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Sample records for antagonist induce sensitization

  1. Cocaine-Induced Behavioral Sensitization in Mice: Effects of Microinjection of Dopamine D2 Receptor Antagonist into the Nucleus Accumbens

    Science.gov (United States)

    Jung, Eun-Sol; Lee, Hyo Jin; Sim, Hye-Ri

    2013-01-01

    To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R-/- mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R-/-) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R-/- mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization. PMID:24167417

  2. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

    Science.gov (United States)

    Shekhar, Tanmay M.; Miles, Mark A.; Gupte, Ankita; Taylor, Scott; Tascone, Brianna; Walkley, Carl R.; Hawkins, Christine J.

    2016-01-01

    Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors. PMID:27129149

  3. Prolonged Survival in a Case of Chemotherapy-Sensitive Gastric Cancer That Produced Alpha-Fetoprotein and Protein Induced by Vitamin K Antagonist-II

    OpenAIRE

    Ogasawara, Naotaka; Takahashi, Emiko; Matsumoto, Tomoko; Amaike, Manami; Nohara, Mako; Nagao, Kazuhiro; Ebi, Masahide; Funaki, Yasushi; Sasaki, Makoto; Kasugai, Kunio

    2015-01-01

    The number of reported cases of alpha-fetoprotein (AFP)-producing gastric cancer has gradually increased, with a reported prevalence of 1.3–1.5% of all gastric cancer cases. However, reports of gastric cancer accompanied by elevated serum levels of both AFP and protein induced by vitamin K antagonist-II (PIVKA-II) are rare. The prognosis of AFP- and PIVKA-II-producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential an...

  4. Prolonged Survival in a Case of Chemotherapy-Sensitive Gastric Cancer That Produced Alpha-Fetoprotein and Protein Induced by Vitamin K Antagonist-II

    Directory of Open Access Journals (Sweden)

    Naotaka Ogasawara

    2015-04-01

    Full Text Available The number of reported cases of alpha-fetoprotein (AFP-producing gastric cancer has gradually increased, with a reported prevalence of 1.3-1.5% of all gastric cancer cases. However, reports of gastric cancer accompanied by elevated serum levels of both AFP and protein induced by vitamin K antagonist-II (PIVKA-II are rare. The prognosis of AFP- and PIVKA-II-producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential and the cancer progressed rapidly. We described a case of gastric cancer producing AFP and PIVKA-II in which chemotherapy was effective and resulted in prolonged survival, and these two tumor markers were useful for monitoring the treatment response. Routine health screening using upper abdominal ultrasonography revealed hepatic tumors in an apparently healthy 65-year-old man. Whole-body computed tomography (CT revealed multiple hepatic tumors, and an esophagogastroduodenoscopy (EGD revealed a Bormann type 3 tumor in the lower stomach. A biopsy specimen confirmed that the tumor was immunohistochemically positive for AFP, PIVKA-II, and human epidermal growth factor receptor 2. After chemotherapy, the gastric tumor appeared as a small elevated lesion on EGD, and CT revealed a remarkable reduction in the size of the metastatic liver tumors. The patient is still alive, 35 months after the initial chemotherapy.

  5. Prolonged Survival in a Case of Chemotherapy-Sensitive Gastric Cancer That Produced Alpha-Fetoprotein and Protein Induced by Vitamin K Antagonist-II.

    Science.gov (United States)

    Ogasawara, Naotaka; Takahashi, Emiko; Matsumoto, Tomoko; Amaike, Manami; Nohara, Mako; Nagao, Kazuhiro; Ebi, Masahide; Funaki, Yasushi; Sasaki, Makoto; Kasugai, Kunio

    2015-01-01

    The number of reported cases of alpha-fetoprotein (AFP)-producing gastric cancer has gradually increased, with a reported prevalence of 1.3-1.5% of all gastric cancer cases. However, reports of gastric cancer accompanied by elevated serum levels of both AFP and protein induced by vitamin K antagonist-II (PIVKA-II) are rare. The prognosis of AFP- and PIVKA-II-producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential and the cancer progressed rapidly. We described a case of gastric cancer producing AFP and PIVKA-II in which chemotherapy was effective and resulted in prolonged survival, and these two tumor markers were useful for monitoring the treatment response. Routine health screening using upper abdominal ultrasonography revealed hepatic tumors in an apparently healthy 65-year-old man. Whole-body computed tomography (CT) revealed multiple hepatic tumors, and an esophagogastroduodenoscopy (EGD) revealed a Bormann type 3 tumor in the lower stomach. A biopsy specimen confirmed that the tumor was immunohistochemically positive for AFP, PIVKA-II, and human epidermal growth factor receptor 2. After chemotherapy, the gastric tumor appeared as a small elevated lesion on EGD, and CT revealed a remarkable reduction in the size of the metastatic liver tumors. The patient is still alive, 35 months after the initial chemotherapy. PMID:26034473

  6. Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers.

    Science.gov (United States)

    Alcaro, Maria C; Vinci, Valerio; D'Ursi, Anna M; Scrima, Mario; Chelli, Mario; Giuliani, Sandro; Meini, Stefania; Di Giacomo, Marcello; Colombo, Lino; Papini, Anna Maria

    2006-05-01

    Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers. PMID:16504505

  7. Behavioral sensitization to apomorphine in pigeons (Columba livia) : blockade by the D₁ dopamine antagonist SCH-23390

    OpenAIRE

    Acerbo, Martin J.; Delius, Juan

    2004-01-01

    Repeated administration of apomorphine leads to a context-dependent pecking response sensitization. Previously sensitized pigeons (Columba livia) challenged with saline in the same context show a conditioned response (CR). The authors studied the effects of intrastriatal injections of the dopamine (D₁) antagonist SCH-23390 on both the sensitized response and the CR. When coadministered with apomorphine, SCH-23390 inhibited the initial response to apomorphine, prevented the development of sens...

  8. In vitro sensitivity of antagonistic Trichoderma atroviride to herbicides

    OpenAIRE

    Patricia Helena Santoro; Silvia Akimi Cavaguchi; Talita Moretto Alexandre; Janaina Zorzetti; Pedro Manuel Oliveira Janeiro Neves

    2014-01-01

    Trichoderma atroviride was tested in vitro for its sensitivity to different herbicides. The dosages tested were recommended dosage (RD), half dosage (½RD), and double dosage (2RD). Germination, colony-forming units (CFU), radial growth, and spore production were evaluated. Carfentrazone-ethyl and sulfentrazone inhibited the germination at RD and 2RD. A reduction in the CFU was observed for glufosinate-ammonium, atrazine, carfentrazone-ethyl, diuron + paraquat dichloride, imazapyr, oxyfluorfen...

  9. In vitro sensitivity of antagonistic Trichoderma atroviride to herbicides

    Directory of Open Access Journals (Sweden)

    Patricia Helena Santoro

    2014-04-01

    Full Text Available Trichoderma atroviride was tested in vitro for its sensitivity to different herbicides. The dosages tested were recommended dosage (RD, half dosage (½RD, and double dosage (2RD. Germination, colony-forming units (CFU, radial growth, and spore production were evaluated. Carfentrazone-ethyl and sulfentrazone inhibited the germination at RD and 2RD. A reduction in the CFU was observed for glufosinate-ammonium, atrazine, carfentrazone-ethyl, diuron + paraquat dichloride, imazapyr, oxyfluorfen, and sulfentrazone at each of the tested dosages. Radial growth was influenced by ametryn, atrazine, carfentrazone-ethyl, oxyfluorfen, and sulfentrazone herbicides, with an 80% reduction of the colonial area. Spore production was affected by carfentrazone-ethyl, oxyfluorfen, and sulfentrazone with colonial area reductions of over 70%. It was concluded that 2,4 D, clomazone, and imazapyr herbicides showed the least toxicity to T. atroviride and should be used in the crops where the fungus has been applied for phytopathogen control.

  10. AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels

    International Nuclear Information System (INIS)

    In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing

  11. A representative retinoid X receptor antagonist UVI3003 induced teratogenesis in zebrafish embryos.

    Science.gov (United States)

    Zheng, Liang; Xu, Ting; Li, Daoji; Zhou, Junliang

    2015-03-01

    Retinoid X receptor (RXR) interfering activity has been detected in different water resources. To study RXR disruptor-induced toxicological effects on vertebrates, embryos of zebrafish (Danio rerio) were exposed to a representative RXR antagonist UVI3003. Results showed that the teratogenic index (LC50 /EC50 ) of UVI3003 was as high as 5.4. UVI3003 induced multiple malformations of embryos, including deformed fins, reduced brains, small jaws, bent tails and edema in hearts, the degree of which became more severe with increasing exposure concentration. Although no significant difference was observed in the hatching rates between the exposure group and control, the whole body length was significantly reduced by 6.5% and 8.9% when exposed to 200 and 300 µg l(-1) of UVI3003, respectively. The heart rate also significantly decreased by 8.8-50.2% during exposure. Further experiments revealed that the pharyngula stage was the most sensitive development phase in terms of embryo response to UVI3003. The results demonstrated severe teratogenicity of RXR antagonist in zebrafish embryos and provided important data for ecotoxicological evaluation of RXR antagonists. PMID:25186191

  12. Medium-Induced Antagonistic Behavior in Staphylococcus Aureus.

    Science.gov (United States)

    Benathen, Isaiah A.

    1992-01-01

    Antagonism is the production of substances by microorganisms that inhibit or prevent the growth of other bacteria. This paper demonstrates the antagonistic behavior of gram-positive coccus on the B. subtilis and Enterococcus faecalis gram-positive microorganisms, showing that the process of antagonism is sometimes dependent on the nutritional…

  13. Rapid tolerance against focal cerebral ischemia induced by isoflurane anesthesia is attenuated by adenosine A1 receptor antagonist in rats

    Institute of Scientific and Technical Information of China (English)

    刘艳红; 熊利泽

    2003-01-01

    The brief anesthesia with isoflurane induces rapid tolerance against focal cerebral ischemia in rats and adenosine A1 receptor antagonist, DPCPX, attenuates the beneficial effect of isoflurane preconditioning.

  14. Cardiac β 2-adrenoceptor sensitization by chronic β1-selective antagonist treatment in patients with essential hypertension

    Institute of Scientific and Technical Information of China (English)

    Peng Yingxin; Qi Xiaoyong; Xue Hao; Zhang Jianqing; Ma Shuping

    2002-01-01

    Objective:It has been hypothesized that with drawal of treatment with β 1-selective antagonist leads to increased sensitivity of β - adrenoceptor stimulation with isoproterenol.Several studies in vitro have shown that cardiac β 2- adrenoceptor was sensitized by β 1-selective antagonist treatment in patients with coronary heart disease.Therefore,the object of the present study was to explore in vivo to demonstrate that the cardiac β 2- adrenoceptor is sensitized in patients with essential hypertension by the chronic β 1-selective antagonis. Methods: β - adrenoceptor in peripheral lymphocytes was assessed by 3H-dihydyoalprenolol(3H-DHA) radio ligand binding. β - adrenaleptor responsiveness was measured by sulbtamol( β 2-selective agonist) in male patients with essential hypertension after β 1-selective antagonist treatment for at least 4 months (twenty cases)and.with drugs other than β 1-antagonist for at least 4 months(twenty cases).Results:In patients with β 1-selective antagonist treatment and those with non- β -antagonist treatment the maximal number of binding sites( β max)in peripheral lymphocytes was not significantly different(528+104fmol/107cell v s.571±98fmol/107cell ,P>0.05) In β 1-selective antagonist treatment group the chronotropic dose of sulbtamol(in) required to increase heart rate by 30beats/min.(CD30) was significantly lower than that in non - β -antagonist treatment group(1.8±0.3 μ g/kg v s.2.7±0.2 μ g/kg,P<0.001).The maximal fall of diastolic pressure(0.96±0.50kPa v s.0.91±0.42kPa) were not significatn changed(P>0.05) after sulbtamol injection. Conclusion:The treatment with β 1-selective antagonist led to sensitization of β 2-adrenoceptor function,while no change in β 2- adrenoceptors density in peripheral lymphocytes in vivo in patients with essential hypertension,the dissociation between function and density of cardiac β 2- adrenoceptors may partially explain the mechanism of β -antagonist withdrawal syndrome.

  15. Pathological gambling induced by dopamine antagonists: a case report.

    Science.gov (United States)

    Grötsch, Philipp; Lange, Claudia; Wiesbeck, Gerhard A; Lang, Undine

    2015-03-01

    Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.

  16. 5-Hydroxytryptamine antagonists and the 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions.

    Science.gov (United States)

    Archer, T

    1987-01-01

    The ability of various compounds to antagonise the 5-MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5-hydroxytryptamine (5-HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5-MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5-HT antagonists for blocking 5-MeODMT changes of PDCs was roughly of the order mianserin greater than cinanserin greater than methysergide greater than methergoline. Pirenperone, the 5-HT2 antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5-MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5-2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5-MeODMT induced changes of PDCs are mediated via 5-HT1 receptors and thus a reliable model to combine with other measures of spinal function is suggested. PMID:3562388

  17. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists

    NARCIS (Netherlands)

    Meijer, W.M.; Walle, H.E.K.de; Kerstjens-Frederikse, W.S; de Jong-van den Berg, Lolkje Theodora Wilhelmina

    2005-01-01

    Since the protective effect of folic acid (FA) on birth defects is well known, it is reasonable to assume intrauterine exposure to FA antagonists increases the risk on these defects. We have therefore performed case-control analyses to investigate the risk of intrauterine exposure to FA antagonists,

  18. Dynamics of Antagonistic Potency of Rhodobacter capsulatus PG Lipopolysaccharide against Endotoxin-Induced Effects.

    Science.gov (United States)

    Kabanov, D S; Serov, D A; Zubova, S V; Grachev, S V; Prokhorenko, I R

    2016-03-01

    The dynamics of antagonistic potency of lipopolysaccharide (LPS) isolated from Rhodobacter capsulatus PG on the synthesis of proinflammatory (TNF-α, IL-1β, IL-8, IL-6, IFN-γ) and antiinflammatory (IL-10, IL-1Ra) cytokines induced by highly stimulatory endotoxins from Escherichia coli or Salmonella enterica have been studied. Using human whole blood, we have shown that R. capsulatus PG LPS inhibited most pronouncedly the endotoxin-induced synthesis of TNF-α, IL-1β, IL-8, and IL-6 during the first 6 h after endotoxin challenge. Similarly, the endotoxin-induced release of IFN-γ was abolished by R. capsulatus PG LPS as well (24 h). In contrast to the above-mentioned cytokines, the relatively weak antagonistic activity of R. capsulatus PG LPS against endotoxin-triggered production of IL-6 and IL-8 was revealed. Since R. capsulatus PG LPS displays more potent antagonistic activity against deleterious effects of S. enterica LPS than those of E. coli LPS in the cases of such cytokines as IL-1β (6 and 24 h), IL-6 and IL-8 (4 h), we conclude that the effectiveness of protective action of antagonist is mostly determined by the primary lipid A structure of the employed agonist.

  19. Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep.

    Science.gov (United States)

    Padmanabhan, Vasantha; Veiga-Lopez, Almudena; Herkimer, Carol; Abi Salloum, Bachir; Moeller, Jacob; Beckett, Evan; Sreedharan, Rohit

    2015-07-01

    Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30-90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level. PMID:25919188

  20. Antagonistic Coevolution Drives Whack-a-Mole Sensitivity in Gene Regulatory Networks.

    Directory of Open Access Journals (Sweden)

    Jeewoen Shin

    2015-10-01

    Full Text Available Robustness, defined as tolerance to perturbations such as mutations and environmental fluctuations, is pervasive in biological systems. However, robustness often coexists with its counterpart, evolvability--the ability of perturbations to generate new phenotypes. Previous models of gene regulatory network evolution have shown that robustness evolves under stabilizing selection, but it is unclear how robustness and evolvability will emerge in common coevolutionary scenarios. We consider a two-species model of coevolution involving one host and one parasite population. By using two interacting species, key model parameters that determine the fitness landscapes become emergent properties of the model, avoiding the need to impose these parameters externally. In our study, parasites are modeled on species such as cuckoos where mimicry of the host phenotype confers high fitness to the parasite but lower fitness to the host. Here, frequent phenotype changes are favored as each population continually adapts to the other population. Sensitivity evolves at the network level such that point mutations can induce large phenotype changes. Crucially, the sensitive points of the network are broadly distributed throughout the network and continually relocate. Each time sensitive points in the network are mutated, new ones appear to take their place. We have therefore named this phenomenon "whack-a-mole" sensitivity, after a popular fun park game. We predict that this type of sensitivity will evolve under conditions of strong directional selection, an observation that helps interpret existing experimental evidence, for example, during the emergence of bacterial antibiotic resistance.

  1. Antagonists of sensory neuropeptides inhibit the secondary phase of increased circulation following thermally induced inflammation.

    Science.gov (United States)

    Löfgren, O; Qi, Y; Lundeberg, T; Gazelius, B

    1998-11-01

    A model of thermally induced inflammation in the anesthetized rat was used to measure acute microcirculatory reactions after heat exposure. The thermal injury was inflicted by dipping the right hindpaw into hot water at 60 degrees for 20 s. Local blood flow was recorded simultaneously in both hindpaws and continuously by laser Doppler flowmetry before, during and for 2 h after the thermal injury and the mean arterial blood pressure (MAP) was displayed on a chart recorder. To assess the contribution of the nervous system to the vascular changes seen, neuropeptide antagonists directed toward substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) were administered. The neurokinin antagonists (NK1, NK2) and the CGRP antagonist (CGRP8-37) were injected via a catheter into the jugular vein. During the first few minutes after thermal injury to the controls, an immediate increase in blood perfusion of about 351% was recorded, followed by a slow decrease of circulation. At 30 min after thermal injury, there was a secondary phase of increased microcirculation of approximately 329%. A slow decline of cutaneous circulation then followed and, after another 30 min, the value stabilized at a level about 100% above the level before injury. Pretreatment with intravenous injections of the NK1 antagonist, NK2 antagonist, and CGRP8-37 attenuated the first phase and almost abolished the secondary phase. No significant change of perfusion was observed on the unscalded paw. The MAP remained at a stable level throughout the experiment and was not affected by the thermal injury or by the administration of the antagonists as compared to controls. Our results show that sensory neuropeptides play a significant role in the blood flow increase seen following thermal injury. PMID:9828161

  2. CGP 35348, a new GABAB antagonist, prevents antinociception and muscle-relaxant effect induced by baclofen.

    OpenAIRE

    Malcangio, M.; Ghelardini, C.; Giotti, A.; Malmberg-Aiello, P.; Bartolini, A.

    1991-01-01

    1. CGP 35348, a new GABAB antagonist, was examined on antinociception induced by (+/-)-baclofen by use of the hot plate and writhing tests in mice and the paw pressure test in rats. CGP 35348 was also studied in mice on (+/-)-baclofen-induced impairment of rota-rod performance. 2. CGP 35348, injected either i.p. (60-100 mg kg-1 in mouse) or intracerebroventricularly (i.c.v.) (0.5-2.5 micrograms per mouse; 25 micrograms per rat) prevented (+/-)-baclofen-induced antinociception. 3. CGP 35348 di...

  3. Studies of the voltage-sensitive calcium channels in smooth muscle, neuronal, and cardiac tissues using 1,4-dihydropyridine calcium channel antagonists and activators

    International Nuclear Information System (INIS)

    This study describes the investigation of the voltage-sensitive Ca+ channels in vascular and intestinal smooth muscle, chick neural retina cells and neonatal rat cardiac myocytes using 1,4-dihydropyridine Ca2+ channel antagonists and activators. In rat aorta, the tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) produced Ca2+-dependent contractile responses. The responses to TPA were blocked by the Ca2+ channel antagonists. The effects of the enantiomers of Bay K 8644 and 202-791 were characterized in both rat tail artery and guinea pig ileal longitudinal smooth muscle preparations using pharmacologic and radioligand binding assays. The (S)-enantiomers induced contraction and potentiated the responses to K+ depolarization. The (R)-enantiomers inhibited the tension responses to K+. All the enantiomers inhibited specific [3H]nitrendipine binding. The pharmacologic activities of both activator and antagonist ligands correlated on a 1:1 basis with the binding affinities. In chick neural retina cells the (S)-enantiomers of Bay K 8644 and 202-791 enhanced Ca2+ influx. In contrast, the (R)-enantiomers inhibited Ca2+ influx. The enantiomers of Bay K 8644 and 202-791 inhibited specific [3H]PN 200-110 binding competitively. Binding of 1,4-dihydropyridines was characterized in neonatal rat heart cells

  4. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth

    DEFF Research Database (Denmark)

    Greenberger, Lee M; Horak, Ivan D; Filpula, David;

    2008-01-01

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in angiogenesis, survival, metastasis, drug resistance, and glucose metabolism. Elevated expression of the alpha-subunit of HIF-1 (HIF-1alpha), which occurs in response to hypoxia or activation of growth factor...... pathways, is associated with poor prognosis in many types of cancer. Therefore, down-regulation of HIF-1alpha protein by RNA antagonists may control cancer growth. EZN-2968 is a RNA antagonist composed of third-generation oligonucleotide, locked nucleic acid, technology that specifically binds and inhibits...... the expression of HIF-1alpha mRNA. In vitro, in human prostate (15PC3, PC3, and DU145) and glioblastoma (U373) cells, EZN-2968 induced a potent, selective, and durable antagonism of HIF-1 mRNA and protein expression (IC(50), 1-5 nmol/L) under normoxic and hypoxic conditions associated with inhibition of tumor...

