökhan M.

    2014-01-01

    Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β2-adrenergic receptor (β2AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β2AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β2AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the β2AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β2AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by β2AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events. PMID:24865431

  19. Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    LeBlanc, A.; Matsumoto, T.; Jones, J.; Shapiro, J.; Lang, T.; Shackelford, L.; Smith, S.; Evans, H.; Spector, E.; Ploutz-Snyder, R.; Sibonga, J.; Nakamura, T.; Kohri, K.; Ohshima, H.

    2011-01-01

    This poster reviews the possibility of using Bisphosphonates to counter the bone loss that is experienced during space flight. The Hypothesis that is tested in this experiment is that the combined effect of anti-resorptive drugs plus in-flight exercise regimen will attenuate space flight induced loss in bone mass and strength and reduce renal stone risk. The experiment design, the status and the results are described.

  20. Attenuation of Vaccinia Virus.

    PubMed

    Yakubitskiy, S N; Kolosova, I V; Maksyutov, R A; Shchelkunov, S N

    2015-01-01

    Since 1980, in the post-smallpox vaccination era the human population has become increasingly susceptible compared to a generation ago to not only the variola (smallpox) virus, but also other zoonotic orthopoxviruses. The need for safer vaccines against orthopoxviruses is even greater now. The Lister vaccine strain (LIVP) of vaccinia virus was used as a parental virus for generating a recombinant 1421ABJCN clone defective in five virulence genes encoding hemagglutinin (A56R), the IFN-γ-binding protein (B8R), thymidine kinase (J2R), the complement-binding protein (C3L), and the Bcl-2-like inhibitor of apoptosis (N1L). We found that disruption of these loci does not affect replication in mammalian cell cultures. The isogenic recombinant strain 1421ABJCN exhibits a reduced inflammatory response and attenuated neurovirulence relative to LIVP. Virus titers of 1421ABJCN were 3 lg lower versus the parent VACV LIVP when administered by the intracerebral route in new-born mice. In a subcutaneous mouse model, 1421ABJCN displayed levels of VACV-neutralizing antibodies comparable to those of LIVP and conferred protective immunity against lethal challenge by the ectromelia virus. The VACV mutant holds promise as a safe live vaccine strain for preventing smallpox and other orthopoxvirus infections. PMID:26798498

  1. Homeostatic action of adenosine A3 and A1 receptor agonists on proliferation of hematopoietic precursor cells.

    PubMed

    Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Holá, Jirina; Streitová, Denisa; Vacek, Antonín

    2008-07-01

    Two adenosine receptor agonists, N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and N6-cyclopentyladenosine (CPA), which selectively activate adenosine A3 and A1 receptors, respectively, were tested for their ability to influence proliferation of granulocytic and erythroid cells in femoral bone marrow of mice using morphological criteria. Agonists were given intraperitoneally to mice in repeated isomolar doses of 200 nmol/kg. Three variants of experiments were performed to investigate the action of the agonists under normal resting state of mice and in phases of cell depletion and subsequent regeneration after treatment with the cytotoxic drug 5-fluorouracil. In the case of granulopoiesis, IB-MECA 1) increased by a moderate but significant level proliferation of cells under normal resting state; 2) strongly increased proliferation of cells in the cell depletion phase; but 3) did not influence cell proliferation in the regeneration phase. CPA did not influence cell proliferation under normal resting state and in the cell depletion phase, but strongly suppressed the overshooting cell proliferation in the regeneration phase. The stimulatory effect of IB-MECA on cell proliferation of erythroid cells was observed only when this agonist was administered during the cell depletion phase. CPA did not modulate erythroid proliferation in any of the functional states investigated, probably due to the lower demand for cell production as compared with granulopoiesis. The results indicate opposite effects of the two adenosine receptor agonists on proliferation of hematopoietic cells and suggest the plasticity and homeostatic role of the adenosine receptor expression.

  2. Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice.

    PubMed

    Quang, Phuong N; Schmidt, Brian L

    2010-05-01

    Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

  3. Phytoestrogens in the prevention of postmenopausal bone loss.

    PubMed

    Lagari, Violet S; Levis, Silvina

    2013-01-01

    Postmenopausal osteoporosis is a condition associated with low bone mass resulting from the increased bone resorption that occurs following a decline in estrogen levels. Phytoestrogens are plant-derived compounds that have affinity to the estrogen receptor and are able to act as either estrogen agonists or antagonists. Because of their structural similarity to 17-beta-estradiol, they have been studied extensively for their role in the prevention of postmenopausal bone loss. An extensive number of studies employing different types of isoflavone preparations (including soy foods, soy-enriched foods, and soy isoflavone tablets) have been conducted in a wide range of populations, including Western and Asian women. Although there is considerable variability in study design and duration, study population, type of soy isoflavone employed in the intervention, and study outcomes, the evidence points to a lack of a protective role of soy isoflavones in the prevention of postmenopausal bone loss.

  4. Novel Receptor-Based Countermeasures to Microgravity-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    OMalley, Bert W.

    1999-01-01

    The biological actions mediated by the estrogen receptor (ER), vitamin D receptor (VDR) and Ca(sup 2+) (sub o) -sensing receptor (CaR) play key roles in the normal control of bone growth and skeletal turnover that is necessary for skeletal health. These receptors act by controlling the differentiation and/or function of osteoblasts and osteoclasts, and other cell types within the bone and bone marrow microenvironment. The appropriate use of selective ER modulators (SERMS) which target bone, vitamin D analogs that favor bone formation relative to resorption, and CaR agonists may both stimulate osteoblastogenesis and inhibit osteoclastogenesis and the function of mature osteoclasts, should make it possible to prevent the reduction in bone formation and increase in bone resorption that normally contribute to the bone loss induced by weightlessness. Indeed, there may be synergistic interactions among these receptors that enhance the actions of any one used alone. Therefore, we proposed to: 1) assess the in vitro ability of novel ER, VDR and CaR agonists, alone or in combination, to modulate osteoblastogenesis and mature osteoblast function under conditions of 1g and simulated microgravity; 2) assess the in vitro ability of novel ER, VDR and CaR agonists, alone or in combination, to modulate osteoclastogenesis and bone resorption under conditions of lg and simulated microgravity; and 3) carry out baseline studies on the skeletal localization of the CaR in normal rat bone as well as the in vivo actions of our novel ER- and VDR-based therapeutics in the rat in preparation for their use, alone or in combination, in well-established ground-based models of microgravity and eventually in space flight.

  5. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  6. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  7. Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats.

    PubMed

    Gu, Xiaohuan; Wei, Zheng Zachory; Espinera, Alyssa; Lee, Jin Hwan; Ji, Xiaoya; Wei, Ling; Dix, Thomas A; Yu, Shan Ping

    2015-05-01

    Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201

  8. Pharmacologically Induced Hypothermia Attenuates Traumatic Brain Injury in Neonatal Rats

    PubMed Central

    Espinera, Alyssa; Lee, Jin Hwan; Ji, Xiaoya; Wei, Ling; Dix, Thomas A.; Yu, Shan Ping

    2015-01-01

    Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A six-hour hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15 min or 2 hr after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and Caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the

  9. Peripheral δ-opioid receptors attenuate the exercise pressor reflex.

    PubMed

    Leal, Anna K; Yamauchi, Katsuya; Kim, Joyce; Ruiz-Velasco, Victor; Kaufman, Marc P

    2013-10-15

    In rats with ligated femoral arteries, the exercise pressor reflex is exaggerated, an effect that is attenuated by stimulation of peripheral μ-opioid receptors on group IV metabosensitive afferents. In contrast, δ-opioid receptors are expressed mostly on group III mechanosensitive afferents, a finding that prompted us to determine whether stimulation of these opioid receptors could also attenuate the exaggerated exercise pressor reflex in "ligated" rats. We found femoral arterial injection of [D-Pen2,D-Pen5]enkephalin (DPDPE; 1.0 μg), a δ-opioid agonist, significantly attenuated the pressor and cardioaccelerator components of the exercise pressor reflex evoked by hindlimb muscle contraction in both rats with ligated and patent femoral arteries. DPDPE significantly decreased the pressor responses to muscle mechanoreflex activation, evoked by tendon stretch, in ligated rats only. DPDPE (1.0 μg) had no effect in either group on the pressor and cardioaccelerator responses to capsaicin (0.2 μg), which primarily stimulates group IV afferents. DPDPE (1.0 μg) had no effect on the pressor and cardioaccelerator responses to lactic acid (24 mM), which stimulates group III and IV afferents, in rats with patent femoral arteries but significantly decreased the pressor response in ligated rats. Western blots revealed the amount of protein comprising the δ-opioid receptor was greater in dorsal root ganglia innervating hindlimbs with ligated femoral arteries than in dorsal root ganglia innervating hindlimbs with patent femoral arteries. Our findings support the hypothesis that stimulation of δ-opioid receptors on group III afferents attenuated the exercise pressor reflex.

  10. Hit to lead studies on (hetero)arylpyrimidines--agonists of the canonical Wnt-beta-catenin cellular messaging system.

    PubMed

    Gilbert, Adam M; Bursavich, Matthew G; Alon, Nippa; Bhat, Bheem M; Bex, Frederick J; Cain, Michael; Coleburn, Valerie; Gironda, Virginia; Green, Paula; Hauze, Diane B; Kharode, Yogendra; Krishnamurthy, Girija; Kirisits, Matthew; Lam, Ho-Sun; Liu, Yao-Bin; Lombardi, Sabrina; Matteo, Jeanne; Murrills, Richard; Robinson, John A; Selim, Sally; Sharp, Michael; Unwalla, Raymond; Varadarajan, Usha; Zhao, Weiguang; Yaworsky, Paul J

    2010-01-01

    A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone. PMID:19897365

  11. Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction.

    PubMed

    Park, Jeong Rang; Ahn, Jong Hwa; Jung, Myeong Hee; Koh, Jin-Sin; Park, Yongwhi; Hwang, Seok-Jae; Jeong, Young-Hoon; Kwak, Choong Hwan; Lee, Young Soo; Seo, Han Geuk; Kim, Jin Hyun; Hwang, Jin-Yong

    2016-01-01

    Peroxisome proliferator-activated receptor-delta (PPAR-δ)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg) was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-δ expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC) recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect. PMID:26862756

  12. Bone lesion biopsy

    MedlinePlus

    Benign (noncancerous) bone tumors include: Bone cyst Fibroma Osteoblastoma Osteoid osteoma Cancerous tumors include: Ewing sarcoma Multiple myeloma Osteosarcoma Other types of cancer that may have spread to the bone Abnormal ...

  13. Smoking and Bone Health

    MedlinePlus

    ... direct relationship between tobacco use and decreased bone density. Analyzing the impact of cigarette smoking on bone ... hard to determine whether a decrease in bone density is due to smoking itself or to other ...

  14. Menopause and Bone Loss

    MedlinePlus

    ... You reach your highest bone mass (size and density) at about age 30. Then, sometime between age ... your bones, your doctor may do a bone density test (DEXA scan). This test gives exact measurements ...

  15. Facts about Broken Bones

    MedlinePlus

    ... las fracturas de huesos Your bones are tough stuff — but even tough stuff can break. Like a wooden pencil, bones will ... that? Get a lot of physical activity, especially stuff like jumping and running. Feed your bones the ...

  16. Bone marrow aspiration

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003658.htm Bone marrow aspiration To use the sharing features on this page, please enable JavaScript. Bone marrow is the soft tissue inside bones that helps ...

  17. Green tea polyphenols supplementation improves bone microstructure in orchidectomized middle-Aged rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our recent study shows that green tea polyphenols (GTP) attenuate trabecular bone loss in ovariectomized middle-aged female rats. To investigate whether GTP prevents bone loss in male rats, 40 rats with and without oriectomy (ORX) were assigned to 4 groups in a 2 (sham vs. ORX)× 2 (no GTP and 0.5% G...

  18. Antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists.

    PubMed

    Labrie, F; Bélanger, A; Kelly, P A; Séguin, C; Cusan, L; Lefebvre, F A; Reeves, J J; Lemay, A; Faure, N; Gourdeau, Y; Raynaud, J P

    1981-01-01

    This paper reviews the mechanisms responsible for the antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists. Large doses of the LHRH agonist LHRH-EA lead to a marked reduction of testicular and secondary sex organ weight, LH receptor levels, and plasma testosterone concentration. A marked inhibition of basal testicular and testosterone concentrations is obtained after daily administration of the LHRH agonists at doses greater than 10 ng. Treatment with low doses of the LHRH agonist can lead to an increased steroidogenic response to LH. Treatment with low doses of LHRH agonists could stimulate Leydig cell function while high doses are history. A study of the effects of longterm treatment with an LHRH agonsist on spermatogenesis revelaed that testis, prostate, and seminal vesicle weight decreased and plasma LH and FSH levels increased over 12 weeks. Comparison of the effects of increasing doses of LHRH agonist on testicular and ovarian gonadotropin receptors and steroidogenesis in male rats indicates that single or repeated administration of LHRH agonists can lead to loss of testicular LH receptors in the absence of the pituitary gland. The loss of ovarian gonadotropin receptors in female rats is also investigated. Antifertility effects of LHRH ethylamide are accompanied by a marked loss of LH/hCG and FSH receptors in ovarian tissue. The injection of 1,3, or 10 ng LHRH-EA in intact rats has no significant effect on ovarian LH receptor levels. A study of the direct action of LHRH agonists at the ovarian level demonstrates a close relationship between the binding activity of a large series of LHRH agonists and antagonists in the anterior pituitary gland and the ovary. Inhibition of testicular steroidogenesis in man by treatment with a potent LHRH agonist is also demonstrated. Intranasal administration of LHRH ethylamide has luteolytic effects in normal women. Daily administration of LHRH-EA inhibited ovulation in all but 2 of 89 treatment

  19. A Dual TLR Agonist Adjuvant Enhances the Immunogenicity and Protective Efficacy of the Tuberculosis Vaccine Antigen ID93

    PubMed Central

    Orr, Mark T.; Beebe, Elyse A.; Hudson, Thomas E.; Moon, James J.; Fox, Christopher B.; Reed, Steven G.; Coler, Rhea N.

