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Sample records for antagonist usag-1 ameliorates

  1. Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.

    Science.gov (United States)

    Tanaka, Mari; Asada, Misako; Higashi, Atsuko Y; Nakamura, Jin; Oguchi, Akiko; Tomita, Mayumi; Yamada, Sachiko; Asada, Nariaki; Takase, Masayuki; Okuda, Tomohiko; Kawachi, Hiroshi; Economides, Aris N; Robertson, Elizabeth; Takahashi, Satoru; Sakurai, Takeshi; Goldschmeding, Roel; Muso, Eri; Fukatsu, Atsushi; Kita, Toru; Yanagita, Motoko

    2010-03-01

    The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.

  2. Antagonistic Functions of USAG-1 and RUNX2 during Tooth Development.

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    Yumiko Togo

    Full Text Available Supernumerary teeth and tooth agenesis are common morphological anomalies in humans. We previously obtained evidence that supernumerary maxillary incisors form as a result of the successive development of the rudimentary maxillary incisor tooth germ in Usag-1 null mice. The development of tooth germs is arrested in Runx2 null mice, and such mice also exhibit lingual epithelial buds associated with the upper molars and incisors. The aim of this study is to investigate the potential crosstalk between Usag-1 and Runx2 during tooth development. In the present study, three interesting phenomena were observed in double null Usag-1-/-/Runx2-/- mice: the prevalence of supernumerary teeth was lower than in Usag-1 null mice; tooth development progressed further compared than in Runx2 null mice; and the frequency of molar lingual buds was lower than in Runx2 null mice. Therefore, we suggest that RUNX2 and USAG-1 act in an antagonistic manner. The lingual bud was completely filled with odontogenic epithelial Sox2-positive cells in the Usag-1+/+/Runx2-/- mice, whereas almost no odontogenic epithelial Sox2-positive cells contributed to supernumerary tooth formation in the rudimentary maxillary incisors of the Usag-1-/-/Runx2+/+ mice. Our findings suggest that RUNX2 directly or indirectly prevents the differentiation and/or proliferation of odontogenic epithelial Sox2-positive cells. We hypothesize that RUNX2 inhibits the bone morphogenetic protein (BMP and/or Wnt signaling pathways regulated by USAG-1, whereas RUNX2 expression is induced by BMP signaling independently of USAG-1.

  3. The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats

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    Nermin Eissa

    2018-02-01

    Full Text Available The role of Histamine H3 receptors (H3Rs in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP and novel object recognition (NOR task in adult male rats, using donepezil (DOZ as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p. significantly ameliorated memory deficits induced with MK801 in PAP (all P < 0.05, n = 7. The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p. was reversed when rats were co-injected with the H3R agonist R-(α-methylhistamine (RAMH, 10 mg/kg, i.p. (p = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, n = 6. In the NOR paradigm, DL77 (5 mg/kg, i.p. counteracted long-term memory (LTM deficits induced with MK801 (P < 0.05, n = 6–8, and the DL77-provided effect was similar to that of DOZ (p = 0.788, n = 6–8, and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p. (p = 0.877, n = 6, as compared to the (MK801-amnesic group. However, DL77 (5 mg/kg, i.p. did not alter short-term memory (STM impairment in NOR test (p = 0.772, n = 6–8, as compared to (MK801-amnesic group. Moreover, DL77 (5 mg/kg failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM (p = 0.67 for percentage of time spent exploring the open arms, p = 0.52 for number of entries into the open arms, p = 0.76 for percentage of entries into the open arms, and p = 0.73 number of closed arm entries as compared to saline-treated groups, all n = 6, demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating

  4. Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

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    Michinaga, Shotaro; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Koyama, Yutaka

    2014-01-01

    Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

  5. Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

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    Shotaro Michinaga

    Full Text Available Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice. Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV administration of BQ788 (ETB antagonist, IRL-2500 (ETB antagonist, or FR139317 (ETA antagonist prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

  6. Follistatin, an Activin Antagonist, Ameliorates Renal Interstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction

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    Akito Maeshima

    2014-01-01

    Full Text Available Activin, a member of the TGF-β superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO. The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial α-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of α-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.

  7. Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1 regulate supernumerary organ formations.

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    Honoka Kiso

    Full Text Available Bone morphogenetic proteins (BMPs are highly conserved signaling molecules that are part of the transforming growth factor (TGF-beta superfamily, and function in the patterning and morphogenesis of many organs including development of the dentition. The functions of the BMPs are controlled by certain classes of molecules that are recognized as BMP antagonists that inhibit BMP binding to their cognate receptors. In this study we tested the hypothesis that USAG-1 (uterine sensitization-associated gene-1 suppresses deciduous incisors by inhibition of BMP-7 function. We learned that USAG-1 and BMP-7 were expressed within odontogenic epithelium as well as mesenchyme during the late bud and early cap stages of tooth development. USAG-1 is a BMP antagonist, and also modulates Wnt signaling. USAG-1 abrogation rescued apoptotic elimination of odontogenic mesenchymal cells. BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced. Using explant culture and subsequent subrenal capsule transplantation of E15 USAG-1 mutant maxillary incisor tooth primordia supplemented with BMP-7 demonstrated in USAG-1+/- as well as USAG-1-/- rescue and supernumerary tooth development. Based upon these results, we conclude that USAG-1 functions as an antagonist of BMP-7 in this model system. These results further suggest that the phenotypes of USAG-1 and BMP-7 mutant mice reported provide opportunities for regenerative medicine and dentistry.

  8. Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats.

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    Yamazaki, Mayako; Okabe, Mayuko; Yamamoto, Noriyuki; Yarimizu, Junko; Harada, Katsuya

    2015-03-01

    Despite the human 5-HT5A receptor being cloned in 1994, the biological function of this receptor has not been extensively characterized due to a lack of specific ligands. We recently reported that the selective 5-HT5A receptor antagonist ASP5736 ameliorated cognitive impairment in several animal models of schizophrenia. Given that areas of the brain with high levels of 5-HT5A receptor expression, such as the hippocampus and cerebral cortex, have important functions in cognition and memory, we evaluated the chemically diverse, potent and brain-penetrating 5-HT5A receptor antagonists ASP5736, AS2030680, and AS2674723 in rodent models of cognitive dysfunction associated with dementia. Each of these compounds exhibited a high affinity for recombinant 5-HT5A receptors that was comparable to that of the non-selective ligand of this receptor, lysergic acid diethylamide (LSD). Although each compound had a low affinity for other receptors, 5-HT5A was the only receptor for which all three compounds had a high affinity. Each of the three compounds ameliorated scopolamine-induced working memory deficit in mice and improved reference memory impairment in aged rats at similar doses. Further, ASP5736 decreased the binding of LSD to 5-HT5A receptors in the olfactory bulb of rats in a dose-dependent manner and occupied 15%-50% of brain 5-HT5A receptors at behaviorally effective doses. These results indicate that the 5-HT5A receptor is involved in learning and memory and that treatment with 5-HT5A receptor antagonists might be broadly effective for cognitive impairment associated with not only schizophrenia but also dementia. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  9. The AT1 Receptor Antagonist, L-158,809, Prevents or Ameliorates Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

    International Nuclear Information System (INIS)

    Robbins, Mike E.; Payne, Valerie B.S.; Tommasi, Ellen B.S.; Diz, Debra I.; Hsu, Fang-Chi; Brown, William R.; Wheeler, Kenneth T.; Olson, John; Zhao Weiling

    2009-01-01

    Purpose: We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Materials and Methods: Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of γ rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additional group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation. Results: Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively. Conclusions: Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients

  10. Lexipafant (BB-882), a platelet activating factor receptor antagonist, ameliorates mucosal inflammation in an animal model of colitis

    NARCIS (Netherlands)

    Meenan, J.; Grool, T. A.; Hommes, D. W.; Dijkhuizen, S.; ten Kate, F. J.; Wood, M.; Whittaker, M.; Tytgat, G. N.; van Deventer, S. J.

    1996-01-01

    To assess the anti-inflammatory action of lexipafant (BB-882), a platelet activating factor antagonist, in an animal model of acute colitis. An animal intervention study. Following the rectal instillation of formalin 0.75% into male New Zealand White (NZW) rabbits, 0.85 ml of aggregated

  11. Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia.

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    Nakashima, Masato; Imada, Haruka; Shiraishi, Eri; Ito, Yuki; Suzuki, Noriko; Miyamoto, Maki; Taniguchi, Takahiko; Iwashita, Hiroki

    2018-04-01

    The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, ( N -{(1 S )-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3- b ]pyrazine-4(1 H )-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  12. Maraviroc, a CCR5 antagonist, ameliorates the development of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD).

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    Pérez-Martínez, Laura; Pérez-Matute, Patricia; Aguilera-Lizarraga, Javier; Rubio-Mediavilla, Susana; Narro, Judit; Recio, Emma; Ochoa-Callejero, Laura; Oteo, José-Antonio; Blanco, José-Ramón

    2014-07-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. The NAFLD spectrum ranges from simple steatosis to cirrhosis. The chemokine CCL5/RANTES plays an important role in the progression of hepatic inflammation and fibrosis. The objective of this study was to examine the effects of maraviroc, a CCR5 antagonist, on liver pathology in a NAFLD mouse model. A total of 32 male C57BL/6 mice were randomly assigned to one of four groups: (i) control group (chow diet plus tap water); (ii) maraviroc group (chow diet plus maraviroc in drinking water); (iii) high-fat diet (HFD) group (HFD plus tap water); and (iv) maraviroc/HFD group (HFD plus maraviroc). All mice were sacrificed 16 weeks after the beginning of the experiment. Biochemical analyses and liver examinations were performed. Mice in the HFD group showed a tendency towards increased body mass gain and liver damage compared with the maraviroc/HFD group. Moreover, liver weight in the HFD group was significantly higher than in the maraviroc/HFD group. Hepatic triglyceride concentration in the maraviroc/HFD group was significantly lower than in the HFD group. Interestingly, the maraviroc/HFD group exhibited a lower degree of steatosis. Furthermore, hepatic CCL5/RANTES expression was significantly lower in the maraviroc/HFD group than in the HFD group. Overall, no differences were observed between the control group and the maraviroc group. Maraviroc ameliorates hepatic steatosis in an experimental model of NAFLD. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. A CD1d-dependent lipid antagonist to NKT cells ameliorates atherosclerosis in ApoE-/- mice by reducing lesion necrosis and inflammation.

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    Li, Yi; Kanellakis, Peter; Hosseini, Hamid; Cao, Anh; Deswaerte, Virginie; Tipping, Peter; Toh, Ban-Hock; Bobik, Alex; Kyaw, Tin

    2016-02-01

    Atherosclerosis-related deaths from heart attacks and strokes remain leading causes of global mortality, despite the use of lipid-lowering statins. Thus, there is an urgent need to develop additional therapies. Reports that NKT cells promote atherosclerosis and an NKT cell CD1d-dependent lipid antagonist (DPPE-PEG350, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethyleneglycol)-350]) reduces allergen-induced inflammation led us to investigate its therapeutic potential in preventing the development and progression of experimental atherosclerosis. DPPE-PEG350 was administered to hyperlipidaemic ApoE(-/-) mice with/without established atherosclerosis. Atherosclerosis and immune cells were assessed in the aortic sinus lesions. Lesion expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) responsible for inflammatory immune cell recruitment as well as mRNA expression of IFNγ and its plasma levels were investigated. Necrotic cores and lesion smooth muscle and collagen contents important in plaque stability were determined as were plasma lipid levels. DPPE-PEG350 reduced atherosclerosis development and delayed progression of established atherosclerosis without affecting plasma lipids. CD4 and CD8 T cells and B cells in atherosclerotic lesions were decreased in DPPE-PEG350-treated mice. Lesion MCP-1 and VCAM-1 protein expression and necrotic core size were reduced without affecting lesion smooth muscle and collagen content. IFNγ and lymphocytes were unaffected by the treatment. The attenuation of progression of established atherosclerosis together with reduced development of atherosclerosis in hyperlipidaemic mice by the NKT antagonist, without affecting NKT cell or other lymphocyte numbers, suggests that targeting lesion inflammation via CD1d-dependent activation of NKT cells using DPPE-PEG350 has a therapeutic potential in treating atherosclerosis. Published on behalf of the European Society of

  14. The Non-Peptide Vasopressin V1b Receptor Antagonist, SSR149415, Ameliorates Spermatogenesis Function in a Mouse Model of Chronic Social Defeat Stress.

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    Wang, Bin; Zhou, Jian; Zhuang, Yan-Yan; Wang, Liang-Liang; Pu, Jin-Xian; Huang, Yu-Hua; Xia, Fei; Lv, Jin-Xing

    2017-11-01

    To determine the effects of SSR149415 on testis and spermatogenesis in male mice subjected to chronic social defeat stress, C57BL/6 male mice were divided into two groups: Control and Stress. Then Stress group was subdivided into four subgroups administered water, SSR149415 (1 mg/kg/day), SSR149415 (10 mg/kg/day), SSR149415 (30 mg/kg/day), respectively. The behavioral alterations revealed by social interaction test and open field test were measured. The physical indices, including body weight and gonad weight (testis and epididymis) as well as testis/body weight and cauda epididymis/body weight were detected. Serum hormones, including testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined. Sperm count and abnormality as well as testicular histology structure were assessed. The germ cells apoptosis were also evaluated. Chronic social defeat stress-induced behavioral abnormality, as well as gonad atrophy (testis and epididymis) was significantly alleviated in stressed male mice exposed to SSR149415. Regressed serum testosterone levels and elevated serum FSH and LH levels exhibited by stressed male mice were observably reversed following SSR149415 administration. Chronic social defeat stress-induced damage in testicular histology structure and semen quality were also improved after SSR149415 administration. In addition, SSR149415 significantly reversed chronic social defeat stress-induced germ cells apoptosis. Overall, we provide clear evidence indicating the amelioration of chronic social defeat stress-induced behavioral abnormality and testicular dysfunction via SSR149415, promoting the development of drug-directed therapy against this disease. J. Cell. Biochem. 118: 3891-3898, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  15. Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090.

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    Contreras-Ruiz, Laura; Mir, Fayaz A; Turpie, Bruce; Krauss, Achim H; Masli, Sharmila

    2016-02-01

    Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p syndrome. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. ACTH antagonists

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    Adrian John Clark

    2016-08-01

    Full Text Available ACTH acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1 Cushing’s disease and ectopic ACTH syndrome – especially whilst preparing for definitive treatment of a causative tumour, or in refractory cases, or (2 congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role.

  17. Ameliorative percutaneous lumbar discectomy

    International Nuclear Information System (INIS)

    Xiao Chengjiang; Su Huanbin; He Xiaofeng; Li Yanhao

    2005-01-01

    Objective: To ameliorate the percutaneous lumbar discectomy (APLD) for improving the effectiveness and amplifying the indicative range of PLD. Methods: To ameliorate percutaneous punctured route based on classic PLD and discectomy of extracting pulp out of the herniated disc with special pulpforceps. The statistical analysis of the therapeutic results on 750 disc protrusions of 655 cases undergone APLD following up from 6 to 54 months retrospectively. Results: The effective ratios were excellent in 40.2%, good for 46.6% and bad of 13.3%. No occurrance of intervertebral inflammation and paradiscal hematoma, there were only 1 case complicated with injuried cauda equina, and 4 cases with broken appliance within disc. Conclusions: APLD is effective and safe, not only indicative for inclusion disc herniation, but also for noninclusion herniation. (authors)

  18. Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia

    OpenAIRE

    Nickla, Debora L.; Totonelly, Kristen

    2011-01-01

    In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form deprivation) or − 10 D lenses attached to the feath...

  19. Dual antagonists of integrins.

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    Nadrah, K; Dolenc, M Sollner

    2005-01-01

    The roles of integrins in pathologies have been studied intensively and only partially explained. This has resulted in the development of several nanomolar antagonists to certain integrins. In most cases, the aim was to produce compounds which are highly selective towards specific integrins. This paradigm has recently shifted a little. Targeting two or more integrins with one compound has become a very attractive concept, especially since it has become clear that several severe disorders, such as pathological angiogenesis, cannot be treated just with highly specific integrin antagonists. This review is aimed to elucidate some aspects regarding the design of drugs with dual activity towards integrins. Integrin structure and tissue distribution will first be described, in order to provide the basis for their functions in various pathologies which will follow. Inhibitors of several pairs of integrins will be described.

  20. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  1. Are peripheral opioid antagonists the solution to opioid side effects?

    LENUS (Irish Health Repository)

    Bates, John J

    2012-02-03

    Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.

  2. Ameliorating effect of hawthorn ( Crataegus oxyacantha ) and ...

    African Journals Online (AJOL)

    Ameliorating effect of hawthorn ( Crataegus oxyacantha ) and physical exercise on ... Conclusion: Crataegus oxyacantha extract has shown positive affect to ameliorate on ... Key words: Crataegus oxyacantha, physical activity, epilepsy, gerbil, ...

  3. Naloxone : actions of an antagonist

    NARCIS (Netherlands)

    Dorp, Eveline Louise Arianna van

    2009-01-01

    The opioid antagonist naloxone has a special place in pharmacology – it has no intrinsic action of its own, but it is able to save lives in the case of life threatening side-effects caused by other drugs. Naloxone is an antagonist for all opioid receptors, but most specifically for the μ-opioid

  4. Carbon adaptation influence the antagonistic ability of ...

    African Journals Online (AJOL)

    Jane

    2011-10-24

    Oct 24, 2011 ... INTRODUCTION. The use of antagonistic bacteria to control soil-borne ... plant was used to evaluate the antifungal activities of antagonistic bacteria. ..... antagonistic bacteria and cloning of its phenazine carboxylic acid genes.

  5. ANTAGONISTIC POTENTIAL OF FLUORESCENT Pseudomonas ...

    African Journals Online (AJOL)

    Prof. Adipala Ekwamu

    GROWTH OF TOMATO CHALLENGED WITH PHTOPATHOGENS ... This study focused on the antagonistic potential of fluorescent Pseudomonas in vitro, and its inoculation effect on growth .... the 5 days old culture in starch agar with Lugol's.

  6. Naltrexone ameliorates functional network abnormalities in alcohol‐dependent individuals

    Science.gov (United States)

    Baek, Kwangyeol; Tait, Roger; Elliott, Rebecca; Ersche, Karen D.; Flechais, Remy; McGonigle, John; Murphy, Anna; Nestor, Liam J.; Orban, Csaba; Passetti, Filippo; Paterson, Louise M.; Rabiner, Ilan; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor M.; Bullmore, Edward T.; Lingford‐Hughes, Anne R.; Deakin, Bill; Nutt, David J.; Sahakian, Barbara J.; Robbins, Trevor W.; Voon, Valerie

    2017-01-01

    Abstract Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50‐mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly‐drug‐dependent individuals compared with 36 healthy volunteers. Graph theoretic and network‐based statistical analysis of resting‐state functional magnetic resonance imaging (MRI) data revealed that alcohol‐dependent subjects had reduced functional connectivity of a dispersed network compared with both poly‐drug‐dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol‐dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly‐substance‐dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology. PMID:28247526

  7. Acute Radiation Sickness Amelioration Analysis

    Science.gov (United States)

    1994-05-01

    Emetic Drugs 16. PRICE CODE Antagonists 17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19, SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT OF...102 UNCLASSIFIED mcuIw IA IIIcaIIin or Isis PAW CLASSFIED BY: N/A since Unclassified. DECLASSIFY ON: N/A since Unclassified. SECURITY CLASSIFICATION OF...Approximately 2000 documents relevant to the development of the candidate anti-emetic drugs ondansetron (Zofran, Glaxo Pharmaceuticals) and granisetron

  8. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  9. Specific immunotherapy ameliorates ulcerative colitis.

    Science.gov (United States)

    Cai, Min; Zeng, Lu; Li, Lin-Jing; Mo, Li-Hua; Xie, Rui-Di; Feng, Bai-Sui; Zheng, Peng-Yuan; Liu, Zhi-Gang; Liu, Zhan-Ju; Yang, Ping-Chang

    2016-01-01

    Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients. Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules. After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-α were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC. UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics.

  10. Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain.

    Science.gov (United States)

    Inta, Ioana; Vogt, Miriam A; Vogel, Anne S; Bettendorf, Markus; Gass, Peter; Inta, Dragos

    2016-10-01

    NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

  11. Histologic and inflammatory lamellar changes in horses with oligofructose-induced laminitis treated with a CXCR1/2 antagonist

    OpenAIRE

    Lima, Leonardo R. de; Mendes, Heloisa M.F.; Soriani, Frederico M.; Souza, Danielle G. de; Alves, Geraldo Eleno S.; Teixeira, Mauro M.; Faleiros, Rafael R.

    2016-01-01

    Abstract: With the hypothesis that blocking chemokine signaling can ameliorate acute laminitis, the aim was to evaluate the therapeutic effect of intravenous DF1681B, a selective antagonist for CXCR1 and CXCR2 (chemokine receptors), in an oligofructose equine laminitis model. To twelve mixed breed clinically healthy hoses with no previous history of hoof-related lameness was administered oligofructose (10g/kg given by nasogastric tube) and divided into two groups: treated (intravenous DF1681B...

  12. Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.

    Directory of Open Access Journals (Sweden)

    Katsuya Morita

    Full Text Available Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2 protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

  13. From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.

    Science.gov (United States)

    Fakhfouri, Gohar; Mousavizadeh, Kazem; Mehr, Sharam Ejtemaei; Dehpour, Ahmad Reza; Zirak, Mohammad Reza; Ghia, Jean-Eric; Rahimian, Reza

    2015-12-01

    5-HT3 receptor antagonists are extensively used as efficacious agents in counteracting chemotherapy-induced emesis. Recent investigations have shed light on other potential effects (analgesic, anxiolytic, and anti-psychotic). Some studies have reported neuroprotective properties for the 5-HT3 receptor antagonists in vitro and in vivo. When administered to Aβ-challenged rat cortical neurons, 5-HT3 receptor antagonists substantially abated apoptosis, elevation of cytosolic Ca(2), glutamate release, reactive oxygen species (ROS) generation, and caspase-3 activity. In addition, in vivo studies show that 5-HT3 receptor antagonists possess, alongside their anti-emetic effects, notable immunomodulatory properties in CNS. We found that pretreatment with tropisetron significantly improved neurological deficits and diminished leukocyte transmigration into the brain, TNF-α level, and brain infarction in a murine model of embolic stroke. Our recent investigation revealed that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and -independent pathways. Tropisetron, in vitro, was found to be an efficacious inhibitor of the signaling pathway leading to the activation of pro-inflammatory NF-κB, a transcription factor pivotal to the upregulation of several neuroinflammatory mediators in brain. This mini review summarizes novel evidence concerning effects of 5-HT3 antagonists and their possible mechanisms of action in ameliorating neurodegenerative diseases including Alzheimer, multiple sclerosis, and stroke. Further, we discuss some newly synthesized 5-HT3 receptor antagonists with dual properties of 5-HT3 receptor blockade/alpha-7 nicotinic receptor activator and their potential in management of memory impairment. Since 5-HT3 receptor antagonists possess a large therapeutic window, they can constitute a scaffold for design and synthesis of new neuroprotective medications.

  14. Ameliorative Effect of Different Concentration of Mushroom ...

    African Journals Online (AJOL)

    Prof. Ogunji

    ameliorative effect of mushroom in the post-experimental stage. Samples of liver and ... except in the liver which showed mild periportal chronic inflammatory cell. However, the .... alcohol for 12 hours and through absolute alcohol to remove ...

  15. Portulaca oleracea Linn seed extract ameliorates hydrogen ...

    African Journals Online (AJOL)

    Portulaca oleracea Linn seed extract ameliorates hydrogen ... induced cell death by inhibiting oxidative stress and ROS generation. Keywords: ... culture medium; therefore the stock solutions of ... acetic acid (1 %) and ethanol (50 %) to extract.

  16. Ameliorative effects of selenium and zinc

    African Journals Online (AJOL)

    Methidathion-induced hematological, biochemical and hepatohistological alterations in rat: Ameliorative effects of selenium and zinc. L Barkat, A Boumendjel, C Abdennour, MS Boulakoud, A El Feki, M Messarah ...

  17. Black ginseng extract ameliorates hypercholesterolemia in rats

    Directory of Open Access Journals (Sweden)

    Evelyn Saba

    2016-04-01

    Conclusion: Administration of BG extracts to Sprague Dawley rats fed with high-cholesterol diet ameliorated hypercholesterolemia, which was mediated via modulation of cholesterol-metabolizing marker genes. This data throw a light on BG's cardioprotective effects.

  18. Dietary Amelioration of Helicobacter Infection

    Science.gov (United States)

    Fahey, Jed W.; Stephenson, Katherine K.; Wallace, Alison J.

    2015-01-01

    We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on: (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H. pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H. pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability and cultural acceptability. This review therefore highlights specific foods, food components, and food products, grouped as follows: bee products (e.g. honey and propolis), probiotics, dairy products, vegetables, fruits, oils, essential oils, and herbs, spices and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and pre-clinical evidence must now be followed up with rationally designed, unambiguous human trials. PMID:25799054

  19. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  20. 5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Ferguson, Marcus C; Nayyar, Tultul; Deutch, Ariel Y; Ansah, Twum A

    2010-01-01

    Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. Published by Elsevier Ltd.

  1. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity....

  2. Ghrelin ameliorates acute lung injury induced by oleic acid via inhibition of endoplasmic reticulum stress.

    Science.gov (United States)

    Tian, Xiuli; Liu, Zhijun; Yu, Ting; Yang, Haitao; Feng, Linlin

    2018-03-01

    Acute lung injury (ALI) is associated with excessive mortality and lacks appropriate therapy. Ghrelin is a novel peptide that protects the lung against ALI. This study aimed to investigate whether endoplasmic reticulum stress (ERS) mediates the protective effect of ghrelin on ALI. We used a rat oleic acid (OA)-induced ALI model. Pulmonary impairment was detected by hematoxylin and eosin (HE) staining, lung mechanics, wet/dry weight ratio, and arterial blood gas analysis. Plasma and lung content of ghrelin was examined by ELISA, and mRNA expression was measured by quantitative real-time PCR. Protein levels were detected by western blot. Rats with OA treatment showed significant pulmonary injury, edema, inflammatory cellular infiltration, cytokine release, hypoxia and CO 2 retention as compared with controls. Plasma and pulmonary content of ghrelin was reduced in rats with ALI, and mRNA expression was downregulated. Ghrelin (10nmol/kg) treatment ameliorated the above symptoms, but treatment with the ghrelin antagonists D-Lys 3 GHRP-6 (1μmol/kg) and JMV 2959 (6mg/kg) exacerbated the symptoms. ERS induced by OA was prevented by ghrelin and augmented by ghrelin antagonist treatment. The ERS inducer, tunicamycin (Tm) prevented the ameliorative effect of ghrelin on ALI. The decreased ratio of p-Akt and Akt induced by OA was improved by ghrelin treatment, and was further exacerbated by ghrelin antagonists. Ghrelin protects against ALI by inhibiting ERS. These results provide a new target for prevention and therapy of ALI. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Interleukin-1 antagonists for diabetes

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, Thomas

    2013-01-01

    pathways. The testing of specific anti-inflammatory biologics targeting single pro-inflammatory cytokines has provided clinical proof-of-concept. EXPERT OPINION: IL-1 antagonists have so far failed to meet primary end points in recent-onset type 1 diabetes in Phase IIa, and promising Phase I and IIa trials......INTRODUCTION: Diabetes is a currently incurable, epidemically growing global health concern. Contemporary symptomatic treatment targets acute and chronic metabolic consequences of relative or absolute insulin deficiency. Intensive multifactorial therapy is required to attenuate morbidity...... and mortality from late micro- and macrovascular complications, and despite current best clinical practice diabetes is still associated with shortened lifespan. There is an unmet need for interventions targeting pathogenetic mechanisms in diabetes, and the market for such therapies is huge. AREAS COVERED...

  4. Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats.

    Science.gov (United States)

    Yamada, Koji; Kobayashi, Minoru; Shiozaki, Shizuo; Ohta, Teruko; Mori, Akihisa; Jenner, Peter; Kanda, Tomoyuki

    2014-07-01

    Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A1/A2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the β-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline. Istradefylline exerts antidepressant-like effects via modulation of A2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.

  5. Ameliorative effect of Lentinus squarrosulus mycomeat against ...

    African Journals Online (AJOL)

    Ameliorative effect of Lentinus squarrosulus mycomeat against Pseudomonas aeruginosa infection using albino rat as animal model. ... Morphological appearance and behavior of the rats were used as the assessment method for adverse reactions. After a period of 26 days, the rats were sacrificed with the liver, spleen and ...

  6. Histamine ameliorates spatial memory deficits induced by MK-801 infusion into ventral hippocampus as evaluated by radial maze task in rats

    Institute of Scientific and Technical Information of China (English)

    Li-sha XU; Li-xia YANG; Wei-wei HU; Xiao YU; Li MA; Lu-ying LIU; Er-qing WEI; Zhong CHEN

    2005-01-01

    Aim: To investigate the role of histamine in memory deficits induced by MK-801 infusion into the ventral hippocampus in rats. Methods: An 8-arm radial maze (4arms baited) was used to assess spatial memory. Results: Bilateral ventral intrahippocampal (ih) infusion of MK-801 (0.3 μg/site), an N-methyl-D-aspartate (NMDA) antagonist, impaired the retrieval process in both working memory and reference memory. Intrahippocampal injection of histamine (25 or 50 ng/site) or intraperitoneal (ip) injection of histidine (25, 50 or 100 mg/kg) markedly ameliorated the spatial memory deficits induced by MK-801. Both the histamine H1 antagonist pyrilamine (0.5 or 1.0 μg/site, ih) and the H2 antagonist cimetidine (2.5 μg/site,ih) abolished the ameliorating effect of histidine (100 mg/kg, ip) on reference memory deficits, but not that on working memory deficits induced by MK-801. Conclusion:The results indicate that histamine in the ventral hippocampus can ameliorate MK-801-induced spatial memory deficits, and that histamine's effect on reference memory is mediated by postsynaptic histamine H1 and H2 receptors.

  7. Antagonistic Phenomena in Network Dynamics

    Science.gov (United States)

    Motter, Adilson E.; Timme, Marc

    2018-03-01

    Recent research on the network modeling of complex systems has led to a convenient representation of numerous natural, social, and engineered systems that are now recognized as networks of interacting parts. Such systems can exhibit a wealth of phenomena that not only cannot be anticipated from merely examining their parts, as per the textbook definition of complexity, but also challenge intuition even when considered in the context of what is now known in network science. Here, we review the recent literature on two major classes of such phenomena that have far-reaching implications: (a) antagonistic responses to changes of states or parameters and (b) coexistence of seemingly incongruous behaviors or properties - both deriving from the collective and inherently decentralized nature of the dynamics. They include effects as diverse as negative compressibility in engineered materials, rescue interactions in biological networks, negative resistance in fluid networks, and the Braess paradox occurring across transport and supply networks. They also include remote synchronization, chimera states, and the converse of symmetry breaking in brain, power-grid, and oscillator networks as well as remote control in biological and bioinspired systems. By offering a unified view of these various scenarios, we suggest that they are representative of a yet broader class of unprecedented network phenomena that ought to be revealed and explained by future research.

  8. Calcium antagonists for aneurysmal subarachnoid haemorrhage

    NARCIS (Netherlands)

    Dorhout Mees, S. M.; Rinkel, G. J. E.; Feigin, V. L.; Algra, A.; van den Bergh, W. M.; Vermeulen, M.; van Gijn, J.

    2007-01-01

    BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing factor. Experimental studies have suggested that calcium antagonists can prevent or reverse

  9. An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

    Science.gov (United States)

    Kenyon, Nicholas J.; Liu, Ruiwu; O’Roark, Erin M.; Huang, Wenzhe; Peng, Li; Lam, Kit S.

    2008-01-01

    Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity α4β1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic α4β1 antagonist LLP2A. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin lbumin, presumably by improving the circulating half-life of the drug. PMID:19103195

  10. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  11. Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice.

    Science.gov (United States)

    Jeon, Se Jin; Kim, Eunji; Lee, Jin Su; Oh, Hee Kyong; Zhang, Jiabao; Kwon, Yubeen; Jang, Dae Sik; Ryu, Jong Hoon

    2017-11-01

    Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists.

    Science.gov (United States)

    Moore, N A; Blackman, A; Awere, S; Leander, J D

    1993-06-11

    In the present study, we investigated the ability of NMDA receptor antagonists to inhibit catalepsy induced by haloperidol, or SCH23390 and clebopride, selective dopamine D1 and D2 receptor antagonists respectively. Catalepsy was measured by recording the time the animal remained with its forepaws placed over a rod 6 cm above the bench. Pretreatment with either the non-competitive NMDA receptor antagonist, MK-801 (0.25-0.5 mg/kg i.p.) or the competitive antagonist, LY274614 (10-20 mg/kg i.p.) reduced the cataleptic response produced by haloperidol (10 mg/kg), SCH23390 (2.5-10 mg/kp i.p.) or clebopride (5-20 mg/kg i.p.). This demonstrates that NMDA receptor antagonists will reduce both dopamine D1 and D2 receptor antagonist-induced catalepsy. Muscle relaxant doses of chlordiazepoxide (10 mg/kg i.p.) failed to reduce the catalepsy induced by haloperidol, suggesting that the anticataleptic effect of the NMDA receptor antagonists was not due to a non-specific action. These results support the hypothesis that NMDA receptor antagonists may have beneficial effects in disorders involving reduced dopaminergic function, such as Parkinson's disease.

  13. A toll-like receptor 9 antagonist improves bladder function and white matter sparing in spinal cord injury.

    Science.gov (United States)

    David, Brian T; Sampath, Sujitha; Dong, Wei; Heiman, Adee; Rella, Courtney E; Elkabes, Stella; Heary, Robert F

    2014-11-01

    Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due to alterations in the inflammatory milieu. These findings indicate that the TLR9 antagonist has beneficial effects not only in reducing sensory deficits, but also on bladder dysfunction and tissue preservation. Thus, modulation of innate immune receptor signaling in the spinal cord can impact the effects of SCI.

  14. Acetylcholinesterase inhibition ameliorates deficits in motivational drive

    Directory of Open Access Journals (Sweden)

    Martinowich Keri

    2012-03-01

    Full Text Available Abstract Background Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. Methods We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. Results CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Conclusions Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive.

  15. The performance of maize crop during acid amelioration with ...

    African Journals Online (AJOL)

    Tanzania Journal of Science ... This study evaluated acid ameliorative potential and their effects on maize growth of four organic residues namely wild spikenard, cordia, cowpea and pigeon peas ... The finding suggests different acid ameliorating potential of residues, pigeon peas and cordia being the most effective.

  16. Antagonistic properties of microogranisms associated with cassava ...

    African Journals Online (AJOL)

    The antagonistic properties of indigenous microflora from cassava starch, flour and grated cassava were investigated using the conventional streak, novel ring and well diffusion methods. Antagonism was measured by zone of inhibition between the fungal plug and bacterial streak/ring. Bacillus species were more effective ...

  17. Carbon adaptation influence the antagonistic ability of ...

    African Journals Online (AJOL)

    Influences of carbon adaptation on antagonistic activities of three Pseudomonas aeruginosa strains V4, V7 and V10 against Fusarium oxysporum f. sp. melonis were determined in this study. Results from this study showed that the P. aeruginosa strains and their adapted strains significantly inhibited the growth of mycelium ...

  18. Small molecule antagonists of integrin receptors.

    Science.gov (United States)

    Perdih, A; Dolenc, M Sollner

    2010-01-01

    The complex and widespread family of integrin receptors is involved in numerous physiological processes, such as tissue remodeling, angiogenesis, development of the immune response and homeostasis. In addition, their key role has been elucidated in important pathological disorders such as cancer, cardiovascular diseases, osteoporosis, autoimmune and inflammatory diseases and in the pathogenesis of infectious diseases, making them highly important targets for modern drug design campaigns. In this review we seek to present a concise overview of the small molecule antagonists of this diverse and highly complex receptor family. Integrin antagonists are classified according to the targeted integrin receptor and are discussed in four sections. First we present the fibrinogen alpha(IIb)beta3 and the vitronectin alpha (V)beta(3) receptor antagonists. The remaining selective integrin antagonists are examined in the third section. The final section is dedicated to molecules with dual or multiple integrin activity. In addition, the use of antibodies and peptidomimetic approaches to modulate the integrin receptors are discussed, as well providing the reader with an overall appreciation of the field.

  19. Use of Coffee Pulp and Minerals for Natural Soil Ameliorant

    Directory of Open Access Journals (Sweden)

    Pujiyanto Pujiyanto

    2007-05-01

    Full Text Available In coffee plantation, solid waste of coffee pulp is usually collected as heap nearby processing facilities for several months prior being used as compost. The practice is leading to the formation of odor and liquid which contaminate the environment. Experiments to evaluate the effect of natural soil ameliorant derived from coffee pulp and minerals were conducted at The Indonesian Coffee and Cocoa Research Institute in Jember, East Java. The experiments were intended to optimize the use of coffee pulp to support farming sustainability and minimize negative impacts of solid waste disposal originated from coffee cherry processing. Prior to applications, coffee pulp was hulled to organic paste. The paste was then mixed with 10% minerals (b/b. Composition of the minerals was 50% zeolite and 50% rock phosphate powder. The ameliorant was characterized for their physical and chemical properties. Agronomic tests were conducted on coffee and cocoa seedling. The experiments were arranged according to Randomized Completely Design with 2 factors, consisted of natural ameliorant and inorganic fertilizer respectively. Natural ameliorant derived from coffee pulp was applied at 6 levels: 0, 30, 60, 90, 120 and 150 g dry ameliorant/seedling of 3 kg soil, equivalent to 0, 1, 2, 3, 4 and 5% (b/b of ameliorant respectively. Inorganic fertilizer was applied at 2 levels: 0 and 2 g fertilizer/application of N-P-K compound fertilizer of 15-15-15 respectively. The inorganic fertilizer was applied 4 times during nursery of coffee and cocoa. The result of the experiment indicated that coffee pulp may be used as natural soil ameliorant. Composition of ameliorant of 90% coffee pulp and 10% of minerals has good physical and chemical characteristics for soil amelioration. The composition has high water holding capacity; cations exchange capacity, organic carbon and phosphorus contents which are favorable to increase soil capacity to support plant growth. Application of

  20. antagonistic effect of native bacillus isolates against black root rot

    African Journals Online (AJOL)

    ACSS

    A number of fungi and bacteria are known to be very effective .... Round. Convex. Smooth. Wrinkled. Slow. BS024. Irregular and spreading. Flat. Wavy .... Antibiotic effect of bacterial antagonist ..... antagonistic Bacillus and Trichoderma isolates ...

  1. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

    Science.gov (United States)

    Tritos, Nicholas A; Biller, Beverly M K

    2017-02-01

    To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n = 141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

  2. Interactions of CB1 and mGlu5 receptor antagonists in food intake, anxiety and memory models in rats.

    Science.gov (United States)

    Varga, Balázs; Kassai, Ferenc; Gyertyán, István

    2012-12-01

    CB(1) receptor antagonists proved to be effective anti-obesity drugs, however, their depressive and anxiogenic effects became also evident. Finding solution to overcome these psychiatric side effects is still in focus of research. Based on the available clinical and preclinical results we hypothesized that the combination of CB(1) and mGlu(5) receptor antagonisms may result in a pharmacological intervention, where the anxiolytic mGlu(5) receptor inhibition may counteract the anxiogenic psychiatric side effects of CB(1) antagonism, while CB(1) antagonism may ameliorate the memory impairing effect of mGlu(5) receptor antagonism. Further, the two components will synergistically interact in blocking food-intake and reducing obesity. For testing the interaction of mGlu(5) and CB(1) receptor antagonism MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pridine; SIB-1757, 6-methyl-2-(phenylazo)-3-pyridinol)] (mGlu(5) antagonist) and rimonabant [(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)hydrochloride] (CB(1) antagonist) were used. All experiments were carried out in rats. Effects of the compounds on anxiety were tested in two foot shock induced ultrasonic vocalization paradigms, appetite suppression was assessed in the food intake test, while memory effects were tested in a context conditioned ultrasonic vocalization setup. MTEP abolished the anxiogenic effect of rimonabant, while there was an additive cooperation in suppressing appetite. However, rimonabant did not ameliorate the memory impairing effect of MTEP. By combination of CB(1) and mGluR5 antagonism, anxiety related side effects might be attenuated, appetite suppression maintained, nevertheless, the possible emergence of unwanted memory impairments can overshadow its therapeutic success. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism.

    Science.gov (United States)

    Lippiello, P M

    2006-01-01

    Evidence supports the hypothesis that normalization of cholinergic tone by selective antagonism of neuronal nicotinic acetylcholine receptors (NNRs) may ameliorate the core symptoms of autism. As often is the case, epidemiology has provided the first important clues. It is well recognized that psychiatric patients are significantly more often smokers than the general population. The only known exceptions are obsessive-compulsive disorder (OCD), catatonic schizophrenia and interestingly, autism. In this regard, clinical studies with nicotine have demonstrated amelioration of symptoms of a number of diseases and disorders, including Alzheimer's disease, Parkinson's disease, ADHD and Tourette's syndrome. Nicotine's agonist properties at CNS NNRs have been implicated in these effects and support the concept of self-medication as a strong motivation for smoking in cognitively compromised individuals. On the other hand, the inverse correlation between autism and smoking suggests that smoking does not provide symptomatic relief and may actually be indicative of an active avoidance of nicotine's agonist effects in this disorder. Neuroanatomical evidence is consistent with this idea based on the presence of hypercholinergic architecture in the autistic brain, particularly during the first few years of development, making the avoidance of further stimulation of an already hyperactive cholinergic system plausible. This may also explain why stimulants (known to increase dopamine levels as do NNR agonists) appear to aggravate autistic symptoms and why studies with cholinesterase inhibitors that increase acetylcholine levels in the brain have yielded variable effects in autism. Taken together, the evidence suggests the possibility that nicotinic cholinergic antagonism may in fact be palliative. Pharmacological evidence supports this hypothesis. For example, antidepressants, many of which are now known to be non-competitive NNR antagonists, have been used successfully to treat a

  4. Antagonistic parent-offspring co-adaptation.

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    Mathias Kölliker

    2010-01-01

    Full Text Available In species across taxa, offspring have means to influence parental investment (PI. PI thus evolves as an interacting phenotype and indirect genetic effects may strongly affect the co-evolutionary dynamics of offspring and parental behaviors. Evolutionary theory focused on explaining how exaggerated offspring solicitation can be understood as resolution of parent-offspring conflict, but the evolutionary origin and diversification of different forms of family interactions remains unclear.In contrast to previous theory that largely uses a static approach to predict how "offspring individuals" and "parental individuals" should interact given conflict over PI, we present a dynamic theoretical framework of antagonistic selection on the PI individuals obtain/take as offspring and the PI they provide as parents to maximize individual lifetime reproductive success; we analyze a deterministic and a stochastic version of this dynamic framework. We show that a zone for equivalent co-adaptation outcomes exists in which stable levels of PI can evolve and be maintained despite fast strategy transitions and ongoing co-evolutionary dynamics. Under antagonistic co-adaptation, cost-free solicitation can evolve as an adaptation to emerging preferences in parents.We show that antagonistic selection across the offspring and parental life-stage of individuals favors co-adapted offspring and parental behavior within a zone of equivalent outcomes. This antagonistic parent-offspring co-adaptation does not require solicitation to be costly, allows for rapid divergence and evolutionary novelty and potentially explains the origin and diversification of the observed provisioning forms in family life.

  5. Medicinal Chemistry of Competitive Kainate Receptor Antagonists

    Science.gov (United States)

    2010-01-01

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1−5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure−activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  6. Pharmacological analysis of calcium antagonist receptors

    International Nuclear Information System (INIS)

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)[ 3 H]desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) [ 3 H]desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor

  7. Bacterial mediated amelioration of drought stress in drought tolerant ...

    African Journals Online (AJOL)

    Bacterial mediated amelioration of drought stress in drought tolerant and susceptible cultivars of rice ( Oryza sativa L.) ... and IR-64 (drought sensitive) cultivars of rice (Oryza sativa L.) under different level of drought stress. ... from 32 Countries:.

  8. Improvement for Amelioration Inventory Model with Weibull Distribution

    Directory of Open Access Journals (Sweden)

    Han-Wen Tuan

    2017-01-01

    Full Text Available Most inventory models dealt with deteriorated items. On the contrary, just a few papers considered inventory systems under amelioration environment. We study an amelioration inventory model with Weibull distribution. However, there are some questionable results in the amelioration paper. We will first point out those questionable results in the previous paper that did not derive the optimal solution and then provide some improvements. We will provide a rigorous analytical work for different cases dependent on the size of the shape parameter. We present a detailed numerical example for different ranges of the sharp parameter to illustrate that our solution method attains the optimal solution. We developed a new amelioration model and then provided a detailed analyzed procedure to find the optimal solution. Our findings will help researchers develop their new inventory models.