  5. Performance of Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) for Hepatocellular Carcinoma Screening in Chinese Population

    OpenAIRE

    Yu, Rentao; Ding, Shitao; Tan, Wenting; Tan, Shun; Tan, Zhaoxia; Xiang, Shiqing; Zhou, Yi; Mao, Qing; Deng, Guohong

    2015-01-01

    Background: Alpha-fetoprotein (AFP) has long been used as an effective biomarker for hepatocellular carcinoma (HCC) screening; however, not all HCC patients can be detected with an elevated AFP level, especially in early HCC patients. Protein Induced by vitamin K absence or antagonist-II (PIVKA-II) is another serum biomarker linked to HCC; however, sensitivity and specificity remain controversial and data in Chinese groups is even rarer. Objectives: To evaluate the performance of PIVKA-II alo...

  6. Postoperative changes in protein-induced vitamin K absence or antagonist II levels after hepatectomy in patients with hepatocellular carcinoma: relationship to prognosis

    OpenAIRE

    Nanashima, A.; Sumida, Y.; Tobinaga, S.; Shibata, K.; Shindo, H; Obatake, M.; Shibasaki, S.; Ide, N.; Nagayasu, Takeshi

    2006-01-01

    Background. α-Fetoprotein (AFP) has been used as a marker for hepatocellular carcinoma (HCC). However, AFP levels are often high in patients with chronic hepatitis or cirrhosis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is more sensitive for the diagnosis of HCC and prediction of patient survival. Changes in these markers after treatment may reflect treatment curability and patient outcome. Methods. We conducted a retrospective analysis of prognosis of 63 HCC patients with...

  7. Effects of oral cetirizine, a selective H1 antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma.

    LENUS (Irish Health Repository)

    Gong, H

    1990-03-01

    The protective efficacy of oral cetirizine, a selective and potent H1-receptor antagonist, against the immediate bronchoconstrictive response to allergen inhalation and exercise challenge was evaluated in 16 subjects with stable, predominantly mild asthma. The subjects underwent double-blind, crossover pretreatments in randomized order in two separate protocols with (1) three daily oral doses of 20 mg of cetirizine and placebo, followed by allergen inhalation, and (2) single oral doses of cetirizine (5, 10, and 20 mg), albuterol (4 mg), and placebo, followed by exercise with cold-air inhalation. Cetirizine failed to decrease bronchial sensitivity to inhaled allergen in eight of 10 subjects. Neither cetirizine nor albuterol uniformly inhibited exercise-induced bronchoconstriction. Serum concentrations of cetirizine were consistent with systemic H1-blocking activity. Modest bronchodilation occurred after administration of cetirizine and albuterol before exercise but not after the third dose of cetirizine in the allergen protocol. One subject developed moderate drowsiness during multiple dosing with cetirizine. Thus, cetirizine, in the doses studied, is not uniformly effective in preventing allergen- or exercise-induced bronchoconstriction. Histamine is one of many mediators participating in immediate asthmatic responses, and selective H1 antagonists do not completely block these airway events. However, cetirizine may still clinically benefit some patients with asthma, such as patients with allergic rhinitis or urticaria.

  8. Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide

    International Nuclear Information System (INIS)

    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 [3H] SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for [3H] SCH-23390 binding, and no change in the KD. Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of [3H] spiroperidol to striatal homogenates by 70-80%

  9. Reduction of sodium deoxycholic acid-induced scratching behaviour by bradykinin B2 receptor antagonists

    OpenAIRE

    Hayashi, Izumi; Majima, Masataka

    1999-01-01

    Subcutaneous injection of sodium deoxycholic acid into the anterior of the back of male ddY mice elicited dose-dependent scratching of the injected site with the forepaws and hindpaws.Up to 100 μg of sodium deoxycholic acid induced no significant increase in vascular permeability at the injection site as assessed by a dye leakage method.Bradykinin (BK) B2 receptor antagonists, FR173657 and Hoe140, significantly decreased the frequency of scratching induced by sodium deoxycholic acid.Treatment...

  10. Behavioral consequences of NMDA antagonist-induced neuroapoptosis in the infant mouse brain.

    Directory of Open Access Journals (Sweden)

    Carla M Yuede

    Full Text Available BACKGROUND: Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP, or saline, on postnatal day 2 (P2 or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7. CONCLUSIONS: These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathological and neurobehavioral consequences than a single treatment.

  11. PROTECTIVE EFFECTS OF CALCIUM ANTAGONIST ON VASCULAR SYSTEM AGAINST TOXICITY INDUCED BY MERCURIC CHLORIDE

    Institute of Scientific and Technical Information of China (English)

    马欣; 厉英倩; 白宇飞; 刘明

    2004-01-01

    Objective To explore the toxic effects of mercuric chloride (HgCl2) on vascular smooth muscle as well as its relationship to calcium antagonist. Methods By using isolated vascular tension methods, we studied the effect of HgCl2 on isolated rabbit aortic rings. Results HgCl2 (1-100μmol*L-1) caused a concentration-dependent contraction of rabbit aortic rings, which did not change with phentolamin or without endothelium. In KH solution with Ca2+ , the maximum contraction amplitude reduced by(61.2±3.3)%. Nifedipine produced a concentration-dependent decrease of the maximum contraction amplitude. Conclusion Calcium antagonist has protective effects on vascular smooth muscle against damage induced by HgCl2.

  12. Protein induced by vitamin K absence or antagonist II-producing gastric cancer

    OpenAIRE

    Takahashi, Yoshihisa; Inoue, Tohru; Fukusato, Toshio

    2010-01-01

    Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a putative specific marker of hepatocellular carcinoma (HCC), but it may also be produced by a small number of gastric cancers. To date, 16 cases of PIVKA-II-producing gastric cancer have been reported, 2 of which were reported by us and all of which were identified in Japan. There are no symptoms specific to PIVKA-II-producing gastric cancer, and the representative clinical symptoms are general fatigue, appetite loss, and up...

  13. THE MUSCARINIC ANTAGONIST SCOPOLAMINE ATTENUATES CHLORPYRIFOS INDUCED HYPOTHERMIA IN THE DEVELOPING RAT.

    Science.gov (United States)

    Chlorpyrifos (CHP), an anticholinesterase organophosphate (OP) pesticide, induces acute hypothermia in adult and developing rats. Previously we demonstrated that thermoregulation in preweanling pups is markedly more sensitive to the neurotoxic effects of CHP than in adults. The c...

  14. Characterization of mechanisms involved in presynaptic inhibition of sympathetic pressor effects induced by some 5-HT1 receptor antagonists.

    Science.gov (United States)

    Fernández, M M; Calama, E; Morán, A; Martín, M L; San Román, L

    2000-01-01

    1. In a previous study, we showed that the presynaptic inhibitory action of 5-hydroxytryptamine receptor agonists on sympathetic pressor effects obtained in the pithed rats were mainly mediated by activation of 5-HT1A and 5-HT1D receptor subtypes. At the time, we observed that some 5-HT1 receptors antagonists - WAY 100,635 and NAN-190 (both 5-HT1A receptor antagonists), methiothepin (a 5-HT1,2,5,6,7 receptor antagonist) and spiperone (a 5-HT1,2 receptor antagonist) - reduced per se the pressor effects obtained by electrical stimulation. The aim of the present work was to investigate the mechanism participating in this inhibitory effect. 2. The inhibition induced by WAY 100,635 (1000 microg kg-1, i.v.) was blocked after i.v. treatment with idazoxan, an alpha2-adrenoceptor antagonist (300 and 1000 microg kg-1) and was not modified after i.v. treatment with propranolol, a beta-adrenoceptor antagonist (1000 microg kg-1) and sulpiride, a D2 receptor antagonist (1000 microg kg-1). The inhibition induced by spiperone (500 microg kg-1 i.v.) was significantly blocked by sulpiride (1000 microg kg-1) and was not modified by idazoxan or propranolol. 3. Sulpiride (1000 microg kg-1) partially blocked the inhibition induced by methiothepin (50 microg kg-1 i.v.). Only pretreatment with idazoxan (300 microg kg-1) modified the inhibition induced by NAN-190 (100 microg kg-1 i.v.), such inhibition increasing after intravenous administration of idazoxan. 4. All the antagonists used in our experiments failed to inhibit the pressor responses elicited by i.v. noradrenaline administration. 5. The above results suggest that the inhibitory effects of these 5-HT1 receptor antagonists are presynaptic in nature, but not related to the blockade of 5-HT1 receptors subtypes. The simultaneous activation or inhibition of other receptor systems could explain the inhibition produced by each 5-HT1 receptor antagonist studied.

  15. Mediastinal Yolk Sac Tumor Producing Protein Induced by Vitamin K Absence or Antagonist-II.

    Science.gov (United States)

    Akutsu, Noriyuki; Adachi, Yasushi; Isosaka, Mai; Mita, Hiroaki; Takagi, Hideyasu; Sasaki, Shigeru; Yamamoto, Hiroyuki; Arimura, Yoshiaki; Ishii, Yoshifumi; Masumori, Naoya; Endo, Takao; Shinomura, Yasuhisa

    2015-01-01

    Extragonadal yolk sac tumors (YSTs) are rare. We herein report the case of a 66-year-old man with mediastinal, lung and liver tumors. The largest mass was located in the liver and contained a high concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein. Therefore, the lesion was difficult to distinguish from hepatocellular carcinoma. Finally, YST was diagnosed based on the results of a liver biopsy. Although chemotherapy was effective, the patient died of respiratory failure. The autopsy revealed primary mediastinal YST. In the current report, we describe this case of PIVKA-II-producing YST and review previous cases of PIVKA-II-producing tumors other than hepatoma.

  16. Mediastinal Yolk Sac Tumor Producing Protein Induced by Vitamin K Absence or Antagonist-II.

    Science.gov (United States)

    Akutsu, Noriyuki; Adachi, Yasushi; Isosaka, Mai; Mita, Hiroaki; Takagi, Hideyasu; Sasaki, Shigeru; Yamamoto, Hiroyuki; Arimura, Yoshiaki; Ishii, Yoshifumi; Masumori, Naoya; Endo, Takao; Shinomura, Yasuhisa

    2015-01-01

    Extragonadal yolk sac tumors (YSTs) are rare. We herein report the case of a 66-year-old man with mediastinal, lung and liver tumors. The largest mass was located in the liver and contained a high concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein. Therefore, the lesion was difficult to distinguish from hepatocellular carcinoma. Finally, YST was diagnosed based on the results of a liver biopsy. Although chemotherapy was effective, the patient died of respiratory failure. The autopsy revealed primary mediastinal YST. In the current report, we describe this case of PIVKA-II-producing YST and review previous cases of PIVKA-II-producing tumors other than hepatoma. PMID:26073245

  17. Effect of a D3 receptor antagonist on context-induced reinstatement of nicotine seeking.

    Science.gov (United States)

    Sabioni, Pamela; Di Ciano, Patricia; Le Foll, Bernard

    2016-01-01

    Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7 days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation. PMID:26279138

  18. Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance.

    Science.gov (United States)

    Li, Qian

    2012-12-01

    Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance.

  19. An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony-stimulating factor production and early endotoxin tolerance.

    OpenAIRE

    Henricson, B E; Neta, R; Vogel, S N

    1991-01-01

    In this report, administration of a recombinant interleukin-1 receptor antagonist protein to mice was found to inhibit induction of colony-stimulating factor as well as induction of early endotoxin tolerance by lipopolysaccharide. These findings provide direct evidence that interleukin-1 is an intermediate in these two lipopolysaccharide-induced phenomena.

  20. Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate.

    Directory of Open Access Journals (Sweden)

    Galen W Heyne

    Full Text Available The Hedgehog (Hh signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE, clefts of the lip with or without cleft palate (CL/P, and clefts of the secondary palate only (CPO. Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in "non-syndromic" orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.

  1. Definition of Critical Periods for Hedgehog Pathway Antagonist-Induced Holoprosencephaly, Cleft Lip, and Cleft Palate

    Science.gov (United States)

    Heyne, Galen W.; Melberg, Cal G.; Doroodchi, Padydeh; Parins, Kia F.; Kietzman, Henry W.; Everson, Joshua L.; Ansen-Wilson, Lydia J.; Lipinski, Robert J.

    2015-01-01

    The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in “non-syndromic” orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug. PMID:25793997

  2. Administration of orexin receptor 1 antagonist into the rostral ventromedial medulla increased swim stress-induced antinociception in rat

    OpenAIRE

    Neda Soliemani; Alireza Moslem; Ali Shamsizadeh; Hassan Azhdari-Zarmehri

    2016-01-01

    Objective(s): Intracerebroventricular injection of orexin-A (hypocretin-1) antagonist has been shown to inhibit stress-induced analgesia. However the locations of central sites that may mediate these effects have not been totally demonstrated. This study was performed to investigate the role of rostral ventromedial medulla (RVM) orexin receptor 1 in stress-induced analgesia (SIA). Materials and Methods: Forced swim stress in water was employed to adult male rats (200-250 g). Nociceptive respo...

  3. Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Kanakeswary Karisnan

    Full Text Available Chorioamnionitis (inflammation of the fetal membranes is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA lipopolysaccharide (LPS is orchestrated via interleukin 1 (IL-1. We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra (Anakinra; 100 mg or saline (Sal 3 h prior to second IA injections of LPS (4 mg or Sal at 119d gestational age (GA. Preterm lambs were killed after delivery at 121d GA (term = 150 d. Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group was 25% lower than in control lambs (Sal/Sal group; p=0.025. LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.

  4. Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

    International Nuclear Information System (INIS)

    Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p 2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p 2-IsoPs, F4-NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.

  5. Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency.

    Science.gov (United States)

    Zhang, Yu; Gu, Ming; Cai, Wujie; Yu, Lijing; Feng, Li; Zhang, Lu; Zang, Qingqing; Wang, Yahui; Wang, Dongshan; Chen, Hui; Tong, Qingchun; Ji, Guang; Huang, Cheng

    2016-01-01

    Studies on peroxisome proliferator-activated receptor (PPAR)-γ ligands have been focused on agonists. However, PPARγ activation may induce obesity and nonalcoholic fatty liver disease (NAFLD), one of the most challenging medical conditions. Here, we identified that isorhamnetin, a naturally occurring compound in fruits and vegetables and the metabolite of quercetin, is a novel antagonist of PPARγ. Isorhamnetin treatment inhibited the adipocyte differentiation induced by the PPARγ agonist rosiglitazone, reduced obesity development and ameliorated hepatic steatosis induced by both high-fat diet treatment and leptin deficiency. Our results suggest that dietary supplement of isorhamnetin may be beneficial to prevent obesity and steatosis and PPARγ antagonists may be useful to treat hepatic steatosis. PMID:26775807

  6. The depressor response to intracerebroventricular hypotonic saline is sensitive to TRPV4 antagonist RN1734

    Directory of Open Access Journals (Sweden)

    Claire H Feetham

    2015-04-01

    Full Text Available Several reports have shown that the periventricular region of the brain, including the paraventricular nucleus (PVN, is critical to sensing and responding to changes in plasma osmolality. Further studies also implicate the transient receptor potential ion channel, type V4 (TRPV4 channel in this homeostatic behaviour. In previous work we have shown that TRPV4 ion channels couple to calcium-activated potassium channels in the PVN to decrease action potential firing frequency in response to hypotonicity. In the present study we investigated whether, similarly, intracerebroventricular (ICV application of hypotonic solutions modulated cardiovascular parameters, and if so whether this was sensitive to a TRPV4 channel inhibitor. We found that ICV injection of 270mOsmol artificial cerebrospinal fluid (ACSF decreased mean blood pressure, but not heart rate, compared to naïve mice or mice injected with 300mOsmol ACSF. This effect was abolished by treatment with the TRPV4 inhibitor RN1734. These data suggest that periventricular targets within the brain are capable of generating depressor action in response to TRPV4 ion channel activation. Potentially, in the future, the TRPV4 channel, or the TRPV4–KCa coupling mechanism, may serve as a therapeutic target for treatment of cardiovascular disease.

  7. The novel non-imidazole histamine H3 receptor antagonist DL77 reduces voluntary alcohol intake and ethanol-induced conditioned place preference in mice.

    Science.gov (United States)

    Bahi, Amine; Sadek, Bassem; Nurulain, Syed M; Łażewska, Dorota; Kieć-Kononowicz, Katarzyna

    2015-11-01

    It has become clear that histamine H3 receptors (H3R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H3R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 of 2.1 ± 0.2 mg/kg and pKi=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H3R antagonist, DL77 (0, 3, 10 and 30 mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10 mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H1R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H3R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism.

  8. Sensitivity of four Yeasts to Fungicides and CO2 Concentrations and Their Antagonistic Ability in Combination with Fungicide to pathogenic Fungi in vitro

    Institute of Scientific and Technical Information of China (English)

    TIAN Shi-ping; YAO Hong-jie; QIN Guo-zheng; XU Yong; FENG Xiao-yuan

    2004-01-01

    The yeasts Cryptococcus laurentii,Trichosporon pullulans,Rhodotorula glutinis and Trichosporon sp.were used to investigate their sensitivity to four fungicides and different concentrations of CO2,as well as their antagonistic ability to Penicilliumexpansum and Alternaria alternata in vitro when applied with fungicide.There were significant differences in sensitivity to the fungicides among the different yeasts(P = 0.05).R.glutinis was more sensitive to Deccocil,Iprodione and Stroby as compared to other yeasts.Combination antagonistic yeasts with fungicide could more significantly enhance biocontrol ability of the yeasts against the pathogenic fungi in vitro(P = 0.05).C.laurentii was the most effective antagonist among the four yeasts and could completely control spore germination of P.expansum and A.alternata when combined with Stroby at the concentration of 100 μL L-1.The yeasts,except R.glutinis,could grow well on nutrient yeast dextrose agar (NYDA) after 8 d incubation even at 20% CO2 concentration at 25℃.Particularly Trichosporon sp.showeda better adaptability to low temperature as compared to other antagonists.

  9. LSD1 and HY5 Antagonistically Regulate Red Light induced-Programmed Cell Death in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Tingting eChai

    2015-05-01

    Full Text Available Programmed cell death (PCD in plant is triggered by abiotic and biotic stress. Light-dependent PCD is unique to plants. Light-induced PCD also requires reactive oxygen species (ROS and salicylic acid (SA. In this study, lesion simulating disease1 (LSD1 and elongated hypocotyl 5 (HY5 perform opposite roles to regulate excess red light (RL-triggered PCD associated with ROS and SA production. Under RL, the lsd1 mutant released more ROS and SA and displayed a stronger cell death rate than the hy5 mutant. It was shown that active LSD1 converted into inactive form by changing the redox status of the plastoquinone pool, and HY5 interacted with phytochrome B (phyB to promote PCD in response to RL. LSD1 inhibited the enhanced disease susceptibility 1 (EDS1 expression by upregulating SR1, whereas HY5 enhanced the enhanced EDS1 expression by binding to the G-box of the EDS1 promoter. This study suggested that LSD1 and HY5 antagonistically modulated EDS1-dependent ROS and SA signaling; thus, PCD was mediated in response to RL.

  10. LSD1 and HY5 antagonistically regulate red light induced-programmed cell death in Arabidopsis.

    Science.gov (United States)

    Chai, Tingting; Zhou, Jun; Liu, Jian; Xing, Da

    2015-01-01

    Programmed cell death (PCD) in plant is triggered by abiotic and biotic stress. Light-dependent PCD is unique to plants. Light-induced PCD also requires reactive oxygen species (ROS) and salicylic acid (SA). In this study, lesion simulating disease1 (LSD1) and elongated hypocotyl 5 (HY5) perform opposite roles to regulate excess red light (RL)-triggered PCD associated with ROS and SA production. Under RL, the lsd1 mutant released more ROS and SA and displayed a stronger cell death rate than the hy5 mutant. It was shown that active LSD1 converted into inactive form by changing the redox status of the plastoquinone pool, and HY5 interacted with phytochrome B (phyB) to promote PCD in response to RL. LSD1 inhibited the enhanced disease susceptibility 1 (EDS1) expression by upregulating SR1, whereas HY5 enhanced the enhanced EDS1 expression by binding to the G-box of the EDS1 promoter. This study suggested that LSD1 and HY5 antagonistically modulated EDS1-dependent ROS and SA signaling; thus, PCD was mediated in response to RL.