    2014-01-01

    With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4+ T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG. PMID:24404140

  20. Concomitant Cushing's Disease and Marked Hyperprolactinemia: Response to a Dopamine Receptor Agonist.

    PubMed

    Shiraishi, Jun; Koyama, Hidenori; Shirakawa, Manabu; Ishikura, Reiichi; Okazaki, Hirokazu; Kurajoh, Masafumi; Shoji, Takuhito; Moriwaki, Yuji; Yamamoto, Tetsuya; Namba, Mitsuyoshi

    2016-01-01

    A 38-year-old woman was admitted to our hospital because of amenorrhea, multiple bone fractures, and a Cushingoid appearance. Endocrinological investigations revealed that she had co-existing Cushing's disease and prolactinoma, with a serum level of prolactin (PRL) at 1,480 ng/mL, corticotropin (ACTH) at 81.3 pg/mL, and cortisol at 16.6 μg/dL. Due to the lack of indication for transsphenoidal surgery, cabergoline monotherapy was initiated. A 6-month course of treatment resulted in only subtle amelioration of hypercortisolism, while hyperprolactinemia was dramatically improved. In 5 cases of bihormonal (ACTH/PRL) pituitary macroadenoma reported in the English literature, 2 were initially treated with dopaminergic agonists with substantial effectiveness for both PRL and ACTH. We herein report an extremely rare case of bihormonal macroadenoma in which only PRL was responsive to treatment. PMID:27086808

  1. Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Δ(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva).

    PubMed

    Darmani, Nissar A; Chebolu, Seetha; Zhong, Weixia; Trinh, Chung; McClanahan, Bryan; Brar, Rajivinder S

    2014-01-01

    Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ(9)-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Δ(9)-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18 μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ(9)-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3-1.8 mg/kg. Combinations of 1 or 5 μg/kg RTX with varying doses of Δ(9)-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5-50 times lower than Δ(9)-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30 min but not at 2 h. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5mg/kg; however, another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually.

  2. Beta-adrenoceptor agonist mediated relaxation of rat isolated resistance arteries: a role for the endothelium and nitric oxide.

    PubMed Central

    Graves, J.; Poston, L.

    1993-01-01

    1. Isoprenaline (10(-9)-10(-5) M) relaxed rat isolated mesenteric resistance arteries pre-contracted with K+ (30-60 mM) (p EC50 (M) 8.03 +/- 0.40; maximum relaxation 66.79 +/- 2.43%, n = 7). This relaxation was partially attenuated by the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M). 2. The beta 2-adrenoceptor agonist, salbutamol (10(-9)-10(-5) M), produced a modest maximum relaxation (35.93 +/- 2.93%), which was not sensitive to L-NAME. 3. The beta 1-adrenoceptor agonist, dobutamine (10(-9)-10(-5) M), relaxed arteries precontracted with K+. This relaxation was abolished by L-NAME (10(-4) M) and also by propranolol (10(-6) M), but not affected by D-NAME (10(-4) M). The inhibition by L-NAME was partially reversed by L-arginine (10(-3) M). Removal of the endothelium severely attenuated relaxation to dobutamine. 4. Contractile responses to depolarizing K+ solutions were enhanced by the addition of L-NAME, and also by removal of the endothelium. 5. The above findings demonstrate that beta 1-adrenoceptor causes relaxation via NO release from the endothelium of rat mesenteric resistance arteries. In addition, contraction to K+ is modified by release of NO from the endothelium, possibly in response to tension development. PMID:8096781

  3. Bone marrow transplant - discharge

    MedlinePlus

    Transplant - bone marrow - discharge; Stem cell transplant - discharge; Hematopoietic stem cell transplant - discharge; Reduced intensity; Non-myeloablative transplant - discharge; Mini transplant - discharge; Allogenic bone marrow transplant - ...

  4. Classification of bones from MR images in torso PET-MR imaging using a statistical shape model

    NASA Astrophysics Data System (ADS)

    Reza Ay, Mohammad; Akbarzadeh, Afshin; Ahmadian, Alireza; Zaidi, Habib

    2014-01-01

    There have been exclusive features for hybrid PET/MRI systems in comparison with its PET/CT counterpart in terms of reduction of radiation exposure, improved soft-tissue contrast and truly simultaneous and multi-parametric imaging capabilities. However, quantitative imaging on PET/MR is challenged by attenuation of annihilation photons through their pathway. The correction for photon attenuation requires the availability of patient-specific attenuation map, which accounts for the spatial distribution of attenuation coefficients of biological tissues. However, the lack of information on electron density in the MR signal poses an inherent difficulty to the derivation of the attenuation map from MR images. In other words, the MR signal correlates with proton densities and tissue relaxation properties, rather than with electron density and, as such, it is not directly related to attenuation coefficients. In order to derive the attenuation map from MR images at 511 keV, various strategies have been proposed and implemented on prototype and commercial PET/MR systems. Segmentation-based methods generate an attenuation map by classification of T1-weighted or high resolution Dixon MR sequences followed by assignment of predefined attenuation coefficients to various tissue types. Intensity-based segmentation approaches fail to include bones in the attenuation map since the segmentation of bones from conventional MR sequences is a difficult task. Most MR-guided attenuation correction techniques ignore bones owing to the inherent difficulties associated with bone segmentation unless specialized MR sequences such as ultra-short echo (UTE) sequence are utilized. In this work, we introduce a new technique based on statistical shape modeling to segment bones and generate a four-class attenuation map. Our segmentation approach requires a torso bone shape model based on principle component analysis (PCA). A CT-based training set including clearly segmented bones of the torso region

  5. Metal artifacts correction in cone-beam CT bone imaging

    NASA Astrophysics Data System (ADS)

    Zhang, Yan; Ning, Ruola; Conover, David

    2007-03-01

    Cone-beam CT (CBCT) technique is needed by orthopaedists in their new studies to monitor bone volume growth and blood vessel growth of structural bone grafts used in reconstruction surgery. However, titanium plate and screws, which are commonly used to connect bone grafts to host bones, can cause severe streaking artifacts and shading artifact in the reconstructed images due to their high attenuation of x-rays. These metal artifacts will distort the information of the bone and cause difficulties when measuring bone volume growth and the inside blood vessel growth. To solve this problem and help orthopaedists quantitatively record the growth of bone grafts, we present a three-dimensional metal artifact correction technique to correct the streaking artifacts generated by titanium implants. In this project not only the artifacts need to be corrected but also the correct information of the bone is required in the image for the quantitative measurements. Both phantom studies and animal studies were conducted to test this correction method. Images without metal correction and images with metal correction were compared together, as well as the reference bone images acquired without metal. It's shown the streaking and shading artifacts were greatly reduced after metal correction. The accuracy of bone volume measurements was also greatly increased by 79% for phantom studies and 53% for animal studies.

  6. Bone Growth and Turnover in Progesterone Receptor Knockout Mice

    PubMed Central

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jamie C.; Waters, Katrina M.; Lydon, John P.; O’Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    2008-01-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and microcomputed tomography analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 wk of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain, and tibia longitudinal bone growth were normal in PRKO mice. In contrast, total, cancellous, and cortical bone mass were increased in the humerus of 12-wk-old PRKO mice, whereas cortical and cancellous bone mass in the tibia was normal. At 26 wk of age, cancellous bone area in the proximal tibia metaphysis of PRKO mice was 153% greater than age matched wild-type mice. The improved cancellous bone balance in 6-month-old PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice is not essential for bone growth and turnover. However, at some skeletal sites, PR signaling attenuates the accumulation of cortical and cancellous bone mass during adolescence. PMID:18276762

  7. Bone and bone marrow involvement in sarcoidosis.

    PubMed

    Yachoui, Ralph; Parker, Brian J; Nguyen, Thanhcuong T

    2015-11-01

    Bone and bone marrow involvement in sarcoidosis have been infrequently reported. We aimed to describe the clinical features, radiological descriptions, pathological examinations, and outcomes of three patients with osseous sarcoidosis and one patient with bone marrow sarcoidosis seen at our institution. Our case series included fluorodeoxyglucose positron emission tomography descriptions in assessing the whole-body extent of sarcoidosis. In the era of advanced imaging, large bone and axial skeleton sarcoidosis lesions are more common than previously reported.

  8. Method and system for in vivo measurement of bone tissue using a two level energy source

    NASA Technical Reports Server (NTRS)

    Cameron, J. R.; Judy, P. F. (Inventor)

    1976-01-01

    Methods and apparatus are provided for radiologically determining the bone mineral content of living human bone tissue independently of the concurrent presence of adipose and other soft tissues. A target section of the body of the subject is irradiated with a beam of penetrative radiations of preselected energy to determine the attenuation of such beam with respect to the intensity of each of two radiations of different predetermined energy levels. The resulting measurements are then employed to determine bone mineral content.

  9. The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions.

    PubMed

    Pasterk, Lisa; Philipose, Sonia; Eller, Kathrin; Marsche, Gunther; Heinemann, Akos; Schuligoi, Rufina

    2015-01-01

    Platelets express the EP2, EP3 and EP4 receptors. Prostaglandin (PG) E2 has a biphasic effect on platelets. Low concentrations of PGE2 enhance platelet aggregation through the activation of the EP3 receptors, while at high concentrations it attenuates aggregation via the EP4 receptor. Consequently, EP3 receptor inhibition was shown to inhibit artherothrombosis, but had no influence on bleeding time in vivo. In this study, we investigated the role of the EP3 receptor in adhesion and thrombus formation under flow conditions in vitro. The EP3 agonist sulprostone caused an increase in the adhesion of washed platelets to fibrinogen as well as to collagen under low shear stress, an effect that was blocked by the EP3 antagonist L-798106. In contrast, when whole blood was perfused over collagen-coated surfaces, sulprostone did not enhance binding and thrombus formation of platelets on collagen; at high concentrations it even attenuated this response. We conclude that in more physiological models of thrombus formation, the role for EP3 receptors is limited, indirectly suggesting that the primary action of PGE2 in haemostasis might be an inhibitory one. PMID:26228833

  10. Dietary protein level and source differentially affect bone metabolism, strength, and intestinal calcium transporter expression during ad libitum and food-restricted conditions in male rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    High protein diets may attenuate bone loss during energy restriction (ER). The objective of the current study was to determine whether high protein diets suppress bone turnover and improve bone quality in rats during ER and whether dietary protein source affects this relationship. Eighty 12-week o...

  11. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  12. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  13. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25437461

  14. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25326839

  15. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  16. Identification of M-CSF agonists and antagonists

    SciTech Connect

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  17. Group II mGlu receptor agonists fail to protect against various neurotoxic insults induced in murine cortical, striatal and cerebellar granular pure neuronal cultures.

    PubMed

    Moldrich, R X; Giardina, S F; Beart, P M

    2001-07-01

    Since group II metabotropic glutamate (mGlu) receptors are a potential target for the amelioration of neuronal injury, we evaluated the ability of group II mGlu receptor agonists to attenuate toxicity induced by various insults in cortical, striatal and cerebellar granular (CGCs) pure neuronal cultures. The three cultures, when maintained under serum-free, anti-oxidant rich conditions for up to 13 days in vitro (div) were shown by immunocytochemistry to contain a maximum of 2-7% glia. At 6, 9 and 13 div a graded pattern of injury to cortical and striatal cultures was achieved with either hydrogen peroxide (60-110 microM), staurosporine (1 microM), N-methyl-D-aspartate (NMDA, 70 microM), alpha-amino-3-hydroxy-methylisoxazole-4-propionate (AMPA, 100 microM) or kainate (100 microM) over either 4, 24 or 48 h. CGCs were similarly exposed to low K(+) (5.4 mM KCl). Cell viability was examined via phase-contrast microscopy and assessed by a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay. Treatment with group II mGlu receptor agonists (1-300 microM), 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) and N-acetylaspartylglutamate (NAAG) failed to attenuate the toxicity. Pretreatment of cultures with the agonists and treatment following acute insult also failed to attenuate toxicity. Further investigations demonstrated the presence of second messenger activation whereby (2R,4R)-APDC reduced forskolin-stimulated production of cAMP in each culture. Thus, despite receptor coupling to intracellular signaling cascades, and regardless of culture development, agonist concentration, extent and mode of injury, group II mGlu receptor agonists were unable to protect against injury induced in cortical, striatal and cerebellar granular pure neuronal cultures. This result is in contrast to mixed cultures of neurones and glia and implies an

  18. Agonist-induced functional desensitization of the mu-opioid receptor is mediated by loss of membrane receptors rather than uncoupling from G protein.

    PubMed

    Pak, Y; Kouvelas, A; Scheideler, M A; Rasmussen, J; O'Dowd, B F; George, S R

    1996-11-01

    The effects of acute exposure of the opioid peptide [D-Ala2,N-MePhe4, Gly-ol5]enkephalin (DAMGO) on the mu-opioid receptor were examined in Chinese hamster ovary (CHO) K-1 and baby hamster kidney stable transfectants. In the CHO cell line, acute 1-hr treatment with DAMGO decreased the density of receptors without affecting the affinity or proportion of agonist-detected sites and attenuated the ability of the agonist to inhibit forskolin-stimulated cAMP accumulation. In contrast, similar 1-hr treatment of baby hamster kidney cells did not affect receptor density or agonist ability to inhibit cAMP accumulation, but longer duration of agonist exposure resulted in a reduction in membrane receptor, identical to the CHO cells. These results suggested that for the mu-opioid receptor, alteration in receptor density was the major determinant for the observed agonist-induced desensitization. Consistent with this notion, the ratio of the DAMGO concentration yielding half-maximal occupation of the mu receptor to that yielding half-maximal functional response was < 1. This suggests the necessity for a high mu receptor occupancy rate for maximal functional response, so that any loss of cell surface opioid-binding sites was a critical determinant in reducing the maximal response. This hypothesis was further supported by the observation that irreversible inactivation of fixed proportions of opioid-binding sites with beta-chlorn-altrexamine demonstrated that there were few spare receptors, which is in contrast to what has been reported for other G protein-coupled receptors, including the delta-opioid receptor. Taken together, these data suggest that the opioid agonist DAMGO has a high affinity for the mu receptor but must occupy > 70% of the available receptors to generate the maximal second messenger-linked response.