  9. Riboflavin ameliorates cisplatin induced toxicities under photoillumination.

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    Iftekhar Hassan

    Full Text Available BACKGROUND: Cisplatin is an effective anticancer drug that elicits many side effects mainly due to induction of oxidative and nitrosative stresses during prolonged chemotherapy. The severity of these side effects consequently restricts its clinical use under long term treatment. Riboflavin is an essential vitamin used in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Besides, it has excellent photosensitizing property that can be used to ameliorate these toxicities in mice under photodynamic therapy. METHODS AND FINDINGS: Riboflavin, cisplatin and their combinations were given to the separate groups of mice under photoilluminated condition under specific treatment regime. Their kidney and liver were excised for comet assay and histopathological studies. Furthermore, Fourier Transform Infrared Spectroscopy of riboflavin-cisplatin combination in vitro was also conducted to investigate any possible interaction between the two compounds. Their comet assay and histopathological examination revealed that riboflavin in combination with cisplatin was able to protect the tissues from cisplatin induced toxicities and damages. Moreover, Fourier Transform Infrared Spectroscopy analysis of the combination indicated a strong molecular interaction among their constituent groups that may be assigned for the protective effect of the combination in the treated animals. CONCLUSION: Inclusion of riboflavin diminishes cisplatin induced toxicities which may possibly make the cisplatin-riboflavin combination, an effective treatment strategy under chemoradiotherapy in pronouncing its antineoplastic activity and sensitivity towards the cancer cells as compared to cisplatin alone.

  10. Brain-derived neurotrophic factor ameliorates brain stem cardiovascular dysregulation during experimental temporal lobe status epilepticus.

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    Ching-Yi Tsai

    Full Text Available BACKGROUND: Status epilepticus (SE is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM, a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF via an antioxidant action. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of temporal lobe SE (TLSE using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB, angiotensin AT1 receptor subtype (AT1R, nitric oxide synthase II (NOS II or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol, a specific antagonist of NADPH oxidase (apocynin or an AT1R antagonist (losartan blunted significantly the augmented superoxide anion or phosphorylated p47(phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses. CONCLUSIONS/SIGNIFICANCE: We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II

  11. Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

    Science.gov (United States)

    Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

    2015-01-01

    Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.

  12. Black ginseng extract ameliorates hypercholesterolemia in rats.

    Science.gov (United States)

    Saba, Evelyn; Jeon, Bo Ra; Jeong, Da-Hye; Lee, Kija; Goo, Youn-Kyoung; Kim, Seung-Hyung; Sung, Chang-Keun; Roh, Seong-Soo; Kim, Sung Dae; Kim, Hyun-Kyoung; Rhee, Man-Hee

    2016-04-01

    Ginseng (Panax ginseng Meyer) is a well-characterized medicinal herb listed in the classic oriental herbal dictionary as "Shin-nong-bon-cho-kyung." Ginseng has diverse pharmacologic and therapeutic properties. Black ginseng (BG, Ginseng Radix nigra) is produced by repeatedly steaming fresh ginseng nine times. Studies of BG have shown that prolonged heat treatment enhances the antioxidant activity with increased radical scavenging activity. Several recent studies have showed the effects of BG on increased lipid profiles in mice. In this study report the effects of water and ethanol extracts of BG on hypercholesterolemia in rats. To our knowledge, this is the first time such an effect has been reported. Experiments were conducted on male Sprague Dawley rats fed with a high-cholesterol diet supplemented with the water and ethanol extracts of BG (200 mg/kg). Their blood cholesterol levels, serum white blood cell levels, and cholesterol-metabolizing marker genes messenger RNA (mRNA) expression were determined. Liver and adipose tissues were histologically analyzed. We found that BG extracts efficiently reduced the total serum cholesterol levels, low-density lipoprotein (LDL) levels with increased food efficiency ratio and increased number of neutrophil cells. It also attenuated the key genes responsible for lipogenesis, that is, acetyl-coenzyme A (CoA) acetyltransferase 2, 3-hydroxy-3-methyl-glutaryl-CoA reductase, and sterol regulatory element-binding protein 2, at the mRNA level inside liver cells. Furthermore, the BG extract also reduced the accumulation of fat in adipose tissues, and inhibited the neutral fat content in liver cells stained with hematoxylin and eosin and oil red O. Administration of BG extracts to Sprague Dawley rats fed with high-cholesterol diet ameliorated hypercholesterolemia, which was mediated via modulation of cholesterol-metabolizing marker genes. This data throw a light on BG's cardioprotective effects.

  13. Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia.

    Science.gov (United States)

    Nickla, Debora L; Totonelly, Kristen

    2011-11-01

    In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form-deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form-deprivation) or -10 D lenses attached to the feathers with matching rings of Velcro. Each day for 4 days, 10 μl intravitreal injections of the dopamine D2/D4 antagonist spiperone (5 nmoles) or the D1 antagonist SCH-23390, were given under isoflurane anesthesia, and the diffusers (n = 16; n = 5, respectively) or lenses (n = 20; n = 6) were removed for 2 h immediately after. Saline injections prior to vision were done as controls (form-deprivation: n = 11; lenses: n = 10). Two other saline-injected groups wore the lenses (n = 12) or diffusers (n = 4) continuously. Axial dimensions were measured by high frequency A-scan ultrasonography at the start, and on the last day immediately prior to, and 3 h after the injection. Refractive errors were measured at the end of the experiment using a Hartinger's refractometer. In form-deprived eyes, spiperone, but not SCH-23390, prevented the ocular growth inhibition normally effected by the brief periods of vision (change in vitreous chamber depth, spiperone vs saline: 322 vs 211 μm; p = 0.01). By contrast, neither had any effect on negative lens-wearing eyes given similar unrestricted vision (210 and 234 μm respectively, vs 264 μm). The increased elongation in the spiperone-injected form-deprived eyes did not, however, result in a myopic shift, probably due to the inhibitory effect of the drug on anterior chamber growth (drug vs saline: 96 vs 160 μm; p effects of brief periods of unrestricted vision differ for form-deprivation versus negative lens-wear, which may imply different growth

  14. Zinc Ameliorate Oxidative Stress and Hormonal Disturbance Induced by Methomyl, Abamectin, and Their Mixture in Male Rats

    Directory of Open Access Journals (Sweden)

    Sameeh A. Mansour

    2017-12-01

    Full Text Available Exposure to mixtures of toxicants (e.g., pesticides is common in real life and a subject of current concern. The present investigation was undertaken to assess some toxicological effects in male rats following exposure to methomyl (MET, abamectin (ABM, and their combination (MET+ABM, and to evaluate the ameliorative effect of zinc co-administration. Three groups of rats were designated for MET, ABM, and the mixture treatments. Three other groups were designated for zinc in conjunction with the pesticides. Additionally, one group received water only (control, and the other represented a positive zinc treatment. The obtained results revealed that MET was acutely more toxic than ABM. The tested pesticides induced significant elevation in lipid peroxidation and catalase levels, while declined the levels of the other tested parameters e.g., Superoxide dismutase (SOD, Glutathione-S-transferase (GST, Glutathione peroxidase (GPx, Glutathione reductase (GR, Cytochrome P450 (CYP450, testosterone, and thyroxine. Biochemical alterations induced by the mixture were greater than those recorded for each of the individual insecticides. The joint action analysis, based on the obtained biochemical data, revealed the dominance of antagonistic action among MET and ABM. Zinc supplementation achieved noticeable ameliorative effects. It was concluded that zinc may act as a powerful antioxidant, especially in individuals who are occupationally exposed daily to low doses of such pesticides.

  15. Daikenchuto, a traditional Japanese herbal medicine, ameliorates postoperative ileus by anti-inflammatory action through nicotinic acetylcholine receptors.

    Science.gov (United States)

    Endo, Mari; Hori, Masatoshi; Ozaki, Hiroshi; Oikawa, Tetsuro; Hanawa, Toshihiko

    2014-06-01

    Daikenchuto (DKT), a gastrointestinal prokinetic Japanese herbal medicine, is prescribed for patients with postoperative ileus (POI) and adhesive bowel obstruction following abdominal surgery. Several mechanisms for the amelioration of POI by DKT have been suggested; however, it has remained unclear whether DKT shows anti-inflammatory effects in POI. In the present study, we investigated the effects of DKT in a mouse POI model and attempted to clarify the detailed mechanisms of action. Intestinal manipulation (IM) was applied to the distal ileum of mice. DKT was administered orally to the animals 4 times before and after IM. Gastrointestinal transit in vivo, leukocyte infiltration, cytokine mRNA expression and gastrointestinal motility were analyzed. We also investigated the effects of the α7nAChR antagonist methyllycaconitine citrate (MLA) on the DKT-mediated ameliorative action against POI, and we studied the effects of DKT on inflammatory activity in α7nAChR knockout mice. DKT treatment led to recovery of the delayed intestinal transit induced by IM. DKT significantly inhibited the infiltration of neutrophils and CD68-positive macrophages, and inhibited mRNA expressions of TNF-α and MCP-1. MLA significantly reduced the anti-inflammatory action of DKT, and the amelioration of macrophage infiltration by DKT was partially suppressed in α7nAChR knockout mice. In conclusion, in addition to the gastrointestinal prokinetic action, DKT serves as a novel therapeutic agent for POI characterized by its anti-inflammatory potency. The DKT-induced anti-inflammatory activity may be partly mediated by activation of α7nAChR.

  16. Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut.

    Science.gov (United States)

    Yue, Mengfan; Xia, Yufeng; Shi, Can; Guan, Chunge; Li, Yunfan; Liu, Rui; Wei, Zhifeng; Dai, Yue

    2017-09-01

    Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg -1 , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. © 2017 Federation of European Biochemical Societies.

  17. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

    Full Text Available Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness, accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  18. Hypocretin antagonists in insomnia treatment and beyond.

    Science.gov (United States)

    Ruoff, Chad; Cao, Michelle; Guilleminault, Christian

    2011-01-01

    Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

  19. History of the 'geste antagoniste' sign in cervical dystonia.

    Science.gov (United States)

    Poisson, A; Krack, P; Thobois, S; Loiraud, C; Serra, G; Vial, C; Broussolle, E

    2012-08-01

    The geste antagoniste is a voluntary maneuver that temporarily reduces the severity of dystonic posture or movements. It is a classical feature of focal and particularly cervical dystonia. However, the precise historical aspects of geste antagoniste still remain obscure. The goals of this review were (1) to clarify the origin of the geste antagoniste sign; (2) to identify the factors that led to its diffusion in the international literature; (3) to follow the evolution of that term across the twentieth century. We used medical and neurological French, German and English literature of the late nineteenth and early twentieth centuries, and the PubMed database by entering the terms geste antagoniste, antagonistic gesture and sensory trick. The geste antagoniste sign is a legacy of the Paris Neurological School of the end of the nineteenth century. The term was introduced by Meige and Feindel in their 1902 book on tics, written in the vein of their master, Brissaud, who first described this sign in 1893. The almost immediate translations of this book by Giese into German and Kinnier Wilson into English contributed to the rapid spreading of the term geste antagoniste, which is still in use worldwide today. The term antagonistic gesture is the translation proposed by Kinnier Wilson, which also led to the use of the term geste antagonistique. The geste antagoniste sign has long been considered a solid argument for the psychogenic origins of dystonia until the 1980s when Marsden made strong arguments for its organic nature.

  20. Neural correlates underlying naloxone-induced amelioration of sexual behavior deterioration due to an alarm pheromone

    Directory of Open Access Journals (Sweden)

    Tatsuya eKobayashi

    2015-02-01

    Full Text Available Sexual behavior is suppressed by various types of stressors. We previously demonstrated that an alarm pheromone released by stressed male Wistar rats is a stressor to other rats, increases the number of mounts needed for ejaculation, and decreases the hit rate (described as the number of intromissions/sum of the mounts and intromissions. This deterioration in sexual behavior was ameliorated by pretreatment with the opioid receptor antagonist naloxone. However, the neural mechanism underlying this remains to be elucidated. Here, we examined Fos expression in 31 brain regions of pheromone-exposed rats and naloxone-pretreated pheromone-exposed rats 60 min after 10 intromissions. As previously reported, the alarm pheromone increased the number of mounts and decreased the hit rate. In addition, Fos expression was increases in the anterior medial division, anterior lateral division and posterior division of the bed nucleus of the stria terminalis, parvocellular part of the paraventricular nucleus of the hypothalamus, arcuate nucleus, dorsolateral and ventrolateral periaqueductal gray, and nucleus paragigantocellularis. Fos expression decreased in the magnocellular part of the paraventricular nucleus of the hypothalamus. Pretreatment with naloxone blocked the pheromone-induced changes in Fos expression in the magnocellular part of the paraventricular nucleus of the hypothalamus, ventrolateral periaqueductal gray, and nucleus paragigantocellularis. Based on these results, we hypothesize that the alarm pheromone deteriorated sexual behavior by activating the ventrolateral periaqueductal gray-nucleus paragigantocellularis cluster and suppressing the magnocellular part of the paraventricular nucleus of the hypothalamus via the opioidergic pathway.

  1. Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPARδ Regulation in Hyperlipidemic and Hypertensive Conditions

    Directory of Open Access Journals (Sweden)

    Yong-Jik Lee

    2017-01-01

    Full Text Available To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ, phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK, phosphorylated acetyl-CoA carboxylase (p-ACC, malonyl-CoA decarboxylase (MCD, medium chain acyl-CoA dehydrogenase (MCAD, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1, fatty acid synthase (FAS, and tumor necrosis factor-alpha (TNF-α. Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660. Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway.

  2. Zinc Deficiency in Humans and its Amelioration

    Directory of Open Access Journals (Sweden)

    Yashbir Singh Shivay

    2015-01-01

    Full Text Available Zinc (Zn deficiency in humans has recently received considerable attention. Global mortality in children under 5 years of age in 2004 due to Zn deficiency was estimated at 4,53,207 as against 6,66,771 for vitamin A deficiency; 20,854 for iron deficiency and 3,619 for iodine deficiency. In humans 2800-3000 proteins contain Zn prosthetic group and Zn is an integral component of zinc finger prints that regulate DNA transcription. Zinc is a Type-2 nutrient, which means that its concentration in blood does not decrease in proportion of the Zn deficiency. Adverse effects of Zn deficiency vary with age: low weight gain, diarrhoea, aneroxia and neurobehavioral disturbances are observed in infants, while skin changes and dwarfism are frequent in toddlers and adolescents. Common manifestations of Zn deficiency among elderly include hypogeusia, chronic non-healing ulcers and recurrent infections.Ameliorative measures of Zn deficiency in humans can be classified in two groups, namely, nutraceutical and biofortification of food grains. Nutraceutical interventions include pharmaceutical supplements, dietary supplements and dietary diversification, while biofortification of food grains can be achieved by genetic modification (GM of crops or by agronomic techniques that include soil or/and foliar fertilization of crops.The major disadvantage of nutraceutical approaches is that the major beneficiaries are urban people and the poor rural masses that need adequate Zn nutrition most are left out. Genetic biofortification of food grains requires large amounts of funds and a fairly long-period of time. Further, a large number of countries have not yet accepted genetically modified (GM foods. On the other hand agronomic biofortification of food grains yields immediate effects and rural and urban people are equally benefitted. Our studies have shown that Zn concentration in cereals (rice, wheat etc and pulses can be considerably increased by soil or/and foliar

  3. Zinc Deficiency in Humans and its Amelioration

    Directory of Open Access Journals (Sweden)

    Yashbir Singh Shivay

    2015-12-01

    Full Text Available Zinc (Zn deficiency in humans has recently received considerable attention. Global mortality in children under 5 years of age in 2004 due to Zn deficiency was estimated at 4,53,207 as against 6,66,771 for vitamin A deficiency; 20,854 for iron deficiency and 3,619 for iodine deficiency. In humans 2800-3000 proteins contain Zn prosthetic group and Zn is an integral component of zinc finger prints that regulate DNA transcription. Zinc is a Type-2 nutrient, which means that its concentration in blood does not decrease in proportion of the Zn deficiency. Adverse effects of Zn deficiency vary with age: low weight gain, diarrhoea, aneroxia and neurobehavioral disturbances are observed in infants, while skin changes and dwarfism are frequent in toddlers and adolescents. Common manifestations of Zn deficiency among elderly include hypogeusia, chronic non-healing ulcers and recurrent infections. Ameliorative measures of Zn deficiency in humans can be classified in two groups, namely, nutraceutical and biofortification of food grains. Nutraceutical interventions include pharmaceutical supplements, dietary supplements and dietary diversification, while biofortification of food grains can be achieved by genetic modification (GM of crops or by agronomic techniques that include soil or/and foliar fertilization of crops. The major disadvantage of nutraceutical approaches is that the major beneficiaries are urban people and the poor rural masses that need adequate Zn nutrition most are left out. Genetic biofortification of food grains requires large amounts of funds and a fairly long-period of time. Further, a large number of countries have not yet accepted genetically modified (GM foods. On the other hand agronomic biofortification of food grains yields immediate effects and rural and urban people are equally benefitted. Our studies have shown that Zn concentration in cereals (rice, wheat etc and pulses can be considerably increased by soil or/and foliar

  4. Carbachol ameliorates lipopolysaccharide-induced intestinal epithelial tight junction damage by down-regulating NF-{kappa}{beta} and myosin light-chain kinase pathways

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ying [Department of Anesthesia, Critical Care Medicine and Emergency Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, People' s Republic of China (China); Li, Jianguo, E-mail: 2010lijianguo@sina.cn [Department of Anesthesia, Critical Care Medicine and Emergency Medicine Center, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, People' s Republic of China (China)

    2012-11-16

    Highlights: Black-Right-Pointing-Pointer Carbachol reduced the lipopolysaccharide-induced intestinal barrier breakdown. Black-Right-Pointing-Pointer Carbachol ameliorated the lipopolysaccharide-induced ileal tight junction damage. Black-Right-Pointing-Pointer Carbachol prevented the LPS-induced NF-{kappa}{beta} and myosin light-chain kinase activation. Black-Right-Pointing-Pointer Carbachol exerted its beneficial effects in an {alpha}7 nicotinic receptor-dependent manner. -- Abstract: Carbachol is a cholinergic agonist that protects the intestines after trauma or burn injury. The present study determines the beneficial effects of carbachol and the mechanisms by which it ameliorates the lipopolysaccharide (LPS)-induced intestinal barrier breakdown. Rats were injected intraperitoneally with 10 mg/kg LPS. Results showed that the gut barrier permeability was reduced, the ultrastructural disruption of tight junctions (TJs) was prevented, the redistribution of zonula occludens-1 and claudin-2 proteins was partially reversed, and the nuclear factor-kappa beta (NF-{kappa}{beta}) and myosin light-chain kinase (MLCK) activation in the intestinal epithelium were suppressed after carbachol administration in LPS-exposed rats. Pretreatment with the {alpha}7 nicotinic acetylcholine receptor ({alpha}7nAchR) antagonist {alpha}-bungarotoxin blocked the protective action of carbachol. These results suggested that carbachol treatment can protect LPS-induced intestinal barrier dysfunction. Carbachol exerts its beneficial effect on the amelioration of the TJ damage by inhibiting the NF-{kappa}{beta} and MLCK pathways in an {alpha}7nAchR-dependent manner.

  5. Effects of mineralocorticoid receptor antagonists in patients with hypertension and diabetes mellitus: a systematic review and meta-analysis.

    Science.gov (United States)

    Takahashi, S; Katada, J; Daida, H; Kitamura, F; Yokoyama, K

    2016-09-01

    Blood pressure (BP) control is important to ameliorate cardiovascular events in patients with diabetes mellitus (DM). However, achieving the target BP with a single drug is often difficult. The objective of this study was to evaluate the antihypertensive effects of mineralocorticoid receptor antagonists (MRAs) as add-on therapy to renin-angiotensin system (RAS) inhibitor(s) in patients with hypertension and DM. Studies were searched through October 2014 in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. Randomized, controlled trials or prospective, observational studies regarding concomitant administration of MRA and RAS inhibitor(s) in patients with DM were included. Articles were excluded if the mean systolic BP (SBP) was hypertension and DM already taking RAS inhibitors. Serum potassium levels should be monitored to prevent hyperkalemia.

  6. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony

    2015-02-02

    ABSTRACT Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation. This report is adapted from paineurope 2014; Issue 3, ©Haymarket Medical Publications Ltd, and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http:\\/\\/www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

  7. Antiallergic effects of H1-receptor antagonists.

    Science.gov (United States)

    Baroody, F M; Naclerio, R M

    2000-01-01

    The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H1-receptor and provide clinical benefit. However, H1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H1-receptor antagonist, has been shown to have additional actions that should help reduce the

  8. Antagonistic activity of marine sponges associated Actinobacteria

    Directory of Open Access Journals (Sweden)

    Selvakumar Dharmaraj

    2016-06-01

    Full Text Available Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology, nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance, physiological (pH, temperature and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate, soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are

  9. Assay method for organic calcium antagonist drugs and a kit for such an assay

    International Nuclear Information System (INIS)

    Snyder, S. H.; Gould, R. J.

    1985-01-01

    A method for measuring the level of organic calcium antagonist drug in a body fluid comprises preparing a mixture of a radioactive calcium antagonist drug, a body fluid containing a calcium antagonist drug and a calcium antagonist receptor material, measuring the radioactivity of the radioactive calcium antagonist drug bound to said calcium antagonist receptor material and deriving the concentration of the calcium antagonist drug in the body fluid from a standard curve indicating the concentration of calcium antagonist drug versus inhibition of binding of said radioactive calcium antagonist drug to said receptor sites caused by the calcium antagonist drug in said body fluid. A kit for measuring the level of an organic calcium drug comprises a receptacle containing a radioactive calcium antagonist drug, a calcium antagonist receptor material and a standard amount of a nonradioactive calcium antagonist drug

  10. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

    DEFF Research Database (Denmark)

    Tricoci, Pierluigi; Huang, Zhen; Held, Claes

    2012-01-01

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.......Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation....

  11. Adverse cutaneous reactions induced by TNF-alpha antagonist therapy.

    Science.gov (United States)

    Borrás-Blasco, Joaquín; Navarro-Ruiz, Andrés; Borrás, Consuelo; Casterá, Elvira

    2009-11-01

    To review adverse cutaneous drug reactions induced by tumor necrosis factor alpha (TNF-alpha) antagonist therapy. A literature search was performed using PubMed (1996-March 2009), EMBASE, and selected MEDLINE Ovid bibliography searches. All language clinical trial data, case reports, letters, and review articles identified from the data sources were used. Since the introduction of TNF-alpha antagonist, the incidence of adverse cutaneous drug reactions has increased significantly. A wide range of different skin lesions might occur during TNF-alpha antagonist treatment. New onset or exacerbation of psoriasis has been reported in patients treated with TNF-alpha antagonists for a variety of rheumatologic conditions. TNF-alpha antagonist therapy has been associated with a lupus-like syndrome; most of these case reports occurred in patients receiving either etanercept or infliximab. Serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely with the use of TNF-alpha antagonists. As the use of TNF-alpha antagonists continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly important challenge. In patients receiving TNF-alpha antagonist treatment, skin disease should be considered, and clinicians need to be aware of the adverse reactions of these drugs.

  12. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  13. Vitamin K antagonist use and mortality in dialysis patients

    NARCIS (Netherlands)

    Voskamp, Pauline W.M.; Rookmaaker, Maarten B.; Verhaar, Marianne C.; Dekker, Friedo W.; Ocak, Gurbey

    2018-01-01

    Background. The risk-benefit ratio of vitamin K antagonists for different CHA2DS2-VASc scores in patients with end-stage renal disease treated with dialysis is unknown. The aim of this study was to investigate the association between vitamin K antagonist use and mortality for different CHA2DS2-VASc

  14. Evaluation of antagonistic fungi against charcoal rot of sunflower ...

    African Journals Online (AJOL)

    In vitro, sensitivity of Macrophomina phaseolina (Tassi) Goid determined through inhibition zone technique to various antagonistic fungi viz., Aspergillus niger, Aspergillus flavus, Trichoderma viride, Trichoderma harzianum and Penicillium capsulatum amended into PDA medium. All the antagonists reduced the colony ...

  15. Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat

    Directory of Open Access Journals (Sweden)

    Alireza Komaki

    2014-07-01

    Full Text Available Introduction: Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP injection of cannabinoid CB1 receptor antagonist (AM251 in the presence of alpha-1 adrenergic antagonist (Prazosin on rat behavior in the EPM. Methods: In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg, Prazosin (0.3 mg/kg and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg. Results: Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Discussion: Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

  16. Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat.

    Science.gov (United States)

    Komaki, Alireza; Abdollahzadeh, Fatemeh; Sarihi, Abdolrahman; Shahidi, Siamak; Salehi, Iraj

    2014-01-01

    Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM) has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP) injection of cannabinoid CB1 receptor antagonist (AM251) in the presence of alpha-1 adrenergic antagonist (Prazosin) on rat behavior in the EPM. In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg), Prazosin (0.3 mg/kg) and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg). Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

  17. Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

    Science.gov (United States)

    Randall, Patrick A.; Nunes, Eric J.; Janniere, Simone L.; Stopper, Colin M.; Farrar, Andrew M.; Sager, Thomas N.; Baqi, Younis; Hockemeyer, Jörg; Müller, Christa E.

    2012-01-01

    Rationale Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression. PMID:21347642

  18. Yokukansan and Yokukansankachimpihange Ameliorate Aggressive Behaviors in Rats with Cholinergic Degeneration in the Nucleus Basalis of Meynert

    Directory of Open Access Journals (Sweden)

    Masahiro Tabuchi

    2017-04-01

    Full Text Available Yokukansan (YKS and yokukansankachimpihange (YKSCH are traditional Japanese Kampo medicines. The latter comprises YKS along with the medicinal herbs Citrus unshiu peel and Pinellia tuber. Both of these Kampo medicines are indicated for the treatment of night crying and irritability in children and for neurosis and insomnia in adults. In recent clinical trials, YKS exhibited ameliorative effects on the behavioral and psychological symptoms of dementia, such as aggressiveness, excitement, and irritability. In the present study, we aimed to clarify the involvement of cholinergic degeneration in the nucleus basalis of Meynert (NBM in the development of aggressiveness in rats. Subsequently, using this animal model, the effects of YKS and YKSCH on aggressiveness were compared and the mechanisms underlying these effects were investigated. L-Glutamic acid (Glu was injected into the right NBM of rats to induce deterioration of cholinergic neurons. On day 8 after Glu injection, aggressive behaviors were evaluated using resident–intruder tests. After the evaluation, YKS or YKSCH was administered to rats with aggressive behaviors daily for 7 days. In some groups, the 5-HT1A receptor antagonist WAY-100635 was coadministered with YKS or YKSCH over the same period. In other groups, locomotor activity was measured on days 12–14 after Glu injection. On day 15, immunohistochemistry was then performed to examine choline acetyltransferase (ChAT activities in the NBM. Aggressive behaviors had developed on day 8 after Glu injection and were maintained until day 15. YKS and YKSCH significantly ameliorated the aggressive behaviors. These suppressive effects were entirely abolished following coadministration of WAY-100635. Finally, the number of ChAT-positive cells in the right NBM was significantly reduced on day 15 after Glu injection, and treatment with YKS or YKSCH did not ameliorate these reduced cell numbers. Our results show that unilateral Glu injections

  19. Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

    NARCIS (Netherlands)

    R. de Wit (Ronald)

    2003-01-01

    textabstractThe advent of the 5HT3 receptor antagonists (5HT3 antagonists) in the 1990s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients

  20. The Effect of Vitamin E on Ameliorating Primary Dysmenorrhea: A ...

    African Journals Online (AJOL)

    Dysmenorrhea or painful menstruation is one of the most common problems of women. Using systematic review and meta‑analysis, this study aimed to determine the effect of vitamin E on ameliorating the intensity of pain of primary dysmenorrhea. Available databases comprising PubMed, Google Scholar, ISI, Science ...

  1. Designing urban parks that ameliorate the effects of climate change

    NARCIS (Netherlands)

    Brown, R.D.; Vanos, J.; Kenny, N.; Lenzholzer, S.

    2015-01-01

    Many inhabitants of cities throughout the world suffer from health problems and discomfort that are caused by overheating of urban areas, and there is compelling evidence that these problems will be exacerbated by global climate change. Most cities are not designed to ameliorate these effects

  2. Oral Metformin-Ascorbic Acid Co-Administration Ameliorates Alcohol ...

    African Journals Online (AJOL)

    Oral Metformin-Ascorbic Acid Co-Administration Ameliorates Alcohol-Induced Hepatotoxicity In Rats. ... Nigerian Quarterly Journal of Hospital Medicine ... the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure.

  3. Antibiotics can ameliorate circulatory complications of liver cirrhosis

    DEFF Research Database (Denmark)

    Madsen, Bjørn Stæhr; Schaffalitzky de Muckadell, Ove B

    2011-01-01

    . This review focuses on how broad spectrum antibiotics can ameliorate the haemodynamic consequences of bacterial translocation. It is possible that the use of broad spectrum antibiotics in the future may be used to prevent other complications of liver cirrhosis than spontaneous bacterial peritonitis...

  4. Ameliorative effect of the hydroethanolic whole plant extract of ...

    African Journals Online (AJOL)

    At the end of the study, biochemical markers of nitrosative and oxidative stress status were determined. Results: DH (12.5, 50 and 100 mg/kg) significantly ameliorated haloperidol-induced catalepsy (bar test), spontaneous motor and working memory deficits (open field and elevated plus maze tests, respectively), ...

  5. Ameliorative effects of Cnidoscolus aconitifolius on anaemia and ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-06-03

    Jun 3, 2008 ... This study was designed to evaluate the ameliorative effect of ... The group fed with 20% C. aconitifolius in place of 20% soya protein also ... to cholesterol enrichment of the erythrocytes membrane, ... rabbit and horse erythrocytes membrane with 1,2- .... various substances such as iron, vitamins and protein.

  6. Ameliorative effects of Cnidoscolus aconitifolius on anaemia and ...

    African Journals Online (AJOL)

    This study was designed to evaluate the ameliorative effect of dietary supplementation of Cnidoscolus aconitifolius leaf on anaemia and changes in erythrocyte osmotic fragility in protein energy malnourished rats. Protein energy malnutrition has been associated with anaemia and changes in osmotic fragility, deformability ...

  7. The antagonistic effect of Banana bunchy top virus multifunctional protein B4 against Fusarium oxysporum.

    Science.gov (United States)

    Zhuang, Jun; Coates, Christopher J; Mao, Qianzhuo; Wu, Zujian; Xie, Lianhui

    2016-06-01

    The viral-induced banana bunchy top disease and the fungal-induced banana blight are two major causes of concern for industrial scale production of bananas. Banana blight is particularly troublesome, affecting ∼80% of crops worldwide. Strict guidelines and protocols are in place in order to ameliorate the effects of this devastating disease, yet little success has been achieved. From the data presented here, we have found that Banana bunchy top virus (BBTV)-infected bananas are more resistant to Fusarium oxysporum f. sp. cubense (Foc). BBTV appears to be antagonistic towards Foc, thus improving the survivability of plants against blight. The BBTV suppressor of RNA silencing, namely protein B4, displays fungicidal properties in vitro. Furthermore, transgenic tomatoes expressing green fluorescent protein (GFP)-tagged protein B4 demonstrate enhanced resistance to F. oxysporum f. sp. lycopersici (Fol). Differential gene expression analysis indicates that increased numbers of photogenesis-related gene transcripts are present in dark-green leaves of B4-GFP-modified tomato plants relative to those found in WT plants. Conversely, the transcript abundance of immunity-related genes is substantially lower in transgenic tomatoes compared with WT plants, suggesting that plant defences may be influenced by protein B4. This viral-fungal interaction provides new insights into microbial community dynamics within a single host and has potential commercial value for the breeding of transgenic resistance to Fusarium-related blight/wilt. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  8. [Effect of the estrogen antagonist tamoxifen in the treatment of advanced mastocarcinoma (author's transl)].

    Science.gov (United States)

    Szepesi, T; Kärcher, K H

    1977-12-01

    Today the endocrin therapy of the advanced mastocarcinoma is in common use. Besides the already known therapy by estrogens, androgens, gestagens, and steroids, Tamoxifen, and estrogen antagonist, is a very promising therapeutic drug. In the presented study, Tamoxifen was submitted to a critical clinical control during a period of one year from 1st October 1975 until 1st October 1976. After a three months' treatment, a rate of 41% of objective remissions could be obtained. The criteria of success were estimated according to the scheme of Karnofsky. The average remission time is 5,5 months. By a determination of the estrogen receptors it would be possible to realize a therapeutic selection and to achieve a higher remission rate. The authors made an interesting observation, i.e. a probably immuno-stimulating effect which, however, still has to be submitted to further examinations. The side effects are described in detail and the indications are established. Its is astonishing that the subjective ameliorations, i.e. cessation of pains in case of generalized formation of metastases in the bones are much more frequent than the objective remissions. We came to the conclusion that the treatment by Tamoxifen is a valuable alternative in the therapy of the mastocarcinoma, above all in the postmenopausal period if the disease is advanced and incurable.

  9. Antagonistic neural networks underlying differentiated leadership roles

    Science.gov (United States)

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  10. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

    Directory of Open Access Journals (Sweden)

    Richard Eleftherios Boyatzis

    2014-03-01

    Full Text Available The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950’s. Recent research in neuroscience suggests that the division between task oriented and socio-emotional oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks -- the Task Positive Network (TPN and the Default Mode Network (DMN. Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  11. Antagonistic neural networks underlying differentiated leadership roles.

    Science.gov (United States)

    Boyatzis, Richard E; Rochford, Kylie; Jack, Anthony I

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks - the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  12. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  13. A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-01-01

    Full Text Available The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

  14. Characterization and design of antagonistic shape memory alloy actuators

    International Nuclear Information System (INIS)

    Georges, T; Brailovski, V; Terriault, P

    2012-01-01

    Antagonistic shape memory actuators use opposing shape memory alloy (SMA) elements to create devices capable of producing differential motion paths and two-way mechanical work in a very efficient manner. There is no requirement for additional bias elements to ‘re-arm’ the actuators and allow repetitive actuation. The work generation potential of antagonistic shape memory actuators is determined by specific SMA element characteristics and their assembly conditions. In this study, the selected SMA wires are assembled in antagonistic configuration and characterized using a dedicated test bench to evaluate their stress–strain characteristics as a function of the number of cycles. Using these functional characteristics, a so-called ‘working envelope’ is built to assist in the design of such an actuator. Finally, the test bench is used to simulate a real application of an antagonistic actuator (case study). (paper)

  15. The effects of N-methyl D-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis.

    Science.gov (United States)

    Das, Ravi K; Freeman, Tom P; Kamboj, Sunjeev K

    2013-03-01

    Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. 5-HT7 Receptor Antagonists with an Unprecedented Selectivity Profile.

    Science.gov (United States)

    Ates, Ali; Burssens, Pierre; Lorthioir, Olivier; Lo Brutto, Patrick; Dehon, Gwenael; Keyaerts, Jean; Coloretti, Francis; Lallemand, Bénédicte; Verbois, Valérie; Gillard, Michel; Vermeiren, Céline

    2018-04-23

    Selective leads: In this study, we generated a new series of serotonin 5-HT 7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT 7 antagonists with unprecedented high selectivity for the 5-HT 7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway.

    Science.gov (United States)

    Gao, Feng; Yao, Min; Cao, Yanping; Liu, Shuxia; Liu, Qingjuan; Duan, Huijun

    2016-05-01

    The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ-induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice.

  18. Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory.

    Science.gov (United States)

    Abush, Hila; Akirav, Irit

    2013-07-01

    Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory. Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescent rats were exposed to chronic restraint stress for 2 weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object-recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC, and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested. Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.

  19. Biochar from commercially cultivated seaweed for soil amelioration

    OpenAIRE

    Roberts, David A.; Paul, Nicholas A.; Dworjanyn, Symon A.; Bird, Michael I.; de Nys, Rocky

    2015-01-01

    Seaweed cultivation is a high growth industry that is primarily targeted at human food and hydrocolloid markets. However, seaweed biomass also offers a feedstock for the production of nutrient-rich biochar for soil amelioration. We provide the first data of biochar yield and characteristics from intensively cultivated seaweeds (Saccharina, Undaria and Sargassum ? brown seaweeds, and Gracilaria, Kappaphycus and Eucheuma ? red seaweeds). While there is some variability in biochar properties as ...

  20. Pyrolysis temperature influences ameliorating effects of biochars on acidic soil.

    Science.gov (United States)

    Wan, Qing; Yuan, Jin-Hua; Xu, Ren-Kou; Li, Xing-Hui

    2014-02-01

    The biochars were prepared from straws of canola, corn, soybean, and peanut at different temperatures of 300, 500, and 700 °C by means of oxygen-limited pyrolysis.Amelioration effects of these biochars on an acidic Ultisol were investigated with incubation experiments, and application rate of biochars was 10 g/kg. The incorporation of these biochars induced the increase in soil pH, soil exchangeable base cations, base saturation, and cation exchange capacity and the decrease in soil exchangeable acidity and exchangeable Al. The ameliorating effects of biochars on acidic soil increased with increase in their pyrolysis temperature. The contribution of oxygen-containing functional groups on the biochars to their ameliorating effects on the acidic soil decreased with the rise in pyrolysis temperature, while the contribution from carbonates in the biochars changed oppositely. The incorporation of the biochars led to the decrease in soil reactive Al extracted by 0.5mol/L CuCl2, and the content of reactive Al was decreased with the increase in pyrolysis temperature of incorporated biochars. The biochars generated at 300 °C increased soil organically complexed Al due to ample quantity of oxygen-containing functional groups such as carboxylic and phenolic groups on the biochars, while the biochars generated at 500 and 700 °C accelerated the transformation of soil exchangeable Al to hydroxyl-Al polymers due to hydrolysis of Al at higher pH. Therefore, the crop straw-derived biochars can be used as amendments for acidic soils and the biochars generated at relatively high temperature have great ameliorating effects on the soils.

  1. Infiltration in reclaimed mined land ameliorated with deep tillage treatments

    International Nuclear Information System (INIS)

    Chong, S.K.; Cowsert, P.T.

    1997-01-01

    Reclamation of mined land with heavy machinery can result in soil compaction, which increases soil bulk density and reduces porosity, water infiltrability, root elongation and crop productivity. This paper examines the effect on infiltration in reclaimed surface mined land of a deep tillage treatment, and the subsequent changes in infiltration after the amelioration. The experiment was conducted at the Horse Creek Mine near Conant, Ferry County, IL, USA

  2. Biochar from commercially cultivated seaweed for soil amelioration

    Science.gov (United States)

    Roberts, David A.; Paul, Nicholas A.; Dworjanyn, Symon A.; Bird, Michael I.; de Nys, Rocky

    2015-01-01

    Seaweed cultivation is a high growth industry that is primarily targeted at human food and hydrocolloid markets. However, seaweed biomass also offers a feedstock for the production of nutrient-rich biochar for soil amelioration. We provide the first data of biochar yield and characteristics from intensively cultivated seaweeds (Saccharina, Undaria and Sargassum – brown seaweeds, and Gracilaria, Kappaphycus and Eucheuma – red seaweeds). While there is some variability in biochar properties as a function of the origin of seaweed, there are several defining and consistent characteristics of seaweed biochar, in particular a relatively low C content and surface area but high yield, essential trace elements (N, P and K) and exchangeable cations (particularly K). The pH of seaweed biochar ranges from neutral (7) to alkaline (11), allowing for broad-spectrum applications in diverse soil types. We find that seaweed biochar is a unique material for soil amelioration that is consistently different to biochar derived from ligno-cellulosic feedstock. Blending of seaweed and ligno-cellulosic biochar could provide a soil ameliorant that combines a high fixed C content with a mineral-rich substrate to enhance crop productivity. PMID:25856799

  3. Biochar from commercially cultivated seaweed for soil amelioration

    Science.gov (United States)

    Roberts, David A.; Paul, Nicholas A.; Dworjanyn, Symon A.; Bird, Michael I.; de Nys, Rocky

    2015-04-01

    Seaweed cultivation is a high growth industry that is primarily targeted at human food and hydrocolloid markets. However, seaweed biomass also offers a feedstock for the production of nutrient-rich biochar for soil amelioration. We provide the first data of biochar yield and characteristics from intensively cultivated seaweeds (Saccharina, Undaria and Sargassum - brown seaweeds, and Gracilaria, Kappaphycus and Eucheuma - red seaweeds). While there is some variability in biochar properties as a function of the origin of seaweed, there are several defining and consistent characteristics of seaweed biochar, in particular a relatively low C content and surface area but high yield, essential trace elements (N, P and K) and exchangeable cations (particularly K). The pH of seaweed biochar ranges from neutral (7) to alkaline (11), allowing for broad-spectrum applications in diverse soil types. We find that seaweed biochar is a unique material for soil amelioration that is consistently different to biochar derived from ligno-cellulosic feedstock. Blending of seaweed and ligno-cellulosic biochar could provide a soil ameliorant that combines a high fixed C content with a mineral-rich substrate to enhance crop productivity.

  4. Ghrelin Ameliorates Asthma by Inhibiting Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Fu, Tian; Wang, Lei; Zeng, Qingdi; Zhang, Yan; Sheng, Baowei; Han, Liping

    2017-12-01

    This study aimed to confirm the ameliorative effect of ghrelin on asthma and investigate its mechanism. The murine model of asthma was induced by ovalbumin (OVA) treatment and assessed by histological pathology and airway responsiveness to methacholine. The total and differential leukocytes were counted. Tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 levels in bronchoalveolar lavage fluid were quantified by commercial kits. The protein levels in pulmonary tissues were measured by Western blot analysis. Ghrelin ameliorated the histological pathology and airway hyperresponsiveness in the OVA-induced asthmatic mouse model. Consistently, OVA-increased total and differential leukocytes and levels of tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 in bronchoalveolar lavage fluid were significantly attenuated by ghrelin. Ghrelin prevented the increased protein levels of the endoplasmic reticulum stress markers glucose regulated protein 78 and CCAAT/enhancer binding protein homologous protein and reversed the reduced levels of p-Akt in asthmatic mice. Ghrelin might prevent endoplasmic reticulum stress activation by stimulating the Akt signaling pathway, which attenuated inflammation and ameliorated asthma in mice. Ghrelin might be a new target for asthma therapy. Copyright © 2017. Published by Elsevier Inc.

  5. Administration of red ginseng ameliorates memory decline in aged mice.

    Science.gov (United States)

    Lee, Yeonju; Oh, Seikwan

    2015-07-01

    It has been known that ginseng can be applied as a potential nutraceutical for memory impairment; however, experiments with animals of old age are few. To determine the memory enhancing effect of red ginseng, C57BL/6 mice (21 mo old) were given experimental diet pellets containing 0.12% red ginseng extract (approximately 200 mg/kg/d) for 3 mo. Young and old mice (4 mo and 21 mo old, respectively) were used as the control group. The effect of red ginseng, which ameliorated memory impairment in aged mice, was quantified using Y-maze test, novel objective test, and Morris water maze. Red ginseng ameliorated age-related declines in learning and memory in older mice. In addition, red ginseng's effect on the induction of inducible nitric oxide synthase and proinflammatory cytokines was investigated in the hippocampus of aged mice. Red ginseng treatment suppressed the production of age-processed inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-1β expressions. Moreover, it was observed that red ginseng had an antioxidative effect on aged mice. The suppressed glutathione level in aged mice was restored with red ginseng treatment. The antioxidative-related enzymes Nrf2 and HO-1 were increased with red ginseng treatment. The results revealed that when red ginseng is administered over long periods, age-related decline of learning and memory is ameliorated through anti-inflammatory activity.

  6. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

    Science.gov (United States)

    Broussolle, Emmanuel; Laurencin, Chloé; Bernard, Emilien; Thobois, Stéphane; Danaila, Teodor; Krack, Paul

    2015-01-01

    Background Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. Results In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin. Discussion Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia. PMID:26417535

  7. Lactobacillus plantarum (VR1 isolated from an Ayurvedic medicine (Kutajarista ameliorates in vitro cellular damage caused by Aeromonas veronii

    Directory of Open Access Journals (Sweden)

    Patole Milind S

    2011-06-01

    Full Text Available Abstract Background Lactobacillus plantarum is considered as a safe and effective probiotic microorganism. Among various sources of isolation, traditionally fermented foods are considered to be rich in Lactobacillus spp., which can be exploited for their probiotic attribute. Antibacterial property of L. plantarum has been demonstrated against various enteric pathogens in both in vitro and in vivo systems. This study was aimed at characterizing L. plantarum isolated from Kutajarista, an ayurvedic fermented biomedicine, and assessing its antagonistic property against a common enteropathogen Aeromonas veronii. Results We report the isolation of L. plantarum (VR1 from Kutajarista, and efficacy of its cell free supernatant (CFS in amelioration of cytotoxicity caused by Aeromonas veronii. On the part of probiotic attributes, VR1 was tolerant to pH 2, 0.3% bile salts and simulated gastric juice. Additionally, VR1 also exhibited adhesive property to human intestinal HT-29 cell line. Furthermore, CFS of VR1 was antibacterial to enteric pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Aeromonas veronii and clinical isolates of P. aeruginosa and E. coli. Detailed study regarding the effect of VR1 CFS on A. veronii cytotoxicity showed a significant decrease in vacuole formation and detrimental cellular changes in Vero cells. On the other hand, A. veronii CFS caused disruption of tight junction proteins ZO-1 and actin in MDCK cell line, which was prevented by pre-incubation with CFS of VR1. Conclusions This is the first study to report isolation of L. plantarum (VR1 from Kutajarista and characterisation for its probiotic attributes. Our study demonstrates the antagonistic property of VR1 to A. veronii and effect of VR1 CFS in reduction of cellular damage caused by A. veronii in both Vero and MDCK cell lines.