  11. The calcineurin antagonist RCAN1-4 is induced by exhaustive exercise in rat skeletal muscle.

    Science.gov (United States)

    Emrani, Ramin; Rébillard, Amélie; Lefeuvre, Luz; Gratas-Delamarche, Arlette; Davies, Kelvin J A; Cillard, Josiane

    2015-10-01

    The aim of this work was to study the regulation of the calcineurin antagonist regulator of calcineurin 1 (RCAN1) in rat skeletal muscles after exhaustive physical exercise, which is a physiological modulator of oxidative stress. Three skeletal muscles, namely extensor digitorum longus (EDL), gastrocnemius, and soleus, were investigated. Exhaustive exercise increased RCAN1-4 protein levels in EDL and gastrocnemius, but not in soleus. Protein oxidation as an index of oxidative stress was increased in EDL and gastrocnemius, but remained unchanged in soleus. However, lipid peroxidation was increased in all three muscles. CuZnSOD and catalase protein levels were increased at 3 h postexercise in soleus, whereas they remained unchanged in EDL and gastrocnemius. Calcineurin enzymatic activity declined in EDL and gastrocnemius but not in soleus, and its protein expression was decreased in all three muscles. The level of PGC1-α protein remained unchanged, whereas the protein expression of the transcription factor NFATc4 was decreased in all three muscles. Adiponectin expression was increased in all three muscles. RCAN1-4 expression in EDL and gastrocnemius muscles was augmented by the oxidative stress generated from exhaustive exercise. We propose that increased RCAN1-4 expression and the signal transduction pathways it regulates represent important components of the physiological adaptation to exercise-induced oxidative stress. PMID:26122706

  12. Effect of two human growth hormone receptor antagonists on glomerulosclerosis in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Wei LI; Shui-xian SHEN; Li-hua ZHU; En-bi WANG; Zeng-can YE; Jun LIN; Li-he GUO; Fei-hong LUO; Xi-hong LIU; Xin FANG

    2004-01-01

    AIM: To explore the feasibility of human growth hormone (hGH) receptor antagonist in the treatment of end-stage diabetic renal complications. METHODS: Two hGH mutants, hGHA1 (Cys-hGH-dell-4, G120R, K168A, E174A,C182S, de1186-191) and hGHA2 (hGH-H21A, G120R, E174A) were expressed in E coli. The IC50 (Mean±SD)values for the mutants for inhibiting 125I-hGH binding to rabbit growth hormone receptor were (65±10) ng for hGHA1, (27±5.6) ng for hGHA2, and (10±0.6) ng for wild type hGH, respectively. RESULTS: After treatment for 12 weeks, the renal histology analysis showed that treatment with hGHA2 at 4 mg/kg body weight daily markedly suppressed glomerulosclerosis in streptozotocin-induced diabetic Sprague-Dawley (SD) rats; hGHA1 at the same dosage slightly increased the renal damage compared with saline; while wild type hGH at 1 U/kg body weight daily severely worsened the glomerulo-sclerosis in diabetic SD rats. CONCLUSION: The data indicated that hGHA2 inhibited the end-stage glomerulosclerosis in diabetic rats, but hGHA1 mildly increased the glomerulosclerosis.

  13. Exercise-induced bronchoconstriction: The effects of montelukast, a leukotriene receptor antagonist

    Directory of Open Access Journals (Sweden)

    James P Kemp

    2009-11-01

    Full Text Available James P KempClinical Professor of Pediatrics, Division of Immunology and Allergy, University of California School of Medicine, San Diego, CA, USAAbstract: Exercise-induced bronchoconstriction (EIB is very common in both patients with asthma and those who are otherwise thought to be normal. The intensity of exercise as well as the type of exercise is important in producing symptoms. This may make some types of exercise such as swimming more suitable and extended running more difficult for patients with this condition. A better understanding of EIB will allow the physician to direct the patient towards a type of exercise and medications that can result in a more active lifestyle without the same concern for resulting symptoms. This is especially important for schoolchildren who are usually enrolled in physical education classes and elite athletes who may desire to participate in competitive sports. Fortunately several medications (short- and long-acting β2-agonists, cromolyn, nedocromil, inhaled corticosteroids, and more recently leukotriene modifiers have been shown to be effective in preventing or attenuating the effects of exercise in many patients. In addition, inhaled β2-agonists have been shown to quickly reverse the airway obstruction that develops in patients and continue to be the reliever medications of choice. Inhaled corticosteroids are increasingly being recommended as regular therapy now that the role of inflammation and airway injury has been identified in EIB. With the discovery that there is a release of mediators such as histamine and leukotrienes from cells in the airway following exercise with resulting airway obstruction in susceptible individuals, interest has turned to attenuating their effects with mediator antagonists especially those that block the effects of leukotrienes. Studies with an oral leukotriene antagonist, montelukast, have shown beneficial effects in adults and children aged as young as 6 years with EIB

  14. H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice.

    Science.gov (United States)

    Dudek, Magdalena; Kuder, Kamil; Kołaczkowski, Marcin; Olczyk, Adrian; Żmudzka, Elżbieta; Rak, Aleksandra; Bednarski, Marek; Pytka, Karolina; Sapa, Jacek; Kieć-Kononowicz, Katarzyna

    2016-10-01

    The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H1receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant - H3 histamine antagonist - on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia. Forced swim test was conducted to determinate depressive-like effect of olanzapine and antidepressive-like activity during the co-administered pitolisant. The test was performed after the first and fifteenth day of the treatment of the mice. The spontaneous activity of the mice was measured on the fourteenth day of the treatment with a special, innovative RFID-system (Radio-frequency identification system) - TraffiCage (TSE-Systems, Germany). Triglyceride levels were determined on the sixteenth day of the experiment after 15 cycles of drug administration. Daily olanzapine treatment (4 mg/kg b.w., i.p., d.p.d) for 15 days significantly induces sedation (p < 0.05) and prolongs immobility time in forced swim tests (FST) in mice (p < 0.05); and also elevates the level of triglycerides (p < 0.05). Administration of pitolisant (10 mg/kg b.w., i.p.) subsequentto olanzapine normalizes these adverse effects. This study presents a promising alternative for counteracting some behavioral changes and metabolic disturbances which occur in the early period of treatment with antipsychotic drugs. PMID:27216278

  15. Therapeutic effect of the NMDA antagonist MK-801 on low-level laser induced retinal injury

    Science.gov (United States)

    Yan, W.-H.; Wu, J.; Chen, P.; Dou, J.-T.; Pan, C.-Y.; Mu, Y.-M.; Lu, J.-M.

    2009-03-01

    The aim of this article was to explore the mechanism of injury in rat retina after constant low-level helium-neon (He-Ne) laser exposure and therapeutic effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, on laser-induced retinal injury. He-Ne laser lesions were created in the central retina of adult Wistar Kyoto rats and were followed immediately by intraperitoneal injection of MK-801 (2 mg/kg) or saline, macroscopical and microscopical lesion were observed by funduscope and light microscope. Ultrastructural changes of the degenerating cells were examined by electron microscopy. Photoreceptor apoptosis was evaluated by TdT-mediated dUTP nick end-labeling (TUNEL). mRNA levels were measured by in situ hybridization and NMDA receptor expression was determined by immunohistochemistry. Laser induced damage was histologically quantified by image-analysis morphometry. Electroretinograms (ERGs) were recorded at different time point after the cessation of exposure to constant irradiation. There was no visible bleeding, exudation or necrosis under funduscope. TUNEL and electron microscopy showed photoreceptor apoptosis after irradiation. MK-801-treated animals had significantly fewer TUNEL-positive cells in the photoreceptors than saline-treated animals after exposure to laser. In situ hybridization (ISH) showed that the NMDAR mRNA level of MK-801-treated rats decreased in the inner plexiform layer 6 h after the cessation of exposure to constant irradiation when compared with that of saline-treated rats. So did Immunohistochemistry (IHC). Electroretinogram showed that b-wave amplitudes of MK-801-treated group were higher than that of saline-treated group after laser exposure. These findings suggest that Low level laser may cause the retinal pathological changes under given conditions. High expression of NMDAR is one of the possible mechanisms causing experimental retinal laser injury of rats. MK-801 exhibits the therapeutic effect due to promote the

  16. INTRACEREBROVENTRICULAR APPLICATION OF COMPETITIVE AND NONCOMPETITIVE NMDA ANTAGONISTS INDUCE SIMILAR EFFECTS UPON RAT HIPPOCAMPAL ELECTROENCEPHALOGRAM AND LOCAL CEREBRAL GLUCOSE-UTILIZATION

    NARCIS (Netherlands)

    BODDEKE, HWGM; WIEDERHOLD, KH; PALACIOS, JM

    1992-01-01

    In this study we have used electrophysiological and metabolic markers to investigate the effects of competitive and non-competitive NMDA antagonists in rats after central or peripheral administration. The non-competitive antagonist, MK-801, induced dose-dependent suppression of rat hippocampal EEG e

  17. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.

    Science.gov (United States)

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques

    2015-03-18

    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  18. Therapeutic effects of TNF-α antagonist etanercept and methotrexate on antigen-induced arthritis of the temporomandibular joint

    OpenAIRE

    Rafayelyan, Smbat

    2015-01-01

    Background: Juvenile idiopathic arthritis (JIA) of the temporomandibular joint (TMJ) can cause severe growth disturbances of the craniomandibular system. Antigen-induced arthritis (AIA) of the rabbit TMJ is simulating the inflammatory process of the TMJ in JIA. In the first two studies of the present thesis the effect of a systemic administration of the tumor necrosis factor-alpha (TNF-α) antagonist etanercept and methotrexate (MTX) on AIA in young rabbits should be investigate...

  19. 5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

    OpenAIRE

    Archer, T.; Danysz, W; Jonsson, G.; Minor, B. G.; Post, C

    1986-01-01

    The effects of the alpha-adrenoceptor antagonists prazosin, phentolamine and yohimbine upon 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced analgesia were tested in the hot-plate, tail-flick and shock-titration tests of nociception with rats. Intrathecally injected yohimbine and phentolamine blocked or attenuated the analgesia produced by systemic administration of 5-MeODMT in all three nociceptive tests. Intrathecally administered prazosin attenuated the analgesic effects of 5-MeODMT in ...

  20. Plant extracts inhibit ADP-induced platelet activation in humans: their potential therapeutic role as ADP antagonists.

    Science.gov (United States)

    Jagroop, Indera Anita

    2014-01-01

    Adenosine diphosphate (ADP) plays a pivotal role in platelet activation. Platelet hyperactivity is associated with vascular disease and also has a key role in haemostasis and thrombosis. ADP activates platelets through three purinoceptor subtypes, the G(q)-coupled P2Y(1) receptor, G(i)-coupled P2Y(12) receptor and P2X(1) ligand-gated cation channel. Platelet ADP purinergic receptors are therefore suitable targets for antiplatelet drugs. Thienopyridines such as clopidogrel and ticlopidine, as well as other ADP receptor antagonists like prasugrel, ticagrelor, cangrelor and elinogrel have demonstrated clinical benefits via the inhibition of the selective purinergic ADP receptor, P2Y(12). However, they still have limitations in their mode of action and efficacy, like increased risk of bleeding. Thus, the ongoing pursuit to develop newer and more effective antiplatelet agents continues. There is a growing interest in the purinergic antiplatelet properties exhibited by plant extracts. This article considers the following: pomolic acid isolated from Licania pittieri, brazilin isolated from the heartwood of Caesalpinia sappan L, phylligenin isolated from the twigs of Muraltia vulpina, bark oil of Gonystylus velutinus, seed and bark extracts from Aesculus hippocastanum L. and red wine phenolics and catechins isolated from green tea. Moreover, the method used to investigate platelet purinergic receptors should be considered, since using a more sensitive, high-resolution platelet sizer can sometimes detect platelet variations when the light transmission method was not able to do so. The exact mechanisms by which these plant extracts work need further investigation. They all however inhibit ADP-induced activation in human platelets. This could explain, at least in part, the protective effect of plant extracts as antiplatelet agents. PMID:24190032

  1. Antagonistic activities of atipamezole, 4-aminopyridine and yohimbine against medetomidine/ketamine-induced anaesthesia in cats.

    Science.gov (United States)

    Verstegen, J; Fargetton, X; Zanker, S; Donnay, I; Ectors, F

    1991-01-19

    The objectives of this trial were to determine the ability of atipamezole, 4-aminopyridine and yohimbine to reverse the anaesthetic effects of a combination of medetomidine and ketamine in cats. Forty healthy cats were anaesthetised with 80 micrograms/kg medetomidine combined with 5 mg/kg ketamine. Thirty minutes later atipamezole (200 or 500 micrograms/kg), 4-aminopyridine (500 or 1000 micrograms/kg) or yohimbine (250 or 500 micrograms/kg) were injected intramuscularly. The doses of antagonists were randomised, so that each dose was administered to five cats, and 10 cats were injected only with physiological saline. Atipamezole clearly reversed the anaesthesia and bradycardia induced by medetomidine and ketamine. The mean (+/- sd) arousal times were 28 (+/- 4.7), 5.8 (+/- 1.8) and 7 (+/- 2.1) minutes in the placebo group, and the groups receiving 200 and 500 micrograms/kg atipamezole, respectively. The heart rates of the cats receiving 200 micrograms/kg atipamezole rapidly returned to values close to the initial ones, but 15 minutes after the injection of 500 micrograms/kg atipamezole a significant tachycardia was observed. All the cats showed moderate signs of ataxia during the recovery period. A dose of 500 micrograms/kg yohimbine also clearly reversed the anaesthetic effects of medetomidine/ketamine but 250 micrograms/kg was not effective. The dose of 500 micrograms/kg allowed a smooth recovery with no particular side effects except for some signs of incomplete antagonism of the ketamine effects, ie, ataxia and muscular incoordination. With 4-aminopyridine there were no statistically significant effects on the recovery, or the heart and respiratory rates of the cats anaesthetised with medetomidine/ketamine. PMID:2003354

  2. Chikusetsusaponin IVa Butyl Ester (CS-IVa-Be), a Novel IL6R Antagonist, Inhibits IL6/STAT3 Signaling Pathway and Induces Cancer Cell Apoptosis.

    Science.gov (United States)

    Yang, Jie; Qian, Shihui; Cai, Xueting; Lu, Wuguang; Hu, Chunping; Sun, Xiaoyan; Yang, Yang; Yu, Qiang; Gao, S Paul; Cao, Peng

    2016-06-01

    The activation of IL6/STAT3 signaling is associated with the pathogenesis of many cancers. Agents that suppress IL6/STAT3 signaling have cancer-therapeutic potential. In this study, we found that chikusetsusaponin IVa butyl ester (CS-IVa-Be), a triterpenoid saponin extracted from Acanthopanas gracilistylus W.W.Smith, induced cancer cell apoptosis. CS-IVa-Be inhibited constitutive and IL6-induced STAT3 activation, repressed STAT3 DNA-binding activity, STAT3 nuclear translocation, IL6-induced STAT3 luciferase reporter activity, IL6-induced STAT3-regulated antiapoptosis gene expression in MDA-MB-231 cells, and IL6-induced TF-1 cell proliferation. Surprisingly, CS-IVa-Be inhibited IL6 family cytokines rather than other cytokines induced STAT3 activation. Further studies indicated that CS-IVa-Be is an antagonist of IL6 receptor via directly binding to the IL6Rα with a Kd of 663 ± 74 nmol/L and the GP130 (IL6Rβ) with a Kd of 1,660 ± 243 nmol/L, interfering with the binding of IL6 to IL6R (IL6Rα and GP130) in vitro and in cancer cells. The inhibitory effect of CS-IVa-Be on the IL6-IL6Rα-GP130 interaction was relatively specific as CS-IVa-Be showed higher affinity to IL6Rα than to LIFR (Kd: 4,910 ± 1,240 nmol/L) and LeptinR (Kd: 4,990 ± 915 nmol/L). We next demonstrated that CS-IVa-Be not only directly induced cancer cell apoptosis but also sensitized MDA-MB-231 cells to TRAIL-induced apoptosis via upregulating DR5. Our findings suggest that CS-IVa-Be as a novel IL6R antagonist inhibits IL6/STAT3 signaling pathway and sensitizes the MDA-MB-231 cells to TRAIL-induced cell death. Mol Cancer Ther; 15(6); 1190-200. ©2016 AACR.

  3. Investigation of Stress Induced Analgesia with or Without Cck Receptor Agonists and Antagonists in Mice Suffering from Neuropathic Pain Using Hot Plate Test

    Directory of Open Access Journals (Sweden)

    F Samiee

    2004-07-01

    Full Text Available Introduction: Recent studies have shown that cold water swimming stress (CWSS produces analgesia. Although exact mechanism of the analgesia is until unclear, it may attributed to CCK receptors. On the other hand, the effectiveness of analgesic drugs for treatment of neuropathic pain is limited. In the present study, the effects of CCK receptor agonist caerulein and antagonist proglumide , both alone and together on the CWSS- induced analgesia was investigated and compared in normal mice and those whose sciatic nerve was ligated. Material & Methods: In this research, fifty groups of nine male albino mice were used. As a model of neuropathy, the unilateral nerve ligation was made by a surgical procedure on the right hind limb. Pain sensitivity was measured by the hot plate test. Results: Different CWSS regimes (0.5-3 min induced time-dependent analgesia. Nerve ligation did not alter the CWSS induced analgesia. Caerulein (0.025, 0.05 and 0.1 mg/kg induced analgesia in both nerve ligated and intact animals. Different doses of proglumide (20, 40 and 60 mg/kg alone produced analgesic effect. The response of caerulein was not inhibited by proglumide. In the stressed mice, both drugs and the combination of them showed analgesia but there appeared to be no potentiation in CWSS- induced analgesia. Our results indicate no significant relationship between CCK receptors and the CWSS- induced analgesia. Conclusion: Nevertheless, CWSS as an alternative to drug treatment in neuropathic pain requires more studies.

  4. Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy.

    Science.gov (United States)

    Min, Hye Sook; Cha, Jin Joo; Kim, Kitae; Kim, Jung Eun; Ghee, Jung Yeon; Kim, Hyunwook; Lee, Ji Eun; Han, Jee Young; Jeong, Lak Shin; Cha, Dae Ryong; Kang, Young Sun

    2016-09-01

    The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria. PMID:27510383

  5. ENDOTHELIN ACTIVATION OF REACTIVE OXYGEN SPECIES MEDIATES STRESS-INDUCED PRESSOR RESPONSE IN DAHL-SALT SENSITIVE PREHYPERTENSIVE RATS

    OpenAIRE

    D’Angelo, Gerard; Loria, Analia S.; Pollock, David M.; Pollock, Jennifer S.

    2010-01-01

    Experiments were designed to test the hypothesis that endothelin and/or reactive oxygen species contribute to the pressor response induced by acute air jet stress in normotensive Dahl salt-sensitive rats maintained on a normal salt diet (pre-hypertensive). Mean arterial pressure was chronically monitored by telemetry before and after 3-day treatment with the free radical scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol), or endothelin receptor antagonists, ABT-627 (ETA antagonis...

  6. Modulation of bleomycin-induced lung fibrosis by pegylated hyaluronidase and dopamine receptor antagonist in mice.

    Directory of Open Access Journals (Sweden)

    Evgenii Germanovich Skurikhin

    Full Text Available Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA. To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL. Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF-β, interleukin (IL-1β, tumor necrosis factor (TNF-α in the serum and lungs, while spiperone reduced the level of the serum IL-1β. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF-β and the increase level of TNF-α in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31‒ CD34‒ CD45‒ CD44+ CD73+ CD90+ CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan

  7. Antagonistic rhizobacteria and jasmonic acid induce resistance against tomato bacterial spot

    Directory of Open Access Journals (Sweden)

    Hélvio Gledson Maciel Ferraz

    2015-12-01

    Full Text Available AbstractTomato bacterial spot on tomato may be caused by four species of Xanthomonas and among them X. gardneri(Xg is the most destructive one, especially in areas irrigated using a center pivot system in Minas Gerais state and the midwest region of Brazil. Due to the ineffectiveness of chemical control and the lack of cultivars with high levels of genetic resistance, this study investigated the potential of three antagonists (Streptomyces setonii (UFV618, Bacillus cereus (UFV592 and Serratia marcescens (UFV252, and the hormone jasmonic acid (JA as a positive control, to reduce bacterial spot symptoms and to potentiate defense enzymes in the leaves of tomato plants infected by Xg. Tomato seeds were microbiolized with each antagonist, and the soil was drenched with these bacteria. The plants were sprayed with JA 48 h before Xginoculation. The final average severity on the tomato plants was reduced by 29.44, 59.26 and 61.33% in the UFV592, UFV618 and JA treatments, respectively. The UFV618 antagonist was as effective as JA in reducing bacterial spot symptoms on tomatoes, which can be explained by the greater activities of defense enzymes that are commonly involved in host resistance against bacterial diseases. These results suggest that JA and the UFV618 antagonist can be used in the integrated management of bacterial spot on tomatoes.