  19. In vivo treatment with mu and delta, but not kappa-selective opioid agonists reduces [3H]spiperone binding to the guinea-pig striatum: autoradiographic evidence.

    PubMed

    Brent, P J; Bunn, S J

    1994-08-22

    In guinea-pigs, acute treatment with mu and delta receptor opioid agonists induces sedation and immobility [1,5], and attenuates the behavioural activation produced by the dopamine D2 agonist quinpirole [5]. In contrast, kappa-selective opioid agonists induce dystonic-like movements [4,5,8]. This has led us to investigate the possibility of an interaction between acute opioid treatment and the dopamine D2 system. The effect of acute treatment with mu, delta and kappa opioid agonists on [3H]spiperone binding sites (dopamine D2) in guinea-pig brain was studied using receptor autoradiography. The mu preferring agonist morphine (15 mg/kg subcutaneously, SC) given for 2 h, and the delta receptor selective agonist DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen) (20 nM, intracerebroventricularly, ICV) given for 0.5 h, both decreased the density of specific (butaclamol displaceable) [3H]spiperone binding in the caudate putamen by 23.8 +/- 1.7% and 24.2 +/- 2.7% respectively, and in nucleus accumbens by 26.1 +/- 2.7% and 21.9 +/- 4.6% respectively compared to saline treated animals. There were no significant changes in the level of [3H]spiperone binding to other brain regions examined including frontal cortex, hippocampus, substantia nigra, ventral tegmental area, amygdala, hypothalamic nuclei and cerebellum. In other experiments, incubation of coronal slices from various brain regions with [3H]spiperone, in the presence of a high concentration of morphine (20 microM) or DPDPE (10 microM) did not affect the level of binding, thus precluding effects due to residual tissue levels of drugs after in vivo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.

    PubMed

    Ortega, V E

    2014-07-01

    Beta2 (β2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the β2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies.

  1. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.

    PubMed

    Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F; Diamond, Scott L

    2010-07-01

    Prediction of cellular response to multiple stimuli is central to evaluating patient-specific clinical status and to basic understanding of cell biology. Cross-talk between signaling pathways cannot be predicted by studying them in isolation and the combinatorial complexity of multiple agonists acting together prohibits an exhaustive exploration of the complete experimental space. Here we describe pairwise agonist scanning (PAS), a strategy that trains a neural network model based on measurements of cellular responses to individual and all pairwise combinations of input signals. We apply PAS to predict calcium signaling responses of human platelets in EDTA-treated plasma to six different agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF and PGE(2)) at three concentrations (0.1, 1 and 10 x EC(50)). The model predicted responses to sequentially added agonists, to ternary combinations of agonists and to 45 different combinations of four to six agonists (R = 0.88). Furthermore, we use PAS to distinguish between the phenotypic responses of platelets from ten donors. Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu. PMID:20562863

  2. δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice

    PubMed Central

    Pradhan, Amynah A; Smith, Monique L; Zyuzin, Jekaterina; Charles, Andrew

    2014-01-01

    Background and Purpose Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. Experimental Approach Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. Key Results NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that δ-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. Conclusions and Implications These data show that δ-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ-opioid receptors are a promising therapeutic target for this disorder. PMID:24467301

  3. Monoamine receptor agonists, acting preferentially at presynaptic autoreceptors and heteroreceptors, downregulate the cell fate adaptor FADD in rat brain cortex.

    PubMed

    García-Fuster, M Julia; García-Sevilla, Jesús A

    2015-02-01

    FADD is a crucial adaptor of death receptors that can engage apoptosis or survival actions (e.g. neuroplasticity) through its phosphorylated form (p-FADD). Although FADD was shown to participate in receptor mechanisms related to drugs of abuse, little is known on its role in the signaling of classic neurotransmitters (dopamine, noradrenaline, and serotonin) in brain. This study assessed the modulation of FADD (and p-FADD/FADD ratio, as an index of neuroplasticity) and FLIP-L (a neuroprotective FADD interacting partner), as well as the role of MEK-ERK signaling, after activation of monoamine auto/heteroreceptors by selective agonists in rat cortex. Acute depletion of monoamines with reserpine, but not with AMPT or PCPA, reduced FADD (28%) and increased p-FADD/FADD ratio (1.34-fold). Activation of presynaptic α2A-adrenoceptors (UK-14304 and clonidine), 5-HT1A receptors (8-OH-DPAT), and D2 dopamine receptor (bromocriptine) dose-dependently decreased FADD (up to 54%) and increased p-FADD (up to 29%) and p-FADD/FADD ratios (up to 2.93-fold), through specific receptor mechanisms. Activation of rat 5-HT1B autoreceptor in axon terminals by CP-94253 did not modulate FADD forms. Activation of postsynaptic D1 dopamine receptor by SKF-81297 also reduced FADD (25%) and increased p-FADD (32%). Disruption of MEK-ERK activation with SL327 did not modify clonidine (α2A-adrenoceptor)-induced FADD inhibition, indicating that agonist effect was not dependent on ERK signaling. The various monoamine receptor agonists and antagonists did not alter FLIP-L content, or the activation of executioner caspase-3 and PARP-1 cleavage, indicating that the agonists attenuated apoptotic signals and promoted neuroplasticity through FADD regulation. These novel results indicate that inhibition of pro-apoptotic FADD adaptor could function as a common signaling step in the initial activation of monoamine receptors in the brain.

  4. The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.

    PubMed

    Yohn, Samantha E; Santerre, Jessica L; Nunes, Eric J; Kozak, Rouba; Podurgiel, Samantha J; Correa, Mercè; Salamone, John D

    2015-08-01

    Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.

  5. Monoamine receptor agonists, acting preferentially at presynaptic autoreceptors and heteroreceptors, downregulate the cell fate adaptor FADD in rat brain cortex.

    PubMed

    García-Fuster, M Julia; García-Sevilla, Jesús A

    2015-02-01

    FADD is a crucial adaptor of death receptors that can engage apoptosis or survival actions (e.g. neuroplasticity) through its phosphorylated form (p-FADD). Although FADD was shown to participate in receptor mechanisms related to drugs of abuse, little is known on its role in the signaling of classic neurotransmitters (dopamine, noradrenaline, and serotonin) in brain. This study assessed the modulation of FADD (and p-FADD/FADD ratio, as an index of neuroplasticity) and FLIP-L (a neuroprotective FADD interacting partner), as well as the role of MEK-ERK signaling, after activation of monoamine auto/heteroreceptors by selective agonists in rat cortex. Acute depletion of monoamines with reserpine, but not with AMPT or PCPA, reduced FADD (28%) and increased p-FADD/FADD ratio (1.34-fold). Activation of presynaptic α2A-adrenoceptors (UK-14304 and clonidine), 5-HT1A receptors (8-OH-DPAT), and D2 dopamine receptor (bromocriptine) dose-dependently decreased FADD (up to 54%) and increased p-FADD (up to 29%) and p-FADD/FADD ratios (up to 2.93-fold), through specific receptor mechanisms. Activation of rat 5-HT1B autoreceptor in axon terminals by CP-94253 did not modulate FADD forms. Activation of postsynaptic D1 dopamine receptor by SKF-81297 also reduced FADD (25%) and increased p-FADD (32%). Disruption of MEK-ERK activation with SL327 did not modify clonidine (α2A-adrenoceptor)-induced FADD inhibition, indicating that agonist effect was not dependent on ERK signaling. The various monoamine receptor agonists and antagonists did not alter FLIP-L content, or the activation of executioner caspase-3 and PARP-1 cleavage, indicating that the agonists attenuated apoptotic signals and promoted neuroplasticity through FADD regulation. These novel results indicate that inhibition of pro-apoptotic FADD adaptor could function as a common signaling step in the initial activation of monoamine receptors in the brain. PMID:25286119

  6. Inhibition by a retinoic acid receptor γ agonist of extracellular matrix remodeling mediated by human Tenon fibroblasts

    PubMed Central

    Liu, Yang; Orita, Tomoko; Suzuki, Katsuyoshi; Teranishi, Shinichiro; Mori, Takuya; Sonoda, Koh-Hei

    2015-01-01

    Purpose Scar formation is most frequently responsible for the failure of glaucoma filtration surgery. Retinoic acids are vitamin A derivatives that play diverse roles in development, immunity, and tissue repair. The effects of the retinoic acid receptor (RAR) γ agonist R667 on the contractility of human Tenon fibroblasts (HTFs) cultured in a three-dimensional collagen gel as well as on intraocular pressure (IOP) in a rat model of glaucoma filtration surgery were investigated. Methods HTFs were cultured in a type I collagen gel, the contraction of which was evaluated by measurement of the gel diameter. The release of matrix metalloproteinases (MMPs) into culture supernatants was assessed with immunoblot analysis and gelatin zymography. Phosphorylation of focal adhesion kinase (FAK) was examined with immunoblot analysis, and production of fibronectin and type I collagen was measured with immunoassays. Results R667 inhibited transforming growth factor-β1 (TGF-β1)-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner, whereas an RARα agonist inhibited this process to a lesser extent and an RARβ agonist had no effect. TGF-β1-induced MMP-1 and MMP-3 release, FAK phosphorylation, and fibronectin and type I collagen production in HTFs were also attenuated by R667. Furthermore, R667 lowered IOP in rats after glaucoma filtration surgery. Conclusions R667 inhibited TGF-β1-induced contraction and extracellular matrix synthesis in HTFs. Such effects might have contributed to the lowering of IOP by R667 in a rat model of glaucoma filtration surgery. RARγ agonists might thus prove effective for inhibition of scar formation after such surgery. PMID:26788029

  7. The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.

    PubMed

    Yohn, Samantha E; Santerre, Jessica L; Nunes, Eric J; Kozak, Rouba; Podurgiel, Samantha J; Correa, Mercè; Salamone, John D

    2015-08-01

    Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists. PMID:26022661

  8. Blockage of caspase-1 activation ameliorates bone marrow inflammation in mice after hematopoietic stem cell transplantation.

    PubMed

    Qiao, Jianlin; Wu, Jinyan; Li, Yuanyuan; Xia, Yuan; Chu, Peipei; Qi, Kunming; Yan, Zhiling; Yao, Haina; Liu, Yun; Xu, Kailin; Zeng, Lingyu

    2016-01-01

    Conditioning regimens before hematopoietic stem cell transplantation (HSCT), cause damage to bone marrow and inflammation. Whether inflammasomes are involved in bone marrow inflammation remains unclear. The study aims to evaluate the role of inflammasomes in bone marrow inflammation after HSCT. On days 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of bone marrow inflammation, pro-inflammatory cytokines secretion, inflammasomes expression and caspase-1 activation. Bone marrow inflammation with neutrophils and macrophages infiltration was observed after HSCT. Secretion of IL-1β, IL-18, TNF-α and IL-6 were elevated, with increased caspase-1 activation and inflammasomes expression. Caspase-1 inhibitor administration after HSCT significantly reduced infiltration of neutrophils and macrophages into bone marrow and increased the numbers of megakaryocytes and platelets. In conclusion, inflammasomes activation is involved in bone marrow inflammation after HSCT and caspase-1 inhibition attenuates bone marrow inflammation and promoted hematopoietic reconstitution, suggesting targeting caspase-1 might be beneficial for improving HSCT outcomes.

  9. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory

  10. [The pisiform bone: sesamoid or carpal bone?].

    PubMed

    May, O

    1996-01-01

    In man, the pisiform bone occupies an unusual place among the carpal bones. It is situated in an anterior plane to the other bones, sheathed within the tendon of the flexor carpi ulnaris, and ossifying almost four years the last of the carpal bones. Many theories have tried to explain the presence of this "exceptional" bone: the first theory, proposed by Flower and Mivart, suggested the possibility that this bone could be a sesamoid. The second theory supposes a polydactyl hand, assuming that polydactyly preceded pentadactyly; the pisiform would then be a post-minimus vestigial bone according to Bardeleben. Finally, Gegenbauer and Gillies, proposed a primary pentadactyl hand in which the carpus would be composed of three proximal elements, generally two central, and five distal. The pisiform would either be a derivative of the central series, or a distinct element in the carpus. This last theory appears to be the most likely. The primary carpus would therefore have consisted of 12 bones arranged in 3 distinct rows, a proximal row of 3 bones, a central row of 4 bones, and a distal row of 5 bones. According to this theory, the most ulnar of the central would have been displaced to the medial limit of the carpus, to become the pisiform. PMID:9026058

  11. Attenuation of Cocaine's Reinforcing and Discriminative Stimulus Effects via Muscarinic M1 Acetylcholine Receptor StimulationS⃞

    PubMed Central

    Conn, P. Jeffrey; Lindsley, Craig; Wess, Jürgen; Boon, Joon Y.; Fulton, Brian S.; Fink-Jensen, Anders; Caine, S. Barak

    2010-01-01

    Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M1 and/or M4 receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The nonselective muscarinic antagonists scopolamine and methylscopolamine, the nonselective muscarinic agonists oxotremorine and pilocarpine, the M1/M4-preferring agonist xanomeline, the putative M1-selective agonist (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343), and the novel M1-selective agonist 1-(1-2-methylbenzyl)-1,4-bipiperidin-4-yl)-1H benzo[d]imidazol-2(3H)-one (TBPB) were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M1 subtype (oxotremorine < xanomeline < TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M1 and M4 receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M1 receptor activation attenuates cocaine's abuse-related effects, whereas non-M1/M4 receptors probably contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anticocaine

  12. Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

    PubMed

    Wiley, J L; Compton, D R; Gordon, P M; Siegel, C; Singer, M; Dutta, A; Lichtman, A H; Balster, R L; Razdan, R K; Martin, B R

    1996-01-01

    delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects. PMID:9076759

  13. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  14. Bone grafts in dentistry

    PubMed Central

    Kumar, Prasanna; Vinitha, Belliappa; Fathima, Ghousia

    2013-01-01

    Bone grafts are used as a filler and scaffold to facilitate bone formation and promote wound healing. These grafts are bioresorbable and have no antigen-antibody reaction. These bone grafts act as a mineral reservoir which induces new bone formation. PMID:23946565

  15. Bone Health and Osteoporosis.

    PubMed

    Lupsa, Beatrice C; Insogna, Karl

    2015-09-01

    Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue leading to decreased bone strength and an increased risk of low-energy fractures. Central dual-energy X-ray absorptiometry measurements are the gold standard for determining bone mineral density. Bone loss is an inevitable consequence of the decrease in estrogen levels during and following menopause, but additional risk factors for bone loss can also contribute to osteoporosis in older women. A well-balanced diet, exercise, and smoking cessation are key to maintaining bone health as women age. Pharmacologic agents should be recommended in patients at high risk for fracture.