  8. MDM2 Antagonists Counteract Drug-Induced DNA Damage

    Directory of Open Access Journals (Sweden)

    Anna E. Vilgelm

    2017-10-01

    Full Text Available Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.

  9. Gonadotrophin releasing hormone antagonist in IVF/ICSI

    Directory of Open Access Journals (Sweden)

    M S Kamath

    2008-01-01

    Full Text Available Objective : To study the efficacy of gonadotrophin releasing hormone (GnRH antagonist in In-vitro-fertilization/Intracytoplasmic sperm injection (IVF/ICSI cycles. Type of Study : Observational study. Setting: Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, Tamil Nadu. Materials and Methods: GnRH antagonists were introduced into our practice in November 2005. Fifty-two women undergoing the antagonist protocol were studied and information gathered regarding patient profile, treatment parameters (total gonadotrophin dosage, duration of treatment, and oocyte yield, and outcomes in terms of embryological parameters (cleavage rates, implantation rates and clinical pregnancy. These parameters were compared with 121 women undergoing the standard long protocol. The costs between the two groups were also compared. Main Outcome : Clinical pregnancy rate. Results : The clinical pregnancy rate per embryo transfer in the antagonist group was 31.7% which was comparable to the clinical pregnancy rate in women undergoing the standard long protocol (30.63%. The costs between the two groups were comparable. Conclusions : GnRH antagonist protocol was found to be effective and comparable to the standard long protocol regimen. In addition it was simple, convenient, and patient friendly.

  10. Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

    Directory of Open Access Journals (Sweden)

    Wei Chen

    2017-10-01

    Full Text Available The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects. In the current study, a novel compound (TXX-522 was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A. Docking assays indicate that TXX-522 was bound with the CB1R in a mode similar to that of SR141716A. TXX-522 showed good binding, CB1R-selectivity (over the CB2R, and functional antagonist activities in a range of in vitro molecular and cellular assays. In vivo analysis of the steady state distribution of TXX-522 in the rat brain and blood tissues and the assay of its functional effects on CB1R activity collectively showed that TXX-522 showed minimal brain penetration. Moreover, the in vivo pharmacodynamic study further revealed that TXX-522 had good oral bioavailability and a potent anti-obesity effect, and ameliorated insulin resistance in high-fat diet-induced obese mice. No impact on food intake was observed in this model, confirming the limited brain penetration of this compound. Thus, the current study indicates that TXX-522 is a novel and potent peripherally acting selective CB1R antagonist with the potential to control obesity and related metabolic disorders.

  11. First Irish birth following IVF therapy using antagonist protocol.

    LENUS (Irish Health Repository)

    Mocanu, E V

    2012-02-01

    BACKGROUND: During in vitro fertilization (IVF), the prevention of a premature LH surge was traditionally achieved using a gonadotrophin releasing hormone agonist (GnRH-a), and more recently, a GnRH antagonist. AIMS: We report a case of a 37 year old treated using the GnRH antagonist in a second completed cycle of IVF. METHODS: IVF was performed for primary infertility of 5-year duration due to frozen pelvis secondary to endometriosis. RESULTS: Following controlled ovarian hyperstimulation, oocyte recovery and fertilization, cleavage and transfer of two zygotes, a pregnancy established. A twin gestation was diagnosed at 7-weeks scan and pregnancy ended with the delivery of twin girls by emergency caesarean section. CONCLUSION: This is a first report of a delivery following IVF using the antagonist protocol in Ireland. Such therapy is patient friendly and its use should be introduced on a larger scale in clinical practice.

  12. ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

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    ANTARJO DIKIN

    2006-01-01

    Full Text Available Schizophyllum commune Fr., is one of the important fungi, causes brown germ and seed rot of oil palm. Biodiversity of antagonistic bacteria from oil palm plantations in Peninsular Malaysia is expected to support in development of biopesticide. Isolation with liquid assay and screening antagonistic bacteria using dual culture assay were carried out in the bioexploration. A total of 265 bacterial isolates from plant parts of oil palm screened 52 antagonistic bacterial isolates against 5. commune. Bacterial isolates were identified by using Biolog* Identification System i.e. Bacillus macroccanus, B. thermoglucosidasius, Burkholderia cepacia, B. gladioli, B. multivorans, B pyrrocinia, B. spinosa, Corynebacterium agropyri, C. misitidis, Enterobacter aerogenes, Microbacterium testaceum, Pseudomonas aeruginosa, P. citronellolis, Rhodococcus rhodochrous, Serratia ficaria, Serratia sp., S. marcescens, Staphylococcus sciuri, Sternotrophomonas maltophilia.

  13. Ocean acidification ameliorates harmful effects of warming in primary consumer.

    Science.gov (United States)

    Pedersen, Sindre Andre; Hanssen, Anja Elise

    2018-01-01

    Climate change-induced warming and ocean acidification are considered two imminent threats to marine biodiversity and current ecosystem structures. Here, we have for the first time examined an animal's response to a complete life cycle of exposure to co-occurring warming (+3°C) and ocean acidification (+1,600 μatm CO 2 ), using the key subarctic planktonic copepod, Calanus finmarchicus , as a model species. The animals were generally negatively affected by warming, which significantly reduced the females' energy status and reproductive parameters (respectively, 95% and 69%-87% vs. control). Unexpectedly, simultaneous acidification partially offset the negative effect of warming in an antagonistic manner, significantly improving reproductive parameters and hatching success (233%-340% improvement vs. single warming exposure). The results provide proof of concept that ocean acidification may partially offset negative effects caused by warming in some species. Possible explanations and ecological implications for the observed antagonistic effect are discussed.

  14. Endothelin receptor antagonists influence cardiovascular morphology in uremic rats.

    Science.gov (United States)

    Nabokov, A V; Amann, K; Wessels, S; Münter, K; Wagner, J; Ritz, E

    1999-02-01

    In is generally held that renal failure results in blood pressure (BP)-independent structural changes of the myocardium and the vasculature. The contribution, if any, of endothelin (ET) to these changes has been unknown. We morphometrically studied random samples of the left ventricle myocardium and small intramyocardial arteries in subtotally (5/6) nephrectomized (SNx) male Sprague-Dawley rats treated with either the selective ETA receptor antagonist BMS182874 (30 mg/kg/day) or the nonselective ETA/ETB receptor antagonist Ro46-2005 (30 mg/kg/day) in comparison with either sham-operated rats, untreated SNx, or SNx rats treated with the angiotensin-converting enzyme inhibitor trandolapril (0.1 mg/kg/day). Eight weeks later, systolic BP was lower in trandolapril-treated SNx compared with untreated SNx animals. No decrease in BP was seen following either ET receptor antagonist at the dose used. A significantly increased volume density of the myocardial interstitium was found in untreated SNx rats as compared with sham-operated controls. Such interstitial expansion was prevented by trandolapril and either ET receptor antagonist. SNx caused a substantial increase in the wall thickness of small intramyocardial arteries. The increase was prevented by trandolapril or BMS182874 treatment. The arteriolar wall:lumen ratio was significantly lower in all treated groups when compared with untreated SNx. In contrast, only trandolapril, but not the ET receptor antagonists, attenuated thickening of the aortic media in SNx animals. The ETA-selective and ETA/ETB-nonselective receptor antagonists appear to prevent development of myocardial fibrosis and structural changes of small intramyocardial arteries in experimental chronic renal failure. This effect is independent of systemic BP.

  15. Nasal Colivelin treatment ameliorates memory impairment related to Alzheimer's disease.

    Science.gov (United States)

    Yamada, Marina; Chiba, Tomohiro; Sasabe, Jumpei; Terashita, Kenzo; Aiso, Sadakazu; Matsuoka, Masaaki

    2008-07-01

    Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-beta (Abeta) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Abeta induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

  16. A note on inventory model for ameliorating items with time dependent second order demand rate

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    Gobinda Chandra Panda

    2013-03-01

    Full Text Available Background: This paper is concerned with the development of ameliorating inventory models. The ameliorating inventory is the inventory of goods whose utility increases over the time by ameliorating activation. Material and Methods: This study is performed according to two areas: one is an economic order quantity (EOQ model for the items whose utility is ameliorating in accordance with Weibull distribution, and the other is a partial selling quantity (PSQ model developed for selling the surplus inventory accumulated by ameliorating activation with linear demand. The aim of this paper was to develop a mathematical model for inventory type concerned in the paper. Numerical examples were presented show the effect of ameliorating rate on inventory polices.  Results and Conclusions:  The inventory model for items with Weibull ameliorating is developed. For the case of small ameliorating rate (less than linear demand rate, EOQ model is developed, and for the case where ameliorating rate is greater than linear demand rate, PSQ model is developed.  .  

  17. Shared epitope-antagonistic ligands: a new therapeutic strategy in mice with erosive arthritis.

    Science.gov (United States)

    Ling, Song; Liu, Ying; Fu, Jiaqi; Colletta, Alessandro; Gilon, Chaim; Holoshitz, Joseph

    2015-05-01

    The mechanisms underlying bone damage in rheumatoid arthritis (RA) are incompletely understood. We recently identified the shared epitope (SE), an HLA-DRB1-coded 5-amino acid sequence motif carried by the majority of RA patients as a signal transduction ligand that interacts with cell surface calreticulin and accelerates osteoclast (OC)-mediated bone damage in collagen-induced arthritis (CIA). Given the role of the SE/calreticulin pathway in arthritis-associated bone damage, we sought to determine the therapeutic targetability of calreticulin. A library of backbone-cyclized peptidomimetic compounds, all carrying an identical core DKCLA sequence, was synthesized. The ability of these compounds to inhibit SE-activated signaling and OC differentiation was tested in vitro. The effect on disease severity and OC-mediated bone damage was studied by weekly intraperitoneal administration of the compounds to DBA/1 mice with CIA. Two members of the peptidomimetics library were found to have SE-antagonistic effects and antiosteoclast differentiation effects at picomolar concentrations in vitro. The lead mimetic compound, designated HS(4-4)c Trp, potently ameliorated arthritis and bone damage in vivo when administered in picogram doses to mice with CIA. Another mimetic analog, designated HS(3-4)c Trp, was found to lack activity, both in vitro and in vivo. The differential activity of the 2 analogs depended on minor differences in their respective ring sizes and correlated with distinctive geometry when computationally docked to the SE binding site on calreticulin. These findings identify calreticulin as a novel therapeutic target in erosive arthritis and provide sound rationale and early structure/activity relationships for future drug design. © 2015, American College of Rheumatology.

  18. Discovery of tertiary sulfonamides as potent liver X receptor antagonists.

    Science.gov (United States)

    Zuercher, William J; Buckholz, Richard G; Campobasso, Nino; Collins, Jon L; Galardi, Cristin M; Gampe, Robert T; Hyatt, Stephen M; Merrihew, Susan L; Moore, John T; Oplinger, Jeffrey A; Reid, Paul R; Spearing, Paul K; Stanley, Thomas B; Stewart, Eugene L; Willson, Timothy M

    2010-04-22

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  19. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

  20. ELM pace making and amelioration at ASDEX upgrade

    Energy Technology Data Exchange (ETDEWEB)

    Lang, P.T.; Gruber, O.; Haas, G.; Horton, L.D.; Kaufmann, M.; Mertens, V.; Neu, R.; Neuhauser, J.; Puetterich, T.; Schneider, W.; Sihler, C.; Sips, A.C.C.; Suttrop, W.; Treutterer, W. [Max-Planck-Institut fuer Plasmaphysik, Euratom Association, Garching (Germany); Bucalossi, J. [Association Euratom-Confederation Suisse, CRPP-EPFL, Lausanne (Switzerland); Kalvin, S.; Kocsis, G. [Association Euratom, KFKI-RMKI, Budapest (Hungary); Mc Carthy, P.J. [University College Cork, Physics Dept., Association Euratom-DCu, Cork (Ireland)

    2004-07-01

    Different techniques were tried to trigger ELMs (edge localized mode): injection of cryogenic solid pellets or a super-sonic molecular gas jet composed of deuterium or magnetic triggering, relying on a fast motion of the plasma column in a spatially asymmetric flux configuration. Our investigations prove externally imposed control techniques can change the ELM frequency. Frequency enhancement can result in amelioration of the single ELMs. Moreover, the approach can maintain plasma operation at a high performance level. Both pellet injection and magnetic triggering have been shown their potential to act as useful control tools. This yields the option to choose eventually the most appropriate technique for a given scenario.

  1. Mesenchymal Stem Cells May Ameliorate Nephrotic Syndrome Post-Allogeneic Hematopoietic Stem Cell Transplantation-Case Report

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    Xin Zhang

    2017-08-01

    Full Text Available IntroductionBecause of their immunomodulatory and anti-inflammatory effects, mesenchymal stem cells (MSCs have been considered as potential therapeutic agents for treating immune-related or autoimmune diseases, such as graft-versus-host disease (GVHD. Nephrotic syndrome (NS after allogeneic hematopoietic stem cell transplantation (allo-HSCT is an uncommon complication with unclear etiology and pathogenesis. It may be an immune disorder involving immune complex deposition, B cells, regulatory T cells (Tregs, and Th1 cytokines and be a manifestation of chronic GVHD. Corticosteroids and calcium antagonists, alone or in combination, are the most common therapeutic agents in this setting. Rituximab is commonly administered as salvage treatment. However, treatment failure and progressive renal function deterioration has been reported to occur in approximately 20% of patients in a particular cohort.Case presentationWe present a patient who developed NS 10 months after allo-HSCT. After treatment failure with cyclosporine A, prednisone, and rituximab, she achieved a complete response with MSC treatment. The clinical improvement of this patient was accompanied by a decreased B cell population together with an increased frequency of regulatory B cells (Bregs and Tregs after MSC treatment.ConclusionMSCs could modulate NS after allo-HSCT by suppressing B cell proliferation, inducing Tregs and Bregs, and inhibiting inflammatory cytokine production by monocytes and NK cells. Among all these, Bregs might play an important role in ameliorating the NS of this patient.

  2. Apelin ameliorates TNF-α-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ.

    Directory of Open Access Journals (Sweden)

    Jiaojiao Chu

    Full Text Available Apelin, a novel adipokine, is the specific endogenous ligand of G protein-coupled receptor APJ. Consistent with its putative role as an adipokine, apelin has been linked to states of insulin resistance. However, the function of apelin in hepatic insulin resistance, a vital part of insulin resistance, and its underlying mechanisms still remains unclear. Here we define the impacts of apelin on TNF-α-induced reduction of glycogen synthesis in the hepatocytes. Our studies indicate that apelin reversed TNF-α-induced reduction of glycogen synthesis in HepG2 cells, mouse primary hepatocytes and liver tissues of C57BL/6J mice by improving JNK-IRS1-AKT-GSK pathway. Moreover, Western blot revealed that APJ, but not apelin, expressed in the hepatocytes and liver tissues of mice. We found that F13A, a competitive antagonist for G protein-coupled receptor APJ, suppressed the effects of apelin on TNF-α-induced reduction of glycogen synthesis in the hepatocytes, suggesting APJ is involved in the function of apelin. In conclusion, we show novel evidence suggesting that apelin ameliorates TNF-α-induced reduction of glycogen synthesis in the hepatocytes through G protein-coupled receptor APJ. Apelin appears as a beneficial adipokine with anti-insulin resistance properties, and thus as a promising therapeutic target in metabolic disorders.

  3. Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer's disease.

    Science.gov (United States)

    Bagheri, Maryam; Joghataei, Mohammad-Taghi; Mohseni, Simin; Roghani, Mehrdad

    2011-03-01

    Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by increased β-amyloid (Aβ) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10mg/kg) on learning and memory impairments was assessed in intrahippocampal Aβ(1-40)-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of Aβ-lesioned rats. The Aβ-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of Aβ-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates Aβ-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress. Copyright © 2010 Elsevier Inc. All rights reserved.

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

    International Nuclear Information System (INIS)

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

    2012-01-01

    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 −/− mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10 −/− mice. After JWH-133 treatment, the percentage of CD4 + 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 toxicity to colon

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

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Udai P.; Singh, Narendra P. [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States); Singh, Balwan [National Primate Research Center, Emory University, Atlanta GA 30329 (United States); Price, Robert L. [Department of Cell and Developmental Biology, University of South Carolina, Columbia, SC 29208 (United States); Nagarkatti, Mitzi [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States); Nagarkatti, Prakash S., E-mail: Prakash.Nagarkatti@uscmed.sc.edu [Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208 (United States)

    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

  6. Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

    Science.gov (United States)

    Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

    2015-01-01

    Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

  7. Increased orbitofrontal brain activation after administration of a selective adenosine A2A antagonist in cocaine dependent subjects

    Directory of Open Access Journals (Sweden)

    F. Gerard eMoeller

    2012-05-01

    Full Text Available Background: Positron Emission Tomography imaging studies provide evidence of reduced dopamine function in cocaine dependent subjects in the striatum, which is correlated with prefrontal cortical glucose metabolism, particularly in the orbitofrontal cortex. However, whether enhancement of dopamine in the striatum in cocaine dependent subjects would be associated with changes in prefrontal cortical brain activation is unknown. One novel class of medications that enhance dopamine function via heteromer formation with dopamine receptors in the striatum is the selective adenosine A2A receptor antagonists. This study sought to determine the effects administration of the selective adenosine A2A receptor antagonist SYN115 on brain function in cocaine dependent subjects. Methodology/Principle Findings: Twelve cocaine dependent subjects underwent two fMRI scans (one after a dose of placebo and one after a dose of 100 mg of SYN115 while performing a working memory task with 3 levels of difficulty (3, 5, and 7 digits. fMRI results showed that for 7-digit working memory activation there was significantly greater activation from SYN115 compared to placebo in portions of left (L lateral orbitofrontal cortex, L insula, and L superior and middle temporal pole. Conclusion/Significance: These findings are consistent with enhanced dopamine function in the striatum in cocaine dependent subjects via blockade of adenosine A2A receptors producing increased brain activation in the orbitofrontal cortex and other cortical regions. This suggests that at least some of the changes in brain activation in prefrontal cortical regions in cocaine dependent subjects may be related to altered striatal dopamine function, and that enhancement of dopamine function via adenosine A2A receptor blockade could be explored further for amelioration of neurobehavioral deficits associated with chronic cocaine use.

  8. Arginase Inhibition Ameliorates Hepatic Metabolic Abnormalities in Obese Mice

    Science.gov (United States)

    Moon, Jiyoung; Do, Hyun Ju; Cho, Yoonsu; Shin, Min-Jeong

    2014-01-01

    Objectives We examined whether arginase inhibition influences hepatic metabolic pathways and whole body adiposity in diet-induced obesity. Methods and Results After obesity induction by a high fat diet (HFD), mice were fed either the HFD or the HFD with an arginase inhibitor, Nω-hydroxy-nor-L-arginine (nor-NOHA). Nor-NOHA significantly prevented HFD-induced increases in body, liver, and visceral fat tissue weight, and ameliorated abnormal lipid profiles. Furthermore, nor-NOHA treatment reduced lipid accumulation in oleic acid-induced hepatic steatosis in vitro. Arginase inhibition increased hepatic nitric oxide (NO) in HFD-fed mice and HepG2 cells, and reversed the elevated mRNA expression of hepatic genes in lipid metabolism. Expression of phosphorylated 5′ AMPK-activated protein kinase α was increased by arginase inhibition in the mouse livers and HepG2 cells. Conclusions Arginase inhibition ameliorated obesity-induced hepatic lipid abnormalities and whole body adiposity, possibly as a result of increased hepatic NO production and subsequent activation of metabolic pathways involved in hepatic triglyceride metabolism and mitochondrial function. PMID:25057910

  9. Phytoceramide Shows Neuroprotection and Ameliorates Scopolamine-Induced Memory Impairment

    Directory of Open Access Journals (Sweden)

    Seikwan Oh

    2011-10-01

    Full Text Available The function and the role phytoceramide (PCER and phytosphingosine (PSO in the central nervous system has not been well studied. This study was aimed at investigating the possible roles of PCER and PSO in glutamate-induced neurotoxicity in cultured neuronal cells and memory function in mice. Phytoceramide showed neuro-protective activity in the glutamate-induced toxicity in cultured cortical neuronal cells. Neither phytosphingosine nor tetraacetylphytosphingosine (TAPS showed neuroproective effects in neuronal cells. PCER (50 mg/kg, p.o. recovered the scopolamine-induced reduction in step-through latency in the passive avoidance test; however, PSO did not modulate memory function on this task. The ameliorating effects of PCER on spatial memory were confirmed by the Morris water maze test. In conclusion, through behavioral and neurochemical experimental results, it was demonstrated that central administration of PCER produces amelioration of memory impairment. These results suggest that PCER plays an important role in neuroprotection and memory enhancement and PCER could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

  10. IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Jin Kyeong Choi

    2017-10-01

    Full Text Available Multiple sclerosis (MS is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE, the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, the IL-12p35-mediated expansion of Treg and Breg cells and its amelioration of EAE correlated with inhibition of cytokine-induced activation of STAT1/STAT3 pathways. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.

  11. Neuropeptide S ameliorates olfactory spatial memory impairment induced by scopolamine and MK801 through activation of cognate receptor-expressing neurons in the subiculum complex.

    Science.gov (United States)

    Shao, Yu-Feng; Wang, Can; Xie, Jun-Fan; Kong, Xiang-Pan; Xin, Le; Dong, Chao-Yu; Li, Jing; Ren, Wen-Ting; Hou, Yi-Ping

    2016-07-01

    Our previous studies have demonstrated that neuropeptide S (NPS), via selective activation of the neurons bearing NPS receptor (NPSR) in the olfactory cortex, facilitates olfactory function. High level expression of NPSR mRNA in the subiculum complex of hippocampal formation suggests that NPS-NPSR system might be involved in the regulation of olfactory spatial memory. The present study was undertaken to investigate effects of NPS on the scopolamine- or MK801-induced impairment of olfactory spatial memory using computer-assisted 4-hole-board spatial memory test, and by monitoring Fos expression in the subiculum complex in mice. In addition, dual-immunofluorescence microscopy was employed to identify NPS-induced Fos-immunereactive (-ir) neurons that also bear NPSR. Intracerebroventricular administration of NPS (0.5 nmol) significantly increased the number of visits to switched odorants in recall trial in mice suffering from odor-discriminating inability induced by scopolamine, a selective muscarinic cholinergic receptor antagonist, or MK801, a N-methyl-D-aspartate receptor antagonist, after training trials. The improvement of olfactory spatial memory by NPS was abolished by the NPSR antagonist [D-Val(5)]NPS (40 nmol). Ex vivo c-Fos and NPSR immunohistochemistry revealed that, as compared with vehicle-treated mice, NPS markedly enhanced Fos expression in the subiculum complex encompassing the subiculum (S), presubiculum (PrS) and parasubiculum (PaS). The percentages of Fos-ir neurons that also express NPSR were 91.3, 86.5 and 90.0 % in the S, PrS and PaS, respectively. The present findings demonstrate that NPS, via selective activation of the neurons bearing NPSR in the subiculum complex, ameliorates olfactory spatial memory impairment induced by scopolamine and MK801 in mice.

  12. NMDA receptor antagonists for the treatment of neuropathic pain

    NARCIS (Netherlands)

    Collins, S.; Sigtermans, M.J.; Dahan, A.; Zuurmond, W.W.A.; Perez, R.S.G.M.

    2010-01-01

    Objective. The N-methyl-D-Aspartate (NMDA) receptor has been proposed as a primary target for the treatment of neuropathic pain. The aim of the present study was to perform a meta-analysis evaluating the effects of (individual) NMDA receptor antagonists on neuropathic pain, and the response

  13. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    approximately halfway into the solution. All animals were tested at 60, 15 and 0 min before drug injection. For each animal , the first reading was discarded...approval (December 31, 2015), hiring new personnel, conducting baseline testing for procedures not involving animals , testing equipment, developing...treatment; Analgesia; Nociception; Antinociception; Inflammation; Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain

  14. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, Rene dePont; Wang, Shirley V

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...

  15. Komplikationer til langtidsbehandling med vitamin K-antagonister

    DEFF Research Database (Denmark)

    May, O; Garne, E; Mickley, H

    1990-01-01

    Long-term treatment with vitamin K antagonists (vKA) frequently involves complications. The commonest complication is haemorrhage and cases of serious haemorrhage are stated in the literature to occur with a frequency per 1,000 treatment years of 12-108, of which 2-17 are fatal. The majority...

  16. Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy

    NARCIS (Netherlands)

    Roscioni, Sara S.; de Zeeuw, Dick; Bakker, Stephan J. L.; Lambers Heerspink, Hiddo J.

    2012-01-01

    Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients

  17. Effect of Three Calmodulin Antagonists on Subpopulations of CD44 ...

    African Journals Online (AJOL)

    Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus,. International Pharmaceutical ... cancer stem cells. It is not known, however, whether targeting CD44 can alter the fate of cancer stem cells themselves. In this study, the effect of the calmodulin antagonists (N-(10-.

  18. The Effect of Sympathetic Antagonists on the Antidepressant Action ...

    African Journals Online (AJOL)

    Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor ...

  19. The Effect of Antagonist Muscle Sensory Input on Force Regulation.

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

    Full Text Available The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years, healthy subjects performed constant isometric knee flexion contractions (agonist at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%, subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40% between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical are likely involved.

  20. Antagonistic bioactivity of an endophytic bacterium isolated from ...

    African Journals Online (AJOL)

    Antagonistic bioactivity of an endophytic bacterium isolated from Epimedium brevicornu Maxim. R He, G Wang, X Liu, C Zhang, F Lin. Abstract. Endophytic bacteria are one of the most potential biological control agents in plant disease protection. The aim of this work was to evaluate the antimicrobial activities of a strain of ...

  1. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist

    NARCIS (Netherlands)

    van Oosten, B. W.; Killestein, J.; Mathus-Vliegen, E. M. H.; Polman, C. H.

    2004-01-01

    Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence

  2. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  3. Manumycin from a new Streptomyces strain shows antagonistic ...

    African Journals Online (AJOL)

    Manumycin from a new Streptomyces strain shows antagonistic effect against methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant enterococci (VRE) strains from Korean Hospitals. Yun Hee Choi, Seung Sik Cho, Jaya Ram Simkhada, Chi Nam Seong, Hyo Jeong Lee, Hong Seop Moon, Jin Cheol Yoo ...

  4. Effects of calcium antagonists on hypertension and diastolic function ...

    African Journals Online (AJOL)

    Calcium antagonists are known to decrease blood pressure acutely and chronically in hypertensive patients with hypertensive heart disease, and also to improve their systolic function. However, disorders of diastolic function may occur early in hypertensive heart disease. The improvement of diastolic function by nifedipine ...

  5. Sympatho-inhibitory properties of various AT1 receptor antagonists

    NARCIS (Netherlands)

    Balt, Jippe C.; Mathy, Marie-Jeanne; Pfaffendorf, Martin; van Zwieten, Peter A.

    2002-01-01

    It is well known that angiotensin II (Ang II) can facilitate the effects of sympathetic neurotransmission. In the present study, using various experimental models, we investigated the inhibitory effects of several Ang II subtype 1 receptor (AT1) antagonists on this Ang II-induced facilitation. We

  6. Possible site of action of CGRP antagonists in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Olesen, Jes

    2011-01-01

    The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP antagoni...

  7. Christianity and Antagonistic Challenges in Igbo Land of Nigeria: A ...

    African Journals Online (AJOL)

    Christianity and Antagonistic Challenges in Igbo Land of Nigeria: A Reflection. ... The church mission society (CMS) along side the Royal Niger Company was working ... is to win the confidence of the people by establishing agricultural settlements, ... FAQ's · More about AJOL · AJOL's Partners · Terms and Conditions of Use ...

  8. Possible site of action of CGRP antagonists in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Olesen, Jes

    2011-01-01

    The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP...

  9. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Kjaergard, L L; Gluud, C

    2001-01-01

    The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor...... antagonists for hepatic encephalopathy, but the results are conflicting....

  10. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  11. Antagonistic bioactivity of endophytic strains isolated from Salvia ...

    African Journals Online (AJOL)

    The antibiotic-producing potential of endophytic populations from medical plant of Salvia miltiorrhiza was examined. A total of 63 isolates was screened against five fungal and three bacterial species for the production of antimicrobial compounds. It showed that more isolates was antagonistic to fungi than to bacteria.

  12. Screening and Mechanism of Trapping Ligand Antagonist Peptide ...

    African Journals Online (AJOL)

    Purpose: The aim of the present study was to develop peptide H9 as an efficient antagonist of human cytomegalovirus (HCMV) chemokine receptor US28. Methods: US28 gene was amplified from HCMV, and a stable expression system was constructed using NIH/3T3 cells. Interaction between peptide H9 and receptor ...

  13. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, Adrian R.; Di Napoli, Mario; Goldstein, Joshua N.; Schreuder, Floris H B M; Tetri, Sami; Tatlisumak, Turgut; Yan, Bernard; Van Nieuwenhuizen, Koen M.; Dequatre-Ponchelle, Nelly; Lee-Archer, Matthew; Horstmann, Solveig; Wilson, Duncan; Pomero, Fulvio; Masotti, Luca; Lerpiniere, Christine; Godoy, Daniel Agustin; Cohen, Abigail S.; Houben, Rik; Al-Shahi Salman, Rustam; Pennati, Paolo; Fenoglio, Luigi; Werring, David; Veltkamp, Roland; Wood, Edith; Dewey, Helen M.; Cordonnier, Charlotte; Klijn, Catharina J M; Meligeni, Fabrizio; Davis, Stephen M.; Huhtakangas, Juha; Staals, Julie; Rosand, Jonathan; Meretoja, Atte

    2015-01-01

    Objective There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  14. Role of muscarinic receptor antagonists in urgency and nocturia

    NARCIS (Netherlands)

    Michel, Martin C.; de La Rosette, Jean J. M. C. H.

    2005-01-01

    The overactive bladder (OAB) syndrome is defined as urgency, with or without urgency incontinence, usually accompanied by frequency and nocturia. Muscarinic receptor antagonists are the most established form of treatment for OAB, but until recently their effectiveness was only confirmed for symptoms

  15. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    International Nuclear Information System (INIS)

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-01

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K i = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  16. Efficacy and safety of histamine-2 receptor antagonists

    NARCIS (Netherlands)

    van der Pol, Rachel; Langendam, Miranda; Benninga, Marc; van Wijk, Michiel; Tabbers, Merit

    2014-01-01

    Histamine-2 receptor antagonists (H2RAs) are frequently used in the treatment of gastroesophageal reflux disease (GERD) in children; however, their efficacy and safety is questionable. To systematically review the literature to assess the efficacy and safety of H2RAs in pediatric GERD. PubMed,

  17. NK-1 receptor antagonists as anti-cancer drugs

    Indian Academy of Sciences (India)

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, ...

  18. An Antagonistic Dialogue about Chaordic Systems Thinking: Part I

    Science.gov (United States)

    Wafler, Toni

    2004-01-01

    This paper explores the added value of chaordic systems Thinking for organizational renewal, which is defined as transformation instead of reformation. The exploration is presented in the form of an antagonistic dialogue between two "voices," which develop commentaries from distinct theoretical inspirations, namely chaordic systems thinking (CST)…

  19. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or

  20. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G

    2000-01-01

    We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5...

  1. Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats.

    Directory of Open Access Journals (Sweden)

    Agnieszka Nikiforuk

    Full Text Available A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg or amisulpride (3 mg/kg ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.

  2. Antagonistic interactions between plant competition and insect herbivory.

    Science.gov (United States)

    Schädler, Martin; Brandl, Roland; Haase, Josephine

    2007-06-01

    Interspecific competition between plants and herbivory by specialized insects can have synergistic effects on the growth and performance of the attacked host plant. We tested the hypothesis that competition between plants may also negatively affect the performance of herbivores as well as their top-down effect on the host plant. In such a case, the combined effects of competition and herbivory may be less than expected from a simple multiplicative response. In other words, competition and herbivory may interact antagonistically. In a greenhouse experiment, Poa annua was grown in the presence or absence of a competitor (either Plantago lanceolata or Trifolium repens), as well as with or without a Poa-specialist aphid herbivore. Both competition and herbivory negatively affected Poa growth. Competition also reduced aphid density on Poa. This effect could in part be explained by changes in the biomass and the nitrogen content of Poa shoots. In treatments with competitors, reduced aphid densities alleviated the negative effect of herbivory on above- and belowground Poa biomass. Hence, we were able to demonstrate an antagonistic interaction between plant-plant interspecific competition and herbivory. However, response indices suggested that antagonistic interactions between competition and herbivory were contingent on the identity of the competitor. We found the antagonistic effect only in treatments with T. repens as the competitor. We conclude that both competitor identity and the herbivore's ability to respond with changes in its density or activity to plant competition affect the magnitude and direction (synergistic vs. antagonistic) of the interaction between competition and herbivory on plant growth.

  3. 27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

    Science.gov (United States)

    2010-04-01

    ... ameliorates juice or wine, or both, shall maintain a record of the operation and the transaction date. Records...; however, if liquid sugar or invert sugar syrup is used, the quantity of water in such sugar is included as... to be held after that date for completion. When the amelioration of wine included in the record for...

  4. Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation

    DEFF Research Database (Denmark)

    Fosbøl, Emil L; Vinding, Naja Emborg; Lamberts, Morten

    2017-01-01

    Aims: After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran...

  5. Histologic and inflammatory lamellar changes in horses with oligofructose-induced laminitis treated with a CXCR1/2 antagonist

    Directory of Open Access Journals (Sweden)

    Leonardo R. de Lima

    2016-01-01

    Full Text Available Abstract: With the hypothesis that blocking chemokine signaling can ameliorate acute laminitis, the aim was to evaluate the therapeutic effect of intravenous DF1681B, a selective antagonist for CXCR1 and CXCR2 (chemokine receptors, in an oligofructose equine laminitis model. To twelve mixed breed clinically healthy hoses with no previous history of hoof-related lameness was administered oligofructose (10g/kg given by nasogastric tube and divided into two groups: treated (intravenous DF1681B at 30mg/kg 6, 12, 18, and 24h after oligofructose and non-treated groups. Laminar biopsies were performed before and 12, 36, and 72h after administering oligofructose. Samples were stained with periodic acid-Schiff (PAS and scored from 0 to 6 according to epidermal cell and basal membrane changes. The IL-1β, IL-6, and CXCL1 RNA expressions were determined by RT-PCR. Parametric and non-parametric tests were used to compare times within each group (P<0.05. The PAS grades and IL-1β and IL-6 RNA expression increased in the non-treated group, but remained constant in the treated horses. In conclusion, DF1681B therapy reduced laminar inflammation and epidermal deterioration in treated horses. CXCR1/2 blockage should be considered therapeutically for equine acute laminitis.

  6. Amelioration of ongoing experimental autoimmune encephalomyelitis with fluoxetine.

    Science.gov (United States)

    Bhat, Roopa; Mahapatra, Sidharth; Axtell, Robert C; Steinman, Lawrence

    2017-12-15

    In patients with multiple sclerosis, the selective serotonin reuptake inhibitor, fluoxetine, resulted in less acute disease activity. We tested the immune modulating effects of fluoxetine in a mouse model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE). We show that fluoxetine delayed the onset of disease and reduced clinical paralysis in mice with established disease. Fluoxetine had abrogating effects on proliferation of immune cells and inflammatory cytokine production by both antigen-presenting cells and T cells. Specifically, in CD 4 T cells, fluoxetine increased Fas-induced apoptosis. We conclude that fluoxetine possesses immune-modulating effects resulting in the amelioration of symptoms in EAE. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Heregulin ameliorates the dystrophic phenotype in mdx mice

    DEFF Research Database (Denmark)

    Krag, Thomas O B; Bogdanovich, Sasha; Jensen, Claus J

    2004-01-01

    Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin. Utrophin's ability to compensate for dystrophin during development and when....... Therefore, this pathway offers a potential mechanism to modulate utrophin expression in muscle. We tested the ability of heregulin to improve the dystrophic phenotype in the mdx mouse model of DMD. Intraperitoneal injections of a small peptide encoding the epidermal growth factor-like region of heregulin...... ectodomain for 3 months in vivo resulted in up-regulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction mediated damage, and a reduction of muscle pathology. The amelioration of dystrophic phenotype by heregulin-mediated utrophin...

  8. Flurbiprofen ameliorates glucose deprivation-induced leptin resistance

    Directory of Open Access Journals (Sweden)

    Toru Hosoi

    2016-09-01

    Full Text Available Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3 and signal transducer and activator of transcription 5 (STAT5 in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein (CHOP and glucose regulated protein 78 (GRP78 induction, indicating the activation of unfolded protein responses (UPR. Flurbiprofen did not affect the glucose deprivation-induced activation of UPR, but did attenuate the glucose deprivation-mediated induction of AMP-activated protein kinase (AMPK phosphorylation. Flurbiprofen may ameliorate glucose deprivation-induced leptin resistance in neuronal cells.

  9. Flemingia macrophylla Extract Ameliorates Experimental Osteoporosis in Ovariectomized Rats

    Directory of Open Access Journals (Sweden)

    Hui-Ya Ho

    2011-01-01

    Full Text Available Flemingia macrophylla (Leguminosae, a native plant of Taiwan, is used as folk medicine. An in vitro study showed that a 75% ethanolic extract of F. macrophylla (FME inhibited osteoclast differentiation of cultured rat bone marrow cells, and the active component, lespedezaflavanone A (LDF-A, was isolated. It was found that oral administration of FME for 13 weeks suppressed bone loss in ovariectomized rats, an experimental model of osteoporosis. In addition, FME decreased urinary deoxypyridinoline concentrations but did not inhibit serum alkaline phosphatase activities, indicating that it ameliorated bone loss via inhibition of bone resorption. These results suggest that FME may represent a useful remedy for the treatment of bone resorption diseases, such as osteoporosis. In addition, LDF-A could be used as a marker compound to control the quality of FME.

  10. Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

    Science.gov (United States)

    Li, Xintao; Cao, Tingting; Ma, Shuo; Jing, Zehao; Bi, Yue; Zhou, Jicheng; Chen, Chong; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

    2017-11-05

    Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Granisetron ameliorates acetic acid-induced colitis in rats.

    Science.gov (United States)

    Fakhfouri, Gohar; Rahimian, Reza; Daneshmand, Ali; Bahremand, Arash; Rasouli, Mohammad Reza; Dehpour, Ahmad Reza; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem

    2010-04-01

    Inflammatory bowel disease (IBD) is a chronically relapsing inflammation of the gastrointestinal tract, of which the definite etiology remains ambiguous. Considering the adverse effects and incomplete efficacy of currently administered drugs, it is indispensable to explore new candidates with more desirable therapeutic profiles. 5-HT( 3) receptor antagonists have shown analgesic and anti-inflammatory properties in vitro and in vivo. This study aims to investigate granisetron, a 5-HT( 3) receptor antagonist, in acetic acid-induced rat colitis and probable involvement of 5-HT(3) receptors. Colitis was rendered by instillation of 1 mL of 4% acetic acid (vol/vol) and after 1 hour, granisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT( 3) receptor agonist, or granisetron + mCPBG was given intraperitoneally. Twenty-four hours following colitis induction, animals were sacrificed and distal colons were assessed macroscopically, histologically and biochemically (malondialdehyde, myeloperoxidase, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6). Granisetron or dexamethasone significantly (p granisetron were reversed by concurrent administration of mCPBG. Our data suggests that the salutary effects of granisetron in acetic acid colitis could be mediated by 5-HT(3) receptors.

  12. Opioid antagonists with minimal sedation for opioid withdrawal.

    Science.gov (United States)

    Gowing, Linda; Ali, Robert; White, Jason M

    2017-05-29

    Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. We used standard methodological procedures expected by Cochrane. Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha 2 -adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient

  13. GnRH antagonist versus long agonist protocols in IVF

    DEFF Research Database (Denmark)

    Lambalk, C B; Banga, F R; Huirne, J A

    2017-01-01

    BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH...... in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF...

  14. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...... placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary...

  15. Cyclic degradation of antagonistic shape memory actuated structures

    International Nuclear Information System (INIS)

    Sofla, A Y N; Elzey, D M; Wadley, H N G

    2008-01-01

    Antagonistic shape memory actuated structures exploit opposing pairs of one-way shape memory alloy (SMA) linear actuators to create devices capable of a fully reversible response. Unlike many conventional reversible SMA devices they do not require bias force components (springs) to return them to their pre-actuated configuration. However, the repeated use of SMA antagonistic devices results in the accumulation of plastic strain in the actuators which can diminish their actuation stroke. We have investigated this phenomenon and the effect of shape memory alloy pre-strain upon it for near equi-atomic NiTi actuators. We find that the degradation eventually stabilizes during cycling. A thermomechanical treatment has been found to significantly reduce degradation in cyclic response of the actuators

  16. In-silico guided discovery of novel CCR9 antagonists

    Science.gov (United States)

    Zhang, Xin; Cross, Jason B.; Romero, Jan; Heifetz, Alexander; Humphries, Eric; Hall, Katie; Wu, Yuchuan; Stucka, Sabrina; Zhang, Jing; Chandonnet, Haoqun; Lippa, Blaise; Ryan, M. Dominic; Baber, J. Christian

    2018-03-01

    Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.

  17. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  18. Construction, purification, and characterization of a chimeric TH1 antagonist

    Directory of Open Access Journals (Sweden)

    Javier-González Luís

    2006-05-01

    Full Text Available Abstract Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases.

  19. [Leukotriene antagonists: a new approach in the treatment of asthma].

    Science.gov (United States)

    Devillier, P; Bessard, G; Advenier, C

    1997-06-01

    Inflammation plays an essential role in the genesis of airflow obstruction and bronchial hyper-reactivity in the early stages of clinical asthma. The treatment of bronchial inflammation has become an essential element in the therapeutic strategy and principally rests on inhaled glucocorticoids. Amongst a number of inflammatory mediators leukotrienes occupy a privileged place by the power of their inflammatory and constrictor effects on bronchial smooth muscles. These properties have justified the clinical development of inhibitors of their synthesis and of specific antagonists to their receptors. Leukotriene antagonists are specific for a sub type of leukotriene receptors C4, D4 and E4 which is implicated in the majority of the bronchial constrictor and inflammatory effects of leukotrienes. The antagonists of Cys-LT1 receptor but also the inhibitors of the leukotriene synthesis exert an additive bronchodilator effect to those of B2 stimulants confirming an efficacious protection vis a vis bronchial provocation tests and above all they improve the clinical scores, lung function and also enable a decrease in the consumption of beta 2 agonists. The marketing of these products represents a major event because it corresponds to the advent of a new therapeutic class. The ease of administration by the oral route, their demonstrated efficacy and their good tolerance profile (in particular for ICI 204.219, and antagonists to Cys-LT1 receptors) are elements which foresee a success for this new asthmatic treatment. However numerous studies, notably comparative studies vis a vis reference treatments will be necessary to define their place in the strategic approach to the treatment of asthma.

  20. Suvorexant: The first orexin receptor antagonist to treat insomnia

    OpenAIRE

    Dubey, Ashok K.; Handu, Shailendra S.; Mediratta, Pramod K.

    2015-01-01

    Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, hav...

  1. A prototypical Sigma-1 receptor antagonist protects against brain ischemia

    OpenAIRE

    Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

    2007-01-01

    Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

  2. [Necrotic leg ulcer revealing vasculitis induced by vitamin K antagonists].

    Science.gov (United States)

    Chabli, H; Hocar, O; Akhdari, N; Amal, S; Hakkou, M; Hamdaoui, A

    2015-12-01

    Vitamin K antagonists are widely used in thromboembolic diseases. Hemorrhagic complications related to drug overdose represent their main side effect. We report a rare side effect, a severe and unexpected type of skin vasculitis - necrotic leg ulcer - induced by vitamin K antagonist. A 63-year-old female with a history of diabetes developed hyperalgesic necrotic ulcerations on the lower limbs one month after starting an acenocoumarol-based treatment for ischemic heart disease. Histological examination revealed lymphocytic vasculitis with fibrinoid necrosis. Etiological explorations searching for vasculitis were negative. In the absence of a precise etiology, drug-induced ulcer was suspected. Low molecular weight heparin was prescribed to replace acenocoumarol. The lesions slowly resolved with topical treatment. The chronological criteria and the negativity of etiological explorations allowed the diagnosis of vitamin K antagonist-induced necrotic skin ulcer. Clinicians should be aware of this rare complication induced by oral anticoagulants because of its practical therapeutic implications. This is the first case of necrotic leg ulcer induced by acenocoumarol corresponding histologically to necrotising lymphocytic vasculitis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  3. Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

    Science.gov (United States)

    Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

    2016-08-01

    Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.