  8. TGF-.beta. antagonists as mitigators of radiation-induced tissue damage

    Science.gov (United States)

    Barcellos-Hoff, Mary H.

    1997-01-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-.beta. antagonist, such as an anti-TGF-.beta. antibody or a TGF-.beta. latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  9. TGF-{beta} antagonists as mitigators of radiation-induced tissue damage

    Science.gov (United States)

    Barcellos-Hoff, M.H.

    1997-04-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-{beta} antagonist, such as an anti-TGF-{beta} antibody or a TGF-{beta} latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  10. Casopitant: a novel NK(1)-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting

    DEFF Research Database (Denmark)

    Ruhlmann, Christina; Herrstedt, Jørn

    2009-01-01

    Chemotherapy-induced nausea and vomiting (CINV) are among the most feared and distressing symptoms experienced by patients with cancer. The knowledge of the pathogenesis and neuropharmacology of CINV has expanded enormously over the last decades, the most significant discoveries being the role of 5......, whereas the effect on nausea seems to be limited. The first NK(1) receptor antagonist, aprepitant, became clinically available in 2003, and casopitant, the second in this class of antiemetics, has now completed phase III trials. This review delineates the properties and clinical use of casopitant...

  11. Effect of ruthenium red, a ryanodine receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats.

    Science.gov (United States)

    Jain, Swati; Sharma, Bhupesh

    2016-10-01

    Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia by experimental diabetes. This study investigates the efficacy of a ruthenium red, a ryanodine receptor antagonist and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent vascular dementia in rats. Attentional set shifting and Morris water-maze test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of ruthenium red and pioglitazone has significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that ruthenium red, a ryanodine receptor antagonist and pioglitazone, a PPAR-γ agonist may be considered as potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent vascular dementia. Ryanodine receptor may be explored further for their possible benefits in vascular dementia. PMID:27262216

  12. "Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.

    OpenAIRE

    Hung, D. T.; Vu, T K; Wheaton, V I; Charo, I F; Nelken, N A; Esmon, N; Esmon, C T; Coughlin, S R

    1992-01-01

    Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were...

  13. "Interaction of different doses of Aspartame with Morphine-induced antinociception in the presence of MK-801, a NMDA antagonist "

    Directory of Open Access Journals (Sweden)

    Abdollahi M

    2002-07-01

    Full Text Available This study was designed to investigate the relative role of sweetness and comparative effects of different taste sensation of the non - caloric sweetener , aspartame on pain and its interaction with MK - 80] as a non - selective MMDA antagonist by formalin - test in mice. The formalin - test was chosen because it measures the response to a long - lasting nociceptive stimulus and closely resembles to the clinical pain. Morphine induced a dose dependent antinociception in the early and late phases of formalin test. Twelve days pretreatment of animals by aspartame ( 0.08% , 0.16% , 0.32% significantly potentiated morphine - induced (1.5-9 mg/kg analgesia in the early phase but significantly antagonized its analgesic effect in the late phase, dose dependently. Aspartame (0.16% alone showed a reduction in pain response . Naloxone (0.4 mg/kg significantly antagonized the antinociceptive effect of morphine in the presence of aspartame (0-0.32% in the early phase. Increasing the dose of aspartame decreased effects of naloxone. MK-801 (0.1 mg/kg as an N- Methyl - D - Aspartate (NMDA antagonist significantly potentiated the effect of aspartame on morphine - induced antinociception in the early phase. In the late phase, naloxone (0.4 mg/kg increased pain response but MK- 801 (0.1 mg/kg induced anti-inflammatory effect significantly. Treatment of animals with MK- 801 alone, significantly induced analgesia in both phases of formalin - test. This effect was potentiated with aspartame dose - dependently. Possible interaction of aspartame with NMDA receptors and its role to facilitate endogenous opioid system are proposed mechanisms of aspartame in modulating morphine - induced antinociception. Furthermore, the resulting association between morphine and aspartame chronic consumption may be explained as an interactive action rather than simple dose combination of both drugs.

  14. The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin self-administration and heroin-induced reinstatement in rats.

    Science.gov (United States)

    Yue, Kai; Ma, Baomiao; Ru, Qin; Chen, Lin; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2012-07-01

    Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement. PMID:22741173

  15. Endothelin receptor-antagonists suppress lipopolysaccharide-induced cytokine release from alveolar macrophages of non-smokers, smokers and COPD subjects.

    Science.gov (United States)

    Gerlach, Kathrin; Köhler-Bachmann, Stefanie; Jungck, David; Körber, Sandra; Yanik, Sarah; Knoop, Heiko; Wehde, Deborah; Rheinländer, Sonja; Walther, Jörg W; Kronsbein, Juliane; Knobloch, Jürgen; Koch, Andrea

    2015-12-01

    Smoking-induced COPD is characterized by chronic airway inflammation, which becomes enhanced by bacterial infections resulting in accelerated disease progression called exacerbation. Alveolar macrophages (AM) release endothelin-1 (ET-1), IL-6, CCL-2 and MMP-9, all of which are linked to COPD pathogenesis and exacerbation. ET-1 signals via ETA- and ETB-receptors (ETAR, ETBR). This is blocked by endothelin receptor antagonists (ERAs), like bosentan, which targets both receptors, ETAR-selective ambrisentan and ETBR-specific BQ788. Therefore, ERAs could have anti-inflammatory potential, which might be useful in COPD and other inflammatory lung diseases. We hypothesized that ERAs suppress cytokine release from AM of smokers and COPD subjects induced by lipopolysaccharide (LPS), the most important immunogen of gram-negative bacteria. AM were isolated from the broncho-alveolar lavage (BAL) of n=29 subjects (11 non-smokers, 10 current smokers without COPD, 8 smokers with COPD), cultivated and stimulated with LPS in the presence or absence of ERAs. Cytokines were measured by ELISA. Endothelin receptor expression was investigated by RT-PCR and western blot. AM expressed ETAR and ETBR mRNA, but only ETBR protein was detected. LPS and ET-1 both induced IL-6, CCL-2 and MMP-9. LPS-induced IL-6 release was increased in COPD versus non-smokers and smokers. Bosentan, ambrisentan and BQ788 all partially reduced all cytokines without differences between cohorts. Specific ETBR inhibition was most effective. LPS induced ET-1, which was exclusively blocked by BQ788. In conclusion, LPS induces ET-1 release in AM, which in turn leads to CCL-2, IL-6 and MMP-9 expression rendering AM sensitive for ERAs. ERAs could have anti-inflammatory potential in smoking-induced COPD.

  16. Steroidal and Nonsteroidal Mineralocorticoid Receptor Antagonists Cause Differential Cardiac Gene Expression in Pressure Overload-induced Cardiac Hypertrophy.

    Science.gov (United States)

    Grune, Jana; Benz, Verena; Brix, Sarah; Salatzki, Janek; Blumrich, Annelie; Höft, Beata; Klopfleisch, Robert; Foryst-Ludwig, Anna; Kolkhof, Peter; Kintscher, Ulrich

    2016-05-01

    Pharmacological blockade of mineralocorticoid receptors (MR) is known as an efficacious therapy in chronic heart failure. Therapy with steroidal MR antagonists such as spironolactone or eplerenone (EPL) is often limited because of side effects. Recently, a new highly selective and potent, nonsteroidal MR antagonist, finerenone (FIN), has been developed. To investigate the effects of FIN on pressure-induced cardiac hypertrophy, the transverse aortic constriction (TAC) model was used in C57BL/6 mice treated with FIN (10 mg·kg·d), EPL (200 mg·kg·d) or vehicle (VEH). First, we analyzed cardiac gene expression 4 weeks after TAC using a pathway-focused quantitative polymerase chain reaction array. FIN caused a distinct cardiac gene expression profile compared to VEH and EPL, including differential expression of BNP (brain natriuretic peptide) and Tnnt2 (troponin T type 2). FIN treatment led to a significant reduction of TAC-induced left ventricular (LV) wall thickening assessed by echocardiography. In accordance, FIN-treated mice showed a significant lower increase of calculated left ventricular mass compared with VEH- and EPL-treated mice (FIN: 28.4 ± 3.7 mg; EPL: 38.4 ± 4.3 mg; VEH: 39.3 ± 3.1 mg; P < 0.05). These data show beneficial effects of nonsteroidal MR antagonism by FIN on left ventricular mass development in pressure overload associated with a distinct cardiac gene expression profile. PMID:26859196

  17. Levo-tetrahydropalmatine, a natural, mixed dopamine receptor antagonist, inhibits methamphetamine self-administration and methamphetamine-induced reinstatement.

    Science.gov (United States)

    Gong, Xiaokang; Yue, Kai; Ma, Baomiao; Xing, Junqiao; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2016-05-01

    Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l-THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l-THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l-THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l-THP on METH self-administration and METH-induced reinstatement. In our experiments, l-THP (1.25, 2.50 and 5.00 mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l-THP (2.50 and 5.00 mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l-THP (1.25 and 2.50mg/kg, i.p) did not affect locomotor activity following METH injection (1mg/kg) suggesting that the observed effects of l-THP (2.50mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l-THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement. PMID:26806555

  18. Visual contrast sensitivity in drug-induced Parkinsonism.

    Science.gov (United States)

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-01-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way. PMID:2926418

  19. Visual contrast sensitivity in drug-induced Parkinsonism.

    Science.gov (United States)

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-03-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way.

  20. Antagonist targeting microRNA-155 protects against lithium-pilocarpine-induced status epilepticus in C57BL/6 mice by activating brain-derived neurotrophic factor

    Directory of Open Access Journals (Sweden)

    Zhengxu eCai

    2016-05-01

    Full Text Available Epilepsy is a severe brain disorder affecting numerous patients. Recently, it is inferred that modulation of microRNA-155 (miR-155 could serve as a promising treatment of mesial temporal lobe epilepsy (MTLE. In the current study, the therapeutic potential of miR-155 antagonist against TLE was evaluated and the underlying mechanism involved in this regulation was explored. TLE model was induced by lithium-pilocarpine method. The effect of miR-155 antagonist on epilepticus symptoms of TLE mice was assessed using Racine classification and electroencephalogram (EEG recordings. The expression of brain-derived neurotrophic factor (BDNF and its association with miR-155 were also assessed with a series of experiments. Our results showed that level of miR-155 was significantly up-regulated after induction of TLE model. Based on the results of EEG and behavior analyses, seizures in mice were alleviated by miR-155 antagonist. Moreover, administration of miR-155 antagonist also significantly increased the level of BDNF. The results of dual luciferase assay and western blotting showed that miR-155 antagonist exerted its action on status epilepticus by directly regulating the activity of BDNF. Taken all the information together, our results demonstrated that miR-155 antagonist might firstly induce the expression of BDNF, which then contributed to the alleviation of epilepsy in the current study.

  1. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation.

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    Mayte Suárez-Fariñas

    Full Text Available Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the dorsum. Two TLR antagonists were compared: IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8 and 9, both of which previously have been shown to reduce epidermal hyperplasia in this model. Skin gene expression profiles of IL-23-induced inflammation were compared with or without TLR antagonist treatment. IL-23 injection resulted in alteration of 5100 gene probes (fold change ≥ 2, FDR 12-fold reduction, normalized IL-17 induced genes such as beta-defensin and CXCL1, and normalized aberrant expression of keratin 16 (indicating epidermal hyperplasia. These results suggest that IL-23-driven inflammation in mouse skin may be dependent on signaling mediated by TLRs 7, 8, and 9 and that these receptors represent novel therapeutic targets in psoriasis vulgaris and other diseases with similar pathophysiology.

  2. Dose-sensitive steroid-induced hyperglycaemia.

    Science.gov (United States)

    Gannon, Craig; Dando, Nicholas

    2010-10-01

    Steroids cause significant but under-appreciated and poorly managed glucose intolerance. In this case we describe a patient with steroid-induced hyperglycaemia who obtained a large positive impact on glycaemic control from a small reduction in her steroid dose, sufficient to alleviate the need for insulin. Developments in the treatment of steroid-induced hyperglycaemia may mean that a more active approach needs to be considered when treating steroid-related diabetes in patients whose management is palliative. We advise checking for steroid-induced hyperglycaemia by testing capillary blood glucose values 2 hours after the lunchtime meal and recommend a single morning dose of long-acting insulin to treat the condition.

  3. Effect of GNTI,a kappa opioid receptor antagonist, on MK-801-induced hyperlocomotion and stereotypy in mice

    Institute of Scientific and Technical Information of China (English)

    Chun-ting QI; Hong ZOU; Chen-hao ZHANG; Qing-lian XIE; Mei-lei JIN; Lei YU

    2006-01-01

    Aim:To examine the effect of GNTI[5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,-5α-epoxy-3-14-dihydroxy-6,7-2',3'-indolomorphinan],a selective antagonist for the kappa opioid receptor,in the MK-801 (dizocilpine maleate)-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia.Methods:Two doses 0f MK-801 (0.3 mg/kg and 0.6 mg/kg) were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis.Results:GNTI inhibited MK-801-induced hyperlocomotion and stereotypy.In particular,GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg VS 0.6 mg/kg MK-801.Conclusion:Antagonism of kappa opioid receptors attenuates MK-801-induced behavior,suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia.GNTI aDpears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.

  4. Antagonist peptides of human interferon-α2b isolated from phage display library inhibit interferon induced antiviral activity

    Institute of Scientific and Technical Information of China (English)

    Wang TIAN; Gang BAI; Zheng-he LI; Wen-bo YANG

    2006-01-01

    Aim: To screen human interferon (IFN)-α2b antagonist peptides from a phage displayed heptapeptide library. Methods: WISH cells and polyclonal anti-IFN-α2b antibodies were used to select IFN receptor-binding peptides from a phage displayed heptapeptide library. The specific binding of phage clones was examined by phage ELISA and immunohistochemistry. The specific binding activities of synthetic peptides to WISH cells were detected by competition assay. Effects of synthetic peptides to IFN-induced antiviral activity were analyzed by evaluating the cytopathic effect (CPE) using the MTT method. Results: Twenty-three positive clones were obtained after seven rounds of selection. Ten clones were randomly picked from the positive clones and were sequenced. The corresponding amino acid sequences suggested 3 groups homologous to the 3 domains of IFN-α2b, defined by residues 24-41, 43-49, and 148-158 of IFN-α2b. As they presented as corresponding to IFN receptor-binding domains, AB loop and E helix, clone № 26 and 35 were chosen for further characterization and shown to bind to WISH cells. Two peptides corresponding to clone № 26 and 35, designated SP-7(SLSPGLP) and FY-7(FSAPVRY) were shown to compete with GFP-IFN-α2b for binding to its receptor and to inhibit the IFN-α2b-induced antiviral activity. Conclusion: Both IFN-α2b antagonist peptides, SP-7 and FY-7, were able to inhibit the IFN-induced antiviral activity, and could be helpful in laying the foundation for the molecular mechanism of the interaction between IFN and its receptor.

  5. Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice.

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    Philipp Weyermann

    Full Text Available BACKGROUND: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP, the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure. METHODOLOGY/PRINCIPAL FINDINGS: SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass. CONCLUSIONS/SIGNIFICANCE: In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients.

  6. CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice.

    Science.gov (United States)

    Lopez-Rodriguez, Ana Belen; Siopi, Eleni; Finn, David P; Marchand-Leroux, Catherine; Garcia-Segura, Luis M; Jafarian-Tehrani, Mehrnaz; Viveros, Maria-Paz

    2015-01-01

    Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists.

  7. Distinct roles of the Y1 and Y2 receptors on neuropeptide Y-induced sensitization to sedation.

    Science.gov (United States)

    Naveilhan, P; Canals, J M; Arenas, E; Ernfors, P

    2001-09-01

    Intracranial injection of neuropeptide Y (NPY) increases the sensitivity to sodium pentobarbital and ketamin sedation and has similar properties as GABA agonists on sleep. Mice sensitive to sedation have increased levels of NPY in many brain regions and Y1(-/-) mice show a marked resistance to barbiturates. Here we characterized the role of the NPY Y receptors in anesthetic-induced sedation. We show that Y1 and Y2, but not Y5, receptors participate in the modulation of sedation. Administration of a Y1 agonist increased the sodium pentobarbital-induced sedation and Y1(-/-) mice were less sensitive to this anesthetic. However, Y2(-/-) mice display increased sensitivity, showing that Y2 modulates GABAergic induced sedation both pharmacologically and physiologically and has a functionally opposing role to the Y1 receptor. Analysis of Y1(-/-)/Y2(-/-) double mutant mice show that increased sensitivity by Y1 occurs independent of the Y2 receptor, while the decreased sensitivity mediated by Y2 depend on an intact Y1 receptor. In contrast to sodium pentobarbital, both Y1 and Y2 receptors increase the sensitivity in a collaborative fashion to NMDA antagonist-induced sedation. These data demonstrate the physiological and pharmacological impact of the Y1 and Y2 receptors on sedation.

  8. Neuroprotection Against NMDA Induced Cell Death in Rat Nucleus Basalis by Ca2+ Antagonist Nimodipine, Influence of Aging and Developmental Drug Treatment

    NARCIS (Netherlands)

    Luiten, P.G.M.; Douma, B.R.K.; Zee, E.A. van der; Nyakas, C.

    1995-01-01

    In the current study the neuroprotective effect of the L-type calcium channel antagonist nimodipine in rat brain was investigated in N-methyl-D-aspartate-induced neuronal degeneration in vivo. In the present model NMDA was unilaterally injected in the magnocellular nucleus basalis and the neurotoxic

  9. The effects of the β1 antagonist, metoprolol, on methamphetamine-induced changes in core temperature in the rat.

    Science.gov (United States)

    Harrell, Ricki; Speaker, H Anton; Mitchell, Scott L; Sabol, Karen E

    2015-11-16

    Methamphetamine (METH) results in hyperthermia or hypothermia depending on environmental conditions. Here we studied the role of the β1 adrenergic receptor in mediating METH's temperature effects. Core temperature measurements were made telemetrically over a 7.5h session, two days/week, in test chambers regulated at either 18°C, 24°C, or 30°C ambient temperature. Rats were treated with the β1 antagonist metoprolol (5.0, 10.0, and 15.0mg/kg) alone (Experiment 1), or in combination with 5.0mg/kg METH (Experiment 2). In experiment 3, we combined a lower dose range of metoprolol (0.75, 1.5, and 3.0mg/kg) with 5.0mg/kg METH at 18°C and 30°C. Confirming prior findings, METH alone resulted in hyperthermia in warm (30°) and hypothermia in cool environments (18°C). Metoprolol alone induced small but significant increases in core temperature. In combination, however, metoprolol reduced METH-induced changes in core temperature. Specifically, at 30°C, 3.0, 5.0, 10.0, and 15.0mg/kg metoprolol decreased METH-induced hyperthermia; at 18°C, all six doses of metoprolol enhanced METH-induced hypothermia. Our metoprolol findings suggest that one component of METH's temperature effects involves increasing core temperature at all ambient conditions via β1 receptors. Since β receptors are involved in brown adipose tissue (BAT)-mediated thermogenesis, skeletal muscle-mediated thermogenesis, heart rate, and the metabolism of glucose and lipids, we discuss each of these as possible mechanisms for metoprolol's effects on METH-induced changes in core temperature. PMID:26388403

  10. The effects of the β1 antagonist, metoprolol, on methamphetamine-induced changes in core temperature in the rat.

    Science.gov (United States)

    Harrell, Ricki; Speaker, H Anton; Mitchell, Scott L; Sabol, Karen E

    2015-11-16

    Methamphetamine (METH) results in hyperthermia or hypothermia depending on environmental conditions. Here we studied the role of the β1 adrenergic receptor in mediating METH's temperature effects. Core temperature measurements were made telemetrically over a 7.5h session, two days/week, in test chambers regulated at either 18°C, 24°C, or 30°C ambient temperature. Rats were treated with the β1 antagonist metoprolol (5.0, 10.0, and 15.0mg/kg) alone (Experiment 1), or in combination with 5.0mg/kg METH (Experiment 2). In experiment 3, we combined a lower dose range of metoprolol (0.75, 1.5, and 3.0mg/kg) with 5.0mg/kg METH at 18°C and 30°C. Confirming prior findings, METH alone resulted in hyperthermia in warm (30°) and hypothermia in cool environments (18°C). Metoprolol alone induced small but significant increases in core temperature. In combination, however, metoprolol reduced METH-induced changes in core temperature. Specifically, at 30°C, 3.0, 5.0, 10.0, and 15.0mg/kg metoprolol decreased METH-induced hyperthermia; at 18°C, all six doses of metoprolol enhanced METH-induced hypothermia. Our metoprolol findings suggest that one component of METH's temperature effects involves increasing core temperature at all ambient conditions via β1 receptors. Since β receptors are involved in brown adipose tissue (BAT)-mediated thermogenesis, skeletal muscle-mediated thermogenesis, heart rate, and the metabolism of glucose and lipids, we discuss each of these as possible mechanisms for metoprolol's effects on METH-induced changes in core temperature.