  16. Bone Blood Flow During Simulated Microgravity: Physiological and Molecular Mechanisms

    NASA Technical Reports Server (NTRS)

    Bloomfield, Susan A.

    1999-01-01

    determined by 3-point bending (tibia, humerus) or compression (femoral neck) testing to failure. A unique aspect of these studies will be defining the time course of changes in gene expression in bone cell populations with unloading, accomplished with Northern blots, in situ hybridization, and immunohistochemistry. These studies have high relevance for concurrent protocols being proposed by investigators on NSBRI Cardiovascular and Muscle teams, with blood flow data available on a number of tissues other than bone. Further, dobutamine and other Beta-agonists have been tested as countermeasures for altered muscle and cardiovascular function. Results of the intervention tested in our studies have potential relevance for a number of systemic changes seen with prolonged spaceflight.

  17. Sound attenuation in magnetorheological fluids

    NASA Astrophysics Data System (ADS)

    Rodríguez-López, J.; Elvira, L.; Resa, P.; Montero de Espinosa, F.

    2013-02-01

    In this work, the attenuation of ultrasonic elastic waves propagating through magnetorheological (MR) fluids is analysed as a function of the particle volume fraction and the magnetic field intensity. Non-commercial MR fluids made with iron ferromagnetic particles and two different solvents (an olive oil based solution and an Araldite-epoxy) were used. Particle volume fractions of up to 0.25 were analysed. It is shown that the attenuation of sound depends strongly on the solvent used and the volume fraction. The influence of a magnetic field up to 212 mT was studied and it was found that the sound attenuation increases with the magnetic intensity until saturation is reached. A hysteretic effect is evident once the magnetic field is removed.

  18. Beta-adrenergic receptor agonists and antagonists counteract LPS-induced neuronal death in retinal cultures by different mechanisms.

    PubMed

    Arai, Kunizo; Wood, John P M; Osborne, Neville N

    2003-09-26

    Treatment with lipopolysaccharide (LPS) for 72 h was shown to dose-dependently increase nitric oxide production from 6-day-old retinal cultures. Cell death, as determined by lactate dehydrogenase (LDH) release and an increase in neuronal labelling for TUNEL, was elevated concurrently. During treatment there was an increase of both inducible nitric oxide synthase and glial fibrillary acidic protein labelling in glial cells and a reduction in the number of gamma-aminobutyric acid-positive neurones. The NOS inhibitors, N-nitro-L-arginine methyl ester, dexamethasone and indomethacin potently inhibited both nitric oxide stimulation and cell death caused by LPS. In this study, the beta(2)- (ICI-18551), beta(1)- (betaxolol) and mixed beta(1)/beta(2)- (timolol, metipranolol) adrenergic receptor antagonists were all shown to attenuate LPS-induced LDH release from these cultures, but to have no effect on LPS-stimulated nitric oxide production. This effect was mimicked by the calcium channel blocker, nifedipine. Interestingly, the beta-adrenergic receptor agonists, salbutamol, arterenol and isoproterenol were also able to attenuate cell death caused by LPS. Moreover, these compounds also inhibited LPS-stimulated nitric oxide release. These studies suggest that LPS stimulates nitric oxide release from cultured retinal glial cells and that this process leads to neurone death. beta-adrenergic receptor agonists prevent the effects of LPS by inhibiting the stimulation of nitric oxide production. The data also suggest that beta-adrenergic receptor antagonists can attenuate LPS-induced death of neurones, but that these compounds act in a manner that is neurone-dependent, is mimicked by blockade of calcium channels and is independent of the stimulation of nitric oxide release.

  19. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

    PubMed

    Minic, Zeljka; Li, Cailian; O'Leary, Donal S; Scislo, Tadeusz J

    2014-09-15

    Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists.

  20. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

    PubMed

    Minic, Zeljka; Li, Cailian; O'Leary, Donal S; Scislo, Tadeusz J

    2014-09-15

    Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists. PMID:25063794

  1. Exercise and bone mass in adults.

    PubMed

    Guadalupe-Grau, Amelia; Fuentes, Teresa; Guerra, Borja; Calbet, Jose A L

    2009-01-01

    There is a substantial body of evidence indicating that exercise prior to the pubertal growth spurt stimulates bone growth and skeletal muscle hypertrophy to a greater degree than observed during growth in non-physically active children. Bone mass can be increased by some exercise programmes in adults and the elderly, and attenuate the losses in bone mass associated with aging. This review provides an overview of cross-sectional and longitudinal studies performed to date involving training and bone measurements. Cross-sectional studies show in general that exercise modalities requiring high forces and/or generating high impacts have the greatest osteogenic potential. Several training methods have been used to improve bone mineral density (BMD) and content in prospective studies. Not all exercise modalities have shown positive effects on bone mass. For example, unloaded exercise such as swimming has no impact on bone mass, while walking or running has limited positive effects. It is not clear which training method is superior for bone stimulation in adults, although scientific evidence points to a combination of high-impact (i.e. jumping) and weight-lifting exercises. Exercise involving high impacts, even a relatively small amount, appears to be the most efficient for enhancing bone mass, except in postmenopausal women. Several types of resistance exercise have been tested also with positive results, especially when the intensity of the exercise is high and the speed of movement elevated. A handful of other studies have reported little or no effect on bone density. However, these results may be partially attributable to the study design, intensity and duration of the exercise protocol, and the bone density measurement techniques used. Studies performed in older adults show only mild increases, maintenance or just attenuation of BMD losses in postmenopausal women, but net changes in BMD relative to control subjects who are losing bone mass are beneficial in

  2. Exercise and bone mass in adults.

    PubMed

    Guadalupe-Grau, Amelia; Fuentes, Teresa; Guerra, Borja; Calbet, Jose A L

    2009-01-01

    There is a substantial body of evidence indicating that exercise prior to the pubertal growth spurt stimulates bone growth and skeletal muscle hypertrophy to a greater degree than observed during growth in non-physically active children. Bone mass can be increased by some exercise programmes in adults and the elderly, and attenuate the losses in bone mass associated with aging. This review provides an overview of cross-sectional and longitudinal studies performed to date involving training and bone measurements. Cross-sectional studies show in general that exercise modalities requiring high forces and/or generating high impacts have the greatest osteogenic potential. Several training methods have been used to improve bone mineral density (BMD) and content in prospective studies. Not all exercise modalities have shown positive effects on bone mass. For example, unloaded exercise such as swimming has no impact on bone mass, while walking or running has limited positive effects. It is not clear which training method is superior for bone stimulation in adults, although scientific evidence points to a combination of high-impact (i.e. jumping) and weight-lifting exercises. Exercise involving high impacts, even a relatively small amount, appears to be the most efficient for enhancing bone mass, except in postmenopausal women. Several types of resistance exercise have been tested also with positive results, especially when the intensity of the exercise is high and the speed of movement elevated. A handful of other studies have reported little or no effect on bone density. However, these results may be partially attributable to the study design, intensity and duration of the exercise protocol, and the bone density measurement techniques used. Studies performed in older adults show only mild increases, maintenance or just attenuation of BMD losses in postmenopausal women, but net changes in BMD relative to control subjects who are losing bone mass are beneficial in

  3. Probiotics protect mice from ovariectomy-induced cortical bone loss.

    PubMed

    Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H; Farman, Helen H; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

    2014-01-01

    The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice.

  4. Does running strengthen bone?

    PubMed

    Boudenot, Arnaud; Achiou, Zahra; Portier, Hugues

    2015-12-01

    Bone is a living tissue needing mechanical stress to maintain strength. Traditional endurance exercises offer only modest effects on bone. Walking and running produce low impact but lead to bone fatigue. This article is specifically addressed to therapists and explains the mechanisms involved for the effects of exercise on bone. Intermittent exercise limits bone fatigue, and downhill exercises increase ground impact forces and involve eccentric muscle contractions, which are particularly osteogenic. PMID:26562001

  5. Basic bone radiology

    SciTech Connect

    Griffiths, H.J.

    1987-01-01

    This clinical book surveys the skeletal system as seen through radiological imaging. It emphasizing abnormalities, disease, and trauma, and includes vital information on bones, bone growth, and the cells involved in bone pathology. It covers many bone diseases and injuries which are rarely covered in medical texts, as well as descriptions of radiologic procedures that specifically relate to the skeleton. This edition includes many illustrations, information on MR imaging and CT scanning, and discussions of osteoporosis, dysplasias, and metabolic bone disease.

  6. RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists

    PubMed Central

    2012-01-01

    Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates. PMID:24900488

  7. Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual.

    PubMed

    Bajayo, Alon; Bar, Arik; Denes, Adam; Bachar, Marilyn; Kram, Vardit; Attar-Namdar, Malka; Zallone, Alberta; Kovács, Krisztina J; Yirmiya, Raz; Bab, Itai

    2012-09-18

    Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α(2)nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra(Ast)(+/+) mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra(Ast)(+/+) mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.

  8. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-04-01

    In this report we will show results of seismic and well log derived attenuation attributes from a deep water Gulf of Mexico data set. This data was contributed by Burlington Resources and Seitel Inc. The data consists of ten square kilometers of 3D seismic data and three well penetrations. We have computed anomalous seismic absorption attributes on the seismic data and have computed Q from the well log curves. The results show a good correlation between the anomalous absorption (attenuation) attributes and the presence of gas as indicated by well logs.

  9. Bone cysts: unicameral and aneurysmal bone cyst.

    PubMed

    Mascard, E; Gomez-Brouchet, A; Lambot, K

    2015-02-01

    Simple and aneurysmal bone cysts are benign lytic bone lesions, usually encountered in children and adolescents. Simple bone cyst is a cystic, fluid-filled lesion, which may be unicameral (UBC) or partially separated. UBC can involve all bones, but usually the long bone metaphysis and otherwise primarily the proximal humerus and proximal femur. The classic aneurysmal bone cyst (ABC) is an expansive and hemorrhagic tumor, usually showing characteristic translocation. About 30% of ABCs are secondary, without translocation; they occur in reaction to another, usually benign, bone lesion. ABCs are metaphyseal, excentric, bulging, fluid-filled and multicameral, and may develop in all bones of the skeleton. On MRI, the fluid level is evocative. It is mandatory to distinguish ABC from UBC, as prognosis and treatment are different. UBCs resolve spontaneously between adolescence and adulthood; the main concern is the risk of pathologic fracture. Treatment in non-threatening forms consists in intracystic injection of methylprednisolone. When there is a risk of fracture, especially of the femoral neck, surgery with curettage, filling with bone substitute or graft and osteosynthesis may be required. ABCs are potentially more aggressive, with a risk of bone destruction. Diagnosis must systematically be confirmed by biopsy, identifying soft-tissue parts, as telangiectatic sarcoma can mimic ABC. Intra-lesional sclerotherapy with alcohol is an effective treatment. In spinal ABC and in aggressive lesions with a risk of fracture, surgical treatment should be preferred, possibly after preoperative embolization. The risk of malignant transformation is very low, except in case of radiation therapy.

  10. Carpal bone analysis in bone age assessment

    NASA Astrophysics Data System (ADS)

    Zhang, Aifeng; Gertych, Arkadiusz; Kurkowska-Pospiech, Sylwia; Liu, Brent J.; Huang, H. K.

    2006-03-01

    A computer-aided-diagnosis (CAD) method has been previously developed in our Laboratory based on features extracted from regions of interest (ROI) in phalanges in a digital hand atlas. Due to various factors, including, the diversity of size, shape and orientation of carpal bones, non-uniformity of soft tissue, low contrast between the bony structure and soft tissue, the automatic identification and segmentation of bone boundaries is an extremely challenging task. Past research work on carpal bone segmentation has been done utilizing dynamic thresholding. However, due to the discrepancy of carpal bones developments and the limitations of segmentation algorithms, carpal bone ROI has not been taken into consideration in the bone age assessment procedure. In this paper, we present a method for fully automatic carpal bone segmentation and feature analysis in hand X-ray radiograph. The purpose of this paper is to automatically segment the carpal bones by anisotropic diffusion and Canny edge detection techniques. By adding their respective features extracted from carpal bones ROI to the phalangeal ROI feature space, the accuracy of bone age assessment can be improved especially when the image processing in the phalangeal ROI fails in younger children.

  11. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  12. Interstitial ultrasound ablation of tumors within or adjacent to bone: Contributions of preferential heating at the bone surface

    NASA Astrophysics Data System (ADS)

    Scott, Serena J.; Prakash, Punit; Salgaonkar, Vasant; Jones, Peter D.; Cam, Richard N.; Han, Misung; Rieke, Viola; Burdette, E. Clif; Diederich, Chris J.