  4. Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

    Directory of Open Access Journals (Sweden)

    Sachiko Yamada

    Full Text Available Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7 in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1, a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

  5. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

    Science.gov (United States)

    Suzuki, H; Toyota, M; Caraway, H; Gabrielson, E; Ohmura, T; Fujikane, T; Nishikawa, N; Sogabe, Y; Nojima, M; Sonoda, T; Mori, M; Hirata, K; Imai, K; Shinomura, Y; Baylin, S B; Tokino, T

    2008-01-01

    Although mutation of APC or CTNNB1 (β-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a β-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. PMID:18283316

  6. Microbial Herd Protection Mediated by Antagonistic Interaction in Polymicrobial Communities

    Science.gov (United States)

    Wong, Megan J. Q.; Liang, Xiaoye; Smart, Matt; Tang, Le; Moore, Richard; Ingalls, Brian

    2016-01-01

    ABSTRACT In host and natural environments, microbes often exist in complex multispecies communities. The molecular mechanisms through which such communities develop and persist, despite significant antagonistic interactions between species, are not well understood. The type VI secretion system (T6SS) is a lethal weapon commonly employed by Gram-negative bacteria to inhibit neighboring species through the delivery of toxic effectors. It is well established that intraspecies protection is conferred by immunity proteins that neutralize effector toxicities. In contrast, the mechanisms for interspecies protection are not clear. Here we use two T6SS-active antagonistic bacterial species, Aeromonas hydrophila and Vibrio cholerae, to demonstrate that interspecies protection is dependent on effectors. A. hydrophila and V. cholerae do not share conserved immunity genes but could coexist equally in a mixture. However, mutants lacking the T6SS or effectors were effectively eliminated by the competing wild-type strain. Time-lapse microscopic analyses showed that mutually lethal interactions drive the segregation of mixed species into distinct single-species clusters by eliminating interspersed single cells. Cluster formation provides herd protection by abolishing lethal interactions inside each cluster and restricting the interactions to the boundary. Using an agent-based modeling approach, we simulated the antagonistic interactions of two hypothetical species. The resulting simulations recapitulated our experimental observations. These results provide mechanistic insights regarding the general role of microbial weapons in determining the structures of complex multispecies communities. IMPORTANCE Investigating the warfare of microbes allows us to better understand the ecological relationships in complex microbial communities such as the human microbiota. Here we use the T6SS, a deadly bacterial weapon, as a model to demonstrate the importance of lethal interactions in

  7. Microbial herd protection mediated by antagonistic interaction in polymicrobial communities.

    Science.gov (United States)

    Wong, Megan; Liang, Xiaoye; Smart, Matt; Tang, Le; Moore, Richard; Ingalls, Brian; Dong, Tao G

    2016-09-16

    In the host and natural environments, microbes often exist in complex multispecies communities. The molecular mechanisms through which such communities develop and persist - despite significant antagonistic interactions between species - are not well understood. The type VI secretion system (T6SS) is a lethal weapon commonly employed by Gram-negative bacteria to inhibit neighboring species through delivery of toxic effectors. It is well established that intra-species protection is conferred by immunity proteins that neutralize effector toxicities. By contrast, the mechanisms for interspecies protection are not clear. Here we use two T6SS active antagonistic bacteria, Aeromonas hydrophila (AH) and Vibrio cholerae (VC), to demonstrate that interspecies protection is dependent on effectors. AH and VC do not share conserved immunity genes but could equally co-exist in a mixture. However, mutants lacking the T6SS or effectors were effectively eliminated by the other competing wild type. Time-lapse microscopy analyses show that mutually lethal interactions drive the segregation of mixed species into distinct single-species clusters by eliminating interspersed single cells. Cluster formation provides herd protection by abolishing lethal interaction inside each cluster and restricting it to the boundary. Using an agent-based modeling approach, we simulated the antagonistic interactions of two hypothetical species. The resulting simulations recapitulate our experimental observation. These results provide mechanistic insights for the general role of microbial weapons in determining the structures of complex multispecies communities. Investigating the warfare of microbes allows us to better understand the ecological relationships in complex microbial communities such as the human microbiota. Here we use the T6SS, a deadly bacterial weapon, as a model to demonstrate the importance of lethal interactions in determining community structures and exchange of genetic materials

  8. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

    International Nuclear Information System (INIS)

    Cheng, Jian; Zhang, Lin; Dai, Weiqi; Mao, Yuqing; Li, Sainan; Wang, Jingjie; Li, Huanqing; Guo, Chuanyong; Fan, Xiaoming

    2015-01-01

    Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys 3 ]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation

  9. Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.

    Directory of Open Access Journals (Sweden)

    Yumin Xu

    Full Text Available Acute-on-chronic liver failure (ACLF is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor/TNFR (tumor necrosis factor receptor 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc] prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55 pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF.Chronic liver disease (liver fibrosis/cirrhosis was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA, and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN/lipopolysaccharide (LPS i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations.Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA. This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats.sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

  10. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Jian; Zhang, Lin [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China); Dai, Weiqi [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University, Shanghai (China); Mao, Yuqing [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China); Li, Sainan [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University, Shanghai (China); Wang, Jingjie; Li, Huanqing [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China); Guo, Chuanyong [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University, Shanghai (China); Fan, Xiaoming, E-mail: xiaomingfan57@sina.com [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China)

    2015-02-27

    Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys{sup 3}]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation.

  11. Allantoin ameliorates chemically-induced pancreatic β-cell damage through activation of the imidazoline I3 receptors

    Directory of Open Access Journals (Sweden)

    Marie Amitani

    2015-08-01

    Full Text Available Objective. Allantoin is the primary active compound in yams (Dioscorea spp.. Recently, allantoin has been demonstrated to activate imidazoline 3 (I3 receptors located in pancreatic tissues. Thus, the present study aimed to investigate the role of allantoin in the effect to improve damage induced in pancreatic β-cells by streptozotocin (STZ via the I3 receptors.Research Design and Methods. The effect of allantoin on STZ-induced apoptosis in pancreatic β-cells was examined using the ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and Western blottings. The potential mechanism was investigated using KU14R: an I3 receptor antagonist, and U73122: a phospholipase C (PLC inhibitor. The effects of allantoin on serum glucose and insulin secretion were measured in STZ-treated rats.Results. Allantoin attenuated apoptosis and cytotoxicity and increased the viability of STZ-induced β-cells in a dose-dependent manner; this effect was suppressed by KU14R and U73112. Allantoin decreased the level of caspase-3 and increased the level of phosphorylated B-cell lymphoma 2 (Bcl-2 expression detected by Western blotting. The improvement in β-cells viability was confirmed using flow cytometry analysis. Daily injection of allantoin for 8 days in STZ-treated rats significantly lowered plasma glucose and increased plasma insulin levels. This action was inhibited by treatment with KU14R.Conclusion. Allantoin ameliorates the damage of β-cells induced by STZ. The blockade by pharmacological inhibitors indicated that allantoin can activate the I3 receptors through a PLC-related pathway to decrease this damage. Therefore, allantoin and related analogs may be effective in the therapy for β-cell damage.

  12. Huperzine A ameliorates experimental autoimmune encephalomyelitis via the suppression of T cell-mediated neuronal inflammation in mice.

    Science.gov (United States)

    Wang, Jun; Chen, Fu; Zheng, Peng; Deng, Weijuan; Yuan, Jia; Peng, Bo; Wang, Ruochen; Liu, Wenjun; Zhao, Hui; Wang, Yanqing; Wu, Gencheng

    2012-07-01

    Huperzine A (HupA), a sesquiterpene alkaloid and a potent and reversible inhibitor of acetylcholinesterase, possesses potential anti-inflammatory properties and is used for the treatment of certain neurodegenerative diseases such as Alzheimer's disease. However, it is still unknown whether this chemical is beneficial in the treatment of multiple sclerosis, a progressive inflammatory disease of the central nervous system. In this study, we examined the immunomodulatory properties of HupA in experimental autoimmune encephalomyelitis (EAE), a T-cell mediated murine model of multiple sclerosis. The following results were obtained: (1) intraperitoneal injections of HupA significantly attenuate the neurological severity of EAE in mice. (2) HupA decreases the accumulation of inflammatory cells, autoimmune-related demyelination and axonal injury in the spinal cords of EAE mice. (3) HupA down-regulates mRNA levels of the pro-inflammatory cytokines (IFN-γ and IL-17) and chemokines (MCP-1, RANTES, and TWEAK) while enhancing levels of anti-inflammatory cytokines (IL-4 and IL-10) in the spinal cords of EAE mice. (4) HupA inhibits MOG(35-55) stimulation-induced T-cell proliferation and IFN-γ and IL-17 secretion in cultured splenocytes. (5) HupA inhibition of T-cell proliferation is reversed by the nicotinic acetylcholinergic receptor antagonist mecamylamine. We conclude that HupA can ameliorate EAE by suppressing autoimmune responses, inflammatory reactions, subsequent demyelination and axonal injury in the spinal cord. Therefore, HupA may have a potential therapeutic value for the treatment of multiple sclerosis and as a neuroimmunomodulatory drug to control human CNS pathology. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. 17-AAG post-treatment ameliorates memory impairment and hippocampal CA1 neuronal autophagic death induced by transient global cerebral ischemia.

    Science.gov (United States)

    Li, Jianxiong; Yang, Fei; Guo, Jia; Zhang, Rongrong; Xing, Xiangfeng; Qin, Xinyue

    2015-06-12

    Neuro-inflammation plays an important role in global cerebral ischemia (GCI). The 72-kDa heat shock protein (Hsp70) has been reported to be involved in the inflammatory response of many central nervous system diseases. Preclinical findings implicate that 17-allylamino-demethoxygeldanamycin (17-AAG), an anticancer drug in clinical, provide neuroprotection actions in a rat model of traumatic brain injury, and the beneficial effects of 17-AAG were specifically due to up-regulation of Hsp70. However, no experiments have tested whether 17-AAG has beneficial or harmful effects in the setting of GCI. The present study was designed to determine the hypothesis that administration of 17-AAG could attenuate cerebral infarction and improve neuronal survival, thereby ameliorating memory impairment in a rat model of GCI. Furthermore, to test whether any neuroprotective effect of 17-AAG was associated with inflammatory response and neuronal autophagy, we examined the expression of multiplex inflammatory cytokine levels as well as autophagy-associate protein in hippocampal CA1 of rat brain. Our results showed that post-GCI administration of 17-AAG significantly protected rats against GCI induced brain injury, and 17-AAG is also an effective antagonist of the inflammatory response and thereby ameliorates hippocampal CA1 neuronal autophagic death. We therefore believe that the present study provides novel clues in understanding the mechanisms by which 17-AAG exerts its neuroprotective activity in GCI. All data reveal that 17-AAG might be a potential neuroprotective agent for ischemic stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet.

    Science.gov (United States)

    Wada, Tsutomu; Miyashita, Yusuke; Sasaki, Motohiro; Aruga, Yusuke; Nakamura, Yuto; Ishii, Yoko; Sasahara, Masakiyo; Kanasaki, Keizo; Kitada, Munehiro; Koya, Daisuke; Shimano, Hitoshi; Tsuneki, Hiroshi; Sasaoka, Toshiyasu

    2013-12-01

    Because the renin-angiotensin-aldosterone system has been implicated in the development of insulin resistance and promotion of fibrosis in some tissues, such as the vasculature, we examined the effect of eplerenone, a selective mineralocorticoid receptor (MR) antagonist, on nonalcoholic steatohepatitis (NASH) and metabolic phenotypes in a mouse model reflecting metabolic syndrome in humans. We adopted liver-specific transgenic (Tg) mice overexpressing the active form of sterol response element binding protein-1c (SREBP-1c) fed a high-fat and fructose diet (HFFD) as the animal model in the present study. When wild-type (WT) C57BL/6 and liver-specific SREBP-1c Tg mice grew while being fed HFFD for 12 wk, body weight and epididymal fat weight increased in both groups with an elevation in blood pressure and dyslipidemia. Glucose intolerance and insulin resistance were also observed. Adipose tissue hypertrophy and macrophage infiltration with crown-like structure formation were also noted in mice fed HFFD. Interestingly, the changes noted in both genotypes fed HFFD were significantly ameliorated with eplerenone. HFFD-fed Tg mice exhibited the histological features of NASH in the liver, including macrovesicular steatosis and fibrosis, whereas HFFD-fed WT mice had hepatic steatosis without apparent fibrotic changes. Eplerenone effectively ameliorated these histological abnormalities. Moreover, the direct suppressive effects of eplerenone on lipopolysaccharide-induced TNFα production in the presence and absence of aldosterone were observed in primary-cultured Kupffer cells and bone marrow-derived macrophages. These results indicated that eplerenone prevented the development of NASH and metabolic abnormalities in mice by inhibiting inflammatory responses in both Kupffer cells and macrophages.

  15. Nitric oxide synthase inhibition ameliorates nicotine-induced sperm function decline in male rats

    Directory of Open Access Journals (Sweden)

    Ibukun P. Oyeyipo

    2015-09-01

    Conclusion: Taken together, the present data indicate the abilities of l-NAME to ameliorate nicotine-induced spermatotoxic effects in male rats via a mechanism dependent on the circulating testosterone level.

  16. Listening to classical music ameliorates unilateral neglect after stroke.

    Science.gov (United States)

    Tsai, Pei-Luen; Chen, Mei-Ching; Huang, Yu-Ting; Lin, Keh-Chung; Chen, Kuan-Lin; Hsu, Yung-Wen

    2013-01-01

    OBJECTIVE. We determined whether listening to excerpts of classical music ameliorates unilateral neglect (UN) in stroke patients. METHOD. In this within-subject study, we recruited and separately tested 16 UN patients with a right-hemisphere stroke under three conditions within 1 wk. In each condition, participants were asked to complete three subtests of the Behavioral Inattention Test while listening to classical music, white noise, or nothing. All conditions and the presentation of the tests were counterbalanced across participants. Visual analog scales were used to provide self-reported ratings of arousal and mood. RESULTS. Participants generally had the highest scores under the classical music condition and the lowest scores under the silence condition. In addition, most participants rated their arousal as highest after listening to classical music. CONCLUSION. Listening to classical music may improve visual attention in stroke patients with UN. Future research with larger study populations is necessary to validate these findings. Copyright © 2013 by the American Occupational Therapy Association, Inc.

  17. Exenatide with Metformin Ameliorated Visceral Adiposity and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Xuan Du

    2018-01-01

    Full Text Available Background. To study the effectiveness of exenatide with metformin and sequential treatment with exenatide and glargine added to metformin and their influence on insulin sensitivity and adipose distribution. Methods. 20 newly diagnosed obese type 2 diabetic patients were enrolled, and 2-month washout treatment of metformin, 6-month exenatide treatment, and 6-month glargine treatment were administrated sequentially accompanied with previous metformin. Glucolipid metabolic parameters were compared among groups. Adipose distribution was quantified with computerized tomography according to anatomy, dividing into visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT, adding up to total adipose tissue (TAT. Results. The 6-month exenatide treatment dramatically ameliorated the glucose and lipid profile, improved insulin sensitivity, and mainly decreased VAT and also the ratio of VAT/SAT (RVS. The following 6-month glargine treatment increased VAT. The whole 12-month sequential treatment with exenatide and glargine added to metformin basically improved the insulin sensitivity and glucolipid control though VAT rebounded at the end, however without deteriorating the other parameters. Conclusion. Exenatide is an ideal treatment for obese type 2 diabetic patients in the aspect of adipose tissue distribution. Sequential treatment of exenatide and glargine could be an alternative for low-income patients who cannot afford GLP-1 agonist for long time. This trial is registered with ChiCTR-OOC-17013679.

  18. Probiotic BIFICO cocktail ameliorates Helicobacter pylori induced gastritis.

    Science.gov (United States)

    Yu, Hong-Jing; Liu, Wei; Chang, Zhen; Shen, Hui; He, Li-Juan; Wang, Sha-Sha; Liu, Lu; Jiang, Yuan-Ying; Xu, Guo-Tong; An, Mao-Mao; Zhang, Jun-Dong

    2015-06-07

    To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection. Colonization of BIFICO strains in the mouse stomach was determined by counting colony-forming units per gram of stomach tissue. After treatment with or without BIFICO, inflammation and H. pylori colonization in the mouse stomach were analyzed by hematoxylin and eosin and Giemsa staining, respectively. Cytokine levels were determined by enzyme-linked immunosorbent assay and Milliplex. The activation of nuclear factor (NF)-κB and MAPK signaling in human gastric epithelial cells was evaluated by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was used to quantify TLR2, TLR4 and MyD88 mRNA expression in the mouse stomach. We demonstrated that BIFICO, which contains a mixture of Enterococcus faecalis, Bifidobacterium longum and Lactobacillus acidophilus, was tolerant to the mouse stomach environment and was able to survive both the 8-h and 3-d courses of administration. Although BIFICO treatment had no effect on the colonization of H. pylori in the mouse stomach, it ameliorated H. pylori-induced gastritis by significantly inhibiting the expression of cytokines and chemokines such as TNF-α, IL-1β, IL-10, IL-6, G-CSF and MIP-2 (P gastritis by inhibiting the inflammatory response in gastric epithelial cells.

  19. Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction.

    Science.gov (United States)

    Furumoto, Yasuko; Smith, Carolyne K; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L; Trier, Anna M; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T; O'Shea, John J; Kaplan, Mariana J; Gadina, Massimo

    2017-01-01

    Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized. MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice. Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies. Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. © 2016, American College of Rheumatology.

  20. Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice

    International Nuclear Information System (INIS)

    Fouad, Amr A.; Al-Sultan, Ali Ibrahim; Refaie, Shereen M.; Yacoubi, Mohamed T.

    2010-01-01

    The nephroprotective effect of coenzyme Q10 was investigated in mice with acute renal injury induced by a single i.p. injection of cisplatin (5 mg/kg). Coenzyme Q10 treatment (10 mg/kg/day, i.p.) was applied for 6 consecutive days, starting 1 day before cisplatin administration. Coenzyme Q10 significantly reduced blood urea nitrogen and serum creatinine levels which were increased by cisplatin. Coenzyme Q10 significantly compensated deficits in the antioxidant defense mechanisms (reduced glutathione level and superoxide dismutase activity), suppressed lipid peroxidation, decreased the elevations of tumor necrosis factor-α, nitric oxide and platinum ion concentration, and attenuated the reductions of selenium and zinc ions in renal tissue resulted from cisplatin administration. Also, histopathological renal tissue damage mediated by cisplatin was ameliorated by coenzyme Q10 treatment. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the cisplatin-induced overexpression of inducible nitric oxide synthase, nuclear factor-κB, caspase-3 and p53 in renal tissue. It was concluded that coenzyme Q10 represents a potential therapeutic option to protect against acute cisplatin nephrotoxicity commonly encountered in clinical practice.

  1. Cellulose supplementation early in life ameliorates colitis in adult mice.

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    Dorottya Nagy-Szakal

    Full Text Available Decreased consumption of dietary fibers, such as cellulose, has been proposed to promote the emergence of inflammatory bowel diseases (IBD: Crohn disease [CD] and ulcerative colitis [UC] where intestinal microbes are recognized to play an etiologic role. However, it is not known if transient fiber consumption during critical developmental periods may prevent consecutive intestinal inflammation. The incidence of IBD peaks in young adulthood indicating that pediatric environmental exposures may be important in the etiology of this disease group. We studied the effects of transient dietary cellulose supplementation on dextran sulfate sodium (DSS colitis susceptibility during the pediatric period in mice. Cellulose supplementation stimulated substantial shifts in the colonic mucosal microbiome. Several bacterial taxa decreased in relative abundance (e.g., Coriobacteriaceae [p = 0.001], and other taxa increased in abundance (e.g., Peptostreptococcaceae [p = 0.008] and Clostridiaceae [p = 0.048]. Some of these shifts persisted for 10 days following the cessation of cellulose supplementation. The changes in the gut microbiome were associated with transient trophic and anticolitic effects 10 days following the cessation of a cellulose-enriched diet, but these changes diminished by 40 days following reversal to a low cellulose diet. These findings emphasize the transient protective effect of dietary cellulose in the mammalian large bowel and highlight the potential role of dietary fibers in amelioration of intestinal inflammation.

  2. Yangjing Capsule Ameliorates Spermatogenesis in Male Mice Exposed to Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Hongle Zhao

    2015-01-01

    Full Text Available Yangjing capsule (YC, a traditional Chinese compound herbal preparation, has been proven as an effective drug to improve spermatogenesis in clinical practice. However, its pharmacological mechanisms were not fully clarified. This study was designed to investigate the protective effects of YC on spermatogenesis in the mouse model of spermatogenesis dysfunction induced by cyclophosphamide (CP. The administration of YC significantly increased the epididymal index, sperm count, and sperm motility of model mice. Histopathological changes demonstrated that CP caused obvious structural damage to testis, which were reversed by the administration of YC. Results from TUNEL assay showed that treatment with YC dramatically decreased the apoptosis of spermatogenic cell induced by CP. Moreover, YC treatment could inhibit the mRNA and protein expression of Bax to Bcl-2 and also raised expression of AR at both mRNA and protein levels. These data suggest that YC might ameliorate spermatogenesis in male mice exposed to CP through inhibiting the apoptosis of spermatogenic cell and enhancing the actions of testosterone in spermatogenesis.

  3. Cellulose Supplementation Early in Life Ameliorates Colitis in Adult Mice

    Science.gov (United States)

    Nagy-Szakal, Dorottya; Hollister, Emily B.; Luna, Ruth Ann; Szigeti, Reka; Tatevian, Nina; Smith, C. Wayne; Versalovic, James; Kellermayer, Richard

    2013-01-01

    Decreased consumption of dietary fibers, such as cellulose, has been proposed to promote the emergence of inflammatory bowel diseases (IBD: Crohn disease [CD] and ulcerative colitis [UC]) where intestinal microbes are recognized to play an etiologic role. However, it is not known if transient fiber consumption during critical developmental periods may prevent consecutive intestinal inflammation. The incidence of IBD peaks in young adulthood indicating that pediatric environmental exposures may be important in the etiology of this disease group. We studied the effects of transient dietary cellulose supplementation on dextran sulfate sodium (DSS) colitis susceptibility during the pediatric period in mice. Cellulose supplementation stimulated substantial shifts in the colonic mucosal microbiome. Several bacterial taxa decreased in relative abundance (e.g., Coriobacteriaceae [p = 0.001]), and other taxa increased in abundance (e.g., Peptostreptococcaceae [p = 0.008] and Clostridiaceae [p = 0.048]). Some of these shifts persisted for 10 days following the cessation of cellulose supplementation. The changes in the gut microbiome were associated with transient trophic and anticolitic effects 10 days following the cessation of a cellulose-enriched diet, but these changes diminished by 40 days following reversal to a low cellulose diet. These findings emphasize the transient protective effect of dietary cellulose in the mammalian large bowel and highlight the potential role of dietary fibers in amelioration of intestinal inflammation. PMID:23437211

  4. Osteitis pubis ameliorated after tooth extraction: a case report.

    Science.gov (United States)

    Fukushi, Jun-ichi; Nakashima, Yasuharu; Iwamoto, Yukihide

    2013-03-01

    Osteitis pubis is a non-infective inflammation of the symphysis pubis, which is known to be associated with trauma, athletic exertion, urological or gynecological surgery, or with rheumatic conditions such as seronegative spondyloarthropathies. In this report, we describe a case of osteitis pubis whose symptoms were completely ameliorated following tooth extraction attributable to periodontitis. A 57-year-old female patient developed osteitis pubis, presenting with pain in the groin area with an elevated Creactive protein (CRP; 4.4 mg/dl) and radiological erosive changes in symphysis pubis. Prednisolone (5 mg/day) and etodolac were prescribed, but the patient's symptoms improved only partially and remained persistent. One year from the patient's first visit, three teeth were extracted due to severe chronic periodontitis, which she had been suffering from for years. Soon after the above tooth extraction, her symptoms appeared completely resolved, and the patient's CRP was decreased to nearly normal levels in 4 weeks. Human leukocyte antigen (HLA)-typing analysis revealed a positive result for HLA-A11, A24, and B54. Because HLA-B54 cross-reacts with HLA-B27, the patient's osteitis pubis was considered to be a form of reactive arthritis associated with periodontitis.

  5. Blockade of Endothelin-1 Receptor Type B Ameliorates Glucose Intolerance and Insulin Resistance in a Mouse Model of Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Jan Polak

    2018-05-01

    Full Text Available Obstructive sleep apnea (OSA is associated with insulin resistance (IR and glucose intolerance. Elevated endothelin-1 (ET-1 levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH. We examined whether pharmacological blockade of type A and type B ET-1 receptors (ETA and ETB would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ETA antagonist; 200 nmol/kg/day, BQ-788 (ETB antagonist; 200 nmol/kg/day or vehicle (saline or propyleneglycol [PG] for 14 days in C57BL6/J mice (10/group. During treatment, mice were exposed to IH (decreasing the FiO2 from 20.9% to 6%, 60/h or intermittent air (IA. After IH or IA exposure, insulin (0.5 IU/kg or glucose (1 mg/kg was injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC was calculated. Fourteen-day IH increased fasting glucose levels (122 ± 7 vs. 157 ± 8 mg/dL, PG: 118 ± 6 vs. 139 ± 8; both p < 0.05 and impaired glucose tolerance (AUCglucose: 19,249 ± 1105 vs. 29,124 ± 1444, PG AUCglucose: 18,066 ± 947 vs. 25,135 ± 797; both p < 0.05 in vehicle-treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUCglucose: 21,969 ± 662; p < 0.05. Fourteen-day IH also induced IR (AUCglucose: 7185 ± 401 vs. 8699 ± 401; p < 0.05. Treatment with BQ-788 decreased IR under IA (AUCglucose: 5281 ± 401, p < 0.05 and reduced worsening of IR with IH (AUCglucose: 7302 ± 401, p < 0.05. There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.

  6. Does protein binding modulate the effect of angiotensin II receptor antagonists?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  7. Sexually antagonistic "zygotic drive" of the sex chromosomes.

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    William R Rice

    2008-12-01

    Full Text Available Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic "zygotic drive", because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic "arms race" between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.

  8. Central actions of a novel and selective dopamine antagonist

    International Nuclear Information System (INIS)

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D 1 class, which is linked to the stimulation of adenylate cyclase-activity, and the D 2 class which is not. There is much evidence suggesting that it is the D 2 class which is not. There is much evidence suggesting that it is the D 2 dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D 1 class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of [ 3 H]-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D 1 receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for [ 3 H]-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D 1 receptors and [ 3 H]-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D 1 dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated

  9. Modulation of myometrium mitochondrial membrane potential by calmodulin antagonists

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    S. G. Shlykov

    2014-02-01

    Full Text Available Influence of calmodulin antagonists on mitochondrial membrane potential was investigated using­ a flow cytometry method, confocal microscopy and fluorescent potential-sensitive probes TMRM and MTG. Influence of different concentrations of calmodulin antagonists on mitochondrial membrane potential was studied using flow cytometry method and a fraction of myometrium mitochondria of unpregnant rats. It was shown that 1-10 µМ calmidazolium gradually reduced mitochondria membrane potential. At the same time 10-100 µМ trifluope­razine influenced as follows: 10 µМ – increased polarization, while 100 µМ – caused almost complete depolarization of mitochondrial membranes. In experiments which were conducted with the use of confocal microscopy method and myometrium cells it was shown, that MTG addition to the incubation medium­ led to the appearance of fluorescence signal in a green range. Addition of the second probe (ТМRM resulted in the appearance of fluorescent signal in a red range. Mitochondrial membrane depolarization by 1µМ СССР or 10 mМ NaN3 was accompanied by the decline of “red” fluo­rescence intensity, “green” fluorescence was kept. The 10-15 minute incubation of myometrium cells in the presen­ce 10 µМ calmidazolium or 100 µМ trifluoperazine was accompanied by almost complete decrease of the TMRM fluorescent signal. Thus, with the use of potential-sensitive fluorescent probes TMRM and MTG it was shown, that calmodulin antagonists modulate mitochondrial membrane potential of myometrium cells.

  10. Membrane formation in liquids by adding an antagonistic salt

    Science.gov (United States)

    Sadakane, Koichiro; Seto, Hideki

    2018-03-01

    Antagonistic salts are composed of hydrophilic and hydrophobic ions. In a binary mixture, such as water and organic solvent, these ion pairs preferentially dissolve to those phases, respectively, and there is a coupling between the charge density and the composition. The heterogeneous distribution of ions forms a large electric double layer at the interface between these solvents. This reduces the interfacial tension between water and organic solvent, and stabilizes an ordered structure, such as a membrane. These phenomena have been extensively studied from both theoretical and experimental point of view. In addition, the numerical simulations can reproduce such ordered structures.

  11. Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

    Science.gov (United States)

    2014-09-01

    time: Tuesday , Nov 12, 2013, 4:00 PM - 5:00 PM Topic: ++E.08.e Sleep: Systems and behavior Authors: W. LINCOLN1, J. PALMERSTON1, T. NEYLAN2, T...functional impairment results from HcrtR antagonist-induced sleep, we evaluated the performance of rats in the Morris Water Maze in the presence of ALM vs. ZOL... Morris Water Maze. Although the concentrations of ALM and ZOL adminis- tered prior to these tests were equipotent in hypnotic efficacy, the

  12. Membrane Formation in Liquids by Adding an Antagonistic Salt

    Directory of Open Access Journals (Sweden)

    Koichiro Sadakane

    2018-03-01

    Full Text Available Antagonistic salts are composed of hydrophilic and hydrophobic ions. In a binary mixture, such as water and organic solvent, these ion pairs preferentially dissolve to those phases, respectively, and there is a coupling between the charge density and the composition. The heterogeneous distribution of ions forms a large electric double layer at the interface between these solvents. This reduces the interfacial tension between water and organic solvent, and stabilizes an ordered structure, such as a membrane. These phenomena have been extensively studied from both theoretical and experimental point of view. In addition, the numerical simulations can reproduce such ordered structures.

  13. The discovery of tropane-derived CCR5 receptor antagonists.

    Science.gov (United States)

    Armour, Duncan R; de Groot, Marcel J; Price, David A; Stammen, Blanda L C; Wood, Anthony; Perros, Manos; Burt, Catherine

    2006-04-01

    The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

  14. The opiate antagonist, naltrexone, in the treatment of trichotillomania

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N

    2014-01-01

    Trichotillomania (TTM) is characterized by repetitive hair pulling resulting in hair loss. Data on the pharmacological treatment of TTM are limited. This study examined the opioid antagonist, naltrexone, in adults with TTM who had urges to pull their hair. Fifty-one individuals with TTM were...... randomized to naltrexone or placebo in an 8-week, double-blind trial. Subjects were assessed with measures of TTM severity and selected cognitive tasks. Naltrexone failed to demonstrate significantly greater reductions in hair pulling compared to placebo. Cognitive flexibility, however, significantly...

  15. Amelioration and reforestation of sulfurous mine soils in Lusatia (eastern Germany)

    International Nuclear Information System (INIS)

    Katzur, J.; Haubold-Rosar, M.

    1996-01-01

    In Germany nearly 1.550 km 2 have been claimed by brown coal mining until now. Mine soils formed of carboniferous and sulfurous overburden are classified as sulfurous mine soils. They remain vegetation-free for decades and may be cultivated only after soil amelioration. The objective of amelioration is a sustained improvement of soil reaction. Lime requirement for the achievement of a certain pH-value is calculated from acid-base-balance (SBB). Lime fertilizers and base-rich brown coal ashes are used for amelioration. As ashes have several advantages, their application is recommended. The ameliorative application of lime fertilizer or brown coal ash should be incorporated intensively into the soil to a depth of 60 cm, better 100 cm. Amelioration includes a mineral fertilization with N, P and K. Afforestation with Pinus sylvestris, Pinus nigra, Larix decidua, Larix eurolepis. Tilia cordata, Quercus rubra and Quercus petraea on ameliorated mine soils show surprising good results. Multi-species stands have very positive effects on soil formation. Raw humus is formed under pine and larch, and under deciduous trees moder and mull with higher bioactivity and better development of water and nutrient balance in the topsoil are found. 55 refs., 6 figs., 4 tabs

  16. The role of ecology, neutral processes and antagonistic coevolution in an apparent sexual arms race.

    Science.gov (United States)

    Perry, Jennifer C; Garroway, Colin J; Rowe, Locke

    2017-09-01

    Some of the strongest examples of a sexual 'arms race' come from observations of correlated evolution in sexually antagonistic traits among populations. However, it remains unclear whether these cases truly represent sexually antagonistic coevolution; alternatively, ecological or neutral processes might also drive correlated evolution. To investigate these alternatives, we evaluated the contributions of intersex genetic correlations, ecological context, neutral genetic divergence and sexual coevolution in the correlated evolution of antagonistic traits among populations of Gerris incognitus water striders. We could not detect intersex genetic correlations for these sexually antagonistic traits. Ecological variation was related to population variation in the key female antagonistic trait (spine length, a defence against males), as well as body size. Nevertheless, population covariation between sexually antagonistic traits remained substantial and significant even after accounting for all of these processes. Our results therefore provide strong evidence for a contemporary sexual arms race. © 2017 John Wiley & Sons Ltd/CNRS.

  17. Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.

    Science.gov (United States)

    Cordi, Alex A; Desos, Patrice; Ruano, Elisabeth; Al-Badri, Hashim; Fugier, Claude; Chapman, Astrid G; Meldrum, Brian S; Thomas, Jean-Yves; Roger, Anita; Lestage, Pierre

    2002-10-01

    We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses. Considering that some similitude exists between S 17625 and probenecid, a compound known to protect against the nephrotoxicity and/or slow the clearance of different drugs, we decided to synthesise some new analogues of S 17625 incorporating some of the salient features of probenecid. Replacement of the chlorine in position 6 by a sulfonylamine led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Amongst the compounds evaluated, derivatives 7a and 7s appear to be the most promising and are currently evaluated in therapeutically relevant stroke models.

  18. Modification of kindled amygdaloid seizures by opiate agonists and antagonists.

    Science.gov (United States)

    Albertson, T E; Joy, R M; Stark, L G

    1984-03-01

    The effects of 19 opiate agonists and antagonists on kindled amygdaloid seizures in the rat were studied. The mu agonists tended to reduce the length of elicited afterdischarges and behavioral ranks, while markedly increasing postictal electroencephalogram spikes and behavioral arrest time. These effects were reversed by naloxone. The kappa agonists reduced behavioral rank and variably reduced afterdischarge length with a concomitant lengthening of postictal behavioral arrest time and number of electroencephalogram spikes. The putative sigma agonist, SKF 10,047, reduced afterdischarge durations only at the higher doses tested. The decreases found after the sigma agonists in postictal electroencephalogram spiking and time of behavioral arrest were not reversed by naloxone. Only the lower doses of normeperidine were found to decrease seizure thresholds. The mixed agonist/antagonists (MAA) cyclazocine and cyclorphan markedly increased seizure threshold and reduced afterdischarge duration and behavioral rank. Only the MAA pentazocine tended to increase threshold but not suprathreshold afterdischarge durations. The order of ability to modify the ictal events was MAA (selected) greater than kappa agonists greater than mu agonists greater than sigma agonists. The increase in postictal events (behavior arrest and spikes) was caused most effectively by pretreatment with mu agonist greater than kappa agonist greater than selected MAA greater than sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Picrotoxin-induced seizures modified by morphine and opiate antagonists.

    Science.gov (United States)

    Thomas, J; Nores, W L; Kenigs, V; Olson, G A; Olson, R D

    1993-07-01

    The effects of naloxone, Tyr-MIF-1, and MIF-1 on morphine-mediated changes in susceptibility to picrotoxin-induced seizures were studied. Rats were pretreated with naloxone, MIF-1, Tyr-MIF-1, or saline. At 15-min intervals, they received a second pretreatment of morphine or saline and then were tested for seizures following a convulsant dose of picrotoxin. Several parameters of specific categories of seizures were scored. Morphine increased the number of focal seizure episodes, duration of postseizure akinesis, and incidence of generalized clonic seizures. Naloxone tended to block the morphine-mediated changes in susceptibility. Tyr-MIF-1 had effects similar to naloxone on duration of postseizure immobility but tended to potentiate the effects of morphine on focal seizure episodes. The effects of morphine and the opiate antagonists on focal seizure episodes and postseizure duration suggest the general involvement of several types of opiate receptors in these picrotoxin-induced behaviors. However, the observation of antagonistic effects for Tyr-MIF-1 on immobility but agonistic effects for focal seizures suggests that the type of effect exerted by opiate agents may depend upon other neuronal variables.

  20. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    International Nuclear Information System (INIS)

    Yu, Hui; Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi; Wang, Zhanli; Liang, Huaping

    2010-01-01

    Research highlights: → Evodiamine interacted with the AhR. → Evodiamine inhibited the specific binding of [ 3 H]-TCDD to the AhR. → Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K i value of 28.4 ± 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  1. Rogue sperm indicate sexually antagonistic coevolution in nematodes.

    Directory of Open Access Journals (Sweden)

    Ronald E Ellis

    2014-07-01

    Full Text Available Intense reproductive competition often continues long after animals finish mating. In many species, sperm from one male compete with those from others to find and fertilize oocytes. Since this competition occurs inside the female reproductive tract, she often influences the outcome through physical or chemical factors, leading to cryptic female choice. Finally, traits that help males compete with each other are sometimes harmful to females, and female countermeasures may thwart the interests of males, which can lead to an arms race between the sexes known as sexually antagonistic coevolution. New studies from Caenorhabditis nematodes suggest that males compete with each other by producing sperm that migrate aggressively and that these sperm may be more likely to win access to oocytes. However, one byproduct of this competition appears to be an increased probability that these sperm will go astray, invading the ovary, prematurely activating oocytes, and sometimes crossing basement membranes and leaving the gonad altogether. These harmful effects are sometimes observed in crosses between animals of the same species but are most easily detected in interspecies crosses, leading to dramatically lowered fitness, presumably because the competitiveness of the sperm and the associated female countermeasures are not precisely matched. This mismatch is most obvious in crosses involving individuals from androdioecious species (which have both hermaphrodites and males, as predicted by the lower levels of sperm competition these species experience. These results suggest a striking example of sexually antagonistic coevolution and dramatically expand the value of nematodes as a laboratory system for studying postcopulatory interactions.

  2. Carbobenzoxy amino acids: Structural requirements for cholecystokinin receptor antagonist activity

    International Nuclear Information System (INIS)

    Maton, P.N.; Sutliff, V.E.; Jensen, R.T.; Gardner, J.D.

    1985-01-01

    The authors used dispersed acini prepared from guinea pig pancreas to examine 28 carbobenzoxy (CBZ) amino acids for their abilities to function as cholecystokinin receptor antagonists. All amino acid derivatives tested, except for CBZ-alanine, CBZ-glycine, and N alpha-CBZ- lysine, were able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, there was a good correlation between the ability of a carbobenzoxy amino acid to inhibit stimulated amylase secretion and the ability of the amino acid derivative to inhibit binding of 125 I-cholecystokinin. The inhibition of cholecystokinin-stimulated amylase secretion was competitive, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor. The potencies with which the various carbobenzoxy amino acids inhibited the action of cholecystokinin varied 100-fold and CBZ-cystine was the most potent cholecystokinin receptor antagonist. This variation in potency was primarily but not exclusively a function of the hydrophobicity of the amino acid side chain

  3. Combination cancer chemotherapy with one compound: pluripotent bradykinin antagonists.

    Science.gov (United States)

    Stewart, John M; Gera, Lajos; Chan, Daniel C; York, Eunice J; Simkeviciene, Vitalija; Bunn, Paul A; Taraseviciene-Stewart, Laimute

    2005-08-01

    Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant bradykinin antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg)2] (SUIM=suberimidyl; Hyp=4-hydroxyproline; Igl=alpha-(2-indanyl)glycine; Oic=octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-L-tyrosine-N-(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.

  4. Fires can benefit plants by disrupting antagonistic interactions.

    Science.gov (United States)

    García, Y; Castellanos, M C; Pausas, J G

    2016-12-01

    Fire has a key role in the ecology and evolution of many ecosystems, yet its effects on plant-insect interactions are poorly understood. Because interacting species are likely to respond to fire differently, disruptions of the interactions are expected. We hypothesized that plants that regenerate after fire can benefit through the disruption of their antagonistic interactions. We expected stronger effects on interactions with specialist predators than with generalists. We studied two interactions between two Mediterranean plants (Ulex parviflorus, Asphodelus ramosus) and their specialist seed predators after large wildfires. In A. ramosus we also studied the generalist herbivores. We sampled the interactions in burned and adjacent unburned areas during 2 years by estimating seed predation, number of herbivores and fruit set. To assess the effect of the distance to unburned vegetation we sampled plots at two distance classes from the fire perimeter. Even 3 years after the fires, Ulex plants experienced lower seed damage by specialists in burned sites. The presence of herbivores on Asphodelus decreased in burned locations, and the variability in their presence was significantly related to fruit set. Generalist herbivores were unaffected. We show that plants can benefit from fire through the disruption of their antagonistic interactions with specialist seed predators for at least a few years. In environments with a long fire history, this effect might be one additional mechanism underlying the success of fire-adapted plants.

  5. Pregnancy outcome of “delayed start” GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: A clinical trial study

    Directory of Open Access Journals (Sweden)

    Abbas Aflatoonian

    2017-08-01

    Full Text Available Background: Management of poor-responding patients is still major challenge in assisted reproductive techniques (ART. Delayed-start GnRH antagonist protocol is recommended to these patients, but little is known in this regards. Objective: The goal of this study was assessment of delayed-start GnRH antagonist protocol in poor responders, and in vitro fertilization (IVF outcomes. Materials and Methods: This randomized clinical trial included sixty infertile women with Bologna criteria for ovarian poor responders who were candidate for IVF. In case group (n=30, delayed-start GnRH antagonist protocol administered estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin. Control group (n=30 treated with estrogen priming antagonist protocol. Finally, endometrial thickness, the rates of oocytes maturation, , embryo formation, and pregnancy were compared between two groups. Results: Rates of implantation, chemical, clinical, and ongoing pregnancy in delayed-start cycles were higher although was not statistically significant. Endometrial thickness was significantly higher in case group. There were no statistically significant differences in the rates of oocyte maturation, embryo formation, and IVF outcomes between two groups. Conclusion: There is no significant difference between delayed-start GnRH antagonist protocol versus GnRH antagonist protocol.

  6. Therapeutic spaces of care farming: Transformative or ameliorating?

    Science.gov (United States)

    Kaley, Alexandra; Hatton, Chris; Milligan, Christine

    2018-05-04

    Since Wil Gesler's earliest articulation (Gesler, 1992; Gesler, 1996) key thinkers in the field of therapeutic landscapes have sought to emphasise the embodied, contextual and wholly relational nature of the relationship that exists between people and place. However, the extant research has tended to focus on the relational healing experience as this occurs 'in the moment' and with reference to a specific location or site of healing, with less attention being paid to what happens to people when they return to their ordinary or everyday places. In this paper, we reflect on findings from visual ethnographic work (including photography and film) that explored the therapeutic landscape experiences of people with intellectual disabilities engaged in care farming interventions for health and wellbeing. The study also recruited farm staff and family members or carers to take part, and comprised 20 participants in total. Having identified a gap in our understanding, consideration is given to wider impact that engaging in these sorts of activities had on the everyday lives of the participants in this study. We argue that this study has identified two types of therapeutic journey that broadly fit the experiences of study participants. The first type of journey denotes landscape experiences that are transformative. Here the therapeutic power of the care farm landscape resides in the ability of activities conducted on care farms to influence other aspects of participants' lives in ways that promote wellbeing. By contrast, there is another type of journey where the therapeutic power of the care farm resides in its ability to ameliorate challenging or harmful life situations, thus offering people a temporary site of respite or refuge. We conclude that these findings denote an important development for this sub-field of health geography, not only because they draw attention to the transformative power of the therapeutic encounter, but also the broader socio-spatial environments

  7. Ursodeoxycholic Acid Ameliorates Fructose-Induced Metabolic Syndrome in Rats

    Science.gov (United States)

    2014-01-01

    The metabolic syndrome (MS) is characterized by insulin resistance, dyslipidemia and hypertension. It is associated with increased risk of cardiovascular diseases and type-2 diabetes. Consumption of fructose is linked to increased prevalence of MS. Ursodeoxycholic acid (UDCA) is a steroid bile acid with antioxidant, anti-inflammatory activities and has been shown to improve insulin resistance. The current study aims to investigate the effect of UDCA (150 mg/kg) on MS induced in rats by fructose administration (10%) in drinking water for 12 weeks. The effects of UDCA were compared to fenofibrate (100 mg/kg), an agonist of PPAR-α receptors. Treatment with UDCA or fenofibrate started from the 6th week after fructose administration once daily. Fructose administration resulted in significant increase in body weight, elevations of blood glucose, serum insulin, cholesterol, triglycerides, advanced glycation end products (AGEs), uric acid levels, insulin resistance index and blood pressure compared to control rats. Moreover, fructose increased oxidative stress in aortic tissues indicated by significant increases of malondialdehyde (MDA), expression of iNOS and reduction of reduced glutathione (GSH) content. These disturbances were associated with decreased eNOS expression, increased infiltration of leukocytes and loss of aortic vascular elasticity. Treatment with UDCA successfully ameliorated the deleterious effects of fructose. The protective effect of UDCA could be attributed to its ability to decrease uric acid level, improve insulin resistance and diminish oxidative stress in vascular tissues. These results might support possible clinical application of UDCA in MS patients especially those present with liver diseases, taking into account its tolerability and safety. However, further investigations on human subjects are needed before the clinical application of UDCA for this indication. PMID:25202970

  8. NAD+ Biosynthesis Ameliorates a Zebrafish Model of Muscular Dystrophy

    Science.gov (United States)

    Goody, Michelle F.; Kelly, Meghan W.; Reynolds, Christine J.; Khalil, Andre; Crawford, Bryan D.; Henry, Clarissa A.