  11. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype.

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    Leon J Schurgers

    Full Text Available BACKGROUND: Vitamin K-antagonists (VKA are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE(-/- model of atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD. VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE(-/- mice (10 weeks received a Western type diet (WTD for 12 weeks, after which mice were fed a WTD supplemented with vitamin K(1 (VK(1, 1.5 mg/g or vitamin K(1 and warfarin (VK(1&W; 1.5 mg/g & 3.0 mg/g for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden. CONCLUSIONS/SIGNIFICANCE: VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE(-/- mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.

  12. Antagonists of IGF:Vitronectin Interactions Inhibit IGF-I-Induced Breast Cancer Cell Functions.

    Science.gov (United States)

    Kashyap, Abhishek S; Shooter, Gary K; Shokoohmand, Ali; McGovern, Jacqui; Sivaramakrishnan, Manaswini; Croll, Tristan I; Cane, Gaëlle; Leavesley, David I; Söderberg, Ola; Upton, Zee; Hollier, Brett G

    2016-07-01

    We provide proof-of-concept evidence for a new class of therapeutics that target growth factor:extracellular matrix (GF:ECM) interactions for the management of breast cancer. Insulin-like growth factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and the ECM protein vitronectin (VN), and stimulates the survival, migration and invasion of breast cancer cells. For the first time we provide physical evidence for IGFBP-3:VN interactions in breast cancer patient tissues; these interactions were predominantly localized to tumor cell clusters and in stroma surrounding tumor cells. We show that disruption of IGF-I:IGFBP:VN complexes with L(27)-IGF-II inhibits IGF-I:IGFBP:VN-stimulated breast cancer cell migration and proliferation in two- and three-dimensional assay systems. Peptide arrays screened to identify regions critical for the IGFBP-3/-5:VN and IGF-II:VN interactions demonstrated IGFBP-3/-5 and IGF-II binds VN through the hemopexin-2 domain, and VN binds IGFBP-3 at residues not involved in the binding of IGF-I to IGFBP-3. IGFBP-interacting VN peptides identified from these peptide arrays disrupted the IGF-I:IGFBP:VN complex, impeded the growth of primary tumor-like spheroids and, more importantly, inhibited the invasion of metastatic breast cancer cells in 3D assay systems. These studies provide first-in-field evidence for the utility of small peptides in antagonizing GF:ECM-mediated biologic functions and present data demonstrating the potential of these peptide antagonists as novel therapeutics. Mol Cancer Ther; 15(7); 1602-13. ©2016 AACR. PMID:27196774

  13. Antagonist Effects of Veratric Acid against UVB-Induced Cell Damages

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    Deokhoon Park

    2013-05-01

    Full Text Available Ultraviolet (UV radiation induces DNA damage, oxidative stress, and inflammatory processes in human epidermis, resulting in inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effect of UV irradiation is essential. In recent years naturally occurring herbal compounds such as phenolic acids, flavonoids, and high molecular weight polyphenols have gained considerable attention as beneficial protective agents. The simple phenolic veratric acid (VA, 3,4-dimethoxybenzoic acid is one of the major benzoic acid derivatives from vegetables and fruits and it also occurs naturally in medicinal mushrooms which have been reported to have anti-inflammatory and anti-oxidant activities. However, it has rarely been applied in skin care. This study, therefore, aimed to explore the possible roles of veratric acid in protection against UVB-induced damage in HaCaT cells. Results showed that veratric acid can attenuate cyclobutane pyrimidine dimers (CPDs formation, glutathione (GSH depletion and apoptosis induced by UVB. Furthermore, veratric acid had inhibitory effects on the UVB-induced release of the inflammatory mediators such as IL-6 and prostaglandin-E2. We also confirmed the safety and clinical efficacy of veratric acid on human skin. Overall, results demonstrated significant benefits of veratric acid on the protection of keratinocyte against UVB-induced injuries and suggested its potential use in skin photoprotection.

  14. PKCα and HMGB1 antagonistically control hydrogen peroxide-induced poly-ADP-ribose formation

    Science.gov (United States)

    Andersson, Anneli; Bluwstein, Andrej; Kumar, Nitin; Teloni, Federico; Traenkle, Jens; Baudis, Michael; Altmeyer, Matthias; Hottiger, Michael O.

    2016-01-01

    Harmful oxidation of proteins, lipids and nucleic acids is observed when reactive oxygen species (ROS) are produced excessively and/or the antioxidant capacity is reduced, causing ‘oxidative stress’. Nuclear poly-ADP-ribose (PAR) formation is thought to be induced in response to oxidative DNA damage and to promote cell death under sustained oxidative stress conditions. However, what exactly triggers PAR induction in response to oxidative stress is incompletely understood. Using reverse phase protein array (RPPA) and in-depth analysis of key stress signaling components, we observed that PAR formation induced by H2O2 was mediated by the PLC/IP3R/Ca2+/PKCα signaling axis. Mechanistically, H2O2-induced PAR formation correlated with Ca2+-dependent DNA damage, which, however, was PKCα-independent. In contrast, PAR formation was completely lost upon knockdown of PKCα, suggesting that DNA damage alone was not sufficient for inducing PAR formation, but required a PKCα-dependent process. Intriguingly, the loss of PAR formation observed upon PKCα depletion was overcome when the chromatin structure-modifying protein HMGB1 was co-depleted with PKCα, suggesting that activation and nuclear translocation of PKCα releases the inhibitory effect of HMGB1 on PAR formation. Together, these results identify PKCα and HMGB1 as important co-regulators involved in H2O2-induced PAR formation, a finding that may have important relevance for oxidative stress-associated pathophysiological conditions. PMID:27198223

  15. Effects of dopamine agonists and antagonists on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test.

    Science.gov (United States)

    Sams-Dodd, F

    1998-01-01

    Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic psychosis. In animal models of schizophrenia, PCP induces locomotor hyperactivity, stereotyped behaviour and social isolation, and the purpose of the present study was to describe the ability of dopamine agonists and antagonists to mimic or interact with these PCP-induced behaviours in rats. The compounds were administered daily for 3 days in combination with vehicle or 2.0 mg/kg PCP and the rats were tested in the social interaction test on the last day of drug administration. The study showed that D1-agonists with relative differences in efficacy at the DA-stimulated adenylate cyclase had limited effects on the PCP-induced behaviours, whereas the D1-antagonist SCH 23391 could alleviate the PCP-induce social isolation following daily treatment for 3 days. However, following long-term treatment for 21 days, the rats develop tolerance to this effect. These data thus suggested that the D1-receptor system only had a modulatory effect on PCP. In contrast, the D2-receptor family may be more directly involved, because the D2/D3/D4-agonist quinpirole could mimic and potentiate the PCP-induced deficits in social behaviour, and the D2/D3-antagonist (-)sulpiride could alleviate the PCP-induced stereotyped behaviour and social isolation. However, a D4-antagonist did not affect the behaviour of vehicle- and PCP-treated rats, suggesting that this system plays a less direct role in the behavioural effects of PCP. In general, however, the effects of SCH 23391, quinpirole and (-)sulpiride on the PCP-induced behaviours were mirrored in the vehicle-treated control groups and it is therefore possible that non-specific effects may have been important.

  16. The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome

    OpenAIRE

    Steiner, Michel A.; Sciarretta, Carla; Pasquali, Anne; Jenck, Francois

    2013-01-01

    The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS...

  17. 5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

    Science.gov (United States)

    Archer, T; Danysz, W; Jonsson, G; Minor, B G; Post, C

    1986-10-01

    The effects of the alpha-adrenoceptor antagonists prazosin, phentolamine and yohimbine upon 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced analgesia were tested in the hot-plate, tail-flick and shock-titration tests of nociception with rats. Intrathecally injected yohimbine and phentolamine blocked or attenuated the analgesia produced by systemic administration of 5-MeODMT in all three nociceptive tests. Intrathecally administered prazosin attenuated the analgesic effects of 5-MeODMT in the hot-plate and tail-flick tests, but not in the shock titration test. Intrathecal yohimbine showed a dose-related lowering of pain thresholds in saline and 5-MeODMT-treated animals. Phentolamine and prazosin produced normal dose-related curves in the hot-plate test and biphasic effects in the shock titration and tail-flick tests. These results demonstrate a functional interaction between alpha 2-adrenoceptors and 5-HT agonist-induced analgesia at a spinal level in rats. PMID:2877697

  18. Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Shiba, Takahiro; Tamai, Takuma; Sahara, Yurina; Kurohane, Kohta [Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka, 52‐1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422‐8526 (Japan); Watanabe, Tatsuo [Laboratory of Food Chemistry, School of Food and Nutritional Sciences, University of Shizuoka, 52‐1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422‐8526 (Japan); Imai, Yasuyuki, E-mail: imai@u-shizuoka-ken.ac.jp [Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka, 52‐1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422‐8526 (Japan)

    2012-11-01

    Some chemicals contribute to the development of allergies by increasing the immunogenicity of other allergens. We have demonstrated that several phthalate esters, including dibutyl phthalate (DBP), enhance skin sensitization to fluorescein isothiocyanate (FITC) in a mouse contact hypersensitivity model, in which the T-helper type 2 (Th2) response is essential. On the other hand, some phthalate esters were found to activate transient receptor potential ankyrin 1 (TRPA1) cation channels on sensory neurons. We then found a positive correlation between the enhancing effects of several types of phthalate esters on skin sensitization to FITC and their ability to activate TRPA1. Here we examined the involvement of TRPA1 in sensitization to FITC by using TRPA1 agonists other than phthalate esters. During skin sensitization to FITC, the TRPA1 agonists (menthol, carvacrol, cinnamaldehyde and DBP) augmented the ear-swelling response as well as trafficking of FITC-presenting dendritic cells to draining lymph nodes. We confirmed that these TRPA1 agonists induced calcium influx into TRPA1-expressing Chinese hamster ovary (CHO) cells. We also found that TRPA1 antagonist HC-030031 inhibited DBP-induced calcium influx into TRPA1-expressing CHO cells. After pretreatment with this antagonist upon skin sensitization to FITC, the enhancing effect of DBP on sensitization was suppressed. These results suggest that TRPA1 activation will become a useful marker to find chemicals that facilitate sensitization in combination with other immunogenic haptens. -- Highlights: ► Role of TRPA1 activation was revealed in a mouse model of skin sensitization to FITC. ► TRPA1 agonists enhanced skin sensitization as well as dendritic cell trafficking. ► Dibutyl phthalate (DBP) has been shown to enhance skin sensitization to FITC. ► TRPA1 activation by DBP was inhibited by a selective antagonist, HC-030031. ► HC-030031 inhibited the enhancing effect of DBP on skin sensitization to FITC.

  19. [Effect of excitant amino acid antagonists on glutamate receptors in the locust and on convulsions induced by glutamate, aspartate, kynurenine and quinolinic acid in mice].

    Science.gov (United States)

    Ryzhov, I V; Slepokurov, M V; Lapin, I P; Mandel'shtam, Iu E; Aleksandrov, V G

    1986-03-01

    All excitatory amino acid antagonists studied: diethyl esters of aspartic (DEEA) and glutamic (DEEG) acids, 2-amino-3-phosphono-propionic acid (APPA) and 2-amino-4-phosphono-butanoic acid (APBA), diminished the amplitude of excitatory postsynaptic potentials (EPP) of the locust (Locusta migratoria migratorioides) muscle fibers and arbitrary blocked glutamate (GLU) and aspartate (ASP) responses. Kynurenine (KYN) and quinolinic (QUI) acid had no effect on EPP even at a concentration of 2 X 10(-2) M. The antagonists were not strictly selective against intracerebroventricularly administered endogenous convulsants: GLU, ASP, KYN and QUI and in simulation of experimental seizures in mice. The antagonists structurally similar to ASP prevented ASP- and KYN-induced seizures in lower doses than GLU derivatives. Anti-KYN, but not anti-QUI DEEA, DEEG, APPA and APBA efficacy suggests that KYN and QUI act on different structures or binding sites. PMID:2869799

  20. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines

    International Nuclear Information System (INIS)

    It has been recently demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679). We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma

  1. Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

    Directory of Open Access Journals (Sweden)

    Lyte Mark

    2007-01-01

    Full Text Available Abstract Background The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s to which catecholamines (norepinephrine, epinephrine and dopamine may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. Results Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. Conclusion The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

  2. CXCR2 antagonists block the N-Ac-PGP-induced neutrophil influx in the airways of mice, but not the production of the chemokine CXCL1.

    Science.gov (United States)

    Braber, Saskia; Overbeek, Saskia A; Koelink, Pim J; Henricks, Paul A J; Zaman, Guido J R; Garssen, Johan; Kraneveld, Aletta D; Folkerts, Gert

    2011-10-15

    Neutrophils are innate immune cells in chronic inflammatory diseases including chronic obstructive pulmonary disease (COPD) and can be attracted to the site of inflammation via the collagen breakdown product N-acetyl Proline-Glycine-Proline (N-Ac-PGP). To elucidate whether CXCR2 is involved in N-Ac-PGP-induced neutrophil migration and activation, studies using specific antagonists were performed in vivo. N-Ac-PGP and keratinocyte cell-derived chemokine (KC; CXCL1) were administered in C57Bl/6 mice via oropharyngeal aspiration. Intraperitoneal applications of CXCR2 antagonist SB225002 or SB332235 were administered 1h prior and 1h after oropharyngeal aspiration. Six hours after oropharyngeal aspiration mice were sacrificed. Neutrophil counts and CXCL1 levels were determined in bronchoalveolar lavage fluid, myleoperoxidase (MPO) levels were measured in lung tissue homogenates and an immunohistological staining for neutrophils was performed on lung tissue. N-Ac-PGP and CXCL1 induced a neutrophil influx in the bronchoalveolar lavage fluid and lung tissue, which was also reflected by increased MPO levels in lung tissue. The N-Ac-PGP- and CXCL1-induced neutrophil influx and the increased pulmonary tissue MPO levels were inhibited by the CXCR2 antagonists SB225002 and SB332235. Moreover, N-Ac-PGP administration enhanced the CXCL1 levels in bronchoalveolar lavage fluid, which could not be attenuated by both CXCR2 antagonists. In conclusion, neutrophil migration induced by N-Ac-PGP is mediated via direct CXCR2 interaction. The N-Ac-PGP-induced release of CXCL1 is independent of CXCR2. Related to the maximal effect of CXCL1, N-Ac-PGP is more potent at inducing neutrophil migration in the pulmonary tissue than into the bronchoalveolar lavage fluid, or N-ac-PGP may be more potent at inducing MPO levels in the lung tissue.

  3. Effects of angiotensin Ⅱ receptor antagonist on expression of collagen Ⅲ, collagen Ⅴ, and transforming growth factor β1 in the airway walls of sensitized rats

    Institute of Scientific and Technical Information of China (English)

    杜永成; 许建英; 张韶君

    2004-01-01

    Background Repeated attacks of bronchial asthma lead to different degrees of airway remodeling, the mechanism of which is not yet clear. Some evidences indicate that it is related to the excessive expression of some growth promotion factors. Angiotensin Ⅱ is a polypeptide that may be involved in airway remodeling. To evaluate its role in airway remodeling in asthma, we observed the effects of an angiotensin Ⅱ type 1 receptor antagonist (valsartan) on the expression of collagen Ⅲ, collagen Ⅴ, and transforming growth factor β1 (TGF-β1) mRNA and protein in the airway walls of sensitized rats.Methods Forty Wistar rats were randomly divided into 5 groups: control group, sensitized group, and valsartan groups 1, 2, and 3. The rats in the sensitized group and in valsartan groups 1, 2, and 3 were sensitized and challenged with ovalbumin. Rats in control group were sensitized and challenged with 0.9% NaCl. Rats from valsartan groups 1, 2, and 3 were drenched with valsartan (10 μg, 20 μg, or 30 μg, respectively) at the time of the ovalbumin challenges. The expression of collagen Ⅲ, collagen Ⅴ, and TGF-β1 protein were detected using immunohistochemical method in combination with image analysis methods. The expression of TGF-β1 mRNA was detected by in situ hybridization. Results The expression in the airways of collagen Ⅲ and collagen Ⅴ was significantly higher in rats from the sensitized group (7.73±0.81, 1.34±0.28) and from valsartan groups 1, 2, and 3 (5.73±0.64, 1.13±0.15; 4.96±0.51, 0.98±0.08; 4.43±0.35, 0.93±0.06, respectively) than those in the control group (2.65±0.38, 0.67±0.08, P<0.05). In addition, collagen levels were significantly lower in valsartan groups 1, 2, and 3 than those from the sensitized group (P<0.05). The expression of TGF-β1 mRNA and protein in the airways was significantly higher in rats from the sensitized group (20.49%±3.46%, 29.73%±3.25%) and from valsartan groups 1, 2, and 3 (16.47%±1.94%, 19.41%±1.87%; 14

  4. Exercise-induced bronchoconstriction: The effects of montelukast, a leukotriene receptor antagonist

    OpenAIRE

    James P Kemp

    2009-01-01

    James P KempClinical Professor of Pediatrics, Division of Immunology and Allergy, University of California School of Medicine, San Diego, CA, USAAbstract: Exercise-induced bronchoconstriction (EIB) is very common in both patients with asthma and those who are otherwise thought to be normal. The intensity of exercise as well as the type of exercise is important in producing symptoms. This may make some types of exercise such as swimming more suitable and extended running more difficult for pat...

  5. Activation of CB1 inhibits NGF-induced sensitization of TRPV1 in adult mouse afferent neurons.

    Science.gov (United States)

    Wang, Z-Y; McDowell, T; Wang, P; Alvarez, R; Gomez, T; Bjorling, D E

    2014-09-26

    Transient receptor potential vanilloid 1 (TRPV1)-containing afferent neurons convey nociceptive signals and play an essential role in pain sensation. Exposure to nerve growth factor (NGF) rapidly increases TRPV1 activity (sensitization). In the present study, we investigated whether treatment with the selective cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) affects NGF-induced sensitization of TRPV1 in adult mouse dorsal root ganglion (DRG) afferent neurons. We found that CB1, NGF receptor tyrosine kinase A (trkA), and TRPV1 are present in cultured adult mouse small- to medium-sized afferent neurons and treatment with NGF (100ng/ml) for 30 min significantly increased the number of neurons that responded to capsaicin (as indicated by increased intracellular Ca(2 +) concentration). Pretreatment with the CB1 agonist ACEA (10nM) inhibited the NGF-induced response, and this effect of ACEA was reversed by a selective CB1 antagonist. Further, pretreatment with ACEA inhibited NGF-induced phosphorylation of AKT. Blocking PI3 kinase activity also attenuated the NGF-induced increase in the number of neurons that responded to capsaicin. Our results indicate that the analgesic effect of CB1 activation may in part be due to inhibition of NGF-induced sensitization of TRPV1 and also that the effect of CB1 activation is at least partly mediated by attenuation of NGF-induced increased PI3 signaling.

  6. Sensitization of radiation-induced cell death by genistein

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Rim; Kim, In Gyu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2010-03-15

    A number of epidemiological studies as well as biological experiments, showed that genistein, one of the isoflavone, prevents prostate cancer occurrence. In this study, we showed that genistein inhibited the cell proliferation of human promyeoltic leukemia HL-60 cells and induced G2/M phase arrest. In addition, combination of genistein treatment and {gamma}-irradiation displayed synergistic effect in apoptotic cell death of HL-60 cells. This means that the repair of genistein-induced DNA damage was hindered by {gamma}-irradiation and thus cell death was increased. In conclusion, genistein is one of the important chemicals that sensitize radiation-induced cell death.