    2013-02-01

    Preferential heating of bone due to high ultrasound attenuation may enhance thermal ablation performed with cathetercooled interstitial ultrasound applicators in or near bone. At the same time, thermally and acoustically insulating cortical bone may protect sensitive structures nearby. 3D acoustic and biothermal transient finite element models were developed to simulate temperature and thermal dose distributions during catheter-cooled interstitial ultrasound ablation near bone. Experiments in ex vivo tissues and tissue-mimicking phantoms were performed to validate the models and to quantify the temperature profiles and ablated volumes for various distances between the interstitial applicator and the bone surface. 3D patient-specific models selected to bracket the range of clinical usage were developed to investigate what types of tumors could be treated, applicator configurations, insertion paths, safety margins, and other parameters. Experiments show that preferential heating at the bone surface decreases treatment times compared to when bone is absent and that all tissue between an applicator and bone can be ablated when they are up to 2 cm apart. Simulations indicate that a 5-7 mm safety margin of normal bone is needed to protect (thermal dose < 6 CEM43°C and T < 45°C) sensitive structures behind ablated bone. In 3D patient-specific simulations, tumors 1.0-3.8 cm (L) and 1.3-3.0 cm (D) near or within bone were ablated (thermal dose > 240 CEM43°C) within 10 min without damaging the nearby spinal cord, lungs, esophagus, trachea, or major vasculature. Preferential absorption of ultrasound by bone may provide improved localization, faster treatment times, and larger treatment zones in tumors in and near bone compared to other heating modalities.

  13. Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

    PubMed

    Miyazaki, Yusei; Niino, Masaaki; Kanazawa, Ippei; Suzuki, Masako; Mizuno, Masanori; Hisahara, Shin; Fukazawa, Toshiyuki; Takahashi, Eri; Amino, Itaru; Ochi, Ryutaro; Nakamura, Masakazu; Akimoto, Sachiko; Minami, Naoya; Fujiki, Naoto; Doi, Shizuki; Shimohama, Shun; Terayama, Yasuo; Kikuchi, Seiji

    2016-09-15

    Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients. PMID:27609272

  14. Heating of fetal bone by diagnostic ultrasound

    NASA Astrophysics Data System (ADS)

    Doody, Claire

    Most pregnant women in the Western world undergo an ultrasound examination and so it is important to ensure that exposure of the embryo or fetus does not produce unwanted effects. It is known that ultrasound can heat tissue, especially bone, and so this thesis explores the degree to which fetal bone might be heated during a pulsed Doppler examination. This is done both by carrying out measurements and by developing computer models. Thermal measurements on human fetal thoracic vertebrae of gestational age ranging from 14 to 39 weeks are reported. The bone samples were insonated in vitro with an ultrasound beam which had power and intensity values typical of those from a clinical scanner operating in pulsed Doppler mode. Temperature rises ranging from 0.6°C to 1.8°C were observed after five minutes, with approximately 75% of the temperature rise occurring in the first minute. Two approaches to computer modelling are described. These are the heated disc technique, which is commonly used to model the temperature rise generated by an ultrasound beam, and finite element modelling, a more general approach used to obtain solutions to differential equations. The degree to which our limited knowledge of the properties of fetal tissue affect our ability to make accurate predictions of in vivo heating is explored. It is shown that the present uncertainty in the value of the thermal conductivity and attenuation coefficient of fetal bone can lead to significant uncertainty in predictions of heating. The degree to which the simplifications inherent in the heated disc model affect the results will also be discussed. The results from the models are compared with the experimental measurements in order to estimate the attenuation coefficient of the bone.

  15. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  16. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  17. Sound production during agonistic behavior of male Drosophila melanogaster

    PubMed Central

    Jonsson, Thorin; Kravitz, Edward A

    2011-01-01

    Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female-directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID:20953152

  18. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  19. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  20. Tolerance with beta 2-adrenoceptor agonists: time for reappraisal.

    PubMed Central

    Grove, A; Lipworth, B J

    1995-01-01

    1. In spite of the widespread use of beta 2-adrenoceptor agonists in the treatment of asthma controversy continues regarding their possible role in increasing asthma mortality and morbidity. There is however no evidence available to suggest that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. 2. There is no conclusive evidence to suggest that tolerance develops to the bronchodilator effects of short-acting beta 2-adrenoceptor agonists. Tolerance does however appear to develop to the anti-bronchoconstrictor effects of these drugs. 3. With regard to the long-acting beta 2-adrenoceptor agonists, there is evidence to suggest that tolerance develops both to their anti-bronchoconstrictor, and bronchodilator effects. Tolerance was however demonstrated in the presence of improved symptom control, therefore the clinical relevance of this phenomenon is uncertain. 4. Systemic corticosteroids can modulate lymphocyte beta 2-adrenoceptor function both preventing, and reversing tolerance. The situation regarding the effects of systemic or inhaled corticosteroids on modulating bronchodilator responses in asthmatics is less clear. There is some evidence to suggest that inhaled corticosteroids are unable to prevent bronchodilator or systemic tolerance to long-acting beta 2-adrenoceptor agonists. 5. On the basis of the current evidence, the British Thoracic Society guidelines for the management of asthma appear appropriate with regard to their recommendations for the use of long-acting beta 2-adrenoceptor agonists. PMID:7742147

  1. Current issues with beta2-adrenoceptor agonists: historical background.

    PubMed

    Tattersfield, Anne E

    2006-01-01

    The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective beta-agonist, isoproterenol, was isolated in 1940, followed by the development of selective beta2-agonists in the 1960s and the introduction of the long-acting beta2-agonists in the 1990s. The introduction of beta2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The beta2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from beta2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

  2. Bone disease in hypoparathyroidism.

    PubMed

    Clarke, Bart L

    2014-07-01

    Hypoparathyroidism is a rare disorder that may be acquired or inherited. Postsurgical hypoparathyroidism is responsible for the majority of acquired hypoparathyroidism. Bone disease occurs in hypoparathyroidism due to markedly reduced bone remodeling due to the absence or low levels of parathyroid hormone. Chronically reduced bone turnover in patients with hypoparathyroidism typically leads to higher bone mass than in age- and sex-matched controls. Whether this increased bone density reduces fracture risk is less certain, because while increased bone mineralization may be associated with increased brittleness of bone, this does not appear to be the case in hypoparathyroidism. Treatment of hypoparathyroidism with recombinant parathyroid hormone may reduce bone mineral density but simultaneously strengthen the mechanical properties of bone.

  3. Bisphosphonates and bone quality

    PubMed Central

    Pazianas, Michael; van der Geest, Stefan; Miller, Paul

    2014-01-01

    Bisphosphonates (BPs) are bone-avid compounds used as first-line medications for the prevention and treatment of osteoporosis. They are also used in other skeletal pathologies such as Paget's and metastatic bone disease. They effectively reduce osteoclast viability and also activity in the resorptive phase of bone remodelling and help preserve bone micro-architecture, both major determinants of bone strength and ultimately of the susceptibility to fractures. The chemically distinctive structure of each BP used in the clinic determines their unique affinity, distribution/penetration throughout the bone and their individual effects on bone geometry, micro-architecture and composition or what we call ‘bone quality'. BPs have no clinically significant anabolic effects. This review will touch upon some of the components of bone quality that could be affected by the administration of BPs. PMID:24876930

  4. Flagella Overexpression Attenuates Salmonella Pathogenesis

    PubMed Central

    Yang, Xinghong; Thornburg, Theresa; Suo, Zhiyong; Jun, SangMu; Robison, Amanda; Li, Jinquan; Lim, Timothy; Cao, Ling; Hoyt, Teri; Avci, Recep; Pascual, David W.

    2012-01-01

    Flagella are cell surface appendages involved in a number of bacterial behaviors, such as motility, biofilm formation, and chemotaxis. Despite these important functions, flagella can pose a liability to a bacterium when serving as potent immunogens resulting in the stimulation of the innate and adaptive immune systems. Previous work showing appendage overexpression, referred to as attenuating gene expression (AGE), was found to enfeeble wild-type Salmonella. Thus, this approach was adapted to discern whether flagella overexpression could induce similar attenuation. To test its feasibility, flagellar filament subunit FliC and flagellar regulon master regulator FlhDC were overexpressed in Salmonella enterica serovar Typhimurium wild-type strain H71. The results show that the expression of either FliC or FlhDC alone, and co-expression of the two, significantly attenuates Salmonella. The flagellated bacilli were unable to replicate within macrophages and thus were not lethal to mice. In-depth investigation suggests that flagellum-mediated AGE was due to the disruptive effects of flagella on the bacterial membrane, resulting in heightened susceptibilities to hydrogen peroxide and bile. Furthermore, flagellum-attenuated Salmonella elicited elevated immune responses to Salmonella presumably via FliC’s adjuvant effect and conferred robust protection against wild-type Salmonella challenge. PMID:23056473

  5. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-07-01

    In fully-saturated rock and at ultrasonic frequencies, the microscopic squirt flow induced between the stiff and soft parts of the pore space by an elastic wave is responsible for velocity-frequency dispersion and attenuation. In the seismic frequency range, it is the macroscopic cross-flow between the stiffer and softer parts of the rock. We use the latter hypothesis to introduce simple approximate equations for velocity-frequency dispersion and attenuation in a fully water saturated reservoir. The equations are based on the assumption that in heterogeneous rock and at a very low frequency, the effective elastic modulus of the fully-saturated rock can be estimated by applying a fluid substitution procedure to the averaged (upscaled) dry frame whose effective porosity is the mean porosity and the effective elastic modulus is the Backus-average (geometric mean) of the individual dry-frame elastic moduli of parts of the rock. At a higher frequency, the effective elastic modulus of the saturated rock is the Backus-average of the individual fully-saturated-rock elastic moduli of parts of the rock. The difference between the effective elastic modulus calculated separately by these two methods determines the velocity-frequency dispersion. The corresponding attenuation is calculated from this dispersion by using (e.g.) the standard linear solid attenuation model.

  6. Feasibility of bone assessment by using the nonlinear parameter in trabecular bone

    NASA Astrophysics Data System (ADS)

    Lee, Kang Il

    2013-04-01

    The purpose of the present study is to investigate the feasibility of assessing bone status and osteoporosis by using the nonlinear parameter B/A in bovine trabecular bone in vitro. The B/A values measured in 18 bovine femoral trabecular bone samples by using a finite-amplitude through-transmission method ranged from 63.3 to 122.6. The apparent bone density was highly correlated with the B/A and with the existing quantitative ultrasound parameters of the speed of sound (SOS) and the normalized broadband ultrasound attenuation (nBUA), with Pearson's correlation coefficients of r = 0.83 to 0.96. The best univariate predictor of the apparent bone density was the B/A, with an adjusted squared correlation coefficient of r 2 = 0.91. These results suggest that the B/A, in addition to the SOS and the nBUA, may have potential as an index for the assessment of bone status and osteoporosis.

  7. Contribution of conformationally constrained calcitonin (Ct) analogs to the understanding of the structural and conformational requirements of calcitonin bioactivity and to the design of potent agonists.

    PubMed

    Kapurniotu, Aphrodite

    2004-11-01

    Restricting the conformational flexibility of medium-sized linear polypeptides is a valuable approach to identify and characterize the structural and conformational features that define their biological activities and to design analogs with enhanced agonistic or antagonistic properties and with potential therapeutic applications. The calcium-regulating and bone resorption-inhibiting hormone calcitonin (Ct) is a conformationally flexible polypeptide of 32 amino acid residues that has long been applied therapeutically for the treatment of osteoporosis and other bone disorder diseases. This review describes studies on the structural and conformational features of the Ct sequence that are relevant for Ct bioactivity and focuses on research work performed on rationally designed conformationally constrained Ct analogs as tools for the understanding of the molecular basis of Ct bioactivity and as potential candidates or lead structures for novel Ct-based bone disorder therapeutics. PMID:15544479

  8. Retail cut yields of Rambouillet wether lambs fed the beta-adrenergic agonist L644,969.

    PubMed

    Shackelford, S D; Edwards, J W; Smarr, E K; Savell, J W

    1992-01-01

    Twenty Rambouillet wether lambs were given ad libitum access to a diet with (BAA, n = 10) or without (control, n = 10) 1 ppm of the beta-adrenergic agonist L644,969. Lambs were fed to a constant slaughter weight end point of 54.5 kg. Carcasses were fabricated to yield bone-in and boneless cuts that were trimmed progressively to 1.27, .64, .32, and .00 cm of s.c. fat remaining. Addition of BAA did not affect growth traits. Actual and adjusted fat thickness, body wall thickness, and percentage of kidney-pelvic fat did not differ between control and BAA lambs. However, BAA increased longissimus muscle area, longissimus muscle depth, and leg score while decreasing USDA yield grade. The BAA increased carcass conformation scores and decreased flank lean color scores. No other carcass quality measurements were affected by BAA. Addition of BAA did not affect overall carcass yields of bone-in retail cuts. However, BAA increased overall carcass yields of boneless retail cuts regardless of fat trim level. The BAA increased bone-in leg yield. Yield of boneless sirloin, bone-in loin and boneless loin were not affected by BAA. For these cuts, the percentage change from the control was highly dependent on fat trim level. There was no difference in short-cut, shank-off, semiboneless leg yield between control and BAA. Addition of BAA did not affect yield of bone-in rack regardless of fat trim level. However, BAA greatly increased yield of boneless ribeye. The BAA did not affect yield of bone-in or boneless shoulder.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Bone-immune cell crosstalk: bone diseases.

    PubMed

    Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta; Brunetti, Giacomina

    2015-01-01

    Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma. PMID:26000310

  10. Bone-immune cell crosstalk: bone diseases.

    PubMed

    Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta; Brunetti, Giacomina

    2015-01-01

    Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.