    2012-01-01

    Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex– or integrin alpha7–deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin

  9. GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.

    Science.gov (United States)

    Nagahara, Yuki; Shimazawa, Masamitsu; Ohuchi, Kazuki; Ito, Junko; Takahashi, Hitoshi; Tsuruma, Kazuhiro; Kakita, Akiyoshi; Hara, Hideaki

    2017-08-01

    Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Michelle F Goody

    Full Text Available Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction

  11. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

    Directory of Open Access Journals (Sweden)

    J Pedro Fernández-Murray

    2016-01-01

    Full Text Available Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

  12. PEG minocycline-liposomes ameliorate CNS autoimmune disease.

    Directory of Open Access Journals (Sweden)

    Wei Hu

    Full Text Available Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS. Minocycline, a potent inhibitor of matrix metalloproteinase (MMP-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG minocycline liposomes are effective in treating EAE.Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs, we determined that PEG minocycline-liposome preparations stabilized with CaCl(2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number.Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

  13. Esculetin Ameliorates Carbon Tetrachloride-Mediated Hepatic Apoptosis in Rats

    Directory of Open Access Journals (Sweden)

    Chuan-Sung Chiu

    2011-06-01

    Full Text Available Esculetin (ESC is a coumarin that is present in several plants such as Fraxinus rhynchophylla and Artemisia capillaris. Our previous study found that FR ethanol extract (FREtOH significantly ameliorated rats’ liver function. This study was intended to investigate the protective mechanism of ESC in hepatic apoptosis in rats induced by carbon tetrachloride. Rat hepatic apoptosis was induced by oral administration of CCl4. All rats were administered orally with CCl4 (20%, 0.5 mL/rat twice a week for 8 weeks. Rats in the ESC groups were treated daily with ESC, and silymarin group were treated daily with silymarin. Serum alanine aminotransferase (ALT, aspartate aminotransferase (AST as well as the activities of the anti-oxidative enzymes glutathione peroxidase (GPx, superoxide dismutase (SOD, and catalase in the liver were measured. In addition, expression of liver apoptosis proteins and anti-apoptotic proteins were detected. ESC (100, 500 mg/kg significantly reduced the elevated activities of serum ALT and AST caused by CCl4 and significantly increased the activities of catalase, GPx and SOD. Furthermore, ESC (100, 500 mg/kg significantly decreased the levels of the proapoptotic proteins (t-Bid, Bak and Bad and significantly increased the levels of the anti-apoptotic proteins (Bcl-2 and Bcl-xL. ESC inhibited the release of cytochrome c from mitochondria. In addition, the levels of activated caspase-9 and activated caspase-3 were significantly decreased in rats treated with ESC than those in rats treated with CCl4 alone. ESC significantly reduced CCl4-induced hepatic apoptosis in rats.

  14. Economic recession and suicidal behaviour: Possible mechanisms and ameliorating factors.

    Science.gov (United States)

    Haw, Camilla; Hawton, Keith; Gunnell, David; Platt, Stephen

    2015-02-01

    A growing body of research evidence from countries around the world indicates that economic recession is associated with increases in suicide, particularly in males of working age. To explore contributory and ameliorating factors associated with economic recession and suicide and thereby stimulate further research in this area and encourage policy makers to consider how best to reduce the impact of recession on mental health and suicidal behaviour. We conducted a selective review of the worldwide literature focusing on possible risk factors, mechanisms and preventative strategies for suicidal behaviour linked to economic recession. A model of how recession might affect suicide rates is presented. A major and often prolonged effect of recession is on unemployment and job insecurity. Other important effects include those exerted by financial loss, bankruptcy and home repossession. It is proposed these factors may lead directly or indirectly to mental health problems such as depression, anxiety and binge drinking and then to suicidal behaviour. Countries with active labour market programmes and sustained welfare spending during recessions have less marked increases in suicide rates than those that cut spending on welfare and job-search initiatives for the unemployed. Other measures likely to help include targeted interventions for unemployed people, membership of social organisations and responsible media reporting. Good primary care and mental health services are needed to cope with increased demand in times of economic recession but some governments have in fact reduced healthcare spending as an austerity measure. The research evidence linking recession, unemployment and suicide is substantial, but the evidence for the other mechanisms we have investigated is much more tentative. We describe the limitations of the existing body of research as well as make suggestions for future research into the effects of economic recession on suicidal behaviour. © The Author

  15. P2RX7 purinoceptor: a therapeutic target for ameliorating the symptoms of duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Anthony Sinadinos

    2015-10-01

    .038, diaphragm (p = 0.042, and heart muscles (p < 0.001. We show that the amelioration of symptoms was proportional to the extent of receptor depletion and that improvements were observed following administration of two P2RX7 antagonists (CK, p = 0.030 and p = 0.050 without any detectable side effects. However, approaches successful in animal models still need to be proved effective in clinical practice.These results are, to our knowledge, the first to establish that a single treatment can improve muscle function both short and long term and also correct cognitive impairment and bone loss in DMD model mice. The wide-ranging improvements reflect the convergence of P2RX7 ablation on multiple disease mechanisms affecting skeletal and cardiac muscles, inflammatory cells, brain, and bone. Given the impact of P2RX7 blockade in the DMD mouse model, this receptor is an attractive target for translational research: existing drugs with established safety records could potentially be repurposed for treatment of this lethal disease.

  16. The Cultivation of Antagonistic Bacteria in Irradiated Sludge for Biological Control of Soft Rot Erwinias : Screening of Antagonistic Bacteria for biological Control of Soft Rot Erwinias

    International Nuclear Information System (INIS)

    Sermkiattipong, Ng.; Sangsuk, L; Rattanapiriyakul, P; Dejsirilert, S.; Thaveechai, N.

    1998-01-01

    Pure cultures of 57 bacterial isolates for antagonistic activity screening were isolated from three areas of soft rot infested vegetable soil and 58 isolates were obtained from commercial seed compost and seed compost product of Division of Soil and Water Conservation, Department of Land Development. A total of 115 bacterial isolates were evaluated for antagonizing activity against Erwinia carotovora subsp. atroceptica in vitro. Out of them, 18 isolates were antagonists by showing zone of inhibition ranging from 1 to 17 mm by diameter. Most of antagonistic bacteria were identified as Bacillus spp. whereas only one isolate was Pseudomonas vesicularis

  17. HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring μ-opioid receptor in spinal cord.

    Science.gov (United States)

    Hou, Xinran; Weng, Yingqi; Ouyang, Bihan; Ding, Zhuofeng; Song, Zongbin; Zou, Wangyuan; Huang, Changsheng; Guo, Qulian

    2017-08-15

    Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Drug safety is a barrier to the discovery and development of new androgen receptor antagonists.

    Science.gov (United States)

    Foster, William R; Car, Bruce D; Shi, Hong; Levesque, Paul C; Obermeier, Mary T; Gan, Jinping; Arezzo, Joseph C; Powlin, Stephanie S; Dinchuk, Joseph E; Balog, Aaron; Salvati, Mark E; Attar, Ricardo M; Gottardis, Marco M

    2011-04-01

    Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs. Copyright © 2010 Wiley-Liss, Inc.

  19. CREB Overexpression Ameliorates Age-related Behavioral and Biophysical Deficits

    Science.gov (United States)

    Yu, Xiao-Wen

    Age-related cognitive deficits are observed in both humans and animals. Yet, the molecular mechanisms underlying these deficits are not yet fully elucidated. In aged animals, a decrease in intrinsic excitability of pyramidal neurons from the CA1 sub-region of hippocampus is believed to contribute to age-related cognitive impairments, but the molecular mechanism(s) that modulate both these factors has yet to be identified. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents has been shown to facilitate cognition, and increase intrinsic excitability of their neurons. However, how CREB changes with age, and how that impacts cognition in aged animals, is not clear. Therefore, we first systematically characterized age- and training-related changes in CREB levels in dorsal hippocampus. At a remote time point after undergoing behavioral training, levels of total CREB and activated CREB (phosphorylated at S133, pCREB) were measured in both young and aged rats. We found that pCREB, but not total CREB was significantly reduced in dorsal CA1 of aged rats. Importantly, levels of pCREB were found to be positively correlated with short-term spatial memory in both young and aged rats i.e. higher pCREB in dorsal CA1 was associated with better spatial memory. These findings indicate that an age-related deficit in CREB activity may contribute to the development of age-related cognitive deficits. However, it was still unclear if increasing CREB activity would be sufficient to ameliorate age-related cognitive, and biophysical deficits. To address this question, we virally overexpressed CREB in CA1, where we found the age-related deficit. Young and aged rats received control or CREB virus, and underwent water maze training. While control aged animals exhibited deficits in long-term spatial memory, aged animals with CREB overexpression performed at levels comparable to young animals. Concurrently, aged neurons

  20. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    International Nuclear Information System (INIS)

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Kim, Won

    2014-01-01

    deficiency of SIRT2 ameliorates iNOS, NO expression and reactive oxygen species production with suppressing LPS-induced activation of NFκB in macrophages

  1. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Lee, Sik [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of)

    2014-08-08

    deficiency of SIRT2 ameliorates iNOS, NO expression and reactive oxygen species production with suppressing LPS-induced activation of NFκB in macrophages.

  2. Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.

    Science.gov (United States)

    Yuan, Xidi; Klein, Dennis; Kerscher, Susanne; West, Brian L; Weis, Joachim; Katona, Istvan; Martini, Rudolf

    2018-05-09

    Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly. SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging

  3. Research progress of antagonistic interactions among root canal irrigations disease

    Directory of Open Access Journals (Sweden)

    Chen QU

    2013-07-01

    Full Text Available Root canal therapy is the most effective way to treat various pulposis and periapical disease. Simple mechanical apparatus can not clean root canal thoroughly, but may affect tight filling instead. It can achieve a satisfactory cleansing effect only when it is combined with a chemical solution. Irrigation fluid for root canal should possess the properties of tissue dissolution, antimicrobial, lubrication, and removal of smear layer. So far, no solution is able to fulfill all these functions. Therefore, a combined use of multiple irrigation solutions is suggested. It can not only achieve good effect in cleaning and disinfection, also it can lower the concentration of different solutions, thus reducing the side effects. Nevertheless, some experiments proved that antagonism existed among the chemicals used for irrigations. The purpose of present article is to review the antagonistic effect among the chemicals used for irrigation when they are used together for root canal treatment.

  4. Effects of TNF antagonists on immune and neuroendocrine system

    Directory of Open Access Journals (Sweden)

    M. Cutolo

    2011-09-01

    Full Text Available In the article, the literature on the effects of TNFa-antagonists (etanercept, infliximab and adalimumab on the immune system is reviewed. These biologic agents are employed in chronic inflammatory diseases such as rheumatoid arthritis, seronegative spondyloarthritides, as well as psoriasis and Crohn’s disease. The differences of these drugs, testified by the different effects on the immune response, are discussed. These molecules exert their effect through cytokine inhibition, but they present striking differences since they can modulate macrophage activity, T cells apoptosis, leukocyte migration, and angiogenesis to a different degree. Some studies showed that these agents also affect the hypothalamo- pituitary-adrenal axis. The potential immunogenicity of these biologic agents is also discussed.

  5. Identification of Bexarotene as a PPARγ Antagonist with HDX

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    David P. Marciano

    2015-01-01

    Full Text Available The retinoid x receptors (RXRs are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL. The RXRs form heterodimers with several nuclear receptors (NRs, including peroxisome proliferator-activated receptor gamma (PPARγ, to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions.

  6. Rational use of calcium-channel antagonists in Raynaud's phenomenon.

    Science.gov (United States)

    Sturgill, M G; Seibold, J R

    1998-11-01

    Raynaud's phenomenon (RP) is a peripheral circulatory disorder characterized by sudden episodes of digital artery spasm, often precipitated by cold temperature or emotional stress. Although the cause of RP is not fully known, it appears to involve inappropriate adrenergic response to cold stimuli. Treatment of RP is conservative in most patients, but in patients with severe disease includes the use of agents that promote digital vasodilation. The calcium-channel antagonists, particularly the dihydropyridine derivative nifedipine, are the most thoroughly studied drug class for the treatment of RP. Approximately two thirds of patients respond favorably, with significant reductions in the frequency and severity of vasospastic attacks. Nifedipine use is often limited by the appearance of adverse vasodilatory effects such as headache or peripheral edema. The newer second-generation dihydropyridines such as amlodipine, isradipine, nicardipine, and felodipine also appear to be effective in patients with RP and may be associated with fewer adverse effects.

  7. Antagonistic Bioactivity of Endophytic Actinomycetes Isolated from Medicinal Plants

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    M. Gangwar

    2011-10-01

    Full Text Available Endophytic actinomycetes are promising biocontrol agents for use in agriculture and have been isolated from various plant species. In the present study, 40 endophytic actinomycetes were isolated from roots, stems and leaves of three medicinal plants viz. Aloe vera, Mentha arvensis and Ocimum sanctum. The identification revealed that the majority of the isolates were Streptomyces spp. and the rest were identified as Saccharopolyspora spp., Micromonospora spp. and Actinopolyspora spp. The dual tests revealed that nine endophytic actinomycete isolates displayed a wide spectrum activity against nine fungal phytopathogens. Out of 8 isolates, 90% inhibited the growth of at least one or more phytopathogenic fungi and Saccharopolyspora 0-9 (Out of 8 isolates, 90% inhibited the growth of at least one or more phytopathogenic fungi and Saccharopolyspora 0-9 exhibited antagonistic activity against Aspergillus niger, Aspergillus flavus, Alternaria brassicicola, Botrytis cinerea, Penicillium digitatum, Fusarium oxysporum, Penicillium pinophilum, Phytophthora dresclea and Colletotrichum falcatum.

  8. The Effectiveness of Ameliorant to Increase Carbon Stock of Oilpalm and Rubber Plantation on Peatland

    Directory of Open Access Journals (Sweden)

    Ai Dariah

    2015-05-01

    Full Text Available Application of peatland amelioration can improve soil quality, reduce GHG emissions, and increase carbon sequestration. The research aimed to study the effect of peatland amelioration on oil palm and rubber carbon stock improvement. Research was conducted from August 2013 until June 2014. The researches on oil palm were done in Arang-arang Village, Kumpeh Subdistrict, Muaro Jambi District, and in Lubuk Ogong Village, Bandar Seikijang Sub-district, Pelalawan District. Both sites are in Jambi and Riau Province. The research on rubber was done in Jabiren Village, Jabiren Raya Subdistrict, Pulang Pisau District, Central Kalimantan Province. The study used a Randomized Completely Block Design (RCBD, in four treatments and four replications. The treatments were pugam (peat fertilizer enriched by polyvalent cation, manure; empty fruit bunch compost, and control (no application. The measurement of C stock was performed 10 months after application using nondestructive methods. The results showed that peatland amelioration treatments had no significant effect to improve C stock on oil palm in 6 years old and 7 years old of rubber. After 10 months of amelioration application, the treatments increased C - stock of oil palm and rubber were 2.1-2.4 Mg ha-1 and 5-11 Mg ha-1, respectively. Longer time observation may be needed to study the effect of ameliorant on C-stock of annual crops.

  9. Assessment of changes of some functions of Ukrainian acid soils after chemical amelioration

    Directory of Open Access Journals (Sweden)

    Zapko Yurij

    2014-09-01

    Full Text Available The objective of the article was to determine the effectiveness of lime of different origin for chemical amelioration of soils and examine its impact on soil functions such as productivity, habitat, regulation of water quality, and the protective buffer biogeocenotic screen. Limy ameliorants were applied in small local field experiment on Luvic Chernozem, and experiment with lysimeter columns was carried out on Albic Luvisol. The number of the main groups of microflora and enzymatic activity of soil was determined in soil samples taken for the analysis from the root zone. Research concerning the influence of natural and industrial origin ameliorants on soil as habitat showed the correlation of sugar beets productivity with soil biogenic. The increase of biomultiplicity of soil microbiota after addition of a cement dust and negative influence of red sludge on soil as habitat for living organisms was observed. Research involving the influence of ameliorants on soil by lime as the protective buffer biogeocenotic screen was carried out using lysimeter columns. It was stated that the addition of limy ameliorants reduces mobility of heavy metals.

  10. High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists

    Science.gov (United States)

    Fung, Eileen; Sugianto, Priscilla; Hsu, Jason; Damoiseaux, Robert; Ganz, Tomas

    2013-01-01

    Anemia of inflammation (AI) is common in patients with infection, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be reversed, treatment options are limited to erythropoiesis-stimulating agents with or without intravenous iron therapy, modalities that are not always effective and can cause serious adverse effects. Hepcidin, the iron regulatory hormone, has been identified as a pathogenic factor in the development of AI. To explore new therapeutic options for AI and other iron-related disorders caused by hepcidin excess, we developed a cell-based screen to identify hepcidin antagonists. Of the 70,000 small molecules in the library, we identified 14 compounds that antagonized the hepcidin effect on ferroportin. One of these was fursultiamine, a Food and Drug Administration (FDA)–approved thiamine derivative. Fursultiamine directly interfered with hepcidin binding to its receptor, ferroportin, by blocking ferroportin C326 thiol residue essential for hepcidin binding. Consequently, fursultiamine prevented hepcidin-induced ferroportin ubiquitination, endocytosis, and degradation in vitro and allowed continuous cellular iron export despite the presence of hepcidin, with IC50 in the submicromolar range. Thiamine, the fursultiamine metabolite, and benfotiamine, another thiamine derivative, did not interfere with the effect of hepcidin on ferroportin. Other FDA-approved thiol-reactive compounds were at least 1000-fold less potent than fursultiamine in antagonizing hepcidin. In vivo, fursultiamine did not reproducibly antagonize the effect of hepcidin on serum iron, likely because of its rapid conversion to inactive metabolites. Fursultiamine is a unique antagonist of hepcidin in vitro that could serve as a template for the development of drug candidates that inhibit the hepcidin-ferroportin interaction. PMID:23292796

  11. Alpha antagonists and intraoperative floppy iris syndrome: A spectrum

    Directory of Open Access Journals (Sweden)

    Sharif A Issa

    2008-07-01

    Full Text Available Sharif A Issa, Omar H Hadid, Oliver Baylis, Margaret DayanDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UKBackground: To determine occurrence of features of intraoperative floppy iris syndrome (IFIS during cataract surgery in patients taking systemic alpha-antagonists (AA.Methods: We prospectively studied patients on AA and who underwent phacoemulsification. The following were recorded: pupil diameter preoperatively, iris flaccidity, iris prolapse and peroperative miosis.Results: We studied 40 eyes of 31 subjects. Mean age was 78 years. Overall, 14 eyes (13 patients showed signs of IFIS: 9/13 (69% eyes of patients on tamsulosin, 1/18 (6% eyes in the doxazosin group, 2/2 prazosin patients, 1/4 eyes in the indoramin group, and 1/2 eyes in two patients on a combination of doxazosin and tamsulosin. Most cases (92% had only one or two signs of IFIS. Bilateral cataract surgery was undertaken in 9 patients but only one patient (on tamsulosin had features of IFIS in both eyes, while 4 patients (2 on tamsulosin and 2 on other AA showed signs of IFIS in one eye only, and 4 patients did not show IFIS in either eye.Conclusion: Most AA were associated with IFIS, but it tends to present as a spectrum of signs rather than full triad originally described. Tamsulosin was most likely to be associated with IFIS; however, its intake does not necessarily mean that IFIS will occur. For patients on AA, the behavior of the iris intraoperatively in one eye is a poor predictor of the other eye. Surgeons should anticipate the occurrence of IFIS in any patient on AA.Keywords: alpha blocker, alpha antagonist, cataract surgery, intraoperative floppy iris syndrome, tamsulosin.

  12. D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell

    Science.gov (United States)

    Kalyanasundar, B.; Perez, Claudia I.; Luna, Alvaro; Solorio, Jessica; Moreno, Mario G.; Elias, David; Simon, Sidney A.

    2015-01-01

    Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds. PMID:25972577

  13. Purification and reconstitution of the calcium antagonist receptor of the voltage-sensitive calcium channel

    International Nuclear Information System (INIS)

    Curtis, B.M.

    1986-01-01

    Treatment with digitonin solubilized the calcium antagonist receptor as a stable complex with [ 3 H]nitrendipine from rat brain membranes. The solubilized complex retains allosteric coupling to binding sites for diltiazem, verapamil, and inorganic calcium antagonist sites. The calcium antagonist receptor from cardiac sarcolemma and the transverse-tubule membrane of skeletal muscle is also efficiently solubilized with digitonin and the receptor in all three tissues is a large glycoprotein with a sedimentation coefficient of 20 S. The T-tubule calcium antagonist receptor complex was extensively purified by a combination of chromatography on WGA-Sepharose, ion exchange chromatography, and sedimentation on sucrose gradients to yield preparations estimated to be 41% homogeneous by specific activity and 63% homogeneous by SDS gel electrophoresis. Analysis of SDS gels detect three polypeptides termed α(Mr 135,000), β(Mr 50,000), and γ(Mr 32,000) as noncovalently associated subunits of the calcium antagonist receptor. The α and γ subunits are glycosylated polypeptides, and the molecular weight of the core polypeptides are 108,000 and 24,000 respectively. The calcium antagonist receptor was reconstituted into a phospholipid bilayer by adding CHAPS and exogeneous lipid to the purified receptor followed by rapid detergent removal. This procedure resulted in the incorporation of 45% of the calcium antagonist receptor into closed phospholipid vesicles. Data suggests that the α, β, and γ subunits of the T-tubule calcium antagonist receptor are sufficient to form a functional calcium channel

  14. Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy

    DEFF Research Database (Denmark)

    Fisker, Niels; Westergaard, Majken; Hansen, Henrik Frydenlund

    2007-01-01

    We have investigated the effects of different locked nucleic acid modified antisense mRNA antagonists against Survivin in a prostate cancer model. These mRNA antagonists were found to be potent inhibitors of Survivin expression at low nanomolar concentrations. Additionally there was a pronounced ...

  15. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

    NARCIS (Netherlands)

    Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart

    2016-01-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

  16. Benzimidazoles as benzamide replacements within cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists.

    Science.gov (United States)

    Cherney, Robert J; Mo, Ruowei; Meyer, Dayton T; Pechulis, Anthony D; Guaciaro, Michael A; Lo, Yvonne C; Yang, Gengjie; Miller, Persymphonie B; Scherle, Peggy A; Zhao, Qihong; Cvijic, Mary Ellen; Barrish, Joel C; Decicco, Carl P; Carter, Percy H

    2012-10-01

    We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Haematolohical profile of subacute oral toxicity of molybdenum and ameliorative efficacy of copper salt in goats.

    Science.gov (United States)

    Kusum; Raina, R; Verma, P K; Pankaj, N K; Kant, V; Kumar, J; Srivastava, A K

    2010-07-01

    Molybdenum toxicity produces a state of secondary hypocuprosis, resulting into alterations in normal hematological profile. In the present study, ammonium molybdate alone and with copper sulfate (II) pentahydrate (ameliorative agent) was administered orally for 30 consecutive days in healthy goats of group 1 and 2, respectively, to access the effect on the hematological profile on different predetermined days of dosing. Administration of ammonium molybdate alone produced significant decline in the mean values of hemoglobin (Hb), packed cell volume (PCV), total leukocyte count (TLC), total erythrocyte count (TEC), and mean corpuscular hemoglobin concentration (MCHC), with a significant increase in neutrophil level and mean corpuscular volume (MCV). However, values of erythrocyte sedimentation rate, mean corpuscular hemoglobin, and differential leukocyte count were not significantly altered. On comparing observations of ameliorative group with the group 1 goats, it is concluded that the ameliorative copper salt has beneficial effects in alleviating the alterations in the values of Hb, PCV, TLC, TEC, MCV, MCHC, and neutrophils.

  18. Ginger and alpha lipoic acid ameliorate age-related ultrastructural changes in rat liver.

    Science.gov (United States)

    Mahmoud, Y I; Hegazy, H G

    2016-01-01

    Because of the important role that oxidative stress is thought to play in the aging process, antioxidants could be candidates for preventing its related pathologies. We investigated the ameliorative effects of two antioxidant supplements, ginger and alpha lipoic acid (ALA), on hepatic ultrastructural alterations in old rats. Livers of young (4 months) and old (24 months) Wistar rats were studied using transmission electron microscopy. Livers of old rats showed sinusoidal collapse and congestion, endothelial thickening and defenestration, and inconsistent perisinusoidal extracellular matrix deposition. Aged hepatocytes were characterized by hypertrophy, cytoplasmic vacuolization and a significant increase in the volume densities of the nuclei, mitochondria and dense bodies. Lipofuscin accumulation and decreased microvilli in bile canaliculi and space of Disse also were observed. The adverse alterations were ameliorated significantly by both ginger and ALA supplementation; ALA was more effective than ginger. Ginger and ALA appear to be promising anti-aging agents based on their amelioration of ultrastructural alterations in livers of old rats.

  19. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    , in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-ylpropoxyphenylmethanol, and its (S-enantiomer (4 significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R-enantiomer (3 in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. Keywords: histamine, H3 receptor, isomeric antagonists, anticonvulsant activity, stereo­selectivity

  20. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism

    NARCIS (Netherlands)

    van der Heijden, J. F.; Hutten, B. A.; Büller, H. R.; Prins, M. H.

    2002-01-01

    BACKGROUND: People with venous thromboembolism are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin followed by three months of vitamin K antagonists treatment. Treatment with vitamin K antagonists requires regular laboratory

  1. Antagonistic studies and hyphal interactions of the new antagonist Aspergillus piperis against some phytopathogenic fungi in vitro in comparison with Trichoderma harzianum.

    Science.gov (United States)

    El-Debaiky, Samah A

    2017-12-01

    The present study represents, for the first time, the detailed studies about the hyphal interactions of Aspergillus piperis, as a new antagonist, against some isolated plant pathogenic fungi (Alternaria alternata, Alternaria solani, Botrytis cinerea, Sclerotium cepivorum and Sclerotinia sclerotiorum) in vitro. The bio-controlling capability of A. piperis against the tested phytopathogens was tested using the dual culture method. This experiment revealed that A. piperis had antagonistic activity and reduced the growth of the tested phytopathogens and grew over their mycelia in the paired plates. Also, several antagonistic mechanisms were recorded, in this study, between A. piperis and the tested phytopathogens using the microscopic examination. The bio-controlling activity and the antagonistic mechanisms exhibited by the new antagonist, A. piperis were compared with those obtained by the common antagonist, Trichoderma harzianum against the same phytopathogens. The obtained results showed that, A. piperis was more effective than T. harzianum in inhibiting all the tested species in the dual culture plates. The best result was 81.85% inhibition percentage against S. sclerotiorum by A. piperis while, T. harzianum exhibits only 45.18%. Moreover, several antagonistic mechanisms and hyphal interactions were investigated among the hyphae of both A.piperis and T. harzianum and the hyphae of the tested phytopathogens. These mechanisms were summarized as; mycoparasitism (coiling and penetration of the hyphae) and antibiosis in the form of lysis of the hyphal cells and spores, denaturation and breaking of the hyphae. The indirect interaction (antibiosis) and the direct mycoparasitism were observed by A. piperis against all the tested phytopathogens, but it attacked the hyphae and conidiophores of A. alternata by only the antibiosis interaction. The microscopic examination revealed also that T. harzianum attacked the tested phytopathogens by both antibiosis and mycoparasitism

  2. Effects of forest road amelioration techniques on soil bulk density, surface runoff, sediment transport, soil moisture and seedling growth

    Science.gov (United States)

    Randy K. Kolka; Mathew F. Smidt

    2004-01-01

    Although numerous methods have been used to retire roads, new technologies have evolved that can potentially ameliorate soil damage, lessen ,the generation of nonpoint source pollution and increase tree productivity on forest roads. In this study we investigated the effects of three forest road amelioration techniques, subsoiling, recontouring and traditional...

  3. Exploitation of microbial antagonists for the control of postharvest diseases of fruits: a review.

    Science.gov (United States)

    Dukare, Ajinath Shridhar; Paul, Sangeeta; Nambi, V Eyarkai; Gupta, Ram Kishore; Singh, Rajbir; Sharma, Kalyani; Vishwakarma, Rajesh Kumar

    2018-01-16

    Fungal diseases result in significant losses of fruits and vegetables during handling, transportation and storage. At present, post-production fungal spoilage is predominantly controlled by using synthetic fungicides. Under the global climate change scenario and with the need for sustainable agriculture, biological control methods of fungal diseases, using antagonistic microorganisms, are emerging as ecofriendly alternatives to the use of fungicides. The potential of microbial antagonists, isolated from a diversity of natural habitats, for postharvest disease suppression has been investigated. Postharvest biocontrol systems involve tripartite interaction between microbial antagonists, the pathogen and the host, affected by environmental conditions. Several modes for fungistatic activities of microbial antagonists have been suggested, including competition for nutrients and space, mycoparasitism, secretion of antifungal antibiotics and volatile metabolites and induction of host resistance. Postharvest application of microbial antagonists is more successful for efficient disease control in comparison to pre-harvest application. Attempts have also been made to improve the overall efficacy of antagonists by combining them with different physical and chemical substances and methods. Globally, many microbe-based biocontrol products have been developed and registered for commercial use. The present review provides a brief overview on the use of microbial antagonists as postharvest biocontrol agents and summarises information on their isolation, mechanisms of action, application methods, efficacy enhancement, product formulation and commercialisation.

  4. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    International Nuclear Information System (INIS)

    Chen, Yi; Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi; Jing, Qian; Yue, Jiaqi; Liu, Yang; Cheng, Zhong; Li, Jingyi; Song, Haixing; Li, Guoyu; Liu, Rui; Wang, Jinhui

    2016-01-01

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  5. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Jing, Qian; Yue, Jiaqi; Liu, Yang [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Cheng, Zhong [Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Li, Jingyi, E-mail: li--jingyi@hotmail.com [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Song, Haixing [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Li, Guoyu, E-mail: liguoyulisa@163.com [School of Pharmacy, Shihezi University, Shihezi 832003 (China); Liu, Rui, E-mail: liurui_scu@hotmail.com [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Wang, Jinhui [School of Pharmacy, Shihezi University, Shihezi 832003 (China)

    2016-05-20

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  6. Novel Abscisic Acid Antagonists Identified with Chemical Array Screening.

    Science.gov (United States)

    Ito, Takuya; Kondoh, Yasumitsu; Yoshida, Kazuko; Umezawa, Taishi; Shimizu, Takeshi; Shinozaki, Kazuo; Osada, Hiroyuki

    2015-11-01

    Abscisic acid (ABA) signaling is involved in multiple processes in plants, such as water stress control and seed dormancy. Major regulators of ABA signaling are the PYR/PYL/RCAR family receptor proteins, group A protein phosphatases 2C (PP2Cs), and subclass III of SNF1-related protein kinase 2 (SnRK2). Novel ABA agonists and antagonists to modulate the functions of these proteins would not only contribute to clarification of the signaling mechanisms but might also be used to improve crop yields. To obtain small molecules that interact with Arabidopsis ABA receptor PYR1, we screened 24 275 compounds from a chemical library at the RIKEN Natural Products Depository by using a chemical array platform. Subsequent SnRK2 and PP2C assays narrowed down the candidates to two molecules. One antagonized ABA in a competitive manner and inhibited the formation of the PYR1-ABA-PP2C ternary complex. These compounds might have potential as bioprobes to analyze ABA signaling. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Streptomycetes and micromycetes as perspective antagonists of fungal phytopathogens.

    Science.gov (United States)

    Postolaky, O; Syrbu, T; Poiras, N; Baltsat, K; Maslobrod, S; Boortseva, S

    2012-01-01

    Among natural factors that permanently influence on the plants, the soil microorganisms play a special role for the growing of plants as habitants of their rhizosphere. Mainly they are the representatives of actinomycetes genus Streptomyces and fungal genus Penicillium and their metabolic products stimulate plant growth and inhibit the growth of pathogenic fungi and bacteria. The aim of our study was to determine the antagonism of actinomycetes and micromycetes isolated from soils of R. Moldova against the fungal pathogens of agricultural plants. The strains were isolated from 5 types of chernozem (black soil) from central zone of R. Moldova, with different concentration of humus. Most of micromycetes and streptomycetes were isolated from soil sample 1 (monoculture of maize) and soil sample 2 (Poltava road border) with similar humus content (2.4-2.6%). The antifungal activity of micromycetes strains was occurring mostly against Fusarium solani and Thelaviopsis basicola, at streptomycetes against Alternaria alternata and Botrytis cinerea. It was revealed the strains completely inhibit the growth of Alt. alternata (streptomycetes strains 23, 33, 37), B. cinerea (Streptomyces sp. 17), and F. solani (Penicillium sp. 104). Our results allow to consider the actinomycetes Streptomyces sp.9, Streptomyces sp. 12, Streptomyces sp. 17, Streptomyces sp. 37 Streptomyces sp. 66 and micromycetes Penicillium sp. 5, Penicillium sp. 65, Penicillium sp. 104 isolated from soils of R. Moldova, as prospective strains-antagonists against the phytopathogenic fungus, the causative agents of agricultural plants deseasis.

  8. Orexin receptor antagonists as therapeutic agents for insomnia

    Directory of Open Access Journals (Sweden)

    Ana Clementina Equihua

    2013-12-01

    Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  9. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-03-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  10. Blood flow distribution with adrenergic and histaminergic antagonists

    International Nuclear Information System (INIS)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-01-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects

  11. Iontophoresis of endothelin receptor antagonists in rats and men.

    Directory of Open Access Journals (Sweden)

    Matthieu Roustit

    Full Text Available The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA was subsequently performed on the forearm skin of healthy men (n = 5.In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20 were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01. In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

  12. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton

    Science.gov (United States)

    Kinnaird, Catherine R.; Ferris, Daniel P.

    2013-01-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to “fight” the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations. PMID:23307949

  13. Bovine pancreatic polypeptide as an antagonist of muscarinic cholinergic receptors

    International Nuclear Information System (INIS)

    Pan, G.Z.; Lu, L.; Qian, J.; Xue, B.G.

    1987-01-01

    In dispersed acini from rat pancreas, it was found that bovine pancreatic polypeptide (BPP) and its C-fragment hexapeptide amide (PP-6), at concentrations of 0.1 and 30 μM, respectively, could significantly inhibit amylase secretion stimulated by carbachol, and this inhibition by BPP was dose dependent. 45 Ca outflux induced by carbachol was also inhibited by BPP or PP-6, but they had no effect on cholecystokinin octapeptide- (CCK-8) or A23187-stimulated 45 Ca outflux. BPP was also capable of displacing the specific binding of [ 3 H]-quinuclidinyl benzilate to its receptors, and it possessed a higher affinity (K/sub i/35nM) than carbachol (K/sub i/ 1.8 μM) in binding with M-receptors. It is concluded from this study that BPP acts as an antagonist of muscarinic cholinergic receptors in rat pancreatic acini. In addition, BPP inhibited the potentiation of amylase secretion caused by the combination of carbachol plus secretin or vasoactive intestinal peptide. This may be a possible explanation of the inhibitory effect of BPP on secretin-induced pancreatic enzyme secretion shown in vivo, since pancreatic enzyme secretion stimulated by secretin under experimental conditions may be the result of potentiation of enzyme release produced by the peptide in combination with a cholinergic stimulant

  14. NMDA receptor antagonist ketamine impairs feature integration in visual perception.

    Science.gov (United States)

    Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F

    2013-01-01

    Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

  15. NMDA receptor antagonist ketamine impairs feature integration in visual perception.

    Directory of Open Access Journals (Sweden)

    Julia D I Meuwese

    Full Text Available Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

  16. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton.

    Science.gov (United States)

    Gordon, Keith E; Kinnaird, Catherine R; Ferris, Daniel P

    2013-04-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to "fight" the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations.

  17. Discovery and Characterization of an Endogenous CXCR4 Antagonist

    Directory of Open Access Journals (Sweden)

    Onofrio Zirafi

    2015-05-01

    Full Text Available CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

  18. Antagonist effects of calcium on borosilicate glass alteration

    Energy Technology Data Exchange (ETDEWEB)

    Mercado-Depierre, S. [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France); Angeli, F., E-mail: frederic.angeli@cea.fr [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France); Frizon, F. [CEA Marcoule, DTCD SECM LP2C, 30207 Bagnols sur Cèze (France); Gin, S. [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France)

    2013-10-15

    Graphical abstract: Display Omitted -- Highlights: •Kinetic study of glass alteration is investigated in calcium-enriched solutions. •New insights into silicon–calcium interactions in glass/cement systems are proposed. •Glass alteration is controlled by pH, Ca concentration and reaction progress. •Evidence of antagonist effects according to the importance of these parameters. -- Abstract: Numerous studies have been conducted on glass and cement durability in contact with water, but very little work to date has focused directly on interactions between the two materials. These interactions are mostly controlled by silicon–calcium reactivity. However, the physical and chemical processes involved remain insufficiently understood to predict the evolution of coupled glass–cement systems used in several industrial applications. Results are reported from borosilicate glass alteration in calcium-rich solutions. Our data show that four distinct behaviors can be expected according to the relative importance of three key parameters: the pH, the reaction progress (short- or long-term alteration) and the calcium concentration. Glass alteration is thus controlled by specific mechanisms depending on the solution chemistry: calcium complexation at the glass surface, precipitation of calcium silicate hydrates (C–S–H) or calcium incorporation in the altered layer. These findings highlight the impact of silicon–calcium interactions on glass durability and open the way for a better understanding of glass–cement mixing in civil engineering applications as well as in nuclear waste storage.

  19. Antagonistic Activity Of Endophytic Bacteria Isolated From Mentha Rotundifolia L.

    Directory of Open Access Journals (Sweden)

    Elhartiti Abla

    2015-08-01

    Full Text Available Abstract This study is implemented for the isolation purification and identification of endophytic bacteria which produces antifungal substances from the roots of Mentha rotundifolia L. The 59 obtained bacterial isolates were tested for their antagonistic activity by the dual confrontation against the phytopathogenic fungi Fusarium oxysporum Aspergillus Niger and Botrytis cinerea. Eight bacterial strains were selected for their strong antifungal activity. These are strains M21 M23 M3a M4 M14d and M3c which belong to the family Bacillaceae M12 and M3b which belongs to the family of Pseudomonadaceae. Among these three bacterial strains namely M21 M23 and M12 induce 70 of inhibition of mycelial growth of phytopathogenic fungi Fusarium oxysporum and Aspergillus Niger while the five bacterial strains M3a M3c M3b M4 and M14d have proved to be effective in inhibiting more than 60 of mycelial growth of Botrytis cinerea.

  20. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Donlon, M.A.; Melia, J.A.; Helgeson, E.A.; Wolfe, W.W.

    1986-03-01

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor.

  1. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    International Nuclear Information System (INIS)

    Donlon, M.A.; Melia, J.A.; Helgeson, E.A.; Wolfe, W.W.

    1986-01-01

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor

  2. Antagonist effects of calcium on borosilicate glass alteration

    International Nuclear Information System (INIS)

    Mercado-Depierre, S.; Angeli, F.; Frizon, F.; Gin, S.

    2013-01-01

    Graphical abstract: Display Omitted -- Highlights: •Kinetic study of glass alteration is investigated in calcium-enriched solutions. •New insights into silicon–calcium interactions in glass/cement systems are proposed. •Glass alteration is controlled by pH, Ca concentration and reaction progress. •Evidence of antagonist effects according to the importance of these parameters. -- Abstract: Numerous studies have been conducted on glass and cement durability in contact with water, but very little work to date has focused directly on interactions between the two materials. These interactions are mostly controlled by silicon–calcium reactivity. However, the physical and chemical processes involved remain insufficiently understood to predict the evolution of coupled glass–cement systems used in several industrial applications. Results are reported from borosilicate glass alteration in calcium-rich solutions. Our data show that four distinct behaviors can be expected according to the relative importance of three key parameters: the pH, the reaction progress (short- or long-term alteration) and the calcium concentration. Glass alteration is thus controlled by specific mechanisms depending on the solution chemistry: calcium complexation at the glass surface, precipitation of calcium silicate hydrates (C–S–H) or calcium incorporation in the altered layer. These findings highlight the impact of silicon–calcium interactions on glass durability and open the way for a better understanding of glass–cement mixing in civil engineering applications as well as in nuclear waste storage

  3. Return of D4 Dopamine Receptor Antagonists in Drug Discovery.

    Science.gov (United States)

    Lindsley, Craig W; Hopkins, Corey R

    2017-09-14

    The dopamine D 4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D 4 , relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D 4 antagonists that were developed for schizophrenia failed in the clinic. Thus, D 4 fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D 4 ligands with improved selectivity for D 4 against not only D 1-3,5 but also other biogenic amine targets have emerged, and D 4 is once again in the spotlight as a novel target for both addiction and Parkinson's disease (PD), as well as other emerging diseases. This report will review the historical data for D 4 , review the known D 4 ligands, and then highlight new data supporting a role for D 4 inhibition in addiction, PD, and cancer.

  4. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  5. Side Effects of Leukotriene Receptor Antagonists in Asthmatic Children.

    Science.gov (United States)

    Erdem, Semiha Bahceci; Nacaroglu, Hikmet Tekin; Unsal Karkiner, Canan Sule; Gunay, Ilker; Can, Demet

    2015-10-01

    Leukotriene receptor antagonists (LTRAs) are drugs which have been widely used more than ten years. As the use of LTRAs increases, our knowledge with respect to their side effects increases as well. The objective of our study was to evaluat the observed side effects of LTRAs used in patients with astma. 1024 patients treated only with LTRAs owing to asthma or early wheezing were included in the study for a five-year period. The observed side effects of LTRAs in these patients were retrospectively investigated. The side effects were divided into two parts as psychiatric and non-psychiatric. Among the 1024 cases included in the study, 67.5% of the patients out of 41 with side effects were male, 32.5% were female and the average age was 6.5 years. The rate of patients with asthma was 63.41% and 36.58% of the patients had early wheezing. It was determined that sex, age and diagnosis (early wheezing or asthma) of the patients were ineffective in the emergence of side effects. The average period for the emergence of side effects was the first month. It was observed that hyperactivity was the most frequently observed psychiatric side effect and that abdominal pain was the non-psychiatric side effect. The side effects of LTRAs were common in children. Therefore, patients must be informed at the beginning of the treatment and they must be evaluated at certain intervals.

  6. Angiotensin antagonists in the dog with chronic pericardial tamponade

    International Nuclear Information System (INIS)

    Moore, G.J.; Taub, K.J.

    1980-01-01

    Assessing the role played by angiotensin in the pathogenesis and maintenance of the renal function and perfusion abnormalities dogs with chronic pericardial tamponade were used in the experiment as a stable model of chronic low output heart failure. The heptapeptide and octapeptide antagonist were used. The results of the experiments suggest that there is a role for angiotensin in the pathologenesis of congestive heart failure. The renin-angiotensin system was activated in the model. Plasma renin activity was elevated and increased further in response to angiotensin blockade. Under the experiment condition there was no evidence for a role for angiotensin in the maintenance of arterial blood pressure. But there was angiotensin-mediated renal vasoconstriction and a reduction in renal blood flow. Both analogues of angiotensin were able to antagonize this effect in similar fashion. Failure to achieve a natriuresis in response to angiotensin blockade may reflect the redistribution of blood flow that occured and suggests that additional factors are operative in this model. (APR)

  7. A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation.

    Science.gov (United States)

    Connallon, Tim; Clark, Andrew G

    2012-04-01

    Antagonistic selection--where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")--might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range--a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N(e)s > 1, where N(e) is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection.