  7. The excitatory amino acid receptor antagonist MK-801 prevents the hypersensitivity induced by spinal cord ischemia in the rat

    International Nuclear Information System (INIS)

    Protection by the NMDA receptor antagonist MK-801 against transient spinal cord ischemia-induced hypersensitivity was studied in rats. The spinal ischemia was initiated by vascular occlusion resulting from the interaction between the photosensitizing dye Erythrosin B and an argon laser beam. The hypersensitivity, termed allodynia, where the animals reacted by vocalization to nonnoxious mechanical stimuli in the flank area, was consistently observed during several days after induction of the ischemia. Pretreatment with MK-801 (0.1-0.5 mg/kg, iv) 10 min before laser irradiation dose dependently prevented the occurrence of allodynia. The neuroprotective effect of MK-801 was not reduced by maintaining normal body temperature during and after irradiation. There was a significant negative correlation between the delay in the administration of MK-801 after irradiation and the protective effect of the drug. Histological examination revealed slight morphological damage in the spinal cord in 38% of control rats after 1 min of laser irradiation without pretreatment with MK-801. No morphological abnormalities were observed in rats after pretreatment with MK-801 (0.5 mg/kg). The present results provide further evidence for the involvement of excitatory amino acids, through activation of the NMDA receptor, in the development of dysfunction following ischemic trauma to the spinal cord

  8. Antagonistic functions between the RNA chaperone Hfq and an sRNA regulate sensitivity to the antibiotic colicin.

    Science.gov (United States)

    Salvail, Hubert; Caron, Marie-Pier; Bélanger, Justine; Massé, Eric

    2013-10-16

    The RNA chaperone Hfq is a key regulator of the function of small RNAs (sRNAs). Hfq has been shown to facilitate sRNAs binding to target mRNAs and to directly regulate translation through the action of sRNAs. Here, we present evidence that Hfq acts as the repressor of cirA mRNA translation in the absence of sRNA. Hfq binding to cirA prevents translation initiation, which correlates with cirA mRNA instability. In contrast, RyhB pairing to cirA mRNA promotes changes in RNA structure that displace Hfq, thereby allowing efficient translation as well as mRNA stabilization. Because CirA is a receptor for the antibiotic colicin Ia, in addition to acting as an Fur (Ferric Uptake Regulator)-regulated siderophore transporter, translational activation of cirA mRNA by RyhB promotes colicin sensitivity under conditions of iron starvation. Altogether, these results indicate that Fur and RyhB modulate an unexpected feed-forward loop mechanism related to iron physiology and colicin sensitivity. PMID:24065131

  9. Reversal of TMS-induced motor twitch by training is associated with a reduction in excitability of the antagonist muscle

    Directory of Open Access Journals (Sweden)

    Fregni Felipe

    2011-08-01

    Full Text Available Abstract Background A single session of isolated repetitive movements of the thumb can alter the response to transcranial magnetic stimulation (TMS, such that the related muscle twitch measured post-training occurs in the trained direction. This response is attributed to transient excitability changes in primary motor cortex (M1 that form the early part of learning. We investigated; (1 whether this phenomenon might occur for movements at the wrist, and (2 how specific TMS activation patterns of opposing muscles underlie the practice-induced change in direction. Methods We used single-pulse suprathreshold TMS over the M1 forearm area, to evoke wrist movements in 20 healthy subjects. We measured the preferential direction of the TMS-induced twitch in both the sagittal and coronal plane using an optical goniometer fixed to the dorsum of the wrist, and recorded electromyographic (EMG activity from the flexor carpi radialis (FCR and extensor carpi radialis (ECR muscles. Subjects performed gentle voluntary movements, in the direction opposite to the initial twitch for 5 minutes at 0.2 Hz. We collected motor evoked potentials (MEPs elicited by TMS at baseline and for 10 minutes after training. Results Repetitive motor training was sufficient for TMS to evoke movements in the practiced direction opposite to the original twitch. For most subjects the effect of the newly-acquired direction was retained for at least 10 minutes before reverting to the original. Importantly, the direction change of the movement was associated with a significant decrease in MEP amplitude of the antagonist to the trained muscle, rather than an increase in MEP amplitude of the trained muscle. Conclusions These results demonstrate for the first time that a TMS-twitch direction change following a simple practice paradigm may result from reduced corticospinal drive to muscles antagonizing the trained direction. Such findings may have implications for training paradigms in

  10. Stereoselective inhibition of thromboxane-induced coronary vasoconstriction by 1,4-dihydropyridine calcium channel antagonists

    International Nuclear Information System (INIS)

    The biological activity of the (+)-S- and (-)-R-enantiomers of niguldipine, of the (-)-S- and (+)-R-enantiomers of felodipine and nitrendipine, and of rac-nisoldipine and rac-nimodipine was investigated in vitro and in vivo. Inhibition of coronary vasoconstriction due to the thromboxane A2 (TxA2)-mimetic U-46619 in guinea pig Langendorff hearts, displacement of (+)-[3H]isradipine from calcium channel binding sites of guinea pig skeletal muscle T-tubule membranes, and blood pressure reduction in spontaneously hypertensive rats were determined. The enantiomers were obtained by stereoselective synthesis. Cross-contamination was less than 0.5% for both S- and R-enantiomers of niguldipine and nitrendipine and less than 1% for those of felodipine. From the doses necessary for a 50% inhibition of coronary vasoconstriction, stereoselectivity ratios for (+)-(S)-/(-)-(R)-niguldipine, (-)-(S)-/(+)-(R)-felodipine, and (-)-(S)-/(+)-(R)-nitrendipine of 28, 13, and 7, respectively, were calculated. The potency ratio rac-nisoldipine/rac-nimodipine was 3.5. Ratios obtained from binding experiments and antihypertensive activity were (+)-(S)-/(-)-(R)-niguldipine = 45 and 35, (-)-(S)-/(+)-(R)-felodipine = 12 and 13, (-)-(S)-/(+)-(R)-nitrendipine = 8 and 8, and rac-nisoldipine/rac-nimodipine = 8 and 7, respectively. Highly significant correlations were found between the in vitro potency of the substances to prevent U-46619-induced coronary vasoconstriction and their affinity for calcium channel binding sites as well as their antihypertensive activity

  11. Effects of leukotriene receptor antagonist on chronic obstractive pulmonary disease induced pulmonary hypertension

    Institute of Scientific and Technical Information of China (English)

    卜小宁; 王辰; 庞宝森

    2003-01-01

    Objectives To assess the hemodynamic, oxygen-dynamic and ventilative effects of Zafirlukast in chronic obstructive pulmonary disease (COPD) induced chronic cor pulmonale at acute exacerbation stage and the mechanisms of Zafirlukast efficacy.Methods Eleven cases of chronic cor pulmonale at acute exacerbation were examinted using Swan-Ganz catheter and peripheral intra-artery catheter. The hemodynamic, oxygen-dynamic parameters and respiratory rate, plasma endothelium-1 (ET-1) level, and urea leukotriene E4 (LTE4) level were measured before and at the 1st, 3rd, 5th, 7th, 9th, 12th hour after taking 40 mg Zafirlukast orally. Artarial and mixed venous blood gas analyses were done correspondingly.Results The average pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRI) were lowered at the 3rd hour after taking Zafirlukast by 23% and 36.5%, respectively. They returned to the baseline around 12th hour. Respiratory rate decreased significantly within the 3rd-7th hour after taking Zafirlukast. LTE4 and ET-1 levels lowered at the 3rd hour and showed a positive correlation with change of mPAP. Conclusions Zafirlukast can reduce mPAP, pulmonary vascular resistance (PVR) and does not affect the ambulatory blood pressure monitoring (ABPM) and oxygenation in cases of chronic cor pulmonale at acute exacerbation stage. Zafirlukast may play a role as an alternative to decrease PAP in COPD patients.

  12. The effect of acute Lithium and AMI-193, a new 5HT2 antagonist, on Apomorphine-induced pecking in pigeon

    OpenAIRE

    Bagheri T; Ejtemaei Mehr Sh; Shamshirgaran Sh

    2002-01-01

    Intramascular (IM) administration of apomorphine (a mixed D1/D2 dopamine receptors agonist 0.2-1.6 mg/kg) induced pecking, a stereotype behavior in pigeons in a dose- dependent manner. In this study the effect of lithium (Li+, 240 mg/kg, IM) and AMI-193 (a new 5-HT2 antagonist, 0.003 mg/pigeon) on apomorphine-induced peking (AIP) were investigated. This study showed that Li+ and AMI-193 did not induce pecking by itself but administration of each of these agents before apomorphine increased an...

  13. Regional Fos-expression induced by γ-hydroxybutyrate (GHB): comparison with γ-butyrolactone (GBL) and effects of co-administration of the GABAB antagonist SCH 50911 and putative GHB antagonist NCS-382.

    Science.gov (United States)

    van Nieuwenhuijzen, P S; McGregor, I S; Chebib, M; Hunt, G E

    2014-09-26

    γ-Hydroxybutyrate (GHB) has a complex array of neural actions that include effects on its own high-affinity GHB receptor, the release of neuroactive steroids, and agonist actions at GABAA and GABAB receptors. We previously reported partial overlap in the c-Fos expression patterns produced by GHB and the GABAB agonist, baclofen in rats. The present study extends these earlier findings by examining the extent to which GHB Fos expression and behavioral sedation are prevented by (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), a GABAB antagonist, and NCS-382, a putative antagonist at the high-affinity GHB receptor. We also compare Fos expression caused by GHB and its precursor γ-butyrolactone (GBL), which is a pro-drug for GHB but lacks the high sodium content of the parent GHB molecule. Both GHB (1,000 mg/kg) and GBL (600 mg/kg) induced rapid sedation in rats that lasted over 90 min and caused similar Fos expression patterns, albeit with GBL causing greater activation of the nucleus accumbens (core and shell) and dentate gyrus (granular layer). Pretreatment with SCH 50911 (100mg/kg) partly reversed the sedative effects of GHB and significantly reduced GHB-induced Fos expression in only four regions: the tenia tecta, lateral habenula, dorsal raphe and laterodorsal tegmental nucleus. NCS-382 (50mg/kg) had no effect on GHB-induced sedation or Fos expression. When given alone, both NCS-382 and SCH 50911 increased Fos expression in the bed nucleus of the stria terminalis, central amygdala, parasubthalamic nucleus and nucleus of the solitary tract. SCH 50911 alone affected the Islands of Calleja and the medial, central and paraventricular thalamic nuclei. Overall, this study shows a surprising lack of reversal of GHB-induced Fos expression by two relevant antagonists, both of which have marked intrinsic actions. This may reflect the limited doses tested but also suggests that GHB Fos expression reflects mechanisms independent of GHB and GABAB receptors.

  14. Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats

    OpenAIRE

    Yi Pang; Lu-Tai Tien; Hobart Zhu; Juying Shen; Camilla F. Wright; Jones, Tembra K.; Mamoon, Samir A.; Bhatt, Abhay J; Zhengwei Cai; Lir-Wan Fan

    2015-01-01

    Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as reduced tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (I...

  15. SIRT1 IS REQUIRED FOR ANTAGONIST-INDUCED TRANSCRIPTIONAL REPRESSION OF ANDROGEN-RESPONSIVE GENES BY THE ANDROGEN RECEPTOR

    OpenAIRE

    Dai, Yan; Ngo, Duyen; Forman, Lora W.; Qin, David C.; Jacob, Johanna; Faller, Douglas V

    2007-01-01

    Androgen antagonists or androgen deprivation is a primary therapeutic modality for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which the androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this report, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide-dependent histone deacetylase linked to the regulation of ...

  16. Closed headpiece of integrin [alpah]IIb[beta]3 and its complex with an [alpha]IIb[beta]3-specific antagonist that does not induce opening

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Jieqing; Zhu, Jianghai; Negri, Ana; Provasi, Davide; Filizola, Marta; Coller, Barry S.; Springer, Timothy A. (Sinai); (Rockefeller); (CH-Boston)

    2011-08-24

    The platelet integrin {alpha}{sub IIb}{beta}{sub 3} is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the {alpha}{sub IIb}{beta}{sub 3} headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the {alpha}{sub IIb}{beta}{sub 3} headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the {alpha}{sub IIb} subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, {alpha}{sub IIb} Y190 and {alpha}{sub aIIb} D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce {alpha}{sub IIb}{beta}{sub 3} to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.

  17. mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress.

    Science.gov (United States)

    Li, Jing; Shin, Sejeong; Sun, Yang; Yoon, Sang-Oh; Li, Chenggang; Zhang, Erik; Yu, Jane; Zhang, Jianming; Blenis, John

    2016-08-15

    mTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that coinhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816-27. ©2016 AACR. PMID:27197195

  18. Psychological Stress Induces Temporary Masticatory Muscle Mechanical Sensitivity in Rats

    Directory of Open Access Journals (Sweden)

    Fei Huang

    2011-01-01

    Full Text Available To explore the relationship between psychological stress and masticatory muscle pain, we created a communication stress animal model to determine whether psychological stress could induce increased mechanical sensitivity in masticatory muscles and to study the changes of mechanical nociceptive thresholds after stress removal. Forty-eight male Sprague-Dawley rats were divided into a control group (CON, a foot-shocked group (FS, including 3 subgroups recorded as FS-1, FS-2, and FS-3, a psychological stress group (PS, and a drug treatment group (DT. PS and DT rats were confined in a communication box for one hour a day to observe the psychological responses of neighboring FS rats.Measurements of the mechanical nociceptive thresholds of the bilateral temporal and masseter muscles showed a stimulus-response relationship between psychological stress and muscle mechanical sensitivity. The DT rats, who received a diazepam injection, showed almost the same mechanical sensitivity of the masticatory muscles to that of the control in response to psychological stress. Fourteen days after the psychological stressor was removed, the mechanical nociceptive thresholds returned to normal. These findings suggest that psychological stress is directly related to masticatory muscle pain. Removal of the stressor could be a useful method for relieving mechanical sensitivity increase induced by psychological stress.

  19. Sensitivity to Radiation-Induced Cancer in Hemochromatosis

    Energy Technology Data Exchange (ETDEWEB)

    Bull. Richard J.; Anderson, Larry E.

    2000-06-01

    The objectives of this pilot project using HFE-knockout homozygotes and heterozygotes are to (1) determine whether the knock-out mice have greater sensitivity to radiation-induced cancer of the colon, liver and breast, (2) establish the dependence of this sensitivity on the accumulation of iron, (3) determine the extent to which cell replication and apoptosis occur in these target tissues with varying iron load, and (4) correlate the increases in sensitivity with changes in insulin-related signaling in tumors and normal tissue from each target organ. Three experimental designs will be used in the pilot project. The sequence of experiments is designed to first explore the influence of iron load on the response and demonstrate that HFE knockout mice are more sensitive than the wild type to radiation-induced cancer in one or more of three target tissues (liver, colon and breast). The dose response relationships with a broader set of radiation doses will be explored in the second experiment. The final experiment is designed to explore the extent to which heterozygotes display the increased susceptibility to cancer induction and to independently assess the importance of iron load to the initiation versus promotion of tumors.

  20. Effects of an H3R antagonist on the animal model of autism induced by prenatal exposure to valproic acid.

    Directory of Open Access Journals (Sweden)

    Diego Baronio

    Full Text Available Autism spectrum disorders (ASD are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX, an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA. Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data.

  1. Paradoxical reactions induced by tumor necrosis factor-alpha antagonists: A literature review based on 46 cases

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    Rodica Olteanu

    2016-01-01

    Full Text Available Anti-tumor necrosis factor (TNFα agents have acquired a prominent place in the treatment options for inflammatory disorders. Among the side effects of these agents are the so-called paradoxical reactions which have increasingly been reported in recent years. A review of literature was carried out using Medline (PubMed database from January 2010 to December 2014 to collect all published articles on cases of anti-TNFα-induced psoriasis and psoriatic arthritis. Published articles were identified, reviewed and the relevant data extracted. A total of 22 studies (46 patients fulfilled the inclusion criteria and were selected for analysis. Of the 46 patients, 45 (97.8% developed psoriasis and 1 (2.1% psoriatic arthritis. The mean age of patients was 47 years; three (6.5% patients had a past history of psoriasis. Infliximab caused cutaneous reactions in the most number, 26 (56.5% cases. Thirty seven (80.4%. patients developed primary plaque-type psoriasis. Women accounted for 86.9% of patients. There was complete resolution of psoriasis in 12 (26% patients despite differences in the therapeutic approach. Cessation of the incriminated drug led to resolution of cutaneous lesions in 5 (10.8%, switching to another TNFα antagonist led to resolution in 6 (13% and one (2.1% patient improved despite continuation of the drug. As for the lone case of psoriatic arthritis, drug withdrawal did not result in improvement; only switching to another anti-TNFα agent helped. Since our sample was small, it was not adequately powered to draw any firm conclusions. However, in this analysis, we found that paradoxical reactions occurred predominantly in adult women, there were only isolated cases with a personal history of psoriasis, infliximab was responsible for most cases of these reactions and the most prevalent form was plaque-type psoriasis. The decision whether to continue or discontinue the triggering anti-TNFα agent should be individualized as results are highly

  2. Paradoxical reactions induced by tumor necrosis factor-alpha antagonists: A literature review based on 46 cases.

    Science.gov (United States)

    Olteanu, Rodica; Zota, Alexandra

    2016-01-01

    Anti-tumor necrosis factor (TNFα) agents have acquired a prominent place in the treatment options for inflammatory disorders. Among the side effects of these agents are the so-called paradoxical reactions which have increasingly been reported in recent years. A review of literature was carried out using Medline (PubMed) database from January 2010 to December 2014 to collect all published articles on cases of anti-TNFα-induced psoriasis and psoriatic arthritis. Published articles were identified, reviewed and the relevant data extracted. A total of 22 studies (46 patients) fulfilled the inclusion criteria and were selected for analysis. Of the 46 patients, 45 (97.8%) developed psoriasis and 1 (2.1%) psoriatic arthritis. The mean age of patients was 47 years; three (6.5%) patients had a past history of psoriasis. Infliximab caused cutaneous reactions in the most number, 26 (56.5%) cases. Thirty seven (80.4%). patients developed primary plaque-type psoriasis. Women accounted for 86.9% of patients. There was complete resolution of psoriasis in 12 (26%) patients despite differences in the therapeutic approach. Cessation of the incriminated drug led to resolution of cutaneous lesions in 5 (10.8%), switching to another TNFα antagonist led to resolution in 6 (13%) and one (2.1%) patient improved despite continuation of the drug. As for the lone case of psoriatic arthritis, drug withdrawal did not result in improvement; only switching to another anti-TNFα agent helped. Since our sample was small, it was not adequately powered to draw any firm conclusions. However, in this analysis, we found that paradoxical reactions occurred predominantly in adult women, there were only isolated cases with a personal history of psoriasis, infliximab was responsible for most cases of these reactions and the most prevalent form was plaque-type psoriasis. The decision whether to continue or discontinue the triggering anti-TNFα agent should be individualized as results are highly variable

  3. The Antagonistic Effect of Selenium on Lead-Induced Inflammatory Factors and Heat Shock Protein mRNA Level in Chicken Cartilage Tissue.

    Science.gov (United States)

    Zheng, Shufang; Song, Huanyu; Gao, Han; Liu, Chunpeng; Zhang, Ziwei; Fu, Jing

    2016-09-01

    Selenium (Se) is recognized as a necessary trace mineral in animal diets, including those of birds. Lead (Pb) is a toxic heavy metal and can damage organs in humans and animals. Complex antagonistic interactions between Se and heavy metals have been reported in previous studies. However, little is known regarding the effects of Se on Pb-induced toxicity and the expression of inflammatory factors and heat shock proteins (HSPs) in the cartilage of chickens. In this present study, we fed chickens either with Se or Pb or both Se and Pb supplement and later analyzed the mRNA expressions of inflammatory factors (inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2)) and HSPs (Hsp27, Hsp40, Hsp60, Hsp70, and Hsp90). The results showed that Se and Pb influenced the expression of inflammatory factors and HSP genes in the chicken cartilage tissues. Additionally, we also found that antagonistic interaction existed between Se and Pb supplementation. Our findings suggested that Se could exert a antagonistic effect on Pb in chicken cartilage tissues. PMID:26831653

  4. Reversible renal impairment induced by treatment with the angiotensin II receptor antagonist candesartan in a patient with bilateral renal artery stenosis

    Directory of Open Access Journals (Sweden)

    Kjaer Andreas

    2001-05-01

    Full Text Available Abstract Background It is well established that ACE-inhibitors should be avoided in patients with renal artery stenosis. In recent years it has also been recommended that caution should be demonstrated when angiotensin II blockers are used in the same type of patients but the evidence is based only on few cases. Results We describe a case where use of the angiotensin II antagonist candesartan (Atacand induced renal failure in a patient with bilateral renal artery stenosis. The course of the case is enlighted by results from sequential renography, selective renal vein catheterisation for measurement of renin, and angiographic findings. Conclusions In patients with renal artery stenosis the angiotensin II antagonist candesartan should be avoided.

  5. Antagonist-induced conformational changes in dopamine transporter extracellular loop two involve residues in a potential salt bridge.