  11. Stormwater Attenuation by Green Roofs

    NASA Astrophysics Data System (ADS)

    Sims, A.; O'Carroll, D. M.; Robinson, C. E.; Smart, C. C.

    2014-12-01

    Innovative municipal stormwater management technologies are urgently required in urban centers. Inadequate stormwater management can lead to excessive flooding, channel erosion, decreased stream baseflows, and degraded water quality. A major source of urban stormwater is unused roof space. Green roofs can be used as a stormwater management tool to reduce roof generated stormwater and generally improve the quality of runoff. With recent legislation in some North American cities, including Toronto, requiring the installation of green roofs on large buildings, research on the effectiveness of green roofs for stormwater management is important. This study aims to assess the hydrologic response of an extensive sedum green roof in London, Ontario, with emphasis on the response to large precipitation events that stress municipal stormwater infrastructure. A green roof rapidly reaches field capacity during large storm events and can show significantly different behavior before and after field capacity. At field capacity a green roof has no capillary storage left for retention of stormwater, but may still be an effective tool to attenuate peak runoff rates by transport through the green roof substrate. The attenuation of green roofs after field capacity is linked to gravity storage, where gravity storage is the water that is temporarily stored and can drain freely over time after field capacity has been established. Stormwater attenuation of a modular experimental green roof is determined from water balance calculations at 1-minute intervals. Data is used to evaluate green roof attenuation and the impact of field capacity on peak flow rates and gravity storage. In addition, a numerical model is used to simulate event based stormwater attenuation. This model is based off of the Richards equation and supporting theory of multiphase flow through porous media.

  12. The Mineralocorticoid Agonist Fludrocortisone Promotes Survival and Proliferation of Adult Hippocampal Progenitors

    PubMed Central

    Gesmundo, Iacopo; Villanova, Tania; Gargantini, Eleonora; Arvat, Emanuela; Ghigo, Ezio; Granata, Riccarda

    2016-01-01

    Glucocorticoid receptor (GR) activation has been shown to reduce adult hippocampal progenitor cell proliferation and neurogenesis. By contrast, mineralocorticoid receptor (MR) signaling is associated with neuronal survival in the dentate gyrus of the hippocampus, and impairment of hippocampal MR has been linked to pathological conditions, such as depression or neurodegenerative disorders. Here, we aimed to further clarify the protective role of MR in adult hippocampal neurons by studying the survival and proliferative effects of the highly potent MR agonist fludrocortisone (Fludro) in adult rat hippocampal progenitor cells (AHPs), along with the associated signaling mechanisms. Fludro, which upregulated MR but not GR expression, increased survival and proliferation and prevented apoptosis in AHPs cultured in growth factor-deprived medium. These effects were blunted by the MR antagonist spironolactone and by high doses of the GR agonist dexamethasone. Moreover, they involved signaling through cAMP/protein kinase A (PKA)/cAMP response element-binding protein, phosphoinositide 3-kinase (PI3K)/Akt and its downstream targets glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin. Furthermore, Fludro attenuated the detrimental effects of amyloid-β peptide 1–42 (Aβ1–42) on cell survival, proliferation, and apoptosis in AHPs, and increased the phosphorylation of both PI3K/Akt and GSK-3β, which was reduced by Aβ1–42. Finally, Fludro blocked Aβ1–42-induced hyperphosphorylation of Tau protein, which is a main feature of Alzheimer’s disease. Overall, these results are the first to show the protective and proliferative role of Fludro in AHPs, suggesting the potential therapeutic importance of targeting MR for increasing hippocampal neurogenesis and for treating neurodegenerative diseases. PMID:27379018

  13. The liver X receptor agonist TO901317 protects mice against cisplatin-induced kidney injury

    PubMed Central

    Yang, Meng; Wang, Rong; Sun, Jing; Yu, Kezhou; Chen, Bing; Xu, Liang; Zhao, Bing

    2015-01-01

    Liver X receptors are in the nuclear receptor superfamily and are contained in the regulation of lipid and cholesterol metabolism. Besides, liver X receptors are considered crucial regulators of the inflammatory response and innate immunity. The current study evaluates the in vivo effects that the synthetic liver X receptor agonist TO901317 protects against cisplatin-induced kidney injury in mice. Mice received cisplatin administration through a single intraperitoneal injection (20 mg/kg in saline). And then the mice were treated with the TO901317 by daily gavage (10 mg/kg/day) 12 h postcisplatin administration, and cisplatin nephrotoxicity was evaluated. At 72 h after cisplatin treatment, elevated plasma urea and creatinine levels (P < 0.05) were evidenced which indicates the renal dysfunction of the vehicle-treated mice, consistent with tubular necrosis, protein cast, dilation of renal tubules, and desquamation of epithelial cells in renal tubules. In contrast, the severity of renal dysfunction and histological damage was reduced in TO901317 treated mice (P < 0.05). In accordance, circulating tumor necrosis factor alpha levels, renal tumor necrosis factor alpha, p47phox, gp91phox, and protein expression levels and COX-2 mRNA, renal monocyte chemoattractant protein 1, VACAM-1 mRNA and intercellular adhesion molecule-1 contents, and renal prostaglandin E2 amounts, were higher in samples from cisplatin-treated mice in comparison with controls (P < 0.05) but attenuated in the TO901317 treatment group (P < 0.05). Taken together, treatment with the liver X receptor agonist TO901317 ameliorated the inflammatory response and oxidative stress in cisplatin-induced kidney injury in mice. PMID:26062799

  14. G protein-coupled receptors: signalling and regulation by lipid agonists for improved glucose homoeostasis.

    PubMed

    Moran, Brian M; Flatt, Peter R; McKillop, Aine M

    2016-04-01

    G protein-coupled receptors (GPCRs) play a pivotal role in cell signalling, controlling many processes such as immunity, growth, cellular differentiation, neurological pathways and hormone secretions. Fatty acid agonists are increasingly recognised as having a key role in the regulation of glucose homoeostasis via stimulation of islet and gastrointestinal GPCRs. Downstream cell signalling results in modulation of the biosynthesis, secretion, proliferation and anti-apoptotic pathways of islet and enteroendocrine cells. GPR40 and GPR120 are activated by long-chain fatty acids (>C12) with both receptors coupling to the Gαq subunit that activates the Ca(2+)-dependent pathway. GPR41 and GPR43 are stimulated by short-chain fatty acids (C2-C5), and activation results in binding to Gαi that inhibits the adenylyl cyclase pathway attenuating cAMP production. In addition, GPR43 also couples to the Gαq subunit augmenting intracellular Ca(2+) and activating phospholipase C. GPR55 is specific for cannabinoid endogenous agonists (endocannabinoids) and non-cannabinoid fatty acids, which couples to Gα12/13 and Gαq proteins, leading to enhancing intracellular Ca(2+), extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and Rho kinase. GPR119 is activated by fatty acid ethanolamides and binds to Gαs utilising the adenylate cyclase pathway, which is dependent upon protein kinase A. Current research indicates that GPCR therapies may be approved for clinical use in the near future. This review focuses on the recent advances in preclinical diabetes research in the signalling and regulation of GPCRs on islet and enteroendocrine cells involved in glucose homoeostasis.

  15. Calmodulin regulation of basal and agonist-stimulated G protein coupling by the mu-opioid receptor (OP(3)) in morphine-pretreated cell.

    PubMed

    Wang, D; Surratt, C K; Sadée, W

    2000-08-01

    Calmodulin (CaM) has been shown to suppress basal G protein coupling and attenuate agonist-stimulated G protein coupling of the mu-opioid receptor (OP(3)) through direct interaction with the third intracellular (i3) loop of the receptor. Here we have investigated the role of CaM in regulating changes in OP(3)-G protein coupling during morphine treatment, shown to result in CaM release from plasma membranes. Basal and agonist-stimulated G protein coupling by OP(3) was measured before and after morphine pretreatment by incorporation of guanosine 5'-O-(3-[(35)S]thiotriphosphate) into membranes, obtained from HEK 293 cells transfected with human OP(3) cDNA. The opioid antagonist beta-chlornaltrexamine fully suppressed basal G protein coupling of OP(3), providing a direct measure of basal signaling. Pretreatment of the cells with morphine enhanced basal G protein coupling (sensitization). In contrast, agonist-stimulated coupling was diminished (desensitization), resulting in a substantially flattened morphine dose-response curve. To test whether CaM is involved in these changes, we constructed OP(3)-i3 loop mutants with reduced affinity for CaM (K273A, R275A, and K273A/R275A). Basal signaling of these mutant OP(3) receptors was higher than that of the wild-type receptor and, moreover, unaffected by morphine pretreatment, whereas desensitization to agonist stimulation was only slightly attenuated. Therefore, CaM-OP(3) interactions appear to play only a minor role in the desensitization of OP(3). In contrast, release of CaM from the plasma membrane appears to enhance the inherent basal G protein coupling of OP(3), thereby resolving the paradox that OP(3) displays both desensitization and sensitization during morphine treatment.

  16. PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.

    PubMed

    Stechschulte, L A; Czernik, P J; Rotter, Z C; Tausif, F N; Corzo, C A; Marciano, D P; Asteian, A; Zheng, J; Bruning, J B; Kamenecka, T M; Rosen, C J; Griffin, P R; Lecka-Czernik, B

    2016-08-01

    The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease. PMID:27422345

  17. Confounding of the Comparative Safety of Prenatal Opioid Agonist Therapy

    PubMed Central

    Brogly, Susan B; Hahn, Kristen A; Diaz, Sonia Hernandez; Werler, Martha

    2016-01-01

    Prenatal opioid agonist therapy with methadone or buprenorphine prevents maternal illicit opioid use and withdrawal and improves pregnancy outcomes compared to heroin use alone. Historically, methadone has been the first-line opioid agonist therapy for pregnant opioid dependent women; in recent years buprenorphine has become first-line treatment for some opioid dependent pregnant women. While there is some evidence of better outcomes in neonates exposed to buprenorphine vs. methadone, the effect of confounding from differences in women who use buprenorphine and methadone has not been carefully examined in most studies. This review explores mechanisms by which confounding can arise in measuring associations between prenatal buprenorphine vs. methadone exposure on neonatal outcomes using a graphical approach, directed acyclic graphs. The goal of this paper is to facilitate better understanding of the factors influencing neonatal abstinence syndrome and accurate assessment of the comparative safety of opioid agonist therapies on the neonate. PMID:27547489

  18. Adenosine receptor agonists for promotion of dermal wound healing

    PubMed Central

    Valls, María D.; Cronstein, Bruce N.; Montesinos, M. Carmen

    2009-01-01

    Wound healing is a dynamic and complex process that involves a well coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing. PMID:19041853

  19. Design, evaluation, and comparison of ghrelin receptor agonists and inverse agonists as suitable radiotracers for PET imaging.

    PubMed

    Chollet, Constance; Bergmann, Ralf; Pietzsch, Jens; Beck-Sickinger, Annette G

    2012-04-18

    Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga(3+). Complexation with (68)Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the (68)Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH(2) suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity. PMID:22372770

  20. Demineralization–remineralization dynamics in teeth and bone

    PubMed Central

    Abou Neel, Ensanya Ali; Aljabo, Anas; Strange, Adam; Ibrahim, Salwa; Coathup, Melanie; Young, Anne M; Bozec, Laurent; Mudera, Vivek

    2016-01-01

    Biomineralization is a dynamic, complex, lifelong process by which living organisms control precipitations of inorganic nanocrystals within organic matrices to form unique hybrid biological tissues, for example, enamel, dentin, cementum, and bone. Understanding the process of mineral deposition is important for the development of treatments for mineralization-related diseases and also for the innovation and development of scaffolds. This review provides a thorough overview of the up-to-date information on the theories describing the possible mechanisms and the factors implicated as agonists and antagonists of mineralization. Then, the role of calcium and phosphate ions in the maintenance of teeth and bone health is described. Throughout the life, teeth and bone are at risk of demineralization, with particular emphasis on teeth, due to their anatomical arrangement and location. Teeth are exposed to food, drink, and the microbiota of the mouth; therefore, they have developed a high resistance to localized demineralization that is unmatched by bone. The mechanisms by which demineralization–remineralization process occurs in both teeth and bone and the new therapies/technologies that reverse demineralization or boost remineralization are also scrupulously discussed. Technologies discussed include composites with nano- and micron-sized inorganic minerals that can mimic mechanical properties of the tooth and bone in addition to promoting more natural repair of surrounding tissues. Turning these new technologies to products and practices would improve health care worldwide. PMID:27695330

  1. Demineralization–remineralization dynamics in teeth and bone

    PubMed Central

    Abou Neel, Ensanya Ali; Aljabo, Anas; Strange, Adam; Ibrahim, Salwa; Coathup, Melanie; Young, Anne M; Bozec, Laurent; Mudera, Vivek

    2016-01-01

    Biomineralization is a dynamic, complex, lifelong process by which living organisms control precipitations of inorganic nanocrystals within organic matrices to form unique hybrid biological tissues, for example, enamel, dentin, cementum, and bone. Understanding the process of mineral deposition is important for the development of treatments for mineralization-related diseases and also for the innovation and development of scaffolds. This review provides a thorough overview of the up-to-date information on the theories describing the possible mechanisms and the factors implicated as agonists and antagonists of mineralization. Then, the role of calcium and phosphate ions in the maintenance of teeth and bone health is described. Throughout the life, teeth and bone are at risk of demineralization, with particular emphasis on teeth, due to their anatomical arrangement and location. Teeth are exposed to food, drink, and the microbiota of the mouth; therefore, they have developed a high resistance to localized demineralization that is unmatched by bone. The mechanisms by which demineralization–remineralization process occurs in both teeth and bone and the new therapies/technologies that reverse demineralization or boost remineralization are also scrupulously discussed. Technologies discussed include composites with nano- and micron-sized inorganic minerals that can mimic mechanical properties of the tooth and bone in addition to promoting more natural repair of surrounding tissues. Turning these new technologies to products and practices would improve health care worldwide.