  8. Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats

    NARCIS (Netherlands)

    Waanders, Femke; Rienstra, Heleen; Boer, Mark Walther; Zandvoort, Andre; Rozing, Jan; Navis, Gerjan; van Goor, Harry; Hillebrands, Jan-Luuk

    Waanders F, Rienstra H, Walther Boer M, Zandvoort A, Rozing J, Navis G, van Goor H, Hillebrands JL. Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats. Am J Physiol Renal Physiol 296: F1072-F1079, 2009. First published February 25, 2009;

  9. Abscisic acid ameliorates experimental IBD by downregulating cellular adhesion molecule expression and suppressing immune cell infiltration.

    Science.gov (United States)

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-12-01

    Abscisic acid (ABA) has shown effectiveness in ameliorating inflammation in obesity, diabetes and cardiovascular disease models. The objective of this study was to determine whether ABA prevents or ameliorates experimental inflammatory bowel disease (IBD). C57BL/6J mice were fed diets with or without ABA (100mg/kg) for 35 days prior to challenge with 2.5% dextran sodium sulfate (DSS). The severity of clinical disease was assessed daily. Colonic mucosal lesions were evaluated by histopathology, and cellular adhesion molecular and inflammatory markers were assayed by real-time quantitative PCR. Flow cytometry was used to quantify leukocyte populations in the blood, spleen, and mesenteric lymph nodes (MLN). The effect of ABA on cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression in splenocytes was also investigated. ABA significantly ameliorated disease activity, colitis and reduced colonic leukocyte infiltration and inflammation. These improvements were associated with downregulation in vascular cell adhesion marker-1 (VCAM-1), E-selectin, and mucosal addressin adhesion marker-1 (MAdCAM-1) expression. ABA also increased CD4(+) and CD8(+) T-lymphocytes in blood and MLN and regulatory T cells in blood. In vitro, ABA increased CTLA-4 expression through a PPAR γ-dependent mechanism. We conclude that ABA ameliorates gut inflammation by modulating T cell distribution and adhesion molecule expression. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  10. Economic efficiency of the use of the bush vegetation from slopes of the ameliorative canals

    International Nuclear Information System (INIS)

    Titov, V.N.

    2009-01-01

    The results of calculations of the economic efficiency of the use of the bush vegetation from slopes of the ameliorative canals for fuel and energy purposes has been presented. The two variants of disposal of bushes are considered burning and conversion into fuel chips. (authors)

  11. Lipid abnormalities in streptozotocin-diabetes: Amelioration by Morus indica L. cv Suguna leaves

    OpenAIRE

    Andallu, B.; Vinay Kumar, A. V.; Varadacharyulu, N. Ch.

    2009-01-01

    AIM: To observe the influence of mulberry (Morus indica L. cv Suguna) leaves on lipid abnormalities in STZ-diabetic rats. MATERIALS AND METHODS: Treatment with dried mulberry leaf powder for a period of 8 weeks in hyperglycemic and hyperlipidemic STZ-diabetic rats. RESULTS: Mulberry leaves regulated fasting blood glucose, ameliorated the abnormalities in lipid profile as indicated by significant (P

  12. Fermented ginseng, GBCK25, ameliorates hemodynamic function on experimentally induced myocardial injury

    Directory of Open Access Journals (Sweden)

    Adithan Aravinthan

    2016-10-01

    Full Text Available In the present study, we investigated whether treatment with GBCK25 facilitated the recovery of hemodynamic parameters, left ventricle systolic pressure, left ventricular developed pressure, and electrocardiographic changes. GBCK25 significantly prevented the decrease in hemodynamic parameters and ameliorated the electrocardiographic abnormality. These results indicate that GBCK25 has distinct cardioprotective effects in rat heart.

  13. Progresses on Amelioration of Red Soil Acidity with Crop Straw Biochar: A Review

    OpenAIRE

    XU Ren-kou

    2016-01-01

    The research progresses on amelioration of red soil acidity and immobilization of heavy metals in red soils with the biochars generated from crop straws were summarized in this review paper. The developing trends of the research in these areas in future were also predicted.

  14. Amelioration of Anti-Nutritive Effects of Castor Oil Seed ( Ricinus ...

    African Journals Online (AJOL)

    Three hundred and twenty (320) day old male broilers were used to investigate the amelioration of anti-nutritive effects of castor oil seed (Ricinus communis) meal in broilers' ration using natural fermentation and DL-Methionine supplementation. The experimental designed was a 4 × 2 factorial arrangement of dietary ...

  15. Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants, and methylxanthines as prostaglandin agonists and antagonists.

    Science.gov (United States)

    Manku, M S; Horrobin, D F

    1976-11-20

    Chloroquine, quanine, procaine, quinidine, clomipramine, theophylline, and caffeine have been shown to be strong prostaglandin antagonists and weak agonists. The antagonist effect is clearly demonstrable at concentrations reached in human plasma when the drugs are used therapeutically. This suggests that prostaglandins are important in several situations in which their role has hitherto been unsuspected. New approaches to the development of prostaglandin antagonists and new uses for established drugs are indicated. In a preliminary study chloroquine has been successfully used to close patent ductus arteriosus in three infants.

  16. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I; Sester, M; Gomez-Reino, J J

    2010-01-01

    risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-¿ release assays or, as an alternative in individuals without a history...... of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...

  17. West syndrome associated with administration of a histamine H1 antagonist, oxatomide.

    Science.gov (United States)

    Yamashita, Yushiro; Isagai, Takeo; Seki, Yoshitaka; Ohya, Takashi; Nagamitsu, Shinichiro; Matsuishi, Toyojiro

    2004-01-01

    We report a 4-month-old female infant who developed West syndrome eleven days after administration of a histamine H1 antagonist, oxatomide, for atopic dermatitis. It has been reported that some histamine H1 antagonists induce seizures in epileptic patients. The age, the interval between oxatomide administration, and the onset of West syndrome and its clinical course were similar to two previously reported 3-month-old infants with West syndrome associated with ketotifen administration. We should be cautious in using the histamine H1 antagonists, oxatomide and ketotifen, in young infants because such agents could potentially disturb the anticonvulsive central histaminergic system.

  18. EFFECTS OF AMELIORANT COMPOSITIONS ON NITROGEN MINERALIZATION AND UPTAKE BY SWEET CORN IN DEGRADED PEATLAND

    Directory of Open Access Journals (Sweden)

    Eni Maftu’ah

    2014-04-01

    Full Text Available Peat soil is characterized by poor nitrogen (N availability. Ameliorants are expected to rectify this problem. This research  aimed to study the effect of ameliorant on N availability and N uptake by sweet corn plant in degraded peatland. The experiment was conducted in the greenhouse in May-July 2011 and on peatland of Kalampangan Village, Palangkaraya, Central Kalimantan in September-December 2011. Burnt peat soil of Kalampangan was used in the greenhouse experiment and sweet corn was used as an indicator plant. The treatments consisted of two factors, i.e. compositions of ameliorants by weight (A1 = 80% chicken manure + 20% dolomite; A2 = 80% local farm weed + 20% dolomite; A3 = 80% mineral soil + 20% dolomite; A4 = 20% chicken manure + 20% local farm weed + 20% residue of Chinese water chestnut (Eleocharis dulcis + 20% mineral soil + 20% dolomite; and A5 = 19% chicken manure + 71.5% mineral soil + 9.5% dolomite and rates of those ameliorants (5, 10, 15, 20 and 25 t ha-1. The experiment was arranged in a completely randomized block design with three replications. Data were collected every two weeks for five times. Observations were made on soil pH, available N (NH4+, NO3-, plant height, and N uptake in root and shoot. The results showed that  treatment A1 increased soil pH and availability of NH4+ and NO3-  in peat soils at the maximum vegetative stage. Treatment A1 provided the highest N availability and N uptake by the plant. Field experiment showed that N uptake increased  with the plant yield. Optimum yield of fresh corn cob was obtained from treatment A1 at the rate of 20 t ha-1. This research reconfirms the effectiveness of chicken manure and dolomite as peat soil ameliorant.

  19. Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A2A antagonists MSX-3 and SCH58261, but not the adenosine A1 antagonist DPCPX.

    Science.gov (United States)

    Collins, Lyndsey E; Galtieri, Daniel J; Brennum, Lise T; Sager, Thomas N; Hockemeyer, Jörg; Müller, Christa E; Hinman, James R; Chrobak, James J; Salamone, John D

    2010-02-01

    Tremulous jaw movements in rats, which can be induced by dopamine (DA) antagonists, DA depletion, and cholinomimetics, have served as a useful model for studies of tremor. Although adenosine A(2A) antagonists can reduce the tremulous jaw movements induced by DA antagonists and DA depletion, there are conflicting reports about the interaction between adenosine antagonists and cholinomimetic drugs. The present studies investigated the ability of adenosine antagonists to reverse the tremorogenic effect of the muscarinic agonist pilocarpine. While the adenosine A(2A) antagonist MSX-3 was incapable of reversing the tremulous jaw movements induced by the 4.0mg/kg dose of pilocarpine, both MSX-3 and the adenosine A(2A) antagonist SCH58261 reversed the tremulous jaw movements elicited by 0.5mg/kg pilocarpine. Systemic administration of the adenosine A(1) antagonist DPCPX failed to reverse the tremulous jaw movements induced by either an acute 0.5mg/kg dose of the cholinomimetic pilocarpine or the DA D2 antagonist pimozide, indicating that the tremorolytic effects of adenosine antagonists may be receptor subtype specific. Behaviorally active doses of MSX-3 and SCH 58261 showed substantial in vivo occupancy of A(2A) receptors, but DPCPX did not. The results of these studies support the use of adenosine A(2A) antagonists for the treatment of tremor. Copyright 2009 Elsevier Inc. All rights reserved.

  20. Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Borst Mathias M

    2009-12-01

    Full Text Available Abstract Background In idiopathic pulmonary arterial hypertension (IPAH, peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1, to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. Methods In 32 IPAH-patients (19 female, WHO functional class II (n = 10, III (n = 22; (data presented as mean ± standard deviation pulmonary vascular resistance (11 ± 5 Wood units, lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0 m, systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg, and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0 ng/L were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day. Results and Discussion At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p Conclusion This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

  1. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.

    Science.gov (United States)

    Cappato, Riccardo; Ezekowitz, Michael D; Klein, Allan L; Camm, A John; Ma, Chang-Sheng; Le Heuzey, Jean-Yves; Talajic, Mario; Scanavacca, Maurício; Vardas, Panos E; Kirchhof, Paulus; Hemmrich, Melanie; Lanius, Vivian; Meng, Isabelle Ling; Wildgoose, Peter; van Eickels, Martin; Hohnloser, Stefan H

    2014-12-14

    X-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion. We assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67). Oral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion. Clinicaltrials.gov; NCT01674647. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  2. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

    Science.gov (United States)

    Cicardi, Marco; Banerji, Aleena; Bracho, Francisco; Malbrán, Alejandro; Rosenkranz, Bernd; Riedl, Marc; Bork, Konrad; Lumry, William; Aberer, Werner; Bier, Henning; Bas, Murat; Greve, Jens; Hoffmann, Thomas K; Farkas, Henriette; Reshef, Avner; Ritchie, Bruce; Yang, William; Grabbe, Jürgen; Kivity, Shmuel; Kreuz, Wolfhart; Levy, Robyn J; Luger, Thomas; Obtulowicz, Krystyna; Schmid-Grendelmeier, Peter; Bull, Christian; Sitkauskiene, Brigita; Smith, William B; Toubi, Elias; Werner, Sonja; Anné, Suresh; Björkander, Janne; Bouillet, Laurence; Cillari, Enrico; Hurewitz, David; Jacobson, Kraig W; Katelaris, Constance H; Maurer, Marcus; Merk, Hans; Bernstein, Jonathan A; Feighery, Conleth; Floccard, Bernard; Gleich, Gerald; Hébert, Jacques; Kaatz, Martin; Keith, Paul; Kirkpatrick, Charles H; Langton, David; Martin, Ludovic; Pichler, Christiane; Resnick, David; Wombolt, Duane; Fernández Romero, Diego S; Zanichelli, Andrea; Arcoleo, Francesco; Knolle, Jochen; Kravec, Irina; Dong, Liying; Zimmermann, Jens; Rosen, Kimberly; Fan, Wing-Tze

    2010-08-05

    Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

  3. Statin use decreases coagulation in users of vitamin K antagonists.

    Science.gov (United States)

    van Rein, Nienke; Biedermann, J S; Bonafacio, S M; Kruip, M J H A; van der Meer, F J M; Lijfering, W M

    2016-12-01

    The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower. Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.

  4. A novel antagonistic role of natural compound icariin on neurotoxicity of amyloid β peptide

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    2015-01-01

    Interpretation & conclusions: The results indicated a novel antagonistic role of icariin in the neurotoxicity of Aβ1-42 via inhibiting its aggregation, suggesting that icariin might have potential therapeutic benefits to delay or modify the progression of AD.

  5. Efficacité de l'agent antagoniste Trichoderma harzianum sur ...

    African Journals Online (AJOL)

    Efficacité de l'agent antagoniste Trichoderma harzianum sur Fusarium oxysporum f. sp. lycopersiciagent pathogène de la tomate. LS Gnancadja, DHE Tonon, EMO Faton, KO Douro Kpindou, E Dannon, A Akoegninou ...

  6. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomised controlled trial

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    Aim  Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  7. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment : a randomized controlled trial

    NARCIS (Netherlands)

    De Jong, Cor A J; Laheij, Robert J F; Krabbe, Paul F M

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  8. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomized controlled trial.

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  9. Anti-HIV Effect of Liposomes Bearing CXCR4 Receptor Antagonist ...

    African Journals Online (AJOL)

    Keywords: Antagonist, CXCR4, Liposomes, Receptor, Inflammation, HIV. Tropical Journal of ... receptors and inhibits HIV-1 entry mediated through CCR3, CCR5, and ..... circulation, facilitating HIV-targeted drug delivery. By tissue distribution ...

  10. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes...

  11. In vitro suppression of fungi caused by combinations of apparently non-antagonistic soil bacteria

    NARCIS (Netherlands)

    De Boer, W.; Wagenaar, A.M.; Klein Gunnewiek, P.J.A.; Van Veen, J.A.

    2007-01-01

    We hypothesized that apparently non-antagonistic soil bacteria may contribute to suppression of fungi during competitive interactions with other bacteria. Four soil bacteria (Brevundimonas sp., Luteibacter sp., Pedobacter sp. and Pseudomonas sp.) that exhibited little or no visible antifungal

  12. Sympatholytic properties of several AT(1)-receptor antagonists in the isolated rabbit thoracic aorta

    NARCIS (Netherlands)

    Nap, Alexander; Balt, Jippe C.; Pfaffendorf, Martin; van Zwieten, Pieter A.

    2002-01-01

    Objective To evaluate the facilitating effect of angiotensin II on sympathetic neurotransmission to quantitatively compare the sympatho-inhibitory potencies of the selective AT(1)-receptor antagonists losartan, irbesartan and telmisartan in the isolated rabbit thoracic aorta. Design To investigate

  13. Antagonist muscle moment is increased in ACL deficient subjects during maximal dynamic knee extension

    DEFF Research Database (Denmark)

    Alkjær, Tine; Simonsen, Erik B; Magnusson, S Peter

    2012-01-01

    INTRODUCTION: Coactivation of the hamstring muscles during dynamic knee extension may compensate for increased knee joint laxity in anterior cruciate ligament (ACL) deficient subjects. This study examined if antagonist muscle coactivation during maximal dynamic knee extension was elevated...

  14. Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.

    2009-01-01

    between the groups in terms of changes in serum free fatty acids, glycerol, (V) over dotO(2), or relative fat oxidation. Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise. (J Clin Endocrinol......Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...... period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed...

  15. Muscarinic receptor antagonists for overactive bladder treatment: does one fit all?

    NARCIS (Netherlands)

    Witte, Lambertus P. W.; Mulder, Wilhelmina M. C.; de La Rosette, Jean J. M. C. H.; Michel, Martin C.

    2009-01-01

    Purpose of review To review evidence and regulatory dosing recommendations for muscarinic receptor antagonists used in the treatment of overactive bladder symptom complex (darifenacin, fesoterodine oxybutynin propiverine solifenacin tolterodine trospium) in special patient populations. Recent

  16. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; La Marca, Antonio; Mirner Klein, Bjarke

    2013-01-01

    To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol....

  17. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I.; Sester, M.; Gomez-Reino, J.J.

    2010-01-01

    risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-gamma release assays or, as an alternative in individuals without...... a history of bacille Calmette-Guerin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...... and an interferon-gamma release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy...

  18. Successful treatment of hereditary angioedema with bradykinin B2-receptor antagonist icatibant.

    Science.gov (United States)

    Krause, Karoline; Metz, Martin; Zuberbier, Torsten; Maurer, Marcus; Magerl, Markus

    2010-04-01

    The bradykinin B2 receptor antagonist icatibant has recently become available for treating hereditary angioedema. Our observations demonstrate icatibant to be effective and safe for the treatment of both, abdominal and cutaneous attacks in a practice setting beyond clinical studies.

  19. Biological control of fusarium wilt of tomato by antagonist fungi and ...

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... Key words: Biological control, fusarium wilt, tomato, antagonist fungi, cyanobacteria. INTRODUCTION ... severely affected by wilt disease caused by F. oxysporum f. sp. ..... Changing options for the control of deciduous fruit.

  20. CCR5 receptor antagonists: discovery and SAR study of guanylhydrazone derivatives.

    Science.gov (United States)

    Wei, Robert G; Arnaiz, Damian O; Chou, Yuo-Ling; Davey, Dave; Dunning, Laura; Lee, Wheeseong; Lu, Shou-Fu; Onuffer, James; Ye, Bin; Phillips, Gary

    2007-01-01

    High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.

  1. Antagonist wear of monolithic zirconia crowns after 2 years.

    Science.gov (United States)

    Lohbauer, Ulrich; Reich, Sven

    2017-05-01

    The aim of this study was to evaluate the amount of wear on the antagonist occlusal surfaces of clinically placed monolithic zirconia premolar and molar crowns (LAVA Plus, 3M ESPE). Fourteen in situ monolithic zirconia crowns and their opposing antagonists (n = 26) are the subject of an ongoing clinical trial and have been clinically examined at baseline and after 24 months. Silicone impressions were taken and epoxy replicas produced for qualitative SEM analysis and quantitative analysis using optical profilometry. Based on the baseline replicas, the follow-up situation has been scanned and digitally matched with the initial topography in order to calculate the mean volume loss (in mm 3 ) as well as the mean maximum vertical loss (in mm) after 2 years in service. The mean volume loss for enamel antagonist contacts (n = 7) was measured to 0.361 mm 3 and the mean of the maximum vertical loss to 0.204 mm. The mean volume loss for pure ceramic contacts (n = 10) was measured to 0.333 mm 3 and the mean of the maximum vertical loss to 0.145 mm. The wear rates on enamel contacts were not significantly different from those measured on ceramic antagonists. Based on the limitations of this study, it can be concluded for the monolithic zirconia material LAVA Plus that the measured wear rates are in consensus with other in vivo studies on ceramic restorations. Further, that no significant difference was found between natural enamel antagonists and ceramic restorations as antagonists. The monolithic zirconia restorations do not seem to be affected by wear within the first 2 years. The monolithic zirconia crowns (LAVA Plus) show acceptable antagonist wear rates after 2 years in situ, regardless of natural enamel or ceramics as antagonist materials.

  2. Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt

    Science.gov (United States)

    Chen, Yi-Cun; Zhu, Wei; Zhong, Shu-Ping; Zheng, Fu-Chun; Gao, Fen-Fei; Zhang, Yan-Mei; Xu, Han; Zheng, Yan-Shan; Shi, Gang-Gang

    2015-01-01

    BACKGROUND AND PURPOSE Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored. EXPERIMENTAL APPROACH Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists. RESULTS The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3. CONCLUSIONS The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application. PMID:26544729

  3. The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

    Directory of Open Access Journals (Sweden)

    Gorash ZM

    2008-01-01

    Full Text Available Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist. Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments. In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

  4. Isolation and characterization of a novel analyte from Bacillus subtilis SC-8 antagonistic to Bacillus cereus.

    Science.gov (United States)

    Lee, Nam Keun; Yeo, In-Cheol; Park, Joung Whan; Kang, Byung-Sun; Hahm, Young Tae

    2010-09-01

    In this study, an effective substance was isolated from Bacillus subtilis SC-8, which was obtained from traditionally fermented soybean paste, cheonggukjang. The substance was purified by HPLC, and its properties were analyzed. It had an adequate antagonistic effect on Bacilluscereus, and its spectrum of activity was narrow. When tested on several gram-negative and gram-positive foodborne pathogenic bacteria such as Salmonella enterica, Salmonella enteritidis, Staphylococcus aureus, and Listeria monocytogenes, no antagonistic effect was observed. Applying the derivative from B. subtilis SC-8 within the same genus did not inhibit the growth of major soybean-fermenting bacteria such as Bacillus subtilis, Bacillus licheniformis, and Bacillus amyloquefaciens. The range of pH stability of the purified antagonistic substance was wide (from 4.0 to >10.0), and the substance was thermally stable up to 60 degrees C. In the various enzyme treatments, the antagonistic activity of the purified substance was reduced with proteinase K, protease, and lipase; its activity was partially destroyed with esterase. Spores of B. cereus did not grow at all in the presence of 5mug/mL of the purified antagonistic substance. The isolated antagonistic substance was thought to be an antibiotic-like lipopeptidal compound and was tentatively named BSAP-254 because it absorbed to UV radiation at 254nm. Copyright 2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  5. Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower

    Directory of Open Access Journals (Sweden)

    Veronika Zengerer

    2018-02-01

    Full Text Available In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora, the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0.

  6. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.

    Science.gov (United States)

    Patten, M M

    2014-11-01

    Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture. © 2014 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

  8. Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower.

    Science.gov (United States)

    Zengerer, Veronika; Schmid, Michael; Bieri, Marco; Müller, Denise C; Remus-Emsermann, Mitja N P; Ahrens, Christian H; Pelludat, Cosima

    2018-01-01

    In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora , the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430 Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0.

  9. Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation.

    Science.gov (United States)

    Fosbøl, Emil L; Vinding, Naja Emborg; Lamberts, Morten; Staerk, Laila; Gundlund, Anna; Gadsbøll, Kasper; Køber, Lars; Gislason, Gunnar H; Olesen, Jonas Bjerring

    2017-06-28

    After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations. Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%). In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

  10. Penicillium expansum versus antagonist yeasts and patulin degradation in vitro

    Directory of Open Access Journals (Sweden)

    Alexandre Rodrigo Coelho

    2007-07-01

    Full Text Available Taking into account the preliminary antagonistic/biodegradation property showed by Pichia membranifaciens and Sporobolomyces roseus, which decreased the initial patulin concentration of 588.4 to 290.0 µg/mL, ability of P. ohmeri 158 in biocontrol against Penicillium expansum and patulin decrease in vitro was performed. The culture supernatant of P. ohmeri 158 was effective against 66.17% micelial growth, indicating antibiosis related with the killer phenomenon. The initial patulin concentration of 223 µg in the presence of P. ohmeri 158 cells was decreased over 83% of the original concentration, when incubated at 25ºC/2 days and > 99% after 5 days incubation time, with undetectable patulin level after 15 days. The initial pH 4.0 decreased to pH 3.3 along 15 days experiment, suggesting that patulin decrease was an active process and a consequence of yeast metabolism. The results suggested that P. ohmeri 158 could be a promising alternative for the inhibition of P. expansum growth and patulin degradation.Considerando o antagonismo e degradação de patulina detectados em Pichia membranifaciens e Sporobolomyces roseus no estudo preliminar, este trabalho avaliou o efeito antagônico de Pichia ohmeri 158 no desenvolvimento de Penicillium expansum e a degradação de patulina "in vitro". O sobrenadante do cultivo de P. ohmeri 158 inibiu 66,17% do desenvolvimento micelial, indicando antibiose relacionada ao fator killer. A concentração inicial de patulina (223 µg na presença de células íntegras de P. ohmeri foi reduzida em mais de 83% após dois dias de incubação a 25ºC e superior a 99% após 5 dias, com níveis indetectáveis no 15º dia. O decréscimo do pH 4,0 inicial para pH 3,3 sugeriu que a eliminação de patulina é um processo ativo e uma conseqüência do metabolismo da levedura. Os resultados obtidos concluem que P. ohmeri 158 é uma alternativa promissora na inibição do desenvolvimento de P. expansum e na degradação de

  11. FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

    International Nuclear Information System (INIS)

    Yamaguchi, Fuminori; Hirata, Yuko; Akram, Hossain; Kamitori, Kazuyo; Dong, Youyi; Sui, Li; Tokuda, Masaaki

    2013-01-01

    Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p27. MK-801 dephosphorylated

  12. FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

    Science.gov (United States)

    2013-01-01

    Background Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Methods Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. Results NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p

  13. Ameliorative Activity of Ethanolic Extract of Artocarpus heterophyllus Stem Bark on Alloxan-induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Basiru Olaitan Ajiboye

    2018-03-01

    Full Text Available Purpose: Diabetes mellitus is one of the major endocrine disorders, characterized by impaired insulin action and deficiency. Traditionally, Artocarpus heterophyllus stem bark has been reputably used in the management of diabetes mellitus and its complications. The present study evaluates the ameliorative activity of ethanol extract of Artocarpus heterophyllus stem bark in alloxan-induced diabetic rats. Methods: Diabetes mellitus was induced by single intraperitoneal injection of 150 mg/kg body weight of alloxan and the animals were orally administered with 50, 100 and 150 mg/kg body weight ethanol extract of Artocarpus heterophyllus stem bark once daily for 21 days. Results: At the end of the intervention, diabetic control rats showed significant (p0.05 different with non-diabetic rats. Conclusion: The results suggest that ethanol extract of Artocarpus heterophyllus stem bark may be useful in ameliorating complications associated with diabetes mellitus patients.

  14. Characteristics of biomass ashes from different materials and their ameliorative effects on acid soils.

    Science.gov (United States)

    Shi, Renyong; Li, Jiuyu; Jiang, Jun; Mehmood, Khalid; Liu, Yuan; Xu, Renkou; Qian, Wei

    2017-05-01

    The chemical characteristics, element contents, mineral compositions, and the ameliorative effects on acid soils of five biomass ashes from different materials were analyzed. The chemical properties of the ashes varied depending on the source biomass material. An increase in the concrete shuttering contents in the biomass materials led to higher alkalinity, and higher Ca and Mg levels in biomass ashes, which made them particularly good at ameliorating effects on soil acidity. However, heavy metal contents, such as Cr, Cu, and Zn in the ashes, were relatively high. The incorporation of all ashes increased soil pH, exchangeable base cations, and available phosphorus, but decreased soil exchangeable acidity. The application of the ashes from biomass materials with a high concrete shuttering content increased the soil available heavy metal contents. Therefore, the biomass ashes from wood and crop residues with low concrete contents were the better acid soil amendments. Copyright © 2016. Published by Elsevier B.V.

  15. Evaluation of ameliorative potential of supranutritional selenium on enrofloxacin-induced testicular toxicity.

    Science.gov (United States)

    Rungsung, Soya; Khan, Adil Mehraj; Sood, Naresh Kumar; Rampal, Satyavan; Singh Saini, Simrat Pal

    2016-05-25

    The study was designed to assess the ameliorative potential of selenium (Se) on enrofloxacin-induced testicular toxicity in rats. There was a significant decrease in body weight and non-significant decrease in mean testicular weight of enrofloxacin treated rats. In enrofloxacin treated rats, total sperm count and viability decreased where as sperm abnormalities increased. Testicular histopathology revealed dose dependent dysregulation of spermatogenesis and presence of necrotic debris in seminiferous tubules which was marginally improved with Se. Enrofloxacin also produced a dose dependent decrease in testosterone level. The activity of testicular antioxidant enzymes decreased where as lipid peroxidation increased in a dose-dependent manner. Se supplementation partially restored oxidative stress and sperm damage and did not affect the plasma concentrations of enrofloxacin or ciprofloxacain. The results indicate that enrofloxacin produces a dose-dependent testicular toxicity in rats that is moderately ameliorated with supranutritional Se. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. The HDAC Inhibitor TSA Ameliorates a Zebrafish Model of Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Johnson, Nathan M; Farr, Gist H; Maves, Lisa

    2013-09-17

    Zebrafish are an excellent model for Duchenne muscular dystrophy. In particular, zebrafish provide a system for rapid, easy, and low-cost screening of small molecules that can ameliorate muscle damage in dystrophic larvae. Here we identify an optimal anti-sense morpholino cocktail that robustly knocks down zebrafish Dystrophin (dmd-MO). We use two approaches, muscle birefringence and muscle actin expression, to quantify muscle damage and show that the dmd-MO dystrophic phenotype closely resembles the zebrafish dmd mutant phenotype. We then show that the histone deacetylase (HDAC) inhibitor TSA, which has been shown to ameliorate the mdx mouse Duchenne model, can rescue muscle fiber damage in both dmd-MO and dmd mutant larvae. Our study identifies optimal morpholino and phenotypic scoring approaches for dystrophic zebrafish, further enhancing the zebrafish dmd model for rapid and cost-effective small molecule screening.

  17. Amelioration of alkali soil using flue gas desulfurization byproducts: productivity and environmental quality

    Energy Technology Data Exchange (ETDEWEB)

    Wang, S.J.; Chen, C.H.; Xu, X.C.; Li, Y.J. [Tsing Hua University, Beijing (China). Ministry of Education

    2008-01-15

    In this study, flue gas desulfurization (FGD) byproducts are used to ameliorate alkali soil. The average application rates for soils with low exchangeable sodium percentage (ESP), mid ESP, and high ESP are 20.9, 30.6, and 59.3 Mg ha{sup -1} respectively. The experimental results obtained for 3 consecutive years reveal that the emergence ratios and yields of the crops were 1.1-7.6 times and 1.1-13.9 times those of the untreated control, respectively. The concentrations of Cr, Pb, Cd, As, and Hg in the treated soils are far below the background values stipulated by the Environmental Quality Standard for Soils (GB 15618-1995). Their concentrations in the seeds of corn and alfalfa grown in the treated soils are far below the tolerance limits regulated by National Food Standards of China. The results of this research demonstrate that the amelioration of alkali soils using FGD byproducts is promising.

  18. Amelioration of soils contaminated with industrial exhalations in the Chvaletice region

    Energy Technology Data Exchange (ETDEWEB)

    Kozel, J

    1966-01-01

    In the area of the Chvaletice manganese and pyrite works, the pyrite fly dust decomposing into sulfuric acid causes considerable damage to agricultural production. Sulfuric acid is also formed from the escaping sulfur dioxide. The reaction of the affected soils is extremely acid and reaches from 4.5 to 6.5 pH, and in some cases it decreases to 2.5 pH. Soil devastation spreads to distant land in the direction of the predominating winds. Damage is caused to agricultural crops which decreases yields. It was decided to ameliorate the affected soils with high doses of calcareous composts of material obtained from fish-ponds and of marl. The purpose of the experiment, the partial results of which are described, was an operational checking of the suitability of the composts for the amelioration of contaminated soils and an estimation of the doses to be applied.

  19. Antagonistic Activities of Streptomyces against Root Knot Nematode of Kiwifruit

    Directory of Open Access Journals (Sweden)

    S. Bashiri

    2016-02-01

    Full Text Available Introduction: Iran is among the world leading kiwifruit producers with 2.816 ha cultivated and 31.567 tones production. Plant parasitic nematodes cause damages to a variety of agricultural crops throughout the world. Interest in biological control of nematodes has increased because of the need for alternative methods to fumigant and non-fumigant nematicides and overall improvement of IPM programs. Bacterial species with nematicidal activity have also been used with some success for controlling root-knot diseases, including Streptomyces spp., Serratia spp., Bacillus spp. and Pseudomonas spp. The goal of the current study was to isolate, identify and investigate the potential of local Streptomyces bacteria for controlling and reducing root-knot nematode population in the north of Iran. Materials and Methods: In order to evaluate the effect of antagonistic bacteria on control of root-knot nematode of Kiwifruit, 100 isolates of bacteria were collected from Kiwifruit rhizosphere in the north of Iran and screened for pigmented microorganisms especially Streptomyces by applying standard serial dilution plate technique, using starch casein nitrate agar and glycerol asparagine agar. Morphological characterizations were achieved by the microscopic method. The microscopic characterization was done by cover slip culture method. The mycelium structure, color and arrangement of conidiospore and arthrospore on the mycelium were observed through the oil immersion (100X. The observed structure was compared with Bergey’s Manual of Determinative Bacteriology and the organism was identified. Various biochemical tests performed for the identification of the potent isolates are as follows: casein hydrolysis, starch hydrolysis, urea hydrolysis, esculin hydrolysis, acid production from sugar, NaCl resistance, temperature tolerance. Soil samples (100g were collected, and then processed for nematode egg and larvae extraction Hussey method. The suspension was pipetted

  20. Ameliorative effect of antioxidants (vitamins C and E against abamectin toxicity in liver, kidney and testis of male albino rats

    Directory of Open Access Journals (Sweden)

    B. Wilson Magdy

    2016-10-01

    In conclusion, it appears that vitamins C and E, or in combination (as antioxidants ameliorate the hepato-renal and testicular toxicity of abamectin, but are not completely protective, especially in liver tissue.

  1. Lagenaria siceraria ameliorates atheromatous lesions by modulating HMG–CoA reductase and lipoprotein lipase enzymes activity in hypercholesterolemic rats

    Directory of Open Access Journals (Sweden)

    Mithun Singh Rajput

    2014-01-01

    Conclusion: It can be concluded that ethanolic extract of fruits of L. siceraria contains active components which ameliorates the atheromatous lesions in rat aorta and lowers the risk of atherosclerosis in hypercholesterolemic rats.

  2. Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats

    Directory of Open Access Journals (Sweden)

    Chen-Hwan Cherng

    2014-08-01

    Conclusion: The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats.

  3. Comment ameliorer la selection et le traitement des messages verbaux? (How to Improve the Selection and Processing of Verbal Messages)

    National Research Council Canada - National Science Library

    Rivenez, Marie; Darwin, Chris; Guillaume, Anne

    2005-01-01

    L'objectif de cette recherche est d'ameliorer la selection des messages verbaux. Nous cherchons a determiner les facteurs influencant le traitement d'un message verbal lorsque l'attention est portee sur un autre message...

  4. Amelioration of acidic soil increases the toxicity of the weak base carbendazim to the earthworm Eisenia fetida.

    Science.gov (United States)

    Liu, Kailin; Wang, Shaoyun; Luo, Kun; Liu, Xiangying; Yu, Yunlong

    2013-12-01

    Ameliorating acidic soils is a common practice and may affect the bioavailability of an ionizable organic pollutant to organisms. The toxicity of the weak base carbendazim to the earthworm (Eisenia fetida) was studied in an acidic soil (pH-H₂O, 4.6) and in the ameliorated soil (pH-H₂O, 7.5). The results indicated that the median lethal concentration of carbendazim for E. fetida decreased from 21.8 mg/kg in acidic soil to 7.35 mg/kg in the ameliorated soil. To understand why the amelioration increased carbendazim toxicity to the earthworm, the authors measured the carbendazim concentrations in the soil porewater. The authors found increased carbendazim concentrations in porewater, resulting in increased toxicity of carbendazim to earthworms. The increased pore concentrations result from decreased adsorption because of the effects of pH and calcium ions. © 2013 SETAC.

  5. Hypomethylating agent 5-aza-2'-deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models

    DEFF Research Database (Denmark)

    Mangano, Katia; Fagone, Paolo; Bendtzen, Klaus

    2014-01-01

    murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease....... Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3....

  6. Effect of sodium fluoride in maternal and offspring rats and its amelioration

    Directory of Open Access Journals (Sweden)

    Sneha Panchal

    2014-03-01

    Full Text Available High fluoride content is known to cause dental and skeletal abnormalities. In addition, present review indicates that sodium fluoride consumption caused increased number of r=esorptions and dead foetuses. Various skeletal anomalies such as wavy ribs, presence of 14th ribs, lacking 6th sternebrae and incompete ossification of skull occur. All these changes could be due to oxidative stress caused by fluoride consumption. Fluoride-induced changes could be successfully ameliorated by cotreatment with vitamins and calcium.

  7. Modelling of 137Cs behaviour in the soil-plant system following the application of ameliorants

    International Nuclear Information System (INIS)

    Spiridonov, S.; Fesenko, S.; Sanzharova, N.

    2004-01-01

    A set of countermeasures aimed at reducing 137 Cs uptake by plant products includes agrochemical measures based on changes in the soil properties after the application of ameliorants. The dynamic models for studying the effect of the application of potassium fertilizers and dolomite powder on 137 Cs accumulation in plants are presented. Conceptual approaches to the development of models are based on the identification of mechanisms governing a complex of physico-chemical processes in soil after the use of ameliorants. The following assumptions were used in the development of models: - dynamics of 137 Cs distribution in each soil layer depends on the sorption processes characterized by different time to achieve quasi-equilibrium (exchangeable uptake and fixation by clay minerals) as well as on vertical migration process; - change in 137 Cs content in soil solution results from the radionuclide sorption on selective and nonselective exchange sites; - uptake of extra amounts of K + and Ca 2+ in soil solution produces effect on processes of 137 Cs exchangeable sorption and initiate specific processes responsible for 137 Cs fixation in the crystal lattice of clay minerals; - Ca 2+ and K + cations have a competing effect on 137 Cs uptake by plants from soil solution, which along with the fixation processes, causes lower accumulation of this radionuclide by plants during the application of ameliorants. The developed models were parameterized for soils of the coniferous forest located in the Bryansk region in area suffered from the radioactive fallout after the Chernobyl accident. Effects of ameliorants and time of their application on 137 Cs behaviour in the soil-plant system are assessed. The contribution of soil chemical and biological processes to the decrease in the radionuclide uptake by plants is estimated. (author)

  8. Use of vegetation to ameliorate building microclimates: an assessment of energy-conservation potentials

    Energy Technology Data Exchange (ETDEWEB)

    Hutchison, B.A.; Taylor, F.G.; Wendt, R.L.

    1982-04-01

    The space-conditioning energy conservation potentials of landscapes designed to ameliorate building microclimates are evaluated. The physical bases for vegetative modifications of climate are discussed, and results of past study of the effects of vegetation on space-conditioning energy consumption in buildings are reviewed. The state-of-the-art of energy-conserving landscape designs is assessed and recommendations are presented for further research.

  9. Dietary -carbamylglutamate and rumen-protected -arginine supplementation ameliorate fetal growth restriction in undernourished ewes.

    Science.gov (United States)

    Zhang, H; Sun, L W; Wang, Z Y; Deng, M T; Zhang, G M; Guo, R H; Ma, T W; Wang, F

    2016-05-01

    This study was conducted with an ovine intrauterine growth restriction (IUGR) model to test the hypothesis that dietary -carbamylglutamate (NCG) and rumen-protected -Arg (RP-Arg) supplementation are effective in ameliorating fetal growth restriction in undernourished ewes. Beginning on d 35 of gestation, ewes were fed a diet providing 100% of NRC-recommended nutrient requirements, 50% of NRC recommendations (50% NRC), 50% of NRC recommendations supplemented with 20 g/d RP-Arg (providing 10 g/d of Arg), and 50% of NRC recommendations supplemented with 5 g/d NCG product (providing 2.5 g/d of NCG). On d 110, maternal, fetal, and placental tissues and fluids were collected and weighed. Ewe weights were lower ( ewes compared with adequately fed ewes. Maternal RP-Arg or NCG supplementation did not alter ( = 0.26) maternal BW in nutrient-restricted ewes. Weights of most fetal organs were increased ( ewes compared with 50% NRC-fed ewes. Supplementation of RP-Arg or NCG reduced ( ewes but had no effect on concentrations of lactate and GH. Maternal RP-Arg or NCG supplementation markedly improved ( ewes. These novel results indicate that dietary NCG and RP-Arg supplementation to underfed ewes ameliorated fetal growth restriction, at least in part, by increasing the availability of AA in the conceptus and provide support for its clinical use to ameliorate IUGR in humans and sheep industry production.

  10. Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice.

    Science.gov (United States)

    Lee, Hyun Gyu; Cho, Nam-Chul; Jeong, Ae Jin; Li, Yu-Chen; Rhie, Sung-Ja; Choi, Jung Sook; Lee, Kwang-Ho; Kim, Youngsoo; Kim, Yong-Nyun; Kim, Myoung-Hwan; Pae, Ae Nim; Ye, Sang-Kyu; Kim, Byung-Hak

    2016-01-01

    T-cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathologic immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite that multiple pharmacologic properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T-cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited TCR-mediated Akt and NF-κB signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as 2,4,6-trinitrochlorobenzene-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and overall immune responses. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. The amelioration effect of tranexamic acid in wrinkles induced by skin dryness.

    Science.gov (United States)

    Hiramoto, Keiichi; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2016-05-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medical amino acid widely used as an anti-inflammatory and a whitening agent. This study examined the effect of tranexamic acid administration in wrinkle formation following skin dryness. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In these NOA mice, deterioration of transepidermal water loss (TEWL), generation of wrinkles, decrease of collagen type I, and increases in mast cell proliferation and tryptase and matrix metalloproteinase (MMP-1) release were observed. However, these symptoms were improved by tranexamic acid treatment. Moreover, the increase in the β-endorphin level in the blood and the expression of μ-opioid receptor on the surface of fibroblasts increased by tranexamic acid treatment. In addition, when the fibroblasts induced by tranexamic acid treatment were removed, the amelioration effect by tranexamic acid treatment was halved. On the other hand, tranexamic acid treated NOA mice and mast cell removal in tranexamic acid treated NOA mice did not result in changes in the wrinkle amelioration effect. Additionally, the amelioration effect of mast cell deficient NOA mice was half that of tranexamic acid treated NOA mice. These results indicate that tranexamic acid decreased the proliferation of mast cells and increases the proliferation of fibroblasts, subsequently improving wrinkles caused by skin dryness. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Zhong-he Liu

    2015-01-01

    Full Text Available Objective. The effects of Flos Puerariae extract (FPE on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA and total cholesterol (TCH in serum, malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GSH-Px, and acetylcholinesterase (AChE activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain.

  13. β-glycosphingolipids ameliorated non-alcoholic steatohepatitis in the Psammomys obesus model

    Directory of Open Access Journals (Sweden)

    Zigmond E

    2014-10-01

    Full Text Available Ehud Zigmond,1,* Oshrat Tayer-Shifman,1,* Gadi Lalazar,1 Ami Ben Ya'acov,1 Sarah Weksler-Zangen,2 David Shasha,1 Miriam Sklair-Levy,3 Lidya Zolotarov,1 Zvi Shalev,1 Rony Kalman,2 Ehud Ziv,2 Itamar Raz,2 Yaron Ilan1 1Liver Unit, 2Diabetes Unit, 3Department of Radiology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel *These authors contributed equally to this workAbstract: Liver steatosis is a common characteristic of obesity and type 2 diabetes, and fatty liver disease is increasingly recognized as a major health burden. Accumulating evidence suggests that β-glycosphingolipids play an important role in insulin sensitivity and thus could affect hepatic steatosis. To determine the effect associated with β-glycosphingolipid-mediated amelioration of liver injury, seven groups of Psammomys obesus on a high-energy diet were studied. Animals were treated with daily injections of β-glucosylceramide, β-lactosylceramide, or a combination of both. β-glycosphingolipids ameliorated the hepatic injury manifested by decreased liver enzymes, liver weight, and hepatic fat, and improved liver histology. Administration of both β-glucosylceramide and β-lactosylceramide also decreased interferon (IFN-γ serum levels. These effects were associated with improved serum cholesterol and triglyceride levels. These data suggest that β-glycosphingolipids ameliorate liver injury in an animal model of nonalcoholic steatohepatitis.Keywords: NAFLD, glycolipids, STAT, NASH, insulin resistance, diabetes

  14. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  15. Effectiveness of Some Ameliorants in Reducing Co2 and N2o Emission in Corn Planting in Peat Land

    Directory of Open Access Journals (Sweden)

    Eni Maftuah

    2016-04-01

    Full Text Available Amelioration is very important in supporting plant growth in peat land. The use of low emission ameliorant will support the sustainability of agricultural system in peat land. The research is intended to study the effectiveness of some ameliorants in reducing CO2 and N2O emission in corn planting in peat land. The research was conducted in April to October 2013, in Kalampangan Village Palangkaraya Municipality Central Kalimantan. Ameliorant materials used were chicken manure fertilizer, domolite, mineral soil, paddy husk biochar, coconut shell biochar. Ameliorant treatments applied were the type of ameliorant compositions, those were (A1 80% chicken manure fertilizer + 20% dolomite, (A2 20% chicken manure fertilizer + 20% agricultural weeds + 20% spodosol mineral soil + 20% “purun tikus” (eleocharis dulcis compost + 20% dolomite, (A3 19% chicken manure fertilizer + 9% dolomite + 72% mineral soil, (A4 100% coconut shell biochar, (A5 paddy husk biochar, (A6 farmer’s way (20% ash + 40% spodosol mineral soil + 40% chicken manure fertilizer and control. Experiment design used a Randomized Factorial Block Design, with 3 repetitions. Ameliorant dosage used was 7.5 t/ha. The crop used was hybrid corn. Parameters which were observed periodically were emission of CO2 and N2O, ground water level height, soil pH and Eh, once a month for 5 periods. The research result showed that ameliorant was capable of reducing emission of both CO2 and N2O in corn planting in peat land. Coconut shell biochar could reduce emission of CO2 up to 26% as compared with control, whereas paddy husk biochar could reduce emission of N2O up to 52% as compared with control.