    Science.gov (United States)

    Gaffaney, Jon D; Shetty, Madhur; Felts, Bruce; Pramod, Akula-Bala; Foster, James D; Henry, L Keith; Vaughan, Roxanne A

    2014-07-01

    Ligand-induced changes in the conformation of extracellular loop (EL) 2 in the rat (r) dopamine transporter (DAT) were examined using limited proteolysis with endoproteinase Asp-N and detection of cleavage products by epitope-specific immunoblotting. The principle N-terminal fragment produced by Asp-N was a 19kDa peptide likely derived by proteolysis of EL2 residue D174, which is present just past the extracellular end of TM3. Production of this fragment was significantly decreased by binding of cocaine and other uptake blockers, but was not affected by substrates or Zn(2+), indicating the presence of a conformational change at D174 that may be related to the mechanism of transport inhibition. DA transport activity and cocaine analog binding were decreased by Asp-N treatment, suggesting a requirement for EL2 integrity in these DAT functions. In a previous study we demonstrated that ligand-induced protease resistance also occurred at R218 on the C-terminal side of rDAT EL2. Here using substituted cysteine accessibility analysis of human (h) DAT we confirm cocaine-induced alterations in reactivity of the homologous R219 and identify conformational sensitivity of V221. Focused molecular modeling of D174 and R218 based on currently available Aquifex aeolicus leucine transporter crystal structures places these residues within 2.9Å of one another, suggesting their proximity as a structural basis for their similar conformational sensitivities and indicating their potential to form a salt bridge. These findings extend our understanding of DAT EL2 and its role in transport and binding functions. PMID:24269640

  6. The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients

    NARCIS (Netherlands)

    vanMegen, HJGM; Westenberg, HGM; denBoer, JA; Slaap, B; vanEsRadhakishun, F; Pande, AC

    1997-01-01

    The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two differe

  7. RARalpha-mediated teratogenicity in mice is potentiated by an RXR agonist and reduced by an RAR antagonist: dissection of retinoid receptor-induced pathways.

    Science.gov (United States)

    Elmazar, M M; Rühl, R; Reichert, U; Shroot, B; Nau, H

    1997-09-01

    To dissect the complex pattern of retinoid-induced developmental defects, an RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative) was coadministered with an RARalpha-selective agonist (Am580, an arylcarboxamidobenzoic acid derivative) to NMRI mice on Day 8.25 of gestation. AGN191701 was neither fetotoxic nor teratogenic at the doses used, but potentiated Am580-induced resorptions, spina bifida aperta, micrognathia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, tail malformations, fused ribs, and fetal weight retardation. These effects were generally reduced by coadministration of an RAR-selective antagonist (CD2366, an adamantyl-methoxyphenyl-heptatrienoic acid derivative). The incidence of other defects induced by an RARalpha-selective agonist such as exencephaly or cleft palate was neither greatly affected by the RXR-selective agonist nor by the antagonist. These results suggest that some malformations such as the posterior neural tube defect spina bifida as well as urogenital defects may be mediated via liganded RARalpha-RXR heterodimerization, while other defects such as the anterior neural tube defect exencephaly as well as cleft palate are induced by different mechanisms.

  8. Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans

    Science.gov (United States)

    Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

    2016-01-01

    Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity. PMID:27378550

  9. Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

    Science.gov (United States)

    Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

    2016-01-01

    Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity. PMID:27378550

  10. Sensitization for Anticancer Drug-Induced Apoptosis by Betulinic Acid

    Directory of Open Access Journals (Sweden)

    Simone Fulda

    2005-02-01

    Full Text Available We previously described that betulinic acid (BetA, a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actinomycin D. Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation.

  11. Paclitaxel sensitizes gastric cancer cells to TRAIL-induced apoptosis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Objective:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise for cancer therapy as it has unique capacity to selectively trigger apoptosis in cancer cells. We reported here that paclitaxel sensitized gastric cancer cells to TRAIL-induced apoptosis.Methods: After drug exposure, apoptosis rate and caspase activation were examined. Various proteins were detected by western blot. Several interventions, including pharmacological inhibitors and siRNA transfection were used. hTe growth inhibition of tumors was evaluated in SGC-7901-implanted nude mice model.Results:We found gastric cancer cellsshowed a mixed response to TRAIL. Combined treatment with paclitaxel markedly enhanced TARIL-induced apoptosis in vitro and in vivo. The underlying mechanisms involved in synergistical activation of caspase proteins, up-regulation of receptors, down-regulation of antiapoptotic proteins and inactivation of MAPKs.Conclusion:TRAIL-induced cytotoxicity and apoptosis can be synergistically enhanced by paclitaxel, suggesting the therapeutic potential of combining TARIL plus paclitaxel in gastric cancer treatment.

  12. 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis.

    Science.gov (United States)

    Shukla, Lena; Ajram, Laura A; Begg, Malcolm; Evans, Brian; Graves, Rebecca H; Hodgson, Simon T; Lynn, Sean M; Miah, Afjal H; Percy, Jonathan M; Procopiou, Panayiotis A; Richards, Stephen A; Slack, Robert J

    2016-06-10

    A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [(125)I]-TARC binding assay with a pKi of 8.8, and the [(35)S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors. PMID:26991939

  13. Monomeric tartrate resistant acid phosphatase induces insulin sensitive obesity.

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    Pernilla Lång

    Full Text Available BACKGROUND: Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear. Tartrate resistant acid phosphatase (TRAP is an enzyme expressed by subsets of macrophages and osteoclasts that exists either as an enzymatically inactive monomer or as an active, proteolytically processed dimer. PRINCIPAL FINDINGS: Using mice over expressing TRAP, we show that over-expression of monomeric, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity i.e. many small fat cells. In vitro, recombinant monomeric, but not proteolytically processed TRAP induced proliferation and differentiation of mouse and human adipocyte precursor cells. In humans, monomeric TRAP was highly expressed in the adipose tissue of obese individuals. In both the mouse model and in the obese humans the source of TRAP in adipose tissue was macrophages. In addition, the obese TRAP over expressing mice exhibited signs of a low-grade inflammatory reaction in adipose tissue without evidence of abnormal adipocyte lipolysis, lipogenesis or insulin sensitivity. CONCLUSION: Monomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity.

  14. Characterization of cutaneous vascular permeability induced by platelet-activating factor in guinea pigs and rats and its inhibition by a platelet-activating factor receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, S.B.; Li, C.L.; Lam, M.H.; Shen, T.Y.

    1985-06-01

    Mechanisms of platelet-activating factor (PAF)-induced increases of cutaneous vascular permeability in guinea pigs and in rats were further explored. PAF so far is the most potent vasoactive mediator, being more than 1000-fold more potent than histamine and bradykinin in both species. In guinea pigs, there is a time delay of 5 to 10 minutes before PAF action, whereas, in the rat, the increased vasopermeability occurs immediately following the intradermal PAF injection. Relative vasoactive potencies of PAF and several structure-related analogues in both species correlate very well with their relative inhibition of the binding of /sup 3/H-PAF to specific receptor sites on isolated rabbit platelet plasma membranes and their aggregatory abilities of rabbit platelets. Furthermore, the PAF-induced cutaneous vascular permeability is inhibitable by a competitive specific PAF receptor antagonist, kadsurenone, suggesting that binding of PAF to its specific receptor site is the first step to initiate its action of increased cutaneous vascular permeability. Several pure cyclooxygenase inhibitors, including indomethacin, diflunisal, and flurbiprofen, and the dual cyclooxygenase/lipoxygenase inhibitor, BW755C, but not the histamine antagonists, inhibit the PAF-induced vasopermeability in guinea pigs. The inhibition by indomethacin or BW755C can be fully reversed by coinjection intradermally with PAF and prostaglandin E1 but not leukotriene B4. Also, prostaglandin E1 but not leukotriene B4 enhances the guinea pig in vivo response to PAF in this model. However, in rats, none of the cyclooxygenase inhibitors, histamine antagonists, or BW755C inhibit the PAF effect of cutaneous phenomena.

  15. SYM 2206 (a potent non-competitive AMPA receptor antagonist) elevates the threshold for maximal electroshock-induced seizures in mice

    OpenAIRE

    Luszczki Jarogniew J.; Leszkowicz Magdalena; Kondrat-Wrobel Maria W.; Florek-Luszczki Magdalena

    2014-01-01

    The aim of this study was to determine the effect of SYM 2206 (a potent non-competitive AMPA receptor antagonist) on the threshold for maximal electroshock (MEST)-induced seizures in mice. Electroconvulsions were produced in mice by means of a current (sinewave, 50 Hz, maximum 500 V, strength from 4 to 14 mA, 0.2-s stimulus duration, tonic hind limb extension taken as the endpoint) delivered via ear-clip electrodes. SYM 2206 administered systemically (i.p.), 30 min before the MEST test, at do...

  16. The effect of acute Lithium and AMI-193, a new 5HT2 antagonist, on Apomorphine-induced pecking in pigeon

    Directory of Open Access Journals (Sweden)

    Bagheri T

    2002-06-01

    Full Text Available Intramascular (IM administration of apomorphine (a mixed D1/D2 dopamine receptors agonist 0.2-1.6 mg/kg induced pecking, a stereotype behavior in pigeons in a dose- dependent manner. In this study the effect of lithium (Li+, 240 mg/kg, IM and AMI-193 (a new 5-HT2 antagonist, 0.003 mg/pigeon on apomorphine-induced peking (AIP were investigated. This study showed that Li+ and AMI-193 did not induce pecking by itself but administration of each of these agents before apomorphine increased and decreased the AIP (apomor-phine 0.8 mg/kg respectively whereas concomitant use of Li+ (240 mg/kg IM and AMI-193 decreased AIP significantly. These results suggested that 5-HT2 antagonists inhibit the inhibitory effect of serotonin on the dopamine release in the raphe-striatal pathway but Li+ can modulate dopamine and serotonin function by different mechanisms and decrease this effect. As a result, it is mechanisms and decrease this effect. As a result, it is concluded serotonin can decrease the AIP through 5-HT2 receptors indirectly by decrease the dopamine release.

  17. The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Fabrice Trovero

    Full Text Available Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg and cyproheptadine (1 mg/kg (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France and cyproheptadine (1 mg/kg could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

  18. The expression of methiopropamine-induced locomotor sensitization requires dopamine D2, but not D1, receptor activation in the rat.

    Science.gov (United States)

    Yoon, Hyung Shin; Cai, Wen Ting; Lee, Young Hun; Park, Kyung Tae; Lee, Yong Sup; Kim, Jeong-Hoon

    2016-09-15

    Methiopropamine (MPA) is a structural analog to methamphetamine and is categorized as a novel psychoactive substance that needs to be controlled. However, no study has been performed to determine whether MPA actually develops an addiction-like behavior similar to those arising from other psychomotor stimulants. Thus, we attempted to determine whether MPA produces locomotor sensitization in a manner similar to amphetamine. In the first experiment, rats were pre-exposed to either saline or one of three different doses of MPA (0.2, 1.0, or 5.0mg/kg, IP) with a total of four injections, respectively. After a 2-week withdrawal period, when they were challenged with the same dose of MPA, only the group that was pre-exposed to high dose of MPA (5.0mg/kg) showed sensitized locomotor activity. In the second experiment, all rats were pre-exposed to MPA (5.0mg/kg) only. Interestingly, the expression of MPA-induced locomotor sensitization was inhibited by a pre-injection of a dopamine D2 receptor antagonist, eticlopride (0.05mg/kg, IP), though not by a dopamine D1 receptor antagonist, SCH23390 (0.01mg/kg, IP). These results suggest that repeated injection of MPA in the rat provokes certain neuronal changes involving specific, likely D2, dopamine receptor-mediated pathways that contribute to the expression of MPA-induced locomotor sensitization. PMID:27265782

  19. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P;

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral...... chromatographic techniques. The absolute stereochemistry of (-)-(R)-phaclofen was established by X-ray crystallographic analysis. (-)-(R)-Phaclofen was shown to inhibit the binding of [3H]-(R)-baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 +/- 13 microM), whereas (+)-(S)-phaclofen was...... inactive in this binding assay (IC50 > 1000 microM). (-)-(R)-Phaclofen (200 microM) was equipotent with (RS)-phaclofen (400 microM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)-(S)-phaclofen (200 microM) was inactive. The structural similarity of the agonist (R)-baclofen...

  20. Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension.

    Science.gov (United States)

    Gadkari, Tushar V; Cortes, Natalie; Madrasi, Kumpal; Tsoukias, Nikolaos M; Joshi, Mahesh S

    2013-11-30

    l-Arginine and its decarboxylated product, agmatine are important mediators of NO production and vascular relaxation. However, the underlying mechanisms of their action are not understood. We have investigated the role of arginine and agmatine in resistance vessel relaxation of Sprague-Dawley (SD) and Dahl salt-sensitive hypertensive rats. Second or 3rd-order mesenteric arterioles were cannulated in an organ chamber, pressurized and equilibrated before perfusing intraluminally with agonists. The vessel diameters were measured after mounting on the stage of a microscope fitted with a video camera. The gene expression in Dahl rat vessel homogenates was ascertained by real-time PCR. l-Arginine initiated relaxations (EC50, 5.8±0.7mM; n=9) were inhibited by arginine decarboxylase (ADC) inhibitor, difluoromethylarginine (DFMA) (EC50, 18.3±1.3mM; n=5) suggesting that arginine-induced vessel relaxation was mediated by agmatine formation. Agmatine relaxed the SD rat vessels at significantly lower concentrations (EC50, 138.7±12.1μM; n=22), which was compromised by l-NAME (l-N(G)-nitroarginine methyl ester, an eNOS inhibitor), RX821002 (α-2 AR antagonist) and pertussis toxin (G-protein inhibitor). The agmatine-mediated vessel relaxation from high salt Dahl rats was abolished as compared to that from normal salt rats (EC50, 143.9±23.4μM; n=5). The α-2A AR, α-2B AR and eNOS mRNA expression was downregulated in mesenteric arterioles of high-salt treated Dahl hypertensive rats. These findings demonstrate that agmatine facilitated the relaxation via activation of α-2 adrenergic G-protein coupled receptor and NO synthesis, and this pathway is compromised in salt-sensitive hypertension.

  1. A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers.

    Directory of Open Access Journals (Sweden)

    Rachel A Gibson

    Full Text Available BACKGROUND: Transient receptor potential vanilloid type 1 (TRPV1 is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and when orally administered has demonstrated pharmacodynamic activity in animal models and clinical studies. OBJECTIVES: To select a topical dose of SB705498 using the TRPV1 agonist capsaicin; to confirm engagement of the TRPV1 antagonistic action of SB705498 and assess whether the dose selected has an effect on itch induced by two challenge agents. METHODS: A clinical study was conducted in 16 healthy volunteers to assess the effects of 3 doses of SB705498 on skin flare induced by capsaicin. Subjects with a robust capsaicin response were chosen to determine if the selected topical formulation of SB705498 had an effect on challenge agent induced itch. RESULTS: Following capsaicin challenge the greatest average reduction in area of flare was seen for the 3% formulation. This dose was selected for further investigation. Itch intensity induced by two challenge agents (cowhage and histamine was assessed on the Computerised Visual Analogue Scale. The difference in average itch intensity (Weighted Mean Over 15 Mins between the 3% dose of SB705498 and placebo for the cowhage challenge was -0.64, whilst the histamine challenge showed on average a -4.65 point change. CONCLUSIONS: The 3% topical formulation of SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. SB705498 is unlikely to be of symptomatic

  2. Modulation of MOS device radiation sensitivity by gate induced strain

    Energy Technology Data Exchange (ETDEWEB)

    Zekeriya, V.

    1986-01-01

    To correlate the radiation sensitivity of MOS devices with the bond strain at the SiO/sub 2/-Si interface, a series of experiments was performed to systematically modulate this strain by subjecting the samples to external mechanical stress. The interfacial strain distribution was changed by varying some of the parameters related to the processing of the gate electrode, and the radiation sensitivity for each case was determined. In particular, the strain distribution was varied by (1) subjecting the samples to PMA treatment, (2) using different gate Al thicknesses, (3) making use of a gate Al related stress relaxation effect, (4) using various gate electrode materials with different thermal constants, and (5) using the large stress changes produced at the gate edges of the devices. Results show a strong correlation between interfacial stress distribution and radiation-induced interface trap generation. The generation of positive oxide charge follows the same pattern, although the dependence is not as strong. The trend is such that one can obtain radiation-harder devices by increasing the amount of compressive stress exerted by the gate electrode on the underlying oxide and its silicon interface. In addition to these results, which were obtained by deliberately varying the stress distribution, it was observed that the interface tap density kept increasing with time after irradiation.

  3. Light-induced basilar membrane vibrations in the sensitive cochlea

    Science.gov (United States)

    Grosh, Karl; Ren, Tianying; He, Wenxuan; Fridberger, Anders; Li, Yizeng; Nankali, Amir

    2015-12-01

    The exceptional sensitivity of mammalian hearing organ is attributed to an outer hair cell-mediated active process, where forces produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. A physiologically based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity. The experiments and the theoretical analysis show that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex.

  4. Thromboxane A2 receptor antagonist SQ29548 reduces ischemic stroke-induced microglia/macrophages activation and enrichment, and ameliorates brain injury

    Science.gov (United States)

    Yan, Aijuan; Zhang, Tingting; Yang, Xiao; Shao, Jiaxiang; Fu, Ningzhen; Shen, Fanxia; Fu, Yi; Xia, Weiliang

    2016-01-01

    Thromboxane A2 receptor (TXA2R) activation is thought to be involved in thrombosis/hemostasis and inflammation responses. We have previously shown that TXA2R antagonist SQ29548 attenuates BV2 microglia activation by suppression of ERK pathway, but its effect is not tested in vivo. The present study aims to explore the role of TXA2R on microglia/macrophages activation after ischemia/reperfusion brain injury in mice. Adult male ICR mice underwent 90-min transient middle cerebral artery occlusion (tMCAO). Immediately and 24 h after reperfusion, SQ29548 was administered twice to the ipsilateral ventricle (10 μl, 2.6 μmol/ml, per dose). Cerebral infarction volume, inflammatory cytokines release and microglia/macrophages activation were measured using the cresyl violet method, quantitative polymerase chain reaction (qPCR), and immunofluorescence double staining, respectively. Expression of TXA2R was significantly increased in the ipsilateral brain tissue after ischemia/reperfusion, which was also found to co-localize with activated microglia/macrophages in the infarct area. Administration of SQ29548 inhibited microglia/macrophages activation and enrichment, including both M1 and M2 phenotypes, and attenuated ischemia-induced IL-1ß, IL-6, and TNF-α up-regulation and iNOS release. TXA2R antagonist SQ29548 inhibited ischemia-induced inflammatory response and furthermore reduced microglia/macrophages activation and ischemic/reperfusion brain injury. PMID:27775054

  5. Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists.

    Science.gov (United States)

    Shearman, G T; Tolcsvai, L

    1987-01-01

    The effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by L-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced L-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by L-5-HTP are mediated by 5-HT2 receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT2 receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT. PMID:3114804

  6. Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Rachlin, Kenneth; Moore, Dan H; Yount, Garret

    2013-11-01

    The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting. PMID:23165942

  7. ACTH Antagonists

    Science.gov (United States)

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (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 while preparing for definitive treatment of a causative tumor, 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. PMID:27547198

  8. ACTH antagonists

    Directory of Open Access Journals (Sweden)

    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.

  9. ACTH Antagonists.

    Science.gov (United States)

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (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 while preparing for definitive treatment of a causative tumor, 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. PMID:27547198

  10. Influenza A virus does not encode a tetherin antagonist with Vpu-like activity and induces IFN-dependent tetherin expression in infected cells.

    Directory of Open Access Journals (Sweden)

    Michael Winkler

    Full Text Available The interferon-induced host cell factor tetherin inhibits release of human immunodeficiency virus (HIV from the plasma membrane of infected cells and is counteracted by the HIV-1 protein Vpu. Influenza A virus (FLUAV also buds from the plasma membrane and is not inhibited by tetherin. Here, we investigated if FLUAV encodes a functional equivalent of Vpu for tetherin antagonism. We found that expression of the FLUAV protein NS1, which antagonizes the interferon (IFN response, did not block the tetherin-mediated restriction of HIV release, which was rescued by Vpu. Similarly, tetherin-mediated inhibition of HIV release was not rescued by FLUAV infection. In contrast, FLUAV infection induced tetherin expression on target cells in an IFN-dependent manner. These results suggest that FLUAV escapes the antiviral effects of tetherin without encoding a tetherin antagonist with Vpu-like activity.