  2. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    SciTech Connect

    Raufman, Jean-Pierre; Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre

  3. Factors that characterize bone health with aging in healthy postmenopausal women.

    PubMed

    Ikegami, Shota; Uchiyama, Shigeharu; Nakamura, Yukio; Mukaiyama, Keijiro; Hirabayashi, Hiroki; Kamimura, Mikio; Nonaka, Kiichi; Kato, Hiroyuki

    2015-07-01

    The exponential increase in the incidence of fragility fractures in older people is attributed to attenuation of both bone strength and neuromuscular function. Decrease in bone mineral density (BMD) does not entirely explain this increase. The objective of this study is to investigate the effect of age on various parameters related to bone health with aging, and to identify combinations of factors that collectively express the bone metabolic state in healthy postmenopausal women. Height, weight, and grip strength were measured in 135 healthy postmenopausal volunteer women. Hip BMD, biomechanical indices derived from quantitative computed tomography (QCT), cross-sectional areas of muscle and fat of the proximal thigh, and various biochemical markers of bone metabolism were measured. A smaller group of factors explanatory for bone health was identified using factor analysis and each was newly named. As a result, the factors bone mass, bone turnover, bone structure, and muscle strength had the greatest explanatory power for assessing the bone health of healthy postmenopausal women. Whereas dual X-ray absorptiometry parameters only loaded on the factor bone mass, QCT parameters loaded on both the factors bone mass and bone structure. Most bone turnover markers loaded on the factor bone turnover, but deoxypyridinoline loaded on both bone turnover and muscle strength. Age was negatively correlated with bone mass (r = -0.49, p < 0.001) and muscle strength (r = -0.67, p < 0.001). We conclude that aging is associated as much with muscle weakening as with low BMD. More attention should be paid to the effects of muscle weakening during aging in assessments of bone health. PMID:25113438

  4. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  5. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  6. Beta2-agonist extraction procedures for chromatographic analysis.

    PubMed

    dos Ramos, F J

    2000-06-01

    Normally, different procedures were necessary to prepare sample matrices for chromatographic determination of beta2-agonists. The present review includes sampling, pre-treatment and extraction/purification for urine, plasma, liver, meat, feeds, hair and milk powder, as previous steps for chromatographic analysis of beta2-agonists. Six methodologies were especially revised for extraction/purification namely, liquid-liquid extraction, solid-phase extraction (SPE), matrix solid-phase dispersion, immunoaffinity chromatography, dialysis and supercritical fluid extraction. SPE was discussed in detail and five mechanisms were described: adsorption, apolar, polar, ion-exchange and mixed phase. A brief conclusion in this field was also outlined.

  7. Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task.

    PubMed

    Wood, Christopher; Kohli, Shivali; Malcolm, Emma; Allison, Claire; Shoaib, Mohammed

    2016-06-01

    Nicotinic acetylcholine receptors (nAChRs) are considered to be viable targets to enhance cognition in patients diagnosed with schizophrenia. Activation of nAChRs with selective nicotinic receptor agonists may provide effective means to pharmacologically treat cognitive deficits observed in schizophrenia. Cognitive flexibility is one aspect of cognition, which can be assessed in a rodent model of the attentional set-shifting task (ASST). The aim of the present study was two-fold, firstly, to evaluate the efficacy of a series of subtype selective nAChR agonists, such as those that target α7 and α4β2 nAChR subtypes in non-compromised rodents. Secondly, nicotine as a prototypic agonist was evaluated for its effects to restore attentional deficits produced by sub-chronic ketamine exposure in the ASST. Male hooded Lister rats underwent habituation, consisting of a simple odour and medium discrimination with subsequent assessment 24 h later. In experimentally naïve rats, α7 subtype selective agonists, compound-A and SSR180711 along with PNU-120596, an α7 positive allosteric modulator (PAM), were compared against the β2* selective agonist, 5IA-85380. All compounds except for PNU-120596 were observed to significantly improve extra-dimensional (ED) shift performance, nicotine, 5IA-85380 and SSR180711 further enhanced the final reversal (REV3) stage of the task. In another experiment, sub-chronic ketamine treatment produced robust deficits during the ED and the REV3 stages of the discriminations; rodents required significantly more trials to reach criterion during these discriminations. These deficits were attenuated in rodents treated acutely with nicotine (0.1 mg/kg SC) 10 min prior to the ED shift. These results highlight the potential utility of targeting nAChRs to enhance cognitive flexibility, particularly the α7 and β2* receptor subtypes. The improvement with nicotine was much greater in rodents that were impaired following the sub-chronic ketamine

  8. Acute Calcium Ingestion Attenuates Exercise-induced Disruption of Calcium Homeostasis

    PubMed Central

    Barry, Daniel W; Hansen, Kent C; Van Pelt, Rachael E; Witten, Michael; Wolfe, Pamela; Kohrt, Wendy M

    2011-01-01

    Purpose Exercise is associated with a decrease in bone mineral density under certain conditions. One potential mechanism is increased bone resorption due to an exercise-induced increase in parathyroid hormone (PTH), possibly triggered by dermal calcium loss. The purpose of this investigation was to determine whether calcium supplementation either before or during exercise attenuates exercise-induced increases in PTH and C-terminal telopeptide of type I collagen (CTX; a marker of bone resorption). Methods Male endurance athletes (n=20) completed three 35-km cycling time trials under differing calcium supplementation conditions: 1) 1000 mg calcium 20 minutes before exercise and placebo during, 2) placebo before and 250 mg calcium every 15 minutes during exercise (1000 mg total), or 3) placebo before and during exercise. Calcium was delivered in a 1000 mg/L solution. Supplementation was double-blinded and trials were performed in random order. PTH, CTX, bone-specific alkaline phosphatase (BAP; a marker of bone formation), and ionized calcium (iCa) were measured before and immediately after exercise. Results CTX increased and iCa decreased similarly in response to exercise under all test conditions. When compared to placebo, calcium supplementation before exercise attenuated the increase in PTH (55.8 ± 15.0 vs. 74.0 ± 14.2; mean ± SE; p=0.04); there was a similar trend (58.0 ± 17.4; p=0.07) for calcium supplementation during exercise. There were no effects of calcium on changes in CTX, BAP, and iCa. Conclusions Calcium supplementation before exercise attenuated the disruption of PTH. Further research is needed to determine the effects of repeated increases in PTH and CTX on bone (i.e., exercise training), and whether calcium supplementation can diminish any exercise-induced demineralization. PMID:20798655

  9. Bone resorption, metastasis, and diphosphonates

    SciTech Connect

    Garattini, S.

    1985-01-01

    This book contains 17 selections. Some of the titles are: Radiotherapy of Bone Lesions; Methodological Problems; Treatment of Bone Metastasis with Antiresorptive Drugs; Control of Bone Cancer Pain; and Chemotherapy of Bone Metastases.

  10. How Is Bone Cancer Diagnosed?

    MedlinePlus

    ... Topic How is bone cancer staged? How is bone cancer diagnosed? A patient’s symptoms, physical exam, and results ... and other imaging tests. Imaging tests to detect bone cancer X-rays Most bone cancers show up on ...

  11. [Development of a Novel Body Phantom with Bone Equivalent Density for Evaluation of Bone SPECT].

    PubMed

    Ichikawa, Hajime; Miwa, Kenta; Matsutomo, Norikazu; Watanabe, Yoichi; Kato, Toyohiro; Shimada, Hideki

    2015-12-01

    We developed a custom-designed phantom for bone single photon emission computed tomography (SPECT)-specific radioactivity distribution and linear attenuation coefficient. The aim of this study was to evaluate the accuracy of the phantom. The lumbar phantom consisted of the trunk of a body phantom (background) containing a cylinder (vertebral body), a sphere (tumor), and a T-shaped container (processus). The vertebral body, tumor, and processus phantoms contained a K(2)HPO(4) solution of bone equivalent density and 50, 300 and 50 kBq/mL of (99m)Tc, respectively. The body phantom contained 8 kBq/mL of (99m)Tc solution. SPECT images were acquired using low-energy high-resolution collimation, a 128 × 128 matrix and 120 projections over 360° with a dwell time of 15 sec/view × 4 times. Thereafter, CT images were acquired at 130 kV and 70 ref mAs using adaptive dose modulation. The SPECT data were reconstructed with ordered subset expectation maximization with three-dimensional, scatter, and CT-based attenuation correction. Count ratio, linear attenuation coefficient (LAC), and full-width at half-maximum (FWHM) were measured. Count ratios between the background, the vertebral body, and the tumor in SPECT images were 463.8: 2888.0: 15150.3 (1: 6.23: 32.7). The LAC of the background and vertebral body in the CT-derived attenuation map were 0.155 cm⁻¹ and 0.284 cm⁻¹, respectively, and the FWHM measured from the processus was 15.27 mm. The precise counts and LAC indicated that the phantom was accurate and could serve as a tool for evaluating acquisition, reconstruction parameters, and quantitation in bone SPECT images. PMID:26685836

  12. Bone Loss in IBD

    MedlinePlus

    ... DENSITY? Although bone seems as hard as a rock, it’s actually living tissue. Throughout your life, old ... available Bone Loss (.pdf) File: 290 KB 733 Third Avenue, Suite 510, New York, NY 10017 | 800- ...

  13. Bone Marrow Diseases

    MedlinePlus

    ... that help with blood clotting. With bone marrow disease, there are problems with the stem cells or ... marrow makes too many white blood cells Other diseases, such as lymphoma, can spread into the bone ...

  14. What Is Bone?

    MedlinePlus

    ... a soft framework, and calcium phosphate is a mineral that adds strength and hardens the framework. This ... bone formation continues at a faster pace than removal until bone mass peaks during the third decade ...

  15. NSAIDs attenuate hyperalgesia induced by TRP channel activation

    PubMed Central

    Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz; Tsagareli, Merab G.

    2016-01-01

    Transient receptor potential (TRP) cation channels have been extensively investigated as targets for analgesic drug discovery. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins (mediators of inflammation) and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we examined three widely used NSAIDs (diclofenac, ketorolac, and xefocam) on the activation of TRPA1 and TRPV1 channels using thermal paw withdrawal (Hargreaves) test and mechanical paw withdrawal (von Frey) test in male rats. Thermal withdrawal latencies and mechanical thresholds for both hind paws were obtained with 5, 15, 30, 45, 60, and 120 min intraplantar post-injection of TRPA1 agonizts, allyl isothiocyanate (AITC) (a natural compound of mustard oil) and cinnamaldehyde (CA), and TRPV1 agonist capsaicin or vehicle. Twenty minutes prior to the start of the experiment with TRP agonizts, diclofenac, ketorolac or xefocam were pre-injected in the same hindpaw and animals were examined by these two tests. After pretreatment of all three NSAIDs in the ipsilateral (injected) hindpaw that produced strong antinociceptive effects, AITC, CA, and capsaicin caused significant decreases in latency of the thermal withdrawal reflex compared with vehicle or the contralateral hindpaw. The same findings were observed for the paw withdrawal threshold. In approximately 30 min the effects of CA, AITC, and capsaicin returned to baseline. The data are different from our previous evidence, where TRPA1 agonizts AITC and CA and TRPV1 agonist capsaicin produced hyperalgesia for nearly 2 h and resulted in facilitation of these withdrawal reflexes (Tsagareli et al., 2010, 2013). Thus, our data showing that NSAIDs suppress thermal and mechanical hyperalgesia following TRP activation could presumably due to inactivation or desensitization of TRPA1 and TRPV1 channels by NSAIDs. PMID:26909384

  16. A comparison of the behavioural effects of 5-HT2A and 5-HT2C receptor agonists in the pigeon.

    PubMed

    Wolff, M C; Leander, J D

    2000-08-01

    Activity at the 5-HT2A receptor versus that of the 5-HT2C receptor was studied in three behavioural paradigms. In pigeons trained to discriminate 0.32 mg/kg of 1-(2,5-diemethoxy-4-iodophenyl)-2-aminopropane (DOI) (a mixed 5-HT2A/C receptor agonist) from vehicle, quipazine (0.1-1 mg/kg) and m-chlorophenylpiperazine (mCPP) (1-3 mg/kg) substituted for DOI in a dose-related manner, and this generalization was blocked by MDL100907 (0.0001-0.01 mg/kg), a selective 5-HT2A receptor antagonist. RO60-0175 (a relatively selective 5-HT2C agonist) induced partial substitution at 3 mg/kg that was antagonized by both MDL100907 and by 3 mg/kg of SB242084, a relatively selective 5-HT2C antagonist. MK212 (a mixed 5-HT2C/A agonist) induced partial substitution that was antagonized by SB242084, but not by MDL100907. On a progressive ratio 5 operant schedule (PR5) for food reinforcement, DOI, quipazine, mCPP, MK212 and R060-0175 decreased the break point; mCPP, DOI, MK212 and quipazine also induced vomiting. Although MDL100907 antagonized both the reductions of break point and vomiting, SB242084 only partially attenuated the decrease in break point observed with MK212 and DOI, and was unable to eliminate vomiting. Thus pharmacological activity at the 5-HT2A receptor can be behaviourally distinguished from pharmacological activity at the 5-HT2C receptor in the pigeon. Furthermore, the decrease in the break point of a PR5 schedule induced by 5-HT2C receptor agonists may be related to decreased appetite, whereas that induced by 5-HT2A receptor agonists may be due to unrelated factors, such as emesis. PMID:11103887

  17. ENHANCEMENTS TO NATURAL ATTENUATION: SELECTED CASE STUDIES

    SciTech Connect

    Vangelas, K; W. H. Albright, W; E. S. Becvar, E; C. H. Benson, C; T. O. Early, T; E. Hood, E; P. M. Jardine, P; M. Lorah, M; E. Majche, E; D. Major, D; W. J. Waugh, W; G. Wein, G; O. R. West, O

    2007-05-15

    In 2003 the US Department of Energy (DOE) embarked on a project to explore an innovative approach to remediation of subsurface contaminant plumes that focused on introducing mechanisms for augmenting natural attenuation to achieve site closure. Termed enhanced attenuation (EA), this approach has drawn its inspiration from the concept of monitored natural attenuation (MNA).