  16. The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

    OpenAIRE

    Sirohi, Sunil; Dighe, Shveta V.; Madia, Priyanka A.; Yoburn, Byron C.

    2009-01-01

    Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was exa...

  17. SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?

    Science.gov (United States)

    Dalm, Simone U; Haeck, Joost; Doeswijk, Gabriela N; de Blois, Erik; de Jong, Marion; van Deurzen, Carolien H M

    2017-10-01

    Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of 111 In-DOTA-Tyr 3 -octreotate (SSTR agonist) and 111 In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor-positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with 177 Lu-DOTA-Tyr 3 -octreotate or 177 Lu-DOTA-JR11. Results: 111 In-DOTA-JR11 binding to human BC tissue was significantly higher than 111 In-DOTA-Tyr 3 -octreotate binding ( P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2-5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer

  18. Comparison of long GnRH agonist versus GnRH antagonist protocol in poor responders

    Directory of Open Access Journals (Sweden)

    Sadık Şahin

    2014-12-01

    Full Text Available Objective: To compare long GnRH agonist with GnRH antagonist protocol in poor responders. Materials and Methods: Medical charts of 531 poor responder women undergoing in-vitro fertilization (IVF cycle at Zeynep Kamil Maternity and Children’s Hospital, IVF Center were retrospectively analysed. Those who received at least 300 IU/daily gonadotropin and had ≤3 oocytes retrieved were enrolled in the study. Poor responders were categorized into two groups as those who received long GnRH agonist or GnRH antagonist regimen. Results: Treatment duration and total gonadotropin dosage were significantly higher in women undergoing the long GnRH agonist regimen compared with the GnRH antagonist regimen (p<0.001 for both. Although the number of total and mature oocytes retrieved was similar between the groups, good quality embryos were found to be higher in the GnRH antagonist regimen. The day of embryo transfer and number of transferred embryos were similar in the groups. No statistically significant differences were detected in pregnancy (10.5% vs 14.1%, clinical pregnancy (7.7% vs 10.6% and early pregnancy loss rates (27.2% vs 35% between the groups. Conclusion: GnRH antagonist regimen may be preferable to long GnRH regimen as it could decrease the cost and treatment duration in poor responders.

  19. Orexin 1 receptor antagonists in compulsive behaviour and anxiety: possible therapeutic use.

    Directory of Open Access Journals (Sweden)

    Emilio eMerlo-Pich

    2014-02-01

    Full Text Available Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were early on associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders, in this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1 antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioural and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

  20. Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression

    Directory of Open Access Journals (Sweden)

    Laura López-Cruz

    2018-06-01

    Full Text Available Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A1/A2A receptors, and has been demonstrated to modulate behavior in classical animal models of depression. Moreover, selective adenosine receptor antagonists are being assessed for their antidepressant effects in animal studies. This review focuses on how caffeine and selective adenosine antagonists can improve different aspects of depression in humans, as well as in animal models. The effects on motivational symptoms of depression such as anergia, fatigue, and psychomotor slowing receive particular attention. Thus, the ability of adenosine receptor antagonists to reverse the anergia induced by dopamine antagonism or depletion is of special interest. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression.

  1. Evaluation of the protagonist-antagonist dichotomy in Spanish television content targeting children

    Directory of Open Access Journals (Sweden)

    José A. García-Castillo, Ph.D.

    2010-01-01

    Full Text Available The goal of this study is to analyse the profile of the protagonist-antagonist dichotomy in all children’s television content, of all genres, offered by Spanish television channels. The analysis of protagonist and antagonist characters focuses on variables such as: type and number, age, gender, nationality, skills, relationship between the characters, characterisation, means used to achieve goals, consequences of the action of the antagonist over the antagonist and vice versa. The sample consists of 168 series that were analysed using descriptive content analysis and multivariate analysis. The results showed that over 50% of the series do not have an antagonist and that when there is one the most common type is a single human, which appears in more than 15% of the analysed series, followed by the fantastic creature type, which is present in just 10%. In 80% of the series the skills of the protagonists are social and human, and in 45.24% the exhibited skill is intelligence.

  2. Dopamine antagonists during parturition disrupt maternal care and the retention of maternal behavior in rats.

    Science.gov (United States)

    Byrnes, Elizabeth M; Rigero, Beth A; Bridges, Robert S

    2002-11-01

    Brief contact with pups at parturition enables the female rat to establish and retain the full repertoire of maternal behaviors, allowing her to respond rapidly to pups in the future. To determine whether the dopamine system is involved in the retention of maternal behavior, females were continuously infused with dopamine antagonists during the periparturitional period and then allowed either a brief interaction period with pups (3 h) or no interaction with pups (pups removed as they were born). Females were exposed to either the D1-like antagonist SCH 23390 (0.1 or 1.0 mg/kg/day) or the D2-like antagonist clebopride (0.5 or 1.0 mg/kg/day). The high dose of either DA antagonist resulted in significant attenuation of maternal care immediately postpartum. When tested for the retention of maternal behavior 7 days later, however, only the females exposed to the D2 antagonist displayed a delayed response to shown full maternal behavior (FMB) towards donor pups. Thus, while both dopamine receptor subtypes appear necessary for the full and rapid expression of maternal behavior during the early postpartum period, only the D2 receptor subtype appears to be involved in the retention of this behavior.

  3. Effects of sigma(1) receptor ligand MS-377 on D(2) antagonists-induced behaviors.

    Science.gov (United States)

    Karasawa, Jun-ichi; Takahashi, Shinji; Takagi, Kaori; Horikomi, Kazutoshi

    2002-10-01

    (R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.

  4. Novel CRTH2 antagonists: a review of patents from 2006 to 2009.

    Science.gov (United States)

    Ulven, Trond; Kostenis, Evi

    2010-11-01

    The receptor CRTH2 (also known as DP₂) is an important mediator of the inflammatory effects of prostaglandin D₂ and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. The validation of CRTH2 as a therapeutic target and the early antagonists are summarized, CRTH2 antagonists published in the patent literature from 2006 to 2009 are comprehensively covered and a general update on the recent progress in the development of CRTH2 antagonists for the treatment of inflammatory diseases is provided. Insight into the validation of CRTH2 as a therapeutic target, a comprehensive overview of the development of new CRTH2 ligands between 2006 and 2009, and a general overview of the state of the art. Many diverse potent CRTH2 antagonists are now available, and several are in or on the way into the clinic. It is still early to draw final conclusions, but preliminary results give reason for optimism, and the prospect that we will see new CRTH2 antagonists reaching the market for the treatment of asthma, rhinitis, atopic dermatitis and/or COPD seems good.

  5. Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

    Science.gov (United States)

    Mochizuki, Michiyo; Kori, Masakuni; Kobayashi, Katsumi; Yano, Takahiko; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Gyorkos, Albert C; Corrette, Christopher P; Cho, Suk Young; Pratt, Scott A; Aso, Kazuyoshi

    2016-03-24

    Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.

  6. Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia.

    Science.gov (United States)

    Garami, Andras; Shimansky, Yury P; Pakai, Eszter; Oliveira, Daniela L; Gavva, Narender R; Romanovsky, Andrej A

    2010-01-27

    Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.

  7. Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

    Science.gov (United States)

    Li, Minyong; Xia, Lin

    2007-11-01

    In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

  8. Structural refinement and prediction of potential CCR2 antagonists through validated multi-QSAR modeling studies.

    Science.gov (United States)

    Amin, Sk Abdul; Adhikari, Nilanjan; Baidya, Sandip Kumar; Gayen, Shovanlal; Jha, Tarun

    2018-01-03

    Chemokines trigger numerous inflammatory responses and modulate the immune system. The interaction between monocyte chemoattractant protein-1 and chemokine receptor 2 (CCR2) may be the cause of atherosclerosis, obesity, and insulin resistance. However, CCR2 is also implicated in other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma, and neuropathic pain. Therefore, there is a paramount importance of designing potent and selective CCR2 antagonists despite a number of drug candidates failed in clinical trials. In this article, 83 CCR2 antagonists by Jhonson and Jhonson Pharmaceuticals have been considered for robust validated multi-QSAR modeling studies to get an idea about the structural and pharmacophoric requirements for designing more potent CCR2 antagonists. All these QSAR models were validated and statistically reliable. Observations resulted from different modeling studies correlated and validated results of other ones. Finally, depending on these QSAR observations, some new molecules were proposed that may exhibit higher activity against CCR2.

  9. Opioid antagonist naltrexone for the treatment of pathological gambling in Parkinson disease.

    Science.gov (United States)

    Bosco, Domenico; Plastino, Massimiliano; Colica, Carmela; Bosco, Francesca; Arianna, Spanò; Vecchio, Antonino; Galati, Francesco; Cristiano, Dario; Consoli, Arturo; Consoli, Domenico

    2012-01-01

    Pathological gambling (PG) is a potential complication related to the treatment of Parkinson disease (PD) with dopamine agonists (DA). The cause of this disorder is unknown, but altered dopamine neurotransmission may be involved. We evaluated the efficacy and tolerability of the opioid antagonist naltrexone in the treatment of PG in PD. Our cases included 3 patients with PD who developed PG after DA treatment. Pathological gambling did not improve after reduction or discontinuation of DA. These patients responded poorly to serotonin reuptake inhibitors, whereas treatment with opioid antagonist naltrexone resulted in the remission of PG. Naltrexone treatment was well tolerated. In one patient, higher dose of naltrexone resulted in hepatic abnormalities, which resolved after dosage reduction. The opioid antagonist naltrexone could be an effective option for the treatment of PG in PD.

  10. Secreted Wnt antagonists in leukemia: A road yet to be paved.

    Science.gov (United States)

    Pehlivan, Melek; Çalışkan, Ceyda; Yüce, Zeynep; Sercan, Hakki Ogun

    2018-03-28

    Wnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist

    Science.gov (United States)

    Storgard, Chris M.; Stupack, Dwayne G.; Jonczyk, Alfred; Goodman, Simon L.; Fox, Robert I.; Cheresh, David A.

    1999-01-01

    Rheumatoid arthritis (RA) is an inflammatory disease associated with intense angiogenesis and vascular expression of integrin αvβ3. Intra-articular administration of a cyclic peptide antagonist of integrin αvβ3 to rabbits with antigen-induced arthritis early in disease resulted in inhibition of synovial angiogenesis and reduced synovial cell infiltrate, pannus formation, and cartilage erosions. These effects were not associated with lymphopenia or impairment of leukocyte function. Furthermore, when administered in chronic, preexisting disease, the αvβ3 antagonist effectively diminished arthritis severity and was associated with a quantitative increase in apoptosis of the angiogenic blood vessels. Therefore, angiogenesis appears to be a central factor in the initiation and persistence of arthritic disease, and antagonists of integrin αvβ3 may represent a novel therapeutic strategy for RA. PMID:9884333

  12. Recent progress in the development of small-molecule glucagon receptor antagonists.

    Science.gov (United States)

    Sammons, Matthew F; Lee, Esther C Y

    2015-10-01

    The endocrine hormone glucagon stimulates hepatic glucose output via its action at the glucagon receptor (GCGr) in the liver. In the diabetic state, dysregulation of glucagon secretion contributes to abnormally elevated hepatic glucose output. The inhibition of glucagon-induced hepatic glucose output via antagonism of the GCGr using small-molecule ligands is a promising mechanism for improving glycemic control in the diabetic state. Clinical data evaluating the therapeutic potential of small-molecule GCGr antagonists is currently emerging. Recently disclosed clinical data demonstrates the potential efficacy and possible therapeutic limitations of small-molecule GCGr antagonists. Recent pre-clinical work on the development of GCGr antagonists is also summarized. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Study on Ca2+ antagonistic effect and mechanism of Chinese herbal drugs using 45Ca

    International Nuclear Information System (INIS)

    Yang Yuanyou; Liu Ning; Mo Shangwu; Qiu Mingfeng; Jin Jiannan; Liao Jiali

    2002-01-01

    The Ca 2+ antagonistic effect and mechanism of Chinese herbal drugs are studied by using 45 Ca. The results indicate that potential-dependent Ca 2+ channel (PDC) and receptor-operated Ca 2+ channel (ROC) in cell membranes of smooth muscle can be blocked by several Chinese herbal drugs, including as Crocus sativus L., Carthamus L., Di-ao-xin-xue-kang (DAXXG) and Ginkgo biloba L. leaves. Among them Crocus sativus L. has the strongest antagonistic effect on Ca 2+ channel, while Ginkgo biloba L. leaves has no obvious effect. The whole prescription and the other functional drugs have significant effect on ROC and PDC. The compositions extracted by hexane have the strongest antagonistic. The wrinkled giant hyssop have five active compositions and Pei-lan have two active compositions

  14. Nonpeptidic angiotensin II AT₁ receptor antagonists derived from 6-substituted aminocarbonyl and acylamino benzimidazoles.

    Science.gov (United States)

    Zhang, Jun; Wang, Jin-Liang; Yu, Wei-Fa; Zhou, Zhi-Ming; Tao, Wen-Chang; Wang, Yi-Cheng; Xue, Wei-Zhe; Xu, Di; Hao, Li-Ping; Han, Xiao-Feng; Fei, Fan; Liu, Ting; Liang, Ai-Hua

    2013-11-01

    Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT₁ receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT₁ receptor binding affinity and high AT₁ receptor selectivity over AT₂ receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT₁ IC₅₀ = 3 nM, AT₂ IC₅₀ > 10,000 nM, PA₂ = 8.51) and 11g (AT₁ IC₅₀ = 0.1 nM, AT₂ IC₅₀ = 149 nM, PA₂ = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT₁ receptor antagonists in spontaneous hypertensive rats. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Antagonist Anti-CD28 Therapeutics for the Treatment of Autoimmune Disorders

    Directory of Open Access Journals (Sweden)

    Bernard Vanhove

    2017-11-01

    Full Text Available The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.

  16. Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

    Science.gov (United States)

    Zorrilla, Eric P.; Heilig, Markus; de Wit, Harriet; Shaham, Yavin

    2013-01-01

    Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence. PMID:23294766

  17. Opioid antagonists for pharmacological treatment of gambling disorder: Are they relevant?

    Science.gov (United States)

    Victorri-Vigneau, Caroline; Spiers, Andrew; Caillet, Pascal; Bruneau, Mélanie; Challet-Bouju, Gaëlle; Grall-Bronnec, Marie

    2017-07-18

    Background: To date, no drugs have been approved for gambling disorder. Numerous publications have described the value of opioid antagonists. Indeed, the mesocorticolimbic dopaminergic pathway has been suggested as the underlying cause of reward-seeking behaviour, and it is modulated by the opioid system. Objective: This study aims to evaluate the relevance of opioid antagonists for treating GD. Method A systematic literature review was conducted. A search of the PubMed electronic database, PsycINFO and the Cochrane Systematic Review Database without any limits was performed. Results: There is little information concerning the effects of opioid antagonists on GD. The total search with "nalmefene and gambling" without any limits revealed only 11 articles. The search with "naltrexone and gambling" without any limits generated 47 articles. Nevertheless, the best available data support the use of opioid antagonists, particularly in individuals with a history of alcohol use disorder or strong gambling urges. Conclusion: Future trials are still needed. Indeed, opioid antagonists effectiveness has been investigated in only a limited number of patients, clinical trials do not reflect the heterogeneity of GD and there is little knowledge of the predictive factors of response to treatments. Moreover, differential affinity to nalmefene for kappa receptors may be associated with a particular effect in a yet to be defined addiction phenotype. Head to head comparisons between naltrexone and nalmefene would be helpful in combining with other medication or psychotherapy. The identification of subgroups of patients that are more likely to benefit from opioid antagonists should be a goal. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Isolation, identification, and biocontrol of antagonistic bacterium against Botrytis cinerea after tomato harvest

    Directory of Open Access Journals (Sweden)

    Jun-Feng Shi

    Full Text Available ABSTRACT Tomato is one of the most important vegetables in the world. Decay after harvest is a major issue in the development of tomato industry. Currently, the most effective method for controlling decay after harvest is storage of tomato at low temperature combined with usage of chemical bactericide; however, long-term usage of chemical bactericide not only causes pathogen resistance but also is harmful for human health and environment. Biocontrol method for the management of disease after tomato harvest has great practical significance. In this study, antagonistic bacterium B-6-1 strain was isolated from the surface of tomato and identified as Enterobacter cowanii based on morphological characteristics and physiological and biochemical features combined with sequence analysis of 16SrDNA and ropB gene and construction of dendrogram. Effects of different concentrations of antagonistic bacterium E. cowanii suspension on antifungal activity after tomato harvest were analyzed by mycelium growth rate method. Results revealed that antifungal activity was also enhanced with increasing concentrations of antagonistic bacterium; inhibitory rates of 1 × 105 colony-forming units (cfu/mL antagonistic bacterial solution on Fusarium verticillioides, Alternaria tenuissima, and Botrytis cinerea were 46.31%, 67.48%, and 75.67%, respectively. By using in vivo inoculation method, it was further confirmed that antagonistic bacterium could effectively inhibit the occurrence of B. cinerae after tomato harvest, biocontrol effect of 1 × 109 cfu/mL zymotic fluid reached up to 95.24%, and antagonistic bacterium E. cowanii has biocontrol potential against B. cinerea after harvest of fruits and vegetables.

  19. Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model.

    Science.gov (United States)

    Kai, Zhen-Peng; Zhu, Jing-Jing; Deng, Xi-Le; Yang, Xin-Ling; Chen, Shan-Shan

    2018-04-03

    Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C -terminal amidated octapeptide Manse-AT (6-13). We identified three residues essential for bioactivity (Thr⁴, Arg6 and Phe⁸) by assaying alanine-replacement analogs of Manse-AT (6-13). Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse-ATR) was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10-13), we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10-13) validated our hypothesis. The IC 50 value of antagonist Manse-AT (10-13) is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10-13) was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents.

  20. Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model

    Directory of Open Access Journals (Sweden)

    Zhen-Peng Kai

    2018-04-01

    Full Text Available Insect G protein coupled receptors (GPCRs have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C-terminal amidated octapeptide Manse-AT (6–13. We identified three residues essential for bioactivity (Thr4, Arg6 and Phe8 by assaying alanine-replacement analogs of Manse-AT (6–13. Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse-ATR was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10–13, we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10–13 validated our hypothesis. The IC50 value of antagonist Manse-AT (10–13 is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10–13 was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents.

  1. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  2. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2014-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  3. A marine bacterium, Micrococcus MCCB 104, antagonistic to vibrios in prawn larval rearing systems.

    Science.gov (United States)

    Jayaprakash, N S; Pai, S Somnath; Anas, A; Preetha, R; Philip, Rosamma; Singh, I S Bright

    2005-12-30

    A marine bacterium, Micrococcus MCCB 104, isolated from hatchery water, demonstrated extracellular antagonistic properties against Vibrio alginolyticus, V. parahaemolyticus, V. vulnificus, V. fluviallis, V. nereis, V. proteolyticus, V. mediterranei, V cholerae and Aeromonas sp., bacteria associated with Macrobrachium rosenbergii larval rearing systems. The isolate inhibited the growth of V. alginolyticus during co-culture. The antagonistic component of the extracellular product was heat-stable and insensitive to proteases, lipase, catalase and alpha-amylase. Micrococcus MCCB 104 was demonstrated to be non-pathogenic to M. rosenbergii larvae.

  4. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan

    2011-01-01

    and pharmacological character: (1) chemogenomic lead identification through the first, to our knowledge, ligand inference between two different GPCR families, Families A and C; and (2) the discovery of the most selective GPRC6A allosteric antagonists discovered to date. The unprecedented inference of...... pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors...

  5. Unprecedented NES non-antagonistic inhibitor for nuclear export of Rev from Sida cordifolia.

    Science.gov (United States)

    Tamura, Satoru; Kaneko, Masafumi; Shiomi, Atsushi; Yang, Guang-Ming; Yamaura, Toshiaki; Murakami, Nobutoshi

    2010-03-15

    Bioassay-guided separation from the MeOH extract of the South American medicinal plant Sida cordifolia resulted in isolation of (10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (1) as an unprecedented NES non-antagonistic inhibitor for nuclear export of Rev. This mechanism of action was established by competitive experiment by the biotinylated probe derived from leptomycin B, the known NES antagonistic inhibitor. Additionally, structure-activity relationship analysis by use of the synthesized analogs clarified cooperation of several functionalities in the Rev-export inhibitory activity of 1. Copyright 2010 Elsevier Ltd. All rights reserved.

  6. Effects of estrogen antagonists on estradiol-enhanced radiation transformation in vitro

    International Nuclear Information System (INIS)

    Umans, R.S.; Kenneddy, A.R.

    1988-01-01

    We have previously reported that radiation and 17β-estrediol can induce transformation in vitro in C3H 10T1/2 cells. In the present series of experiments, we have observed that antagonists of estrogen action, such as c-AMP activating agents(Theophylinne and dibutylc-AMP) and the antiestrogens tamoxifen, suppress radiation/17β-estradiol enhanced transformation in vitro. None of these known estrogen antagonists had a significant effect on transformation induced by radiation alone. Our results with added dibutyl c-AMP, theophylline and tamoxifen suggest that estrogen receptor complex formation may play a role in estrogen-enhanced radiation transformation in vitro (author)

  7. Transport of beta-blockers and calcium antagonists by diffusion in cat myocardium

    DEFF Research Database (Denmark)

    Haunsø, Stig; Sejrsen, Per; Svendsen, Jesper Hastrup

    1991-01-01

    Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion. In anesthet......Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion...

  8. Synthesis and evaluation of radioiodinated NPC 22009, a putative CRF receptor antagonist

    International Nuclear Information System (INIS)

    Balasubramanian, V.; Hiner, R.N.; Mavunkel, B.J.; Elliott, R.L.; Abreu, M.E.

    1992-01-01

    Several studies have suggested that corticotropin-releasing factor (CRF) plays a role in stress-related disorders such as anxiety, depression, anorexia nervosa and stress-induced immune suppression. Hence CRF antagonists have potential therapeutic utility. Recently the authors discovered that pyrazolones such as NPC 22009 and the corresponding disulfide behave as CRF antagonists in vitro with micromolar potency. To probe the nature of this CRF antagonism they developed a convenient synthesis of radioiodinated NPC 22009. Details of the synthesis and preliminary pharmacological studies are presented

  9. Data on the oral CRTh2 antagonist QAW039 (fevipiprant in patients with uncontrolled allergic asthma

    Directory of Open Access Journals (Sweden)

    Veit J. Erpenbeck

    2016-12-01

    Full Text Available This article contains data on clinical endpoints (Peak Flow Expiratory Rate, fractional exhaled nitric oxide and total IgE serum levels and plasma pharmacokinetic parameters concerning the use of the oral CRTh2 antagonist QAW039 (fevipiprant in mild to moderate asthma patients. Information on experimental design and methods on how this data was obtained is also described. Further interpretation and discussion of this data can be found in the article “The oral CRTh2 antagonist QAW039 (fevipiprant: a phase II study in uncontrolled allergic asthma” (Erpenbeck et al., in press [1].

  10. The discovery of the benzazepine class of histamine H3 receptor antagonists.

    Science.gov (United States)

    Wilson, David M; Apps, James; Bailey, Nicholas; Bamford, Mark J; Beresford, Isabel J; Briggs, Michael A; Calver, Andrew R; Crook, Barry; Davis, Robert P; Davis, Susannah; Dean, David K; Harris, Leanne; Heightman, Tom D; Panchal, Terry; Parr, Christopher A; Quashie, Nigel; Steadman, Jon G A; Schogger, Joanne; Sehmi, Sanjeet S; Stean, Tania O; Takle, Andrew K; Trail, Brenda K; White, Trevor; Witherington, Jason; Worby, Angela; Medhurst, Andrew D

    2013-12-15

    This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Antagonistic Activities of Purple Non-sulfur Bacterial Extracts Against Antibiotic Resistant Vibrio sp.

    Directory of Open Access Journals (Sweden)

    Chandrasekaran, R.

    2011-01-01

    Full Text Available Solvent extracts of native purple non-sulfur bacterial (PNSB isolates from the effluents of brackish shrimp culture ponds, near Nagapattinam coast (South India were evaluated for antibacterial activity by the disc diffusion method. Best results were shown by the chloroform extracts against oxytetracycline resistant Vibrio harveyi and Vibrio fischerii. Among the purple non-sulfur bacterial isolates, Rhodobacter sphaeroides, showed maximum antagonistic activity. The findings suggest that the antagonistic extracts from Rba. sphaeroides could be used as an effective antibiotic in controlling Vibrio spp., in aquaculture systems.

  12. AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists

    OpenAIRE

    Terry W. Moody; Nicole Tashakkori; Samuel A. Mantey; Paola Moreno; Irene Ramos-Alvarez; Marcello Leopoldo; Robert T. Jensen

    2017-01-01

    While peptide antagonists for the gastrin-releasing peptide receptor (BB2R), neuromedin B receptor (BB1R), and bombesin (BB) receptor subtype-3 (BRS-3) exist, there is a need to develop non-peptide small molecule inhibitors for all three BBR. The BB agonist (BA)1 binds with high affinity to the BB1R, BB2R, and BRS-3. In this communication, small molecule BBR antagonists were evaluated using human lung cancer cells. AM-37 and ST-36 inhibited binding to human BB1R, BB2R, and BRS-3 with similar ...

  13. Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1

    DEFF Research Database (Denmark)

    Rist, Oystein; Grimstrup, Marie; Receveur, Jean-Marie

    2009-01-01

    Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists....... Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional...

  14. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S

    1998-01-01

    Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However...... for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak...

  15. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    International Nuclear Information System (INIS)

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy; Pillai, Ayyappan Harikrishna; Harikumar, Sankaran Kutty; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

    2014-01-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

  16. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    Energy Technology Data Exchange (ETDEWEB)

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Pillai, Ayyappan Harikrishna [Division of Animal Biochemistry, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Harikumar, Sankaran Kutty; Mishra, Santosh Kumar [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Sarkar, Souvendra Nath, E-mail: snsarkar1911@rediffmail.com [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India)

    2014-11-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

  17. Silymarin and Nigella sativa extract ameliorate paracetamol induced oxidative stress and renal dysfunction in male mice

    Directory of Open Access Journals (Sweden)

    Reham Zakaria Hamza

    2015-06-01

    Full Text Available Objective: To evaluate the ameliorative role of silymarin or/and Nigella sativa (N. sativa water extract against N-acetyl-p-aminophenol (APAP-induced renal function deterioration in male mice at the biochemical levels. Methods: The mice were divided into seven groups (10/group. The first group was served as control. The second group was treated with dose of APAP. The third and fourth groups were treated with silymarin alone and N. sativa water extract alone, respectively. The fifth and sixth groups were treated with combination of APAP with silymarin and APAP with N. sativa water extract, respectively. The seventh group was treated with a combination of both ameliorative compounds (silymarin and N. sativa water extract with APAP and all animals were treated for a period of 30 days. Results: Exposure to APAP at the treated dose for mice led to an alteration of kidney function parameters, increase in the level of serum urea and creatinine. Also, paracetamol administration induced oxidative stress in kidney homogenates by increasing malondialdhyde level and decreasing superoxide dismutase and catalase activities and this stress was ameliorated by administration of either silymarin or N. sativa water extract. Conclusions: Administration of silymarin or/and N. sativa water extract to APAP-treated mice alleviate the toxicity of APAP, and this appeared clearly by biochemical improvement of kidney function parameters and antioxidant parameters. But, the alleviation is more pronounced with the both antioxidants. Thus, the pronounce effect of silymarin and N. sativa water extract is most effective in reducing the toxicity induced by APAP and improving the kidney function parameters and antioxidant status of kidney of male mice.

  18. Amelioration of Gamma-hexachlorocyclohexane (Lindane induced renal toxicity by Camellia sinensis in Wistar rats

    Directory of Open Access Journals (Sweden)

    W. L. N. V. Vara Prasad

    2016-11-01

    Full Text Available Aim: A study to assess the toxic effects of gamma-hexachlorocyclohexane (γ-HCH (lindane and ameliorative effects of Camellia sinensis on renal system has been carried out in male Wistar rats. Materials and Methods: Four groups of rats with 18 each were maintained under standard laboratory hygienic conditions and provided feed and water ad libitum. γ-HCH was gavaged at 20 mg/kg b.wt. using olive oil as vehicle to Groups II. C. sinensis at 100 mg/kg b.wt. was administered orally in distilled water to Group IV in addition to γ-HCH 20 mg/kg b.wt. up to 45 days to study ameliorative effects. Groups I and III were treated with distilled water and C. sinensis (100 mg/kg b.wt., respectively. Six rats from each group were sacrificed at fortnight intervals. Serum was collected for creatinine estimation. The kidney tissues were collected in chilled phosphate buffer saline for antioxidant profile and in also 10% buffered formalin for histopathological studies. Results: γ-HCH treatment significantly increased serum creatinine and significantly reduced the renal antioxidative enzymes catalase, superoxide dismutase, and glutathione peroxidase. Grossly, severe congestion was noticed in the kidneys. Microscopically, kidney revealed glomerular congestion, atrophy, intertubular hemorrhages, degenerative changes in tubular epithelium with vacuolated cytoplasm, desquamation of epithelium and urinary cast formation. A significant reduction in serum creatinine levels, significant improvement in renal antioxidant enzyme activities and near to normal histological appearance of kidneys in Group IV indicated that the green tea ameliorated the effects of γ-HCH, on renal toxicity. Conclusion: This study suggested that C. sinensis extract combined with γ-HCH could enhance antioxidant/detoxification system which consequently reduced the oxidative stress thus potentially reducing γ-HCH toxicity and tissue damage.

  19. CD44 antibodies and immune thrombocytopenia in the amelioration of murine inflammatory arthritis.

    Directory of Open Access Journals (Sweden)

    Patrick J Mott

    Full Text Available Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7, also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics.

  20. Human umbilical cord mesenchymal stem cells ameliorate mice trinitrobenzene sulfonic acid (TNBS)-induced colitis.

    Science.gov (United States)

    Liang, Lu; Dong, Chunlan; Chen, Xiaojun; Fang, Zhihong; Xu, Jie; Liu, Meng; Zhang, Xiaoguang; Gu, Dong Sheng; Wang, Ding; Du, Weiting; Zhu, Delin; Han, Zhong Chao

    2011-01-01

    Mesenchymal stem cells (MSCs), which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. In this study we investigated whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) could ameliorate colitis in a trinitrobenzene sulfonic acid (TNBS)-induced colitis model. TNBS-treated colitic mice were infused with hUC-MSCs or vehicle control. The mice were sacrificed on day 1, 3, and 5 after infusion, and their clinical and pathological conditions were evaluated by body weight, colon length, and histological analysis. The expression levels of proinflammatory cytokine proteins in colon were examined by ELISA. The homing of hUC-MSCs was studied by live in vivo imaging and immunofluorescent microscopy. hUC-MSCs were found to migrate to the inflamed colon and effectively treated the colitic mice with improved clinical and pathological signs. The levels of IL-17 and IL-23 as well as IFN-γ and IL-6 were significantly lower in the colon tissues of the hUC-MSC-treated mice in comparison with the vehicle-treated mice. Coculture experiments showed that hUC-MSCs not only could inhibit IFN-γ expression but also significantly inhibit IL-17 production by lamina propria mononuclear cells (LPMCs) or splenocytes of the colitic mice or by those isolated from normal animals and stimulated with IL-23. Systemically infused hUC-MSCs could home to the inflamed colon and effectively ameliorate colitis. In addition to the known suppressive effects on Th1-type immune responses, hUC-MSC-mediated modulation of IL-23/IL-17 regulated inflammatory reactions also plays an important role in the amelioration of colitis.

  1. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis.

    Science.gov (United States)

    Zhai, Mengen; Li, Buying; Duan, Weixun; Jing, Lin; Zhang, Bin; Zhang, Meng; Yu, Liming; Liu, Zhenhua; Yu, Bo; Ren, Kai; Gao, Erhe; Yang, Yang; Liang, Hongliang; Jin, Zhenxiao; Yu, Shiqiang

    2017-09-01

    Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons

  2. Exercise Ameliorates High Fat Diet Induced Cardiac Dysfunction by Increasing Interleukin 10

    Directory of Open Access Journals (Sweden)

    Varun eKesherwani

    2015-04-01

    Full Text Available Increasing evidence suggests that a sedentary lifestyle and a high fat diet (HFD leads to cardiomyopathy. Moderate exercise ameliorates cardiac dysfunction, however underlying molecular mechanisms are poorly understood. Increased inflammation due to induction of pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α and attenuation of anti-inflammatory cytokine such as interleukin10 (IL-10 contributes to cardiac dysfunction in obese and diabetics. We hypothesized that exercise training ameliorates HFD- induced cardiac dysfunction by mitigating obesity and inflammation through upregulation of IL-10 and downregulation of TNF-α. To test this hypothesis, eight week old, female C57BL/6J mice were fed with HFD and exercised (swimming 1hr/day for 5 days/week for eight weeks. The four treatment groups: normal diet (ND, HFD, HFD + exercise (HFD + Ex and ND + Ex were analyzed for mean body weight, blood glucose level, TNF-α, IL-10, cardiac fibrosis by Masson Trichrome, and cardiac dysfunction by echocardiography. Mean body weights were increased in HFD but comparatively less in HFD + Ex. The level of TNF-α was elevated and IL-10 was downregulated in HFD but ameliorated in HFD + Ex. Cardiac fibrosis increased in HFD and was attenuated by exercise in the HFD + Ex group. The percentage ejection fraction and fractional shortening were decreased in HFD but comparatively increased in HFD + Ex. There was no difference between ND and ND + Ex for the above parameters except an increase in IL-10 level following exercise. Based on these results, we conclude that exercise mitigates HFD- induced cardiomyopathy by decreasing obesity, inducing IL-10, and reducing TNF-α in mice.

  3. [Amelioration of secondary bare alkali-saline patches in Songnen Plain through inserting cornstalk].

    Science.gov (United States)

    He, Nianpeng; Wu, Ling; Jiang, Shicheng; Zhou, Daowei

    2004-06-01

    Based on the field experiment on Songnen grassland, a new method was established to ameliorate the secondary bare alkali-saline patches (SAP) through inserting cornstalk. The experiment was rested on the assumption that through inserting cornstalk in the secondary bare alkali-saline patches (SAP) to retain seeds moving over its surface, the necessary seed source could be gained; and these seeds should be able to germinate and survive successfully on the cornstalk itself or in its neighborhood, where should be more fit to grow than other sites in SAP, due to the decomposition of cornstalk and its special role, so that, the aim to restore vegetation of SAP could be achieved at a pretty low cost and rapid speed. The results showed that the seed bank in soil was increased significantly, owing to the inserted cornstalk and its operating processes. The seed number in ameliorated soil was 4020.0 +/- 1773.6 seeds x m(-2), while that in the secondary bare alkali-saline patches (SAP) was only 10.0 +/- 31.6 seeds x m(-2). Although the soil chemical and physical characters in ameliorated zone were improved to some extent, the overall situation of soil was still bad for plant growth, as the pH, soluble saline ion and organic matter were concerned. Most of Chloris virgata grew around or on the cornstalk, the plants around each cornstalk being 3.9 +/- 2.2, and the total being 48.64 +/- 38.72 g x m(-2). Therefore, this method demanded a few resources, and needed simple technology and low cost, which is potentially deserved to popularize.

  4. Resveratrol ameliorates mitochondrial dysfunction but increases the risk of hypoglycemia following hemorrhagic shock

    DEFF Research Database (Denmark)

    Widlund, Anne Lykkegaard; Wang, H.; Guan, Y.

    2014-01-01

    for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model AssessmentYInsulin Resistance index was used to quantify insulin resistance. Results: RSV supplementation following HS significantly improved mitochondrial function...... resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss. Methods: With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before.......2 mg/dL vs. 359.0 ± 79.5 mg/dL, p Model...

  5. Curcumin ameliorates skeletal muscle atrophy in type 1 diabetic mice by inhibiting protein ubiquitination.

    Science.gov (United States)

    Ono, Taisuke; Takada, Shingo; Kinugawa, Shintaro; Tsutsui, Hiroyuki

    2015-09-01

    What is the central question of this study? We sought to examine whether curcumin could ameliorate skeletal muscle atrophy in diabetic mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress. What is the main finding and its importance? We found that curcumin ameliorated skeletal muscle atrophy in streptozotocin-induced diabetic mice by inhibiting protein ubiquitination without affecting protein synthesis. This favourable effect of curcumin was possibly due to the inhibition of inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type 1 diabetes mellitus. Skeletal muscle atrophy develops in patients with diabetes mellitus (DM), especially in type 1 DM, which is associated with chronic inflammation. Curcumin, the active ingredient of turmeric, has various biological actions, including anti-inflammatory and antioxidant properties. We hypothesized that curcumin could ameliorate skeletal muscle atrophy in mice with streptozotocin-induced type 1 DM. C57BL/6 J mice were injected with streptozotocin (200 mg kg(-1) i.p.; DM group) or vehicle (control group). Each group of mice was randomly subdivided into two groups of 10 mice each and fed a diet with or without curcumin (1500 mg kg(-1) day(-1)) for 2 weeks. There were significant decreases in body weight, skeletal muscle weight and cellular cross-sectional area of the skeletal muscle in DM mice compared with control mice, and these changes were significantly attenuated in DM+Curcumin mice without affecting plasma glucose and insulin concentrations. Ubiquitination of protein was increased in skeletal muscle from DM mice and decreased in DM+Curcumin mice. Gene expressions of muscle-specific ubiquitin E3 ligase atrogin-1/MAFbx and MuRF1 were increased in DM and inhibited in DM+Curcumin mice. Moreover, nuclear factor-κB activation, concentrations of the inflammatory cytokines tumour necrosis factor-α and interleukin-1β and oxidative

  6. Ameliorating Hemorheology by Direct Hemoperfusion with a Polymyxin B-immobilized Adsorbent

    Institute of Scientific and Technical Information of China (English)

    Li Yuan; Wang Xiang; Gao Wei; Cai Shaoxi

    2004-01-01

    Direct hemoperfusion (DHP) with an adsorbent column using polymyxin B-immobilized polystyrene beads has been used to investigate the changes of hemorheology in rabbits with endotoxemia. We measured whole blood viscosity and hemotocrit before and after DHP with polymyxin B-immobilized polystyrene beads. Reduction in blood endotoxin concentration by DHP therapy positively correlated with improvement in hemorheological indexs. Our findings indicate that the amelioration in hemorheology was related directly to endotoxin removal by the adsorbent column with polymyxin B-immobilize polystyrene beads. So DHP with polymyxin B-immobilized polystyrene beads seems to be an important therapeutic strategy for endotoxemia.

  7. Amelioration of soil PAH and heavy metals by combined application of fly ash and biochar

    Science.gov (United States)

    Masto, Reginald; George, Joshy; Ansari, Md; Ram, Lal

    2016-04-01

    Generation of electricity through coal combustion produces huge quantities of fly ash. Sustainable disposal and utilization of these fly ash is a major challenge. Fly ash along with other amendments like biochar could be used for amelioration of soil. In this study, fly ash and biochar were used together for amelioration of polycyclic aromatic hydrocarbon (PAH) contaminated soil. Field experiment was conducted to investigate the effects of fly ash and biochar on the amelioration of soil PAH, and the yield of Zea mays. The treatments were control, biochar (4 t/ha), fly ash (4 t/ha), ash + biochar ( 2 + 2 t/ha). Soil samples were collected after the harvest of maize crop and analysed for chemical and biological parameters. Thirteen PAHs were analysed in the postharvest soil samples. Soil PAHs were extracted in a microwave oven at 120 °C using hexane : acetone (1:1) mixture. The extracted solutions were concentrated, cleaned and the 13 PAHs [Acenaphthene (Ace), fluorene (Flr), phenanthrene (Phn), anthracene(Ant), pyrene(Pyr), benz(a)anthracene (BaA), chrysene (Chy), benzo(b)fluoranthene (BbF), benzo(k)fluoranthene (BkF), benzo(a)pyrene, benzo(g,h,i)perylene (BghiP), dibenzo(a,h)anthracene, and indeno(1,2,3-cd)pyrene)(Inp)] were analysed using GC-MS. The mean pH increased from 6.09 in control to 6.64 and 6.58 at biochar and fly ash treated soils, respectively. N content was not affected, whereas addition of biochar alone and in combination with fly ash, has significantly increased the soil organic carbon content. P content was almost double in combined (9.06 mg/kg) treatment as compared to control (4.32 mg/kg). The increase in K due to biochar was 118%, whereas char + ash increased soil K by 64%. Soil heavy metals were decreased: Zn (-48.4%), Ni (-41.4%), Co (-36.9%), Cu (-35.7%), Mn (-34.3%), Cd (-33.2%), and Pb (-30.4%). Soil dehydrogenase activity was significantly increased by ash and biochar treatments and the maximum activity was observed for the combined

  8. Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Towards the therapeutics of cognitive impairment of schizophrenia

    Directory of Open Access Journals (Sweden)

    Takashi eUehara

    2014-09-01

    Full Text Available Rationale Augmentation therapy with serotonin-1A (5-HT1A receptor partial agonists has been suggested to improve cognitive deficits in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production.Objectives and methods The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days of tandospirone (0.05 and 5 mg/kg on brain energy metabolism, as represented by extracellular lactate concentration (eLAC in the medial prefrontal cortex (mPFC of young adult rats..Results Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot shock stress (FS. Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment.Conclusions These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism based on brain energy metabolism by which 5-HT1A agonism improve cognitive impairment in schizophrenia and related disorders.

  9. A preliminary study of the metabolic stability of a series of benzoxazinone derivatives as potent neuropeptide Y5 antagonists.

    Science.gov (United States)

    Dordal, Alberto; Lipkin, Mike; Macritchie, Jackie; Mas, Josep; Port, Adriana; Rose, Sally; Salgado, Leonardo; Savic, Vladimir; Schmidt, Wolfgang; Serafini, Maria Teresa; Spearing, William; Torrens, Antoni; Yeste, Sandra

    2005-08-15

    The metabolic stability of benzoxazinone derivatives, a potent series of NPY Y5 antagonists, has been investigated. This study resulted in the identification of the structural moieties prone to metabolic transformations and which strongly influenced the in vitro half-life. This provides opportunities to optimize the structure of this new class of NPY Y5 antagonists.

  10. Effect of antagonistic fungi against Fusarium graminearum and F. culmorum on stubble of different cereals and at different temperatures

    NARCIS (Netherlands)

    El-Naggar, M.; Haas, de B.H.; Köhl, J.

    2003-01-01

    Bioassays were carried out with antagonists to suppress sporulation by F. culmorum and F. graminearum on cereal debris. A differential effect was found for temperatures on the effect of antagonistic fungal isolates. Isolates 10 and 11 were more effective at low temperature of 5 °C, while isolate 2

  11. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR), which may compensate for diminished AR activity. The

  12. Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression

    NARCIS (Netherlands)

    Czeh, B; Pudovkina, O; van der Hart, MGC; Simon, M; Heilbronner, U; Michaelis, T; Watanabe, T; Frahm, J; Fuchs, E

    Rationale: Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds. Objectives: We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews. Methods: Animals

  13. 5-HT6 receptor antagonist attenuates the memory deficits associated with neuropathic pain and improves the efficacy of gabapentinoids.