  11. Micronuclei: sensitivity for the detection of radiation induced damage

    International Nuclear Information System (INIS)

    The in vitro cytokinesis-block (CB) micronucleus (MN) assay for human peripheral blood has been used extensively for the assessment of chromosomal damage induced by ionizing radiation and chemicals and considered a suitable biological dosimeter for estimating in vivo whole body exposures, particularly in the case of large scale radiation accidents. One of the major drawbacks of the MN assay is its reduced sensitivity for the detection of damage induced by low doses of low LET radiation, due to the high variability among the spontaneous MN frequencies. It is suggested that age, smoking habit and sex are the main confounding factors that contribute to the observed variability. Previous work in our laboratory, shows a significant positive correlation of the spontaneous and radiation induced MN frequencies with age and smoking habit, the latter being the strongest confounder. These findings led to in vitro studies of the dose-response relationships for smoking and non smoking donors evaluated separately, using 60Co γ rays. The objectives of the present work are: 1-To increase the amount of data of the dose-response relationships, using γ rays from a 60Co source, for smoking and non smoking donors, in order to find, if applicable, a correction factor for the calibration curve that takes into account the smoking habit of the individual in the case of accidental overexposure dose assessment, particularly in the low dose range. 2-To establish general conclusions on the current state of the technique. The sample for smoking and non smoking calibration curves was enlarged in the range of 0Gy to 2Gy. The fitting of both curves, performed up to the 2Gy dose, resulted in a linear quadratic model. MN distribution among bi nucleated cells was found to be over dispersed with respect to Poisson distribution, the average ratio of variance to mean being 1.13 for non smokers and 1.17 for smokers. Each fitted calibration curve, for smoking and non smoking donors, fell within the 95

  12. Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

    LENUS (Irish Health Repository)

    Robinson, G B

    1991-10-18

    The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg\\/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

  13. Effects of L-type Ca2+ channel antagonists on in vitro excystment of Paragonimus ohirai metacercariae induced by sodium cholate.

    Science.gov (United States)

    Ikeda, Teruaki

    2006-09-01

    The inhibitory effects of L-type Ca2+ channel antagonists on Na cholate-induced in vitro excystment (CIIE) of Paragonimus ohirai metacercariae were studied. At concentrations of 10 microM, nicardipine and nimodipine inhibited CIIE completely and by approximately 92%, respectively. Nitrendipine and (+/-)-verapamil inhibited CIIE by about one half and one third, respectively. Nifedipine and diltiazem did not inhibit CIIE significantly. At higher concentrations, nitrendipine at 20 microM completely inhibited CIIE, and (+/-)-verapamil at 40 microM inhibited CIIE by 93%. Nifedipine and diltiazem inhibited CIIE only slightly and little, respectively, even at 40 microM. Complete inhibition by nicardipine at 10 microM required preincubation of metacercariae with the antagonist for 15 min. The inhibitory effects of nicardipine and nimodipine were reversible, and most of the nimodipine-treated metacercariae could excyst within 1 h after being washed, but the nicardipine-treated ones started to excyst 1 h after washing. Nicardipine suppressed the active movement of encysted juveniles evoked by Na cholate, whereas nimodipine did not suppress this significantly. These results suggested that L-type Ca2+ channels appeared to be involved in CIIE of P. ohirai metacercariae and that the inhibitory effect of the channels was due primarily to factors other than the inhibition of muscular activity, probably involving the secretion and release of enzymes lytic against the metacercarial cyst wall.

  14. Sex and smoking sensitive model of radon induced lung cancer

    International Nuclear Information System (INIS)

    Radon and radon progeny inhalation exposure are recognized to cause lung cancer. Only strong evidence of radon exposure health effects was results of epidemiological studies among underground miners. Any single epidemiological study among population failed to find reliable lung cancer risk due to indoor radon exposure. Indoor radon induced lung cancer risk models were developed exclusively basing on extrapolation of miners data. Meta analyses of indoor radon and lung cancer case control studies allowed only little improvements in approaches to radon induced lung cancer risk projections. Valuable data on characteristics of indoor radon health effects could be obtained after systematic analysis of pooled data from single residential radon studies. Two such analyses are recently published. Available new and previous data of epidemiological studies of workers and general population exposed to radon and other sources of ionizing radiation allow filling gaps in knowledge of lung cancer association with indoor radon exposure. The model of lung cancer induced by indoor radon exposure is suggested. The key point of this model is the assumption that excess relative risk depends on both sex and smoking habits of individual. This assumption based on data on occupational exposure by radon and plutonium and also on the data on external radiation exposure in Hiroshima and Nagasaki and the data on external exposure in Mayak nuclear facility. For non-corrected data of pooled European and North American studies the increased sensitivity of females to radon exposure is observed. The mean value of ks for non-corrected data obtained from independent source is in very good agreement with the L.S.S. study and Mayak plutonium workers data. Analysis of corrected data of pooled studies showed little influence of sex on E.R.R. value. The most probable cause of such effect is the change of men/women and smokers/nonsmokers ratios in corrected data sets in North American study. More correct

  15. Sex and smoking sensitive model of radon induced lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhukovsky, M.; Yarmoshenko, I. [Institute of Industrial Ecology of Ural Branch of Russian Academy of Sciences, Yekaterinburg (Russian Federation)

    2006-07-01

    Radon and radon progeny inhalation exposure are recognized to cause lung cancer. Only strong evidence of radon exposure health effects was results of epidemiological studies among underground miners. Any single epidemiological study among population failed to find reliable lung cancer risk due to indoor radon exposure. Indoor radon induced lung cancer risk models were developed exclusively basing on extrapolation of miners data. Meta analyses of indoor radon and lung cancer case control studies allowed only little improvements in approaches to radon induced lung cancer risk projections. Valuable data on characteristics of indoor radon health effects could be obtained after systematic analysis of pooled data from single residential radon studies. Two such analyses are recently published. Available new and previous data of epidemiological studies of workers and general population exposed to radon and other sources of ionizing radiation allow filling gaps in knowledge of lung cancer association with indoor radon exposure. The model of lung cancer induced by indoor radon exposure is suggested. The key point of this model is the assumption that excess relative risk depends on both sex and smoking habits of individual. This assumption based on data on occupational exposure by radon and plutonium and also on the data on external radiation exposure in Hiroshima and Nagasaki and the data on external exposure in Mayak nuclear facility. For non-corrected data of pooled European and North American studies the increased sensitivity of females to radon exposure is observed. The mean value of ks for non-corrected data obtained from independent source is in very good agreement with the L.S.S. study and Mayak plutonium workers data. Analysis of corrected data of pooled studies showed little influence of sex on E.R.R. value. The most probable cause of such effect is the change of men/women and smokers/nonsmokers ratios in corrected data sets in North American study. More correct

  16. Noise-Induced Increase of Sensitivity in Bacterial Chemotaxis.

    Science.gov (United States)

    He, Rui; Zhang, Rongjing; Yuan, Junhua

    2016-07-26

    Flagellated bacteria, like Escherichia coli, can swim toward beneficial environments by modulating the rotational direction of their flagellar motors through a chemotaxis signal transduction network. The noise of this network, the random fluctuation of the intracellular concentration of the signal protein CheY-P with time, has been identified in studies of single cell behavioral variability, and found to be important in coordination of multiple motors in a bacterium and in enhancement of bacterial drift velocity in chemical gradients. Here, by comparing the behavioral difference between motors of wild-type E. coli and mutants without signal noise, we measured the magnitude of this noise in wild-type cells, and found that the noise increases the sensitivity of the bacterial chemotaxis network downstream at the level of the flagellar motor. This provided a simple mechanism for the noise-induced enhancement of chemotactic drift, which we confirmed by simulating the E. coli chemotactic motion in various spatial profiles of chemo-attractant concentration. PMID:27463144

  17. Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

    Science.gov (United States)

    Collins, Gregory T; Calinski, Diane M; Newman, Amy Hauck; Grundt, Peter; Woods, James H

    2008-05-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect

  18. Effect of pre-existing thermal sensitization on the radiation induced sensitization in type 304 stainless steels

    International Nuclear Information System (INIS)

    It is generally recognized that radiation induced sensitization plays an important role in initiating irradiation assisted stress corrosion cracking (IASCC) of austenitic stainless steels in reactor core internal of light water reactor. However, the synergism between radiation sensitization and prior thermal sensitization is unclear. This situation is likely to occur in most welded core internal structures subjected to neutron irradiation. In this study, the effect of prior thermal treatment on radiation sensitization were investigated on proton irradiated Type 304 stainless steel (SS) of initially as-received (AR) and thermal-sensitized (SEN) conditions. The Cr depletion profiles were measured by field emission gun transmission electron microscopy/energy dispersive spectroscopy (FEGTEM/EDS), and were calculated by a radiation induced segregation (RIS) model. The different initial conditions were input in the RIS model calculations. For the as-received condition, the initial Cr profile was modeled by a uniform concentration distribution. For the initially thermal-sensitized condition, the wider Cr depletion profile measured by FEGTEM/EDS was input as the initial condition. The results showed that radiation sensitization is characterized by a very narrow Cr depleted zone. The Cr content at grain boundary tends to be lower as radiation dose increases. Comparing with the non-sensitized (as-received) specimens with the same dosage, the grain boundary Cr content without prior sensitization is higher than that with sensitization pre-treatment. The deeper grain boundary Cr concentration of irradiated thermally sensitized sample is induced not only from proton irradiation effect, but also resulted from pre-existing Cr depletion

  19. Role of cysteinyl leukotriene receptor-1 antagonists in treatment of experimentally induced mammary tumor: does montelukast modulate antitumor and immunosuppressant effects of doxorubicin?

    Science.gov (United States)

    El-Sisi, Alaa El-Din E; Sokar, Samia S; Salem, Tarek A; Abu Risha, Sally E

    2015-11-01

    It has been reported that a leukotriene (LT)-D4 receptor (i.e. cysteinyl LT1 receptor; CysLT1R) has an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (MON), a CysLT1R antagonist, in a mouse mammary carcinoma model, that is, a solid Ehrlich carcinoma (SEC). Effects of MON on tumor-induced immune dysfunction and the possibility that MON may modulate the antitumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several dosings with MON (10 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, intraperitoneal), were investigated in vivo; end points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that MON induced significant antitumor activity against the SEC. MON treatments also significantly mitigated both tumor- and DOX-induced declines in immune parameters assessed here. Moreover, MON led to decreased NF-κB nuclear expression and, in doing so, appeared to chemosensitize these tumor cells to DOX-induced apoptosis. PMID:26499992

  20. Effect of a somatostatin analogue (SMS 201-995) on antral gastrin cell hyperplasia and hypergastrinemia induced by a histamine H2-receptor antagonist.

    Science.gov (United States)

    Kimura, K

    1993-05-01

    The effect of a somatostatin analogue, SMS 201-995 (SMS), on antral gastrin cell hyperplasia (AGH) and hypergastrinemia associated with 14-day administration of the histamine H2-receptor antagonist (H2-RA) famotidine was studied in rats. When the famotidine group was compared with the control group, the antral gastrin cell (G-cell) number was significantly increased (P SMS group was compared with the famotidine group, the G-cell number was significantly decreased (P < 0.01) by approximately 30%, and the serum gastrin level was significantly decreased (P < 0.01) by approximately 40%. These findings suggest that SMS may be useful for inhibiting AGH and hypergastrinemia induced by long-term H2-RA administration. PMID:8511502

  1. Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice

    DEFF Research Database (Denmark)

    Hansen, RR; Nasser, A; Falk, S;

    2012-01-01

    The purinergic P2X3 and P2X2/3 receptors are in the peripheral nervous system almost exclusively confined to afferent sensory neurons, where they are found both at peripheral and central synapses. The P2X3 receptor is implicated in both neuropathic and inflammatory pain. However, the role of the ......X3 receptor in chronic cancer-induced bone pain is less known. Here we investigated the effect of systemic acute and chronic administration of the selective P2X3, P2X2/3 receptor antagonist (5-[[[(3-Phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1...

  2. NMDA antagonist, but not nNOS inhibitor, requires AMPA receptors in the ventromedial prefrontal cortex (vmPFC) to induce antidepressant-like effects

    DEFF Research Database (Denmark)

    Pereira, V. S.; Wegener, Gregers; Joca, S. R.

    2013-01-01

    of the glutamatergic and nitrergic systems of the vmPFC on the behavioral consequences induced by forced swimming (FS), an animal model of depression. Male Wistar rats (230-260g) with guide cannulas aimed at the prelimbic (PL) region of vmPFC were submitted to a 15min session of FS and, 24h later, they were submitted...... to a 5min session of the FS test when the immobility time (IT) was measured. Injection of LY235959 (LY; NMDA antagonist at 1, 3 and 10nmol/0.2(mu)L), NPA (nNOS inhibitor at 0.01nmol/0.2(mu)L), c-PTIO (NO scavenger at 1.0nmol/0.2(mu)L), ODQ (soluble guanylyl cyclase-sGCinhibitor at 1.0nmol/0.2(mu...

  3. Protease inhibitor-induced nausea and vomiting is attenuated by a peripherally acting, opioid-receptor antagonist in a rat model

    Directory of Open Access Journals (Sweden)

    Mehendale Sangeeta R

    2009-08-01

    Full Text Available Abstract Background Protease inhibitors such as ritonavir can cause nausea and vomiting which is the most common reason for discontinuation. Rats react to nauseous and emetic stimuli by increasing their oral intake of non-nutritive substances like kaolin, known as pica behavior. In this study, we evaluated the effects of methylnaltrexone, a peripherally acting mu-opioid receptor antagonist that does not affect analgesia, on ritonavir-induced nausea and vomiting in a rat pica model. Results We observed that 24 to 48 hr after administration of oral ritonavir 20 mg/kg, kaolin consumption increased significantly in rats (P P P Conclusion These results suggest that methylnaltrexone may have potential clinical utility in reducing nausea and vomiting in HIV patients who take ritonavir.

  4. Synthesis of potential mescaline antagonists.

    Science.gov (United States)

    DeSantis, F; Nieforth, K A

    1976-10-01

    1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

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

    Science.gov (United States)

    Nikiforuk, Agnieszka; Kos, Tomasz; Fijał, Katarzyna; Hołuj, Małgorzata; Rafa, Dominik; Popik, Piotr

    2013-01-01

    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.

  7. Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats

    Directory of Open Access Journals (Sweden)

    Yi Pang

    2015-04-01

    Full Text Available Our previous study showed that a single lipopolysaccharide (LPS treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β levels, as well as reduced tyrosine hydroxylase (TH expression in the substantia nigra (SN of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg with or without IL-1ra (0.1 mg/kg, or sterile saline was injected intracerebrally into postnatal day 5 (P5 Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure.

  8. Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats.

    Science.gov (United States)

    Pang, Yi; Tien, Lu-Tai; Zhu, Hobart; Shen, Juying; Wright, Camilla F; Jones, Tembra K; Mamoon, Samir A; Bhatt, Abhay J; Cai, Zhengwei; Fan, Lir-Wan

    2015-01-01

    Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as reduced tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra) protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg) with or without IL-1ra (0.1 mg/kg), or sterile saline was injected intracerebrally into postnatal day 5 (P5) Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure. PMID:25898410

  9. 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.

  10. Nicotine-induced behavioral sensitization in an adult rat model of attention deficit/hyperactivity disorder (ADHD).

    Science.gov (United States)

    Watterson, Elizabeth; Spitzer, Alexander; Watterson, Lucas R; Brackney, Ryan J; Zavala, Arturo R; Olive, M Foster; Sanabria, Federico

    2016-10-01

    Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. Nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. Nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90° rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance. These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD. PMID:27363925

  11. Combination Therapy of Nifedipine and Sulphonylureas Exhibits a Mutual Antagonistic Effect on the Endothelial Cell Dysfunction Induced by Hyperglycemia Linked to Vascular Disease

    Directory of Open Access Journals (Sweden)

    Li-Ping Wang

    2016-05-01

    Full Text Available Background/Aims: By inducing severe endothelial impairment, hypertension and diabetes are two leading causes of morbidity and mortality. Hypertensive patients with concomitant diabetes must take both antihypertensive and hypoglycaemic medications, for which there is a lack of experimental and clinical guidelines. This study aimed to examine the interaction between these two types of medication on the endothelial cell function. Methods: The effect of antihypertensive (nifedipine and irbesartan and anti-diabetic (metformin and glibenclamide/glimepiride drugs on human umbilical vein cells (HUVECs function was examined using a modified Boyden chamber assay. The intracellular NO and O2- levels of HUVECs were detected through flow cytometry. Results: Our findings showed that nifedipine/sulphonylurea monotherapy significantly attenuated high glucose-induced (33 mM HUVECs migration incapacity, while combination therapy of nifedipine and glibenclamide/glimepiride showed no protective effect. Both nifedipine/metformin monotherapy and combined therapy significantly mitigated the migration incapacity induced by high glucose in HUVECs. Combined with either metformin or sulphonylureas, irbesartan therapy was able to attenuate the high glucose-induced migration incapacity of HUVECs. Nifedipine monotherapy decreased the O2- levels and increased the NO levels in in vitro-cultured HUVECs treated with high glucose. However, the combination therapy of nifedipine and glibenclamide increased the O2- levels and decreased the NO levels compared to the nifedipine monotherapeutic group. Conclusion: The nifedipine and glibenclamide/glimepiride combination exerted a mutual antagonistic effect on the protection from high glucose-induced impairment in endothelial cells, which might be partially attributed to the increased O2- level and decreased NO level. These results imply that calcium channel blockers + sulphonylurea combination therapy warrants further attention in

  12. Melatonin treatment during the incubation of sensitization attenuates methamphetamine-induced locomotor sensitization and MeCP2 expression.

    Science.gov (United States)

    Wu, Jintao; Zhu, Dexiao; Zhang, Jing; Li, Guibao; Liu, Zengxun; Sun, Jinhao

    2016-02-01

    Behavior sensitization is a long-lasting enhancement of locomotor activity after exposure to psychostimulants. Incubation of sensitization is a phenomenon of remarkable augmentation of locomotor response after withdrawal and reflects certain aspects of compulsive drug craving. However, the mechanisms underlying these phenomena remain elusive. Here we pay special attention to the incubation of sensitization and suppose that the intervention of this procedure will finally decrease the expression of sensitization. Melatonin is an endogenous hormone secreted mainly by the pineal gland. It is effective in treating sleep disorder, which turns out to be one of the major withdrawal symptoms of methamphetamine (MA) addiction. Furthermore, melatonin can also protect neuronal cells against MA-induced neurotoxicity. In the present experiment, we treated mice with low dose (10mg/kg) of melatonin for 14 consecutive days during the incubation of sensitization. We found that melatonin significantly attenuated the expression of sensitization. In contrast, the vehicle treated mice showed prominent enhancement of locomotor activity after incubation. MeCP2 expression was also elevated in the vehicle treated mice and melatonin attenuated its expression. Surprisingly, correlation analysis suggested significant correlation between MeCP2 expression in the nucleus accumbens (NAc) and locomotion in both saline control and vehicle treated mice, but not in melatonin treated ones. MA also induced MeCP2 over-expression in PC12 cells. However, melatonin failed to reduce MeCP2 expression in vitro. Our results suggest that melatonin treatment during the incubation of sensitization attenuates MA-induced expression of sensitization and decreases MeCP2 expression in vivo. PMID:26416230

  13. A peptide antagonist of ErbB receptors, Inherbin3, induces neurite outgrowth through ErbB1 inhibition

    DEFF Research Database (Denmark)

    Xu, Ruodan; Pankratova, Stanislava; Christiansen, Søren Hofman Oliveira;

    2013-01-01

    activity and activation of ErbB4 by NRG-1β induced neurite extension, suggesting that ErbB1 and ErbB4 act as negative and positive regulators, respectively, of the neuritogenic response. Inherbin3, inhibited activation not only of ErbB1 but also of ErbB4 in primary neurons, strongly induced neurite...... outgrowth in rat cerebellar granule neurons, indicating that this effect mainly was due to inhibition of ErbB1 activation....

  14. Extreme Thermal Sensitivity and Pain-Induced Sensitization in a Fibromyalgia Patient

    Directory of Open Access Journals (Sweden)

    Fong Wong

    2010-01-01

    Full Text Available During the course of a psychophysical study of fibromyalgia syndrome (FMS, one of the subjects with a long history of headache and facial pain displayed an extraordinarily severe thermal allodynia. Her stimulus-response function for ratings of cutaneous heat pain revealed a sensitivity clearly beyond that of normal controls and most FMS subjects. Specially designed psychophysical methods showed that heat sensitivity sometimes increased dramatically within a series of stimuli. Prior exposure to moderate heat pain served as a trigger for allodynic ratings of series of normally neutral thermal stimulation. These observations document a case of breakthrough pain sensitivity with implications for mechanisms of FMS pain.

  15. SYM 2206 (a potent non-competitive AMPA receptor antagonist elevates the threshold for maximal electroshock-induced seizures in mice

    Directory of Open Access Journals (Sweden