  18. Radionuclide bone imaging

    SciTech Connect

    Bassett, L.W.; Gold, R.H.; Webber, M.M.

    1981-12-01

    Radionuclide bone imaging of the skeleton, now well established as the most important diagnostic procedure in detecting bone metastases, is also a reliable method for the evaluation of the progression or regression of metastatic bone disease. The article concentrates on the technetium-99m agents and the value of these agents in the widespread application of low-dose radioisotope scanning in such bone diseases as metastasis, osteomyelitis, trauma, osteonecrosis, and other abnormal skeletal conditions.

  19. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-01-01

    In Section 1 of this first report we will describe the work we are doing to collect and analyze rock physics data for the purpose of modeling seismic attenuation from other measurable quantities such as porosity, water saturation, clay content and net stress. This work and other empirical methods to be presented later, will form the basis for ''Q pseudo-well modeling'' that is a key part of this project. In Section 2 of this report, we will show the fundamentals of a new method to extract Q, dispersion, and attenuation from field seismic data. The method is called Gabor-Morlet time-frequency decomposition. This technique has a number of advantages including greater stability and better time resolution than spectral ratio methods.

  20. Chlorine signal attenuation in concrete.

    PubMed

    Naqvi, A A; Maslehuddin, M; ur-Rehman, Khateeb; Al-Amoudi, O S B

    2015-11-01

    The intensity of prompt gamma-ray was measured at various depths from chlorine-contaminated silica fume (SF) concrete slab concrete specimens using portable neutron generator-based prompt gamma-ray setup. The intensity of 6.11MeV chloride gamma-rays was measured from the chloride contaminated slab at distance of 15.25, 20.25, 25.25, 30.25 and 35.25cm from neutron target in a SF cement concrete slab specimens. Due to attenuation of thermal neutron flux and emitted gamma-ray intensity in SF cement concrete at various depths, the measured intensity of chlorine gamma-rays decreases non-linearly with increasing depth in concrete. A good agreement was noted between the experimental results and the results of Monte Carlo simulation. This study has provided useful experimental data for evaluating the chloride contamination in the SF concrete utilizing gamma-ray attenuation method.

  1. Bone cysts: unicameral and aneurysmal bone cyst.

    PubMed

    Mascard, E; Gomez-Brouchet, A; Lambot, K

    2015-02-01

    Simple and aneurysmal bone cysts are benign lytic bone lesions, usually encountered in children and adolescents. Simple bone cyst is a cystic, fluid-filled lesion, which may be unicameral (UBC) or partially separated. UBC can involve all bones, but usually the long bone metaphysis and otherwise primarily the proximal humerus and proximal femur. The classic aneurysmal bone cyst (ABC) is an expansive and hemorrhagic tumor, usually showing characteristic translocation. About 30% of ABCs are secondary, without translocation; they occur in reaction to another, usually benign, bone lesion. ABCs are metaphyseal, excentric, bulging, fluid-filled and multicameral, and may develop in all bones of the skeleton. On MRI, the fluid level is evocative. It is mandatory to distinguish ABC from UBC, as prognosis and treatment are different. UBCs resolve spontaneously between adolescence and adulthood; the main concern is the risk of pathologic fracture. Treatment in non-threatening forms consists in intracystic injection of methylprednisolone. When there is a risk of fracture, especially of the femoral neck, surgery with curettage, filling with bone substitute or graft and osteosynthesis may be required. ABCs are potentially more aggressive, with a risk of bone destruction. Diagnosis must systematically be confirmed by biopsy, identifying soft-tissue parts, as telangiectatic sarcoma can mimic ABC. Intra-lesional sclerotherapy with alcohol is an effective treatment. In spinal ABC and in aggressive lesions with a risk of fracture, surgical treatment should be preferred, possibly after preoperative embolization. The risk of malignant transformation is very low, except in case of radiation therapy. PMID:25579825

  2. Wave dispersion and attenuation on human femur tissue.

    PubMed

    Strantza, Maria; Louis, Olivia; Polyzos, Demosthenes; Boulpaep, Frans; van Hemelrijck, Danny; Aggelis, Dimitrios G

    2014-01-01

    Cortical bone is a highly heterogeneous material at the microscale and has one of the most complex structures among materials. Application of elastic wave techniques to this material is thus very challenging. In such media the initial excitation energy goes into the formation of elastic waves of different modes. Due to "dispersion", these modes tend to separate according to the velocities of the frequency components. This work demonstrates elastic wave measurements on human femur specimens. The aim of the study is to measure parameters like wave velocity, dispersion and attenuation by using broadband acoustic emission sensors. First, four sensors were placed at small intervals on the surface of the bone to record the response after pencil lead break excitations. Next, the results were compared to measurements on a bulk steel block which does not exhibit heterogeneity at the same wave lengths. It can be concluded that the microstructure of the tissue imposes a dispersive behavior for frequencies below 1 MHz and care should be taken for interpretation of the signals. Of particular interest are waveform parameters like the duration, rise time and average frequency, since in the next stage of research the bone specimens will be fractured with concurrent monitoring of acoustic emission. PMID:25196011

  3. Bone marrow biopsy

    MedlinePlus

    Biopsy - bone marrow ... A bone marrow biopsy may be done in the health care provider's office or in a hospital. The sample may ... This captures a tiny sample, or core, of bone marrow within the needle. The sample and needle are ...

  4. [Benign bone forming tumors].

    PubMed

    Caufourier, C; Leprovost, N; Guillou-Jamard, M-R; Compère, J-F; Bénateau, H

    2009-09-01

    Benign bone forming tumors typically produce dense bone (osteoma, enostosis) or osteoid tissue (osteoid osteoma, osteoblastoma). Even though these four lesions have distinct characteristics, it is sometimes difficult to tell them apart and to rule out malignant bone forming lesions such as osteosarcoma. The first line treatment is surgical exeresis.

  5. Bone SPECT/CT in skeletal trauma.

    PubMed

    Scharf, Stephen C

    2015-01-01

    The utility of radionuclide bone scanning in skeletal trauma has been greatly enhanced over the last decade by hybrid technology merging multislice CT with SPECT that can take advantage of CT-based correction of attenuation and scatter. The resulting images have been particularly helpful in giving us new insights into the evaluation of foot and ankle injuries and vertebral pathology both before and after surgery. The physiological information and anatomical detail allow a better understanding of the causes of patients' pain and have proven to be particularly useful in planning surgical intervention.

  6. [Bone quality and strength relating with bone remodeling].

    PubMed

    Mori, Satoshi

    2016-01-01

    The bone has the functions of mineral reservoir and mechanical support as skeleton. Bone remodeling is the adult mode of bone metabolism, replacing old bone tissue to new one. Bone strength is determined by bone volume, structure and quality such as micro damage, degree of mineralization and collagen cross linkage, which are all controlled by bone remodeling. Bone strength decreases under high turn-over condition by decreasing bone volume and deterioration of bone structure, which also decreases under low turn-over condition by increased micro damage, increasing mineralization and AGE collagen cross linkage.

  7. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  8. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  9. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants. PMID:27476423

  10. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.

  11. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants.

  12. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease

    PubMed Central

    Wang, Bing; Chen, Li-Hua

    2016-01-01

    In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain. PMID:27747105

  13. Oxytocin and bone

    PubMed Central

    Sun, Li; Zaidi, Mone; Zallone, Alberta

    2014-01-01

    One of the most meaningful results recently achieved in bone research has been to reveal that the pituitary hormones have profound effect on bone, so that the pituitary-bone axis has become one of the major topics in skeletal physiology. Here, we discuss the relevant evidence about the posterior pituitary hormone oxytocin (OT), previously thought to exclusively regulate parturition and breastfeeding, which has recently been established to directly regulate bone mass. Both osteoblasts and osteoclasts express OT receptors (OTR), whose stimulation enhances bone mass. Consistent with this, mice deficient in OT or OTR display profoundly impaired bone formation. In contrast, bone resorption remains unaffected in OT deficiency because, even while OT stimulates the genesis of osteoclasts, it inhibits their resorptive function. Furthermore, in addition to its origin from the pituitary, OT is also produced by bone marrow osteoblasts acting as paracrine-autocrine regulator of bone formation modulated by estrogens. In turn, the power of estrogen to increase bone mass is OTR-dependent. Therefore, OTR−/− mice injected with 17β-estradiol do not show any effects on bone formation parameters, while the same treatment increases bone mass in wild-type mice. These findings together provide evidence for an anabolic action of OT in regulating bone mass and suggest that bone marrow OT may enhance the bone-forming action of estrogen through an autocrine circuit. This established new physiological role for OT in the maintenance of skeletal integrity further suggests the potential use of this hormone for the treatment of osteoporosis. PMID:25209411

  14. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly

  15. Anti-IL-20 monoclonal antibody promotes bone fracture healing through regulating IL-20-mediated osteoblastogenesis

    PubMed Central

    Hsu, Yu-Hsiang; Chiu, Yi-Shu; Chen, Wei-Yu; Huang, Kuo-Yuan; Jou, I-Ming; Wu, Po-Tin; Wu, Chih-Hsing; Chang, Ming-Shi

    2016-01-01

    Bone loss and skeletal fragility in bone fracture are caused by an imbalance in bone remodeling. The current challenge in bone fracture healing is to promote osteoblastogenesis and bone formation. We aimed to explore the role of IL-20 in osteoblastogenesis, osteoblast differentiation and bone fracture. Serum IL-20 was significantly correlated with serum sclerostin in patients with bone fracture. In a mouse model, anti-IL-20 monoclonal antibody (mAb) 7E increased bone formation during fracture healing. In vitro, IL-20 inhibited osteoblastogenesis by upregulating sclerostin, and downregulating osterix (OSX), RUNX2, and osteoprotegerin (OPG). IL-20R1 deficiency attenuated IL-20-mediated inhibition of osteoblast differentiation and maturation and reduced the healing time after a bone fracture. We conclude that IL-20 affects bone formation and downregulates osteoblastogenesis by modulating sclerostin, OSX, RUNX2, and OPG on osteoblasts. Our results demonstrated that IL-20 is involved in osteoregulation and anti-IL-20 mAb is a potential therapeutic for treating bone fracture or metabolic bone diseases. PMID:27075747

  16. Tanshinol Rescues the Impaired Bone Formation Elicited by Glucocorticoid Involved in KLF15 Pathway

    PubMed Central

    Yang, Yajun; Su, Yanjie; Wang, Dongtao; Chen, Yahui; Liu, Yuyu; Luo, Shiying; Wu, Tie

    2016-01-01

    Decreased bone formation is responsible for the pathogenesis of glucocorticoid- (GC-) induced osteoporosis (GIO), while the mechanism remains to be elucidated. The aim was to investigate how natural antioxidant tanshinol attenuates oxidative stress and rescues impaired bone formation elicited by GC in Sprague-Dawley rats and in C2C12 cells and/or MC3T3-E1 cells. The results showed that tanshinol prevented bone loss and decreased biomechanical characteristics and suppressed reduction of biomarkers related to osteogenesis in GIO rats. Further study revealed that tanshinol reversed decrease of transcription activity of Osterix-luc and rescued impairment of osteoblastic differentiation and bone formation involved in induction of KLF15 mRNA. Meanwhile, tanshinol diminished inhibition of protein expression of β-catenin and Tcf4 and transcription activity of Tcf4-luc induced by GC, especially under conditions of KLF siRNA in vitro. Additionally, tanshinol attenuated increase of reactive oxygen species (ROS) generation, phosphorylation of p66Shc expression, TUNEL-positive cells, and caspase-3 activity elicited by KLF15 under conditions of GC. Taken together, the present findings suggest that tanshinol attenuated the decrease of bone formation and bone mass and bone quality elicited by GC involved in KLF15/Wnt signaling transduction and counteracted GC-evoked oxidative stress and subsequent cell apoptosis involved in KLF15/p66Shc pathway cascade. PMID:27051474

  17. Effects of Active Mastication on Chronic Stress-Induced Bone Loss in Mice

    PubMed Central

    Azuma, Kagaku; Furuzawa, Manabu; Fujiwara, Shu; Yamada, Kumiko; Kubo, Kin-ya

    2015-01-01

    Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a wooden stick to chew during the experimental period. Quantitative micro-computed tomography, histologic analysis, and biochemical markers were used to evaluate the bone response. The stress/chewing group exhibited significantly attenuated stress-induced increases in serum corticosterone levels, suppressed bone formation, enhanced bone resorption, and decreased trabecular bone mass in the vertebrae and distal femurs, compared with mice in the stress group. Active mastication during exposure to chronic stress alleviated chronic stress-induced bone density loss in B6 mice. Active mastication during chronic psychologic stress may thus be an effective strategy to prevent and/or treat chronic stress-related osteopenia. PMID:26664256

  18. [Prefabrication of bone transplants].

    PubMed

    Jagodzinski, M; Kokemüller, H; Jehn, P; Vogt, P; Gellrich, N-C; Krettek, C

    2015-03-01

    Prefabrication of bone transplants is a promising option for large defects of the long bones, especially if there is compromised vascularization of the defect. This is especially true for postinfection bone defects and other types of atrophic nonunion. The generation of a foreign body membrane (Masquelet's technique) has been investigated in order to ameliorate the response of the host tissue surrounding the defect. In an experimental animal study, a blood vessel within a bone construct could be used to generate customized, vascularized osteogenic constructs that can be used to treat large bone defects in the future.

  19. Method for fusing bone

    DOEpatents

    Mourant, Judith R.; Anderson, Gerhard D.; Bigio, Irving J.; Johnson, Tamara M.

    1996-01-01

    Method for fusing