    Science.gov (United States)

    Jayarajan, Pradeep; Nirogi, Ramakrishna; Shinde, Anil; Goura, Venkatesh; Babu, Vuyyuru Arun; Yathavakilla, Sumanth; Bhyrapuneni, Gopinadh

    2015-10-01

    Memory deficit is a co-morbid disorder in patients suffering from neuropathic pain. Gabapentin and pregabalin (gabapentinoids) are among the widely prescribed medications for the treatment of neuropathic pain. Memory loss and sedation are the commonly reported side effects with gabapentinoids. Improving the cognitive functions and attenuating drug-induced side effects may play a crucial role in the management of pain. We evaluated the effects of 5-HT6 receptor antagonists on the memory deficits associated with neuropathy. We also studied the effects of 5-HT6 receptor antagonists on the side effects, and the analgesic effects of gabapentinoids. 5-HT6 receptor antagonists attenuated the cognitive deficits in neuropathic rats. Neuropathic rats co-treated with 5-HT6 receptor antagonist and gabapentinoids showed improvement in memory. 5-HT6 receptor antagonists enhanced the analgesic effects of gabapentinoids but had no effect on the motor side effects. The observed effects may not be due to pharmacokinetic interactions. 5-HT6 receptor antagonist attenuate the cognitive deficits associated with neuropathy, and this effect is also seen when co-treated with gabapentinoids. Since, 5-HT6 antagonists improved the effectiveness of gabapentinoids, reduction in the dosage and frequency of gabapentinoids treatment may reduce the side effects. Combining 5-HT6 receptor antagonist with gabapentinoids may offer a novel treatment strategy for neuropathic pain. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  14. The effect of antagonistic micro-organisms on the brood of honeybees (Apis mellifera) and bumblebees (Bombus terrestris) 2003

    NARCIS (Netherlands)

    Steen, van der J.J.M.; Dik, A.J.

    2002-01-01

    Several plant pathogenic fungi enter the plant trough open flowers. Spores of antagonistic micro-organisms present on the flowers can successfully compete with the possible pathogens. Honeybees and bumblebees can be used for transporting these antagonistic micro-organisms from the hive into flowers

  15. Effects of combining opioids and clinically available NMDA receptor antagonists in the treatment of pain.

    NARCIS (Netherlands)

    Snijdelaar, D.G.

    2005-01-01

    This thesis concerns the effects of combining opioids with clinically available NMDA receptor antagonists in the treatment of acute and chronic pain. There are a number of problems with the use of opioids, such as, the development of tolerance/hyperalgesia, the reduced effectiveness in (central)

  16. Use of Vitamins K antagonists in non-valvular atrial fibrillation ...

    African Journals Online (AJOL)

    Introduction: atrial fibrillation is the commonest cardiac rythm disorder. Thromboembolic accidents are common complications that should be prevented by anticoagulant treatment. The aim of our study is to assess the use of vitamins K antagonists in the prevention of thromboembolic risk in atrial fibrillation. Methods: it was a ...

  17. Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules.

    Science.gov (United States)

    Mackenzie, Louise S

    2018-01-01

    Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism. Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people. This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution. © 2018 Elsevier Inc. All rights reserved.

  18. Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Petersen, Ida Nymann; Crestey, François; Jensen, Anders A

    2015-01-01

    Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers...

  19. Synthesis and pharmacological evaluation of DHβE analogs as neuronal nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Jepsen, Tue H.; Jensen, Anders A.; Lund, Mads Henrik

    2014-01-01

    Dihydro-β-erythroidine (DHβE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHβE in complex with an ACh binding protein, we detail the design, synthesis...

  20. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries

    NARCIS (Netherlands)

    L. Edvinsson (Lars); K.Y. Chan (Kayi); S. Eftekhari; E. Nilsson (Elisabeth); R. de Vries (René); H. Säveland (Hans); C.M.F. Dirven (Clemens); A.H.J. Danser (Jan)

    2010-01-01

    textabstractIntroduction: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. Materials and methods: We investigated the effect of the CGRP receptor antagonist, telcagepant, on

  1. Interaction between Ca++-channel antagonists and α2-adrenergic receptors in rabbit ileal cell membrane

    International Nuclear Information System (INIS)

    Homeidan, F.R.; Wicks, J.; Cusolito, S.; El-Sabban, M.E.; Sharp, G.W.G.; Donowitz, M.

    1986-01-01

    An interaction between Ca ++ -channel antagonists and the α 2 -adrenergic receptor on active electrolyte transport was demonstrated in rabbit ileum. Clonidine, an α 2 -agonist, stimulated NaCl absorption apparently by Ca ++ -channel antagonism since it inhibited 45 Ca ++ uptake across the basolateral membrane and decreased total ileal calcium content. This stimulation was inhibited by the Ca ++ -channel antagonists dl- and l-verapamil and cadmium but not by nifedipine. The binding of 3 H-yohimbine, a specific α 2 -adrenergic antagonist, was studied on purified ileal cell membranes using a rapid filtration technique. dl-Verapamil and Cd ++ inhibited the specific binding of 3 H-yohimbine over the same concentration range in which they affected transport. In contrast, nifedipine had no effect on binding, just as it had no effect on clonidine-stimulated NaCl absorption. These data demonstrate that there is an interaction between Ca ++ -channels and α 2 -adrenergic receptors in ileal basolateral membranes. Some Ca ++ -channel antagonists alter α 2 -adrenergic binding to the receptor and α 2 -agonist binding leads to changes in Ca ++ entry. A close spatial relationship between the Ca ++ -channel and the α 2 -receptor could explain the data

  2. Use of Non-Vitamin K Antagonist Oral Anticoagulants 2008-2016

    DEFF Research Database (Denmark)

    Haastrup, Simone; Hellfritzsch, Maja; Rasmussen, Lotte

    2018-01-01

    We aimed to provide detailed utilization data on the total use of non-vitamin K antagonist oral anticoagulants (NOACs) since their introduction in 2008. Using the nationwide Danish National Prescription Registry, we identified all individuals filling prescriptions for NOACs 2008-2016. We reported...

  3. Temporal trends in the prescription of vitamin K antagonists in patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Friberg, J; Gislason, G H; Gadsbøll, N

    2006-01-01

    OBJECTIVES: Anticoagulation therapy is recommended in patients with atrial fibrillation (AF) and risk factors for stroke. We studied the temporal trends in the prescription of vitamin K antagonists (VKA) in patients with a first hospital diagnosis of AF in Denmark, 1995-2002. DESIGN: The Danish...

  4. IL-1 Receptor Antagonist Chimeric Protein: Context-Specific and Inflammation-Restricted Activation

    NARCIS (Netherlands)

    Rider, P.; Carmi, Y.; Yossef, R.; Guttman, O.; Eini, H.; Azam, T.; Dinarello, C.A.; Lewis, E.C.

    2015-01-01

    Both IL-1alpha and IL-1beta are highly inflammatory cytokines mediating a wide spectrum of diseases. A recombinant form of the naturally occurring IL-1R antagonist (IL-1Ra), which blocks IL-1R1, is broadly used to treat autoimmune and autoinflammatory diseases; however, blocking IL-1 increases the

  5. Probable interaction between an oral vitamin K antagonist and turmeric (Curcuma longa).

    Science.gov (United States)

    Daveluy, Amélie; Géniaux, Hélène; Thibaud, Lucile; Mallaret, Michel; Miremont-Salamé, Ghada; Haramburu, Françoise

    2014-01-01

    We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects. © 2014 Société Française de Pharmacologie et de Thérapeutique.

  6. Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication

    NARCIS (Netherlands)

    Horzinek, M.C.; Egberink, H.F.; Clercq, E. de; Vliet, A.L.W. van; Balzarini, J.; Bridger, G.J.; Henson, G.; Schols, D.

    1999-01-01

    Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when

  7. Once-daily glycopyrronium bromide, a long-acting muscarinic antagonist, for chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli

    2012-01-01

    Long-acting bronchodilators are central in the pharmacological management of patients with chronic obstructive pulmonary disease (COPD). The aim of this systematic review is to provide an overview of the studies evaluating the safety and clinical efficacy of inhaled glycopyrronium bromide, a novel...... long-acting muscarinic antagonist, in patients with COPD....

  8. Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 2

    DEFF Research Database (Denmark)

    Grimstrup, Marie; Rist, Øystein; Receveur, Jean-Marie

    2010-01-01

    Structure-activity relationships have been established by exploring the eastern and western side of 5-thiazolyleacetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Benzhydryl motifs in the 2-position of the thiazole was found to be most advanta...

  9. A Time-course Study with the Androgen Receptor Antagonist Flutamide in Fish

    Science.gov (United States)

    Flutamide, a drug registered to treat some types of prostate cancer in humans, has been used for many years as a model androgen receptor (AR) antagonist in studies aimed at characterizing disruption of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis. Various studies hav...

  10. Non-vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Staerk, Laila; Fosbøl, Emil Loldrup; Gadsbøll, Kasper

    2016-01-01

    Among atrial fibrillation (AF) patients, Danish nationwide registries (2011-2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29...

  11. Bleeding and asymptomatic overdose in patients under Vitamin K antagonist therapy: Frequency and risk factors

    Directory of Open Access Journals (Sweden)

    F. Ben Mbarka

    2018-03-01

    Full Text Available Background: Vitamin K antagonists are widely used in the treatment and prevention of thromboembolic disease. However, these drugs can cause serious side effects, especially bleeding. This study aims to evaluate frequency and risk factors of both bleeding and asymptomatic overdose in North African patients undergoing Vitamin K antagonist therapy. Methods: We performed a cross-sectional study in patients undergoing Vitamin K antagonist therapy. A statistical analysis has been conducted to identify overdose and bleeding risk factors by using chi-square test (p < .05. Results: One hundred and eleven patients were included. We recorded 14 cases of bleeding and 26 cases of asymptomatic overdose. Advanced age, poor adherence, concomitant use of paracetamol and history of previous bleeding are significant risk factors of over-anticoagulation. An INR value over 6 at admission, a high therapeutic target range for INR, concomitant use of acetylsalicylic acid, lack of information on overdose signs and measures to be taken in case of bleeding were identified as risk factors for bleeding. Conclusion: Most of the risk factors identified in our study seem to be related to patients lack of information and education. These results highlight the importance of creating a therapeutic patient education program. Keywords: Vitamin K antagonist, Bleeding, Risk factor, Overdose

  12. N-Oxide analogs of WAY-100635 : new high affinity 5-HT (1A) receptor antagonists

    NARCIS (Netherlands)

    Oberwinkler - Marchais, Sandrine; Nowicki, B; Pike, VW; Halldin, C; Sandell, J; Chou, YH; Gulyas, B; Brennum, LT; Farde, L; Wikstrom, H V

    2005-01-01

    WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective

  13. Regarding the unitary theory of agonist and antagonist action at presynaptic adrenoceptors.

    Science.gov (United States)

    Kalsner, S; Abdali, S A

    2001-06-01

    1. The linkage between potentiation of field stimulation-induced noradrenaline release and blockade of the presynaptic inhibitory effect of exogenous noradrenaline by a presynaptic antagonist was examined in superfused rabbit aorta preparations. 2. Rauwolscine clearly potentiated the release of noradrenaline in response to 100 pulses at 2 Hz but reduced the capacity of noradrenaline to inhibit transmitter release to a questionable extent, and then only when comparisons were made with untreated, rather then to rauwolscine-treated, controls. 3. Aortic preparations exposed for 60 min to rauwolscine followed by superfusion with antagonist-free Krebs for 60 min retained the potentiation of stimulation-induced transmitter release but no antagonism of the noradrenaline-induced inhibition could be detected at either of two noradrenaline concentrations when comparisons were made with rauwolscine treated controls. 4. Comparisons of the inhibitory effect of exogenous noradrenaline (1.8 x 10-6 M) on transmitter efflux in the presence and absence of rauwolscine pretreatment revealed that the antagonist enhanced rather than antagonized the presynaptic inhibition by noradrenaline. 5 It is concluded that the unitary hypothesis that asserts that antagonist enhancement of transmitter release and its blockade of noradrenaline induced inhibition are manifestations of a unitary event are not supportable.

  14. GABA-B antagonist potentiates cortical epileptic afterdischarges in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel

    2005-01-01

    Roč. 46, č. S6 (2005), s. 358-358 ISSN 0013-9580. [International Epilepsy Congress /26./. 28.08.2005-01.09.2005, Paris] Institutional research plan: CEZ:AV0Z50110509 Keywords : GAGA-B antagonist * cortical afterdischarges * immature rat Subject RIV: ED - Physiology

  15. Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening

    Science.gov (United States)

    Diao, Yanyan; Jiang, Jing; Zhang, Shoude; Li, Shiliang; Shan, Lei; Huang, Jin; Zhang, Weidong; Li, Honglin

    2018-04-01

    Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 μM and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 μM), compounds 2a and 3a displayed 5-fold and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report.

  16. Preparation and Characterization of an Antibody Antagonist That Targets the Porcine Growth Hormone Receptor

    Directory of Open Access Journals (Sweden)

    Huanzhong Cui

    2016-10-01

    Full Text Available A series of antagonists specifically targeting growth hormone receptors (GHR in different species, such as humans, rats, bovines, and mice, have been designed; however, there are currently no antagonists that target the porcine growth hormone (GH. Therefore, in this study, we developed and characterized a porcine GHR (pGHR antibody antagonist (denoted by AN98 via the hybridoma technique. The results from enzyme-linked immunosorbent assay, fluorescence activated cell sorter, indirect immunoinfluscent assay, and competitive receptor binding analysis showed that AN98 could specifically recognize pGHR, and further experiments indicated that AN98 could effectively inhibit pGH-induced signalling in CHO-pGHR cells and porcine hepatocytes. In addition, AN98 also inhibited GH-induced insulin-like growth factor-1 (IGF-1 secretion in porcine hepatocytes. In summary, these findings indicated that AN98, as a pGHR-specific antagonist, has potential applications in pGH-pGHR-related research on domestic pigs.

  17. Muscle fatigue and metabolic responses following three different antagonist pre-load resistance exercises

    NARCIS (Netherlands)

    Carregaro, Rodrigo; Cunha, Rafael; Oliveira, Carlos Gomes; Brown, Lee E.; Bottaro, Martim

    2013-01-01

    Purpose: Preload of antagonist muscles can be achieved by reciprocal actions (RAs) or by opposing muscle actions. However, evidence concerning neuromuscular and fatigue responses are scarce. Objective: To compare the effects of different knee flexor (KF) preload methods on knee extension (KE) vastus

  18. Impact of peptide ghrelin antagonists on metabolic syndrome in female obese mice

    Czech Academy of Sciences Publication Activity Database

    Maletínská, Lenka; Železná, Blanka; Matyšková, Resha; Maixnerová, Jana; Pýchová, Miroslava; Špolcová, Andrea; Blechová, Miroslava; Jurcovicová, J.; Haluzník, M.

    2010-01-01

    Roč. 16, S1 (2010), s. 116-117 ISSN 1075-2617. [European Peptide Symposium /31./. 05.09.2010-09.09.2010, Copenhagen] R&D Projects: GA ČR GA303/09/0744 Institutional research plan: CEZ:AV0Z40550506 Keywords : DIO * OVX * mice * ghrelin antagonist Subject RIV: CC - Organic Chemistry

  19. Cortical epileptic afterdischarges in immature rats are differently influenced by NMDA receptor antagonists

    Czech Academy of Sciences Publication Activity Database

    Šlamberová, Romana; Mareš, Pavel

    2005-01-01

    Roč. 516, č. 1 (2005), s. 10-17 ISSN 0014-2999 R&D Projects: GA MŠk(CZ) LN00B122 Institutional research plan: CEZ:AV0Z5011922 Keywords : epileptic seizure * cerebral cortex * NMDA receptor antagonist Subject RIV: FH - Neuro logy Impact factor: 2.477, year: 2005

  20. Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide

    International Nuclear Information System (INIS)

    Saleh, M.I.M.

    1988-01-01

    The present study was undertaken in order to determine whether chronic,long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats it was of interest to determine whether PLG would modulate antagonists-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 days from birth with SCH-23390, a selective dopamine D1 antagonist; or spiroperidol, a selective dopamine D2 antagonists; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG, in combination with the other treatments. Animals were decapitated at 5, 8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of [ 3 H] SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for [ 3 H] SCH-23390 binding, and no change in the K D . Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of [ 3 H] spiroperidol to striatal homogenates by 70-80%

  1. THE USE OF GnRH ANTAGONISTS IN OVARIAN STIMULATION FOR INTRAUTERINE INSEMINATION

    Directory of Open Access Journals (Sweden)

    Mete Işıkoğlu

    2013-12-01

    Full Text Available The first paper entitled intrauterine insemination (IUI was published in 1962. By time, several methods involving the technique and the ovulation induction schedules have evolved in order to improve the success rates. Although gonadotrophin releasing hormone antagonists (GnRHa is a crucial part of assisted reproductive treatments now, concerns also arouse regarding the need for the use of it in IUI cycles. These drugs may be considered in IUI programs basically in order to prevent premature LH surges and related cycle cancellations. Although administration of a GnRH antagonist almost completely abolishes premature luteinization, it does not substantially improve the pregnancy rate. The decision of using GnRH antagonists in IUI cycles should be based primarily on the local cost/benefit analysis of individual centers. It will be prudent to limit the involvement of the antagonists in ovulation induction protocols to: patients who frequently exhibit premature LH discharges and therefore either fail to complete treatment or result in unsuccessful outcome; initiated cycles intented for IUI but converted to ART; if it is not possible for logistic reasons (weekend to perform the insemination or for medical centers in which a gynecologist on call is not available and in order to decrease clinical task burden resulting from strict cycle monitoring such as serial transvaginal sonography and/or frequent urine tests.

  2. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists

    NARCIS (Netherlands)

    de Crem, Nico; Peerlinck, Kathelijne; Vanassche, Thomas; Vanheule, Kristine; Debaveye, Barbara; Middeldorp, Saskia; Verhamme, Peter; Peetermans, Marijke

    2015-01-01

    Introduction: Rivaroxaban is a convenient oral anticoagulant for patients with venous thromboembolism (VTE). The impact of rivaroxaban and vitamin K antagonists (VKAs) on abnormal uterine bleeding (AUB) in real life has not been previously explored. Materials and methods: We performed a

  3. Antibodies to the extracellular pore loop of TRPM8 act as antagonists of channel activation.

    Directory of Open Access Journals (Sweden)

    Silke Miller

    Full Text Available The mammalian transient receptor potential melastatin channel 8 (TRPM8 is highly expressed in trigeminal and dorsal root ganglia. TRPM8 is activated by cold temperature or compounds that cause a cooling sensation, such as menthol or icilin. TRPM8 may play a role in cold hypersensitivity and hyperalgesia in various pain syndromes. Therefore, TRPM8 antagonists are pursued as therapeutics. In this study we explored the feasibility of blocking TRPM8 activation with antibodies. We report the functional characterization of a rabbit polyclonal antibody, ACC-049, directed against the third extracellular loop near the pore region of the human TRPM8 channel. ACC-049 acted as a full antagonist at recombinantly expressed human and rodent TRPM8 channels in cell based agonist-induced 45Ca2+ uptake assays. Further, several poly-and monoclonal antibodies that recognize the same region also blocked icilin activation of not only recombinantly expressed TRPM8, but also endogenous TRPM8 expressed in rat dorsal root ganglion neurons revealing the feasibility of generating monoclonal antibody antagonists. We conclude that antagonist antibodies are valuable tools to investigate TRPM8 function and may ultimately pave the way for development of therapeutic antibodies.

  4. Onset of effect of aclidinium, a novel, long-acting muscarinic antagonist, in patients with COPD

    DEFF Research Database (Denmark)

    Vestbo, Jørgen; Vogelmeier, Claus; Creemers, Jacques

    2010-01-01

    ABSTRACT Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium. This ...

  5. 4-Acylamino-and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists

    DEFF Research Database (Denmark)

    Receveur, Jean-Marie; Bjurling, Emelie; Ulven, Trond

    2004-01-01

    Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents....

  6. Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2

    DEFF Research Database (Denmark)

    Zweemer, Annelien J M; Bunnik, Julia; Veenhuizen, Margo

    2014-01-01

    be divided into two groups with most likely two topographically distinct binding sites. The aim of the current study was to identify the binding site of one such group of ligands, exemplified by three allosteric antagonists, CCR2-RA-[R], JNJ-27141491, and SD-24. We first used a chimeric CCR2/CCR5 receptor...

  7. Non-Vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Staerk, L.; Fosbøl, E L; Gadsbøll, K.

    2016-01-01

    Among atrial fibrillation (AF) patients, Danish nationwide registries (2011-2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29...

  8. Does the presence of antagonist remaining teeth affect implant overdenture success? A systematic review.

    Science.gov (United States)

    Ohkubo, C; Baek, K W

    2010-04-01

    Many patients who need implant overdentures are not completely edentulous; they still have antagonist natural teeth or implant fixed prostheses. In such cases, however, little is known about whether existing natural teeth affect the success of implant overdentures positively or act as a complicating factor. This systematic review attempts to clarify the correlation between existing remaining teeth and the survival/success rate of maxillary and mandibular implant overdentures. An assessment of available relevant articles published in English from 1990 to 2009 was performed using an online database and a manual search in libraries. Although the opposing natural dentition was not sufficiently described in the literature, 10 articles about the mandible and 10 articles about the maxilla were selected. As there was no controlled study on the natural teeth opposing implant overdentures, this review could not reach a clear conclusion. The review did reveal a remarkably high success/survival rate for mandibular implant overdentures; maxillary implant overdentures showed a lower rate. The presence of antagonist teeth hardly seems to be a risk factor for success for mandibular implant overdentures. For maxillary implant overdentures, the existence of antagonist teeth might act negatively for implant survival, but they are certainly not a contraindication. Although a few articles stated this relationship, we could not find an apparent correlation between the remaining antagonist teeth and the success of the implant overdentures. A detailed description of the opposing dentate status and results of randomized controlled clinical trials would be required to characterize this evidence-based implant overdenture treatment.

  9. GnRH-agonist versus GnRH-antagonist IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, E G; Pados, G; Grimbizis, G

    2012-01-01

    In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist...

  10. A2A Adenosine Receptor Antagonists as Therapeutic Candidates: are they still an interesting challenge?

    Science.gov (United States)

    Cacciari, Barbara; Federico, Stephanie; Spalluto, Giampiero

    2018-04-22

    In the past decades, many efforts were done to develope ligands for the adenosine receptors, with the purpose to individuate agonists and antagonists affine and selective for each subtypes , named A1, A2A, A2B, and A3. These intense studies allowed a deeper and deeper knowledge of the nature and, moreover, of the pathophysiological roles of all the adenosine receptor subtypes. In particular, the involvment of the A2A adenosine receptor subtype in some physiological mechanisms in the brain, that could be related to important diseases such as the Parkinson's disease, encouraged the research in this field. Particular attention was given to the antagonists endowed with high affinity and selectivity since they could have a real employment in the treatment of Parkinson's disease, and some compounds, such as istradefylline, preladenant and tozadenant, are already studied in clinical trials. Actually, the role of A2A antagonists in Parkinson's disease is becoming contradictory due to contrasting results in the last studies, but, at the same time, new possible employments are emerging for this class of antagonists in cancer pathologies as much interesting to legitimate further efforts in the research of A2A ligands. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. SELECTIVITY PROFILE OF SOME RECENT MUSCARINIC ANTAGONISTS IN BOVINE AND GUINEA-PIG TRACHEA AND HEART

    NARCIS (Netherlands)

    ROFFEL, AF; HAMSTRA, JJ; ELZINGA, CRS; ZAAGSMA, J

    1994-01-01

    The functional affinities of some recently developed subtype-selective muscarinic antagonists towards bovine tracheal smooth muscle muscarinic M(3) receptors were established and compared to binding affinities for bovine cardiac M(2) and functional affinities for guinea-pig tracheal smooth muscle

  12. Mouse bioassay for in vivo screening of oestrogen and progesterone antagonists

    Czech Academy of Sciences Publication Activity Database

    Škarda, Josef; Köhlerová, Eva

    2006-01-01

    Roč. 53, 3 (2006), s. 145-153 ISSN 0931-184X R&D Projects: GA ČR GA524/02/0406; GA AV ČR IBS5045302 Institutional research plan: CEZ:AV0Z50450515 Keywords : antagonists Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 0.627, year: 2006

  13. I. Effects of a Dopamine Receptor Antagonist on Fathead Minnow, Pimephales promelas ,Reproduction

    Science.gov (United States)

    This study used a 21 d fathead minnow (Pimephales promelas) reproduction assay to test the hypothesis that exposure to the dopamine 2 receptor (D2R) antagonist, haloperidol, would impair fish reproduction. Additionally, a 96 h experiment with fathead minnows and zebrafish (Danio ...

  14. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

  15. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

    NARCIS (Netherlands)

    Youssef, Mohamed A. F. M.; van der Veen, Fulco; Al-Inany, Hesham G.; Griesinger, Georg; Mochtar, Monique H.; Aboulfoutouh, Ismail; Khattab, Sherif M.; van Wely, Madelon

    2011-01-01

    Background Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is

  16. In vitro wear of four ceramic materials and human enamel on enamel antagonist.

    Science.gov (United States)

    Nakashima, Jun; Taira, Yohsuke; Sawase, Takashi

    2016-06-01

    The purpose of the present study was to evaluate the wear of four different ceramics and human enamel. The ceramics used were lithium disilicate glass (e.max Press), leucite-reinforced glass (GN-Ceram), yttria-stabilized zirconia (Aadva Zr), and feldspathic porcelain (Porcelain AAA). Hemispherical styli were fabricated with these ceramics and with tooth enamel. Flattened enamel was used for antagonistic specimens. After 100,000 wear cycles of a two-body wear test, the height and volume losses of the styli and enamel antagonists were determined. The mean and standard deviation for eight specimens were calculated and statistically analyzed using a non-parametric (Steel-Dwass) test (α = 0.05). GN-Ceram exhibited greater stylus height and volume losses than did Porcelain AAA. E.max Press, Porcelain AAA, and enamel styli showed no significant differences, and Aadva Zr exhibited the smallest stylus height and volume losses. The wear of the enamel antagonist was not significantly different among GN-Ceram, e.max Press, Porcelain AAA, and enamel styli. Aadva Zr resulted in significantly lower wear values of the enamel antagonist than did GN-Ceram, Porcelain AAA, and enamel styli. In conclusion, leucite-reinforced glass, lithium disilicate glass, and feldspathic porcelain showed wear values closer to those for human enamel than did yttria-stabilized zirconia. © 2016 Eur J Oral Sci.

  17. CHOLECYSTOKININ RECEPTOR ANTAGONIST HALTS PROGRESSION OF PANCREATIC CANCER PRECURSOR LESIONS AND FIBROSIS IN MICE

    Science.gov (United States)

    Smith, Jill P.; Cooper, Timothy K.; McGovern, Christopher O.; Gilius, Evan L.; Zhong, Qing; Liao, Jiangang; Molinolo, Alfredo A.; Gutkind, J. Silvio; Matters, Gail L.

    2014-01-01

    Objectives Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved with the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. Methods The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-KrasG12D transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK-receptor antagonist (proglumide, 0.1mg/ml). Pancreas from mice were removed and examined histologically for number and grade of PanINs after 1, 2 or 4 months of antagonist therapy. Results Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed and progression to advanced lesions arrested in mice treated with proglumide compared to controls (p=0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared to vehicle (pitalic>0.001). Conclusions These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. Use of CCK-receptor antagonists may have a role in cancer prophylaxis in high risk subjects, and may reduce fibrosis in the microenvironment. PMID:25058882

  18. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor

    DEFF Research Database (Denmark)

    Hatse, Sigrid; Princen, Katrien; De Clercq, Erik

    2005-01-01

    The chemokine receptors CCR5 and CXCR4 function as coreceptors for human immunodeficiency virus (HIV) and are attractive targets for the development of anti-HIV drugs. The most potent CXCR4 antagonists described until today are the bicyclams. The prototype compound, AMD3100, exhibits potent and s...

  19. The antagonistic activity of Trichoderma virens strain TvSUT10 ...

    African Journals Online (AJOL)

    In this current study, the beneficial filamentous fungi, Trichoderma virens, isolated from cassava field were investigated for antagonistic mode of action against Lasiodiplodia theobromae, the causal agent of cassava stem rot in Thailand. In vitro screening using the dual culture technique was undertaken to assess the ...

  20. Draft Genome Sequence of the Antagonistic Rhizosphere Bacterium Serratia plymuthica Strain PRI-2C

    NARCIS (Netherlands)

    Garbeva, P.; van Elsas, J.D.; de Boer, W.

    Serratia plymuthica strain PRI-2C is a rhizosphere bacterial strain with antagonistic activity against different plant pathogens. Here we present the 5.39-Mb (G+C content, 55.67%) draft genome sequence of S. plymuthica strain PRI-2C with the aim of providing insight into the genomic basis of its

  1. Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure

    Directory of Open Access Journals (Sweden)

    Nappi J

    2011-06-01

    Full Text Available Jean M Nappi, Adam SiegClinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, Charleston, SC, USAAbstract: Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms

  2. Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists.

    Science.gov (United States)

    Cheng, Han; Lear-Rooney, Calli M; Johansen, Lisa; Varhegyi, Elizabeth; Chen, Zheng W; Olinger, Gene G; Rong, Lijun

    2015-10-01

    Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. Infection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious

  3. Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities.

    Science.gov (United States)

    Zhang, Heng; Kang, Dongwei; Huang, Boshi; Liu, Na; Zhao, Fabao; Zhan, Peng; Liu, Xinyong

    2016-05-23

    CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Mutational analysis of the antagonist-binding site of the histamine H(1) receptor.

    Science.gov (United States)

    Wieland, K; Laak, A M; Smit, M J; Kühne, R; Timmerman, H; Leurs, R

    1999-10-15

    We combined in a previously derived three-dimensional model of the histamine H(1) receptor (Ter Laak, A. M., Timmerman, H., Leurs, H., Nederkoorn, P. H. J., Smit, M. J., and Donne-Op den Kelder, G. M. (1995) J. Comp. Aid. Mol. Design. 9, 319-330) a pharmacophore for the H(1) antagonist binding site (Ter Laak, A. M., Venhorst, J., Timmerman, H., and Donné-Op de Kelder, G. M. (1994) J. Med. Chem. 38, 3351-3360) with the known interacting amino acid residue Asp(116) (in transmembrane domain III) of the H(1) receptor and verified the predicted receptor-ligand interactions by site-directed mutagenesis. This resulted in the identification of the aromatic amino acids Trp(167), Phe(433), and Phe(436) in transmembrane domains IV and VI of the H(1) receptor as probable interaction points for the trans-aromatic ring of the H(1) antagonists. Subsequently, a specific interaction of carboxylate moieties of two therapeutically important, zwitterionic H(1) antagonists with Lys(200) in transmembrane domain V was predicted. A Lys(200) --> Ala mutation results in a 50- (acrivastine) to 8-fold (d-cetirizine) loss of affinity of these zwitterionic antagonists. In contrast, the affinities of structural analogs of acrivastine and cetirizine lacking the carboxylate group, triprolidine and meclozine, respectively, are unaffected by the Lys(200) --> Ala mutation. These data strongly suggest that Lys(200), unique for the H(1) receptor, acts as a specific anchor point for these "second generation" H(1) antagonists.

  5. Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

    Science.gov (United States)

    Tovar-Vidales, Tara; Fitzgerald, Ashley M; Clark, Abbot F

    2016-06-01

    Glaucoma patients have elevated aqueous humor and trabecular meshwork (TM) levels of transforming growth factor-beta2 (TGF-β2). TGF-β2 has been associated with increased extracellular matrix (ECM) deposition (i.e. fibronectin), which is attributed to the increased resistance of aqueous humor outflow through the TM. We have previously demonstrated that bone morphogenetic protein (BMP) 4 selectively counteracts the profibrotic effect of TGF-β2 with respect to ECM synthesis in the TM, and this action is reversed by the BMP antagonist gremlin. Thus, the BMP and TGF-β signaling pathways antagonize each other's antifibrotic and profibrotic roles. The purpose of this study was to determine whether cultured human TM cells: (a) express other BMP antagonists including noggin, chordin, BMPER, BAMBI, Smurf1 and 2, and (b) whether expression of these proteins is regulated by exogenous TGF-β2 treatment. Primary human trabecular meshwork (TM) cells were grown to confluency and treated with TGF-β2 (5 ng/ml) for 24 or 48 h in serum-free medium. Untreated cell served as controls. qPCR and Western immunoblots (WB) determined that human TM cells expressed mRNAs and proteins for the BMP antagonist proteins: noggin, chordin, BMPER, BAMBI, and Smurf1/2. Exogenous TGF-β2 decreased chordin, BMPER, BAMBI, and Smurf1 mRNA and protein expression. In contrast, TGF-β2 increased secreted noggin and Smurf2 mRNA and protein levels. BMP antagonist members are expressed in the human TM. These molecules may be involved in the normal function of the TM as well as TM pathogenesis. Altered expression of BMP antagonist members may lead to functional changes in the human TM. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Structural determinants for antagonist pharmacology that distinguish the rho1 GABAC receptor from GABAA receptors.

    Science.gov (United States)

    Zhang, Jianliang; Xue, Fenqin; Chang, Yongchang

    2008-10-01

    GABA receptor (GABAR) types C (GABACR) and A (GABAAR) are both GABA-gated chloride channels that are distinguished by their distinct competitive antagonist properties. The structural mechanism underlying these distinct properties is not well understood. In this study, using previously identified binding residues as a guide, we made individual or combined mutations of nine binding residues in the rho1 GABACR subunit to their counterparts in the alpha1beta2gamma2 GABAAR or reverse mutations in alpha1 or beta2 subunits. The mutants were expressed in Xenopus laevis oocytes and tested for sensitivities of GABA-induced currents to the GABAA and GABAC receptor antagonists. The results revealed that bicuculline insensitivity of the rho1 GABACR was mainly determined by Tyr106, Phe138 and Phe240 residues. Gabazine insensitivity of the rho1 GABACR was highly dependent on Tyr102, Tyr106, and Phe138. The sensitivity of the rho1 GABACR to 3-aminopropyl-phosphonic acid and its analog 3-aminopropyl-(methyl)phosphinic acid mainly depended on residues Tyr102, Val140, FYS240-242, and Phe138. Thus, the residues Tyr102, Tyr106, Phe138, and Phe240 in the rho1 GABACR are major determinants for its antagonist properties distinct from those in the GABAAR. In addition, Val140 in the GABACR contributes to 3-APA binding. In conclusion, we have identified the key structural elements underlying distinct antagonist properties for the GABACR. The mechanistic insights were further extended and discussed in the context of antagonists docking to the homology models of GABAA or GABAC receptors.

  7. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    Science.gov (United States)

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  8. Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists.

    Science.gov (United States)

    Zloh, Mire; Perez-Diaz, Noelia; Tang, Leslie; Patel, Pryank; Mackenzie, Louise S

    2016-02-01

    Long term use of NSAIDs is linked to side effects such as gastric bleeding and myocardial infarction. Use of in silico methods and pharmacology to investigate the potential for NSAIDs diclofenac, celecoxib and naproxen to bind to nuclear receptors. In silico screening predicted that both diclofenac and celecoxib has the potential to bind to a number of different nuclear receptors; docking analysis confirmed a theoretical ability for diclofenac and celecoxib but not naproxen to bind to TRβ. Results from TRβ luciferase reporter assays confirmed that both diclofenac and celecoxib display TRβ antagonistic properties; celecoxib, IC50 3.6 × 10(-6)M, and diclofenac IC50 5.3 × 10(-6)M, comparable to the TRβ antagonist MLS (IC50 3.1 × 10(-6)M). In contrast naproxen, a cardio-sparing NSAID, lacked TRβ antagonist effects. In order to determine the effects of NSAIDs in whole organ in vitro, we used isometric wire myography to measure the changes to Triiodothyronine (T3) induced vasodilation of rat mesenteric arteries. Incubation of arteries in the presence of the TRβ antagonist MLS000389544 (10(-5)M), as well as diclofenac (10(-5)M) and celecoxib (10(-5)M) but not naproxen significantly inhibited T3 induced vasodilation compared to controls. These results highlight the benefits of computational chemistry methods used to retrospectively analyse well known drugs for side effects. Using in silico and in vitro methods we have shown that both celecoxib and diclofenac but not naproxen exhibit off-target TRβ antagonist behaviour, which may be linked to their detrimental side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    International Nuclear Information System (INIS)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Erchegyi, Judit; Rivier, Jean E.

    2010-01-01

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst 1 -sst 5 ) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst 2 and sst 3 internalization in vitro in HEK293 cells stably expressing the human sst 2 or sst 3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst 2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst 3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst 3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  10. Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders.

    Science.gov (United States)

    Contoreggi, Carlo; Rice, Kenner C; Chrousos, George

    2004-01-01

    Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in 'somatic' disorders. Some rare forms of Cushing's disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of

  11. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour.

    Science.gov (United States)

    Papatsonis, Dimitri N M; Flenady, Vicki; Liley, Helen G

    2013-10-13

    In some women, an episode of preterm labour settles and does not result in immediate preterm birth. Subsequent treatment with tocolytic agents such as oxytocin receptor antagonists may then have the potential to prevent the recurrence of preterm labour, prolonging gestation, and preventing the adverse consequences of prematurity for the infant. To assess the effects of maintenance therapy with oxytocin antagonists administered by any route after an episode of preterm labour in order to delay or prevent preterm birth. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2013), sought ongoing and unpublished trials by contacting experts in the field and searched the reference lists of relevant articles. Randomised controlled trials comparing oxytocin antagonists with any alternative tocolytic agent, placebo or no treatment, used for maintenance therapy after an episode of preterm labour. We used the standard methods of The Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group. Two review authors independently undertook evaluation of methodological quality and extracted trial data. This review includes one trial of 513 women. When compared with placebo, atosiban did not reduce preterm birth before 37 weeks (risk ratio (RR) 0.89; 95% confidence intervals (CI) 0.71 to 1.12), 32 weeks (RR 0.85; 95% CI 0.47 to 1.55), or 28 weeks (RR 0.75; 95% CI 0.28 to 2.01). No difference was shown in neonatal morbidity, or perinatal mortality. There is insufficient evidence to support the use of oxytocin receptor antagonists to inhibit preterm birth after a period of threatened or actual preterm labour. Any future trials using oxytocin antagonists or other drugs as maintenance therapy for preventing preterm birth should examine a variety of important infant outcome measures, including reduction of neonatal morbidity and mortality, and long-term infant follow-up. Future research should also focus on the pathophysiological pathways that

  12. Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

    Science.gov (United States)

    Lowe, Jeovanna; Floyd, Kyle T; Rastogi, Neha; Schultz, Eric J; Chadwick, Jessica A; Swager, Sarah A; Zins, Jonathan G; Kadakia, Feni K; Smart, Suzanne; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E; Raman, Subha V; Janssen, Paul M L; Rafael-Fortney, Jill A

    2016-01-01

    Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

  13. Ameliorative Activity of Ethanolic Extract of Artocarpus heterophyllus Stem Bark on Alloxan-induced Diabetic Rats.

    Science.gov (United States)

    Ajiboye, Basiru Olaitan; Adeleke Ojo, Oluwafemi; Adeyonu, Oluwatosin; Imiere, Oluwatosin; Emmanuel Oyinloye, Babatunji; Ogunmodede, Oluwafemi

    2018-03-01

    Purpose: Diabetes mellitus is one of the major endocrine disorders, characterized by impaired insulin action and deficiency. Traditionally, Artocarpus heterophyllus stem bark has been reputably used in the management of diabetes mellitus and its complications. The present study evaluates the ameliorative activity of ethanol extract of Artocarpus heterophyllus stem bark in alloxan-induced diabetic rats. Methods: Diabetes mellitus was induced by single intraperitoneal injection of 150 mg/kg body weight of alloxan and the animals were orally administered with 50, 100 and 150 mg/kg body weight ethanol extract of Artocarpus heterophyllus stem bark once daily for 21 days. Results: At the end of the intervention, diabetic control rats showed significant (pArtocarpus heterophyllus stem bark most especially at 150 mg/kg body weight which exhibited no significant (p>0.05) different with non-diabetic rats. Conclusion: The results suggest that ethanol extract of Artocarpus heterophyllus stem bark may be useful in ameliorating complications associated with diabetes mellitus patients.

  14. Pathological Effects of Aflatoxin and Their Amelioration by Vitamin E in White Leghorn Layers

    Directory of Open Access Journals (Sweden)

    Wajid A Khan, M Zargham Khan*, Ahrar Khan and Iftikhar Hussain1

    2010-07-01

    Full Text Available White Leghorn layer breeder hens, 30 weeks of age, were divided into 12 groups (A-L. Group A was kept on basal feed and served as control, while group B was offered feed supplemented with vitamin E (100 mg/Kg. Groups C-G were offered feed containing 100, 500, 2,500, 5,000 and 10,000 µg/Kg aflatoxin B1 (AFB1, respectively, whereas groups H-L were offered same dietary levels of AFB1 along with vitamin E (100 mg/Kg. The experimental feeds were offered for three weeks and afterward all the groups were switched over to basal feed for next two weeks. Body weight, absolute and relative weights of liver and kidneys of AF fed birds were significantly higher than control group. Pathological lesions in aflatoxin (AF fed birds included enlarged, pale and friable liver, swollen kidneys and hemorrhages on different organs. Histopathological lesions in liver included fatty change, congestion and hemorrhages, while in kidneys tubular necrosis, cellular infiltration, congestion and hemorrhages were found in groups fed AFB1 at 500 μg/Kg and higher doses. In AF fed hens, no significant ameliorative effects of vitamin E could be observed upon AF induced decrease in feed intake, gross pathology and histopathological alterations and organ weight except body weights. It was concluded that the vitamin E ameliorated the AFB1 induced toxic effects in some of parameters studied.

  15. STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia.

    Science.gov (United States)

    Jiang, Xuechao; Zha, Bingbing; Liu, Xiaoming; Liu, Ronghua; Liu, Jun; Huang, Enyu; Qian, Tingting; Liu, Jiajing; Wang, Zhiming; Zhang, Dan; Wang, Luman; Chu, Yiwei

    2016-12-01

    Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD.

  16. Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats

    Directory of Open Access Journals (Sweden)

    GURPREET KAUR

    2015-03-01

    Full Text Available The present study was designed to investigate the ameliorative potential of Ocimumsanctum and its saponin rich fraction in chronic constriction injury-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, proximal to its trifurcation. The mechanical hyperalgesia, cold allodynia, paw heat hyperalgesia and cold tail hyperalgesia were assessed by performing the pinprick, acetone, hot plate and cold tail immersion tests, respectively. Biochemically, the tissue thio-barbituric acid reactive species, super-oxide anion content (markers of oxidative stress and total calcium levels were measured. Chronic constriction injury was associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia along with an increase in oxidative stress and calcium levels. However, administration of Ocimumsanctum (100 and 200 mg/kg p.o. and its saponin rich fraction (100 and 200 mg/kg p.o. for 14 days significantly attenuated chronic constriction injury-induced neuropathic pain as well as decrease the oxidative stress and calcium levels. It may be concluded that saponin rich fraction of Ocimum sanctum has ameliorative potential in attenuating painful neuropathic state, which may be attributed to a decrease in oxidative stress and calcium levels.

  17. Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition.

    Science.gov (United States)

    Yang, Chao-Qiang; Xu, Jing-Hua; Yan, Dan-Dan; Liu, Bao-Lin; Liu, Kang; Huang, Fang

    2017-09-01

    Adipose tissue hypoxia has been recognized as the initiation of insulin resistance syndromes. The aim of the present study was to investigate the effects of mangiferin on the insulin signaling pathway and explore whether mangiferin could ameliorate insulin resistance caused by hypoxia in adipose tissue. Differentiated 3T3-L1 adipocytes were incubated under normal and hypoxic conditions, respectively. Protein expressions were analyzed by Western blotting. Inflammatory cytokines and HIF-1-dependent genes were tested by ELISA and q-PCR, respectively. The glucose uptake was detected by fluorescence microscopy. HIF-1α was abundantly expressed during 8 h of hypoxic incubation. Inflammatory reaction was activated by up-regulated NF-κB phosphorylation and released cytokines like IL-6 and TNF-α. Glucose uptake was inhibited and insulin signaling pathway was damaged as well. Mangiferin substantially inhibited the expression of HIF-1α. Lactate acid and lipolysis, products released by glycometabolism and lipolysis, were also inhibited. The expression of inflammatory cytokines was significantly reduced and the damaged insulin signaling pathway was restored to proper functional level. The glucose uptake of hypoxic adipocytes was promoted and the dysfunction of adipocytes was relieved. These results showed that mangiferin could not only improve the damaged insulin signaling pathway in hypoxic adipocytes, but also ameliorate inflammatory reaction and insulin resistance caused by hypoxia. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  18. Plumbagin, a vitamin K3 analogue ameliorate malaria pathogenesis by inhibiting oxidative stress and inflammation.

    Science.gov (United States)

    Gupta, Amit Chand; Mohanty, Shilpa; Saxena, Archana; Maurya, Anil Kumar; Bawankule, Dnyaneshwar U

    2018-03-22

    Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

  19. Rikkunshito Ameliorates Cancer Cachexia Partly through Elevation of Glucarate in Plasma

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    Katsuya Ohbuchi

    2015-01-01

    Full Text Available Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient’s morbidity and mortality. We previously showed that rikkunshito (RKT, a Japanese traditional herbal medicine (Kampo, ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma.

  20. Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

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    Géraldine H Petit

    Full Text Available Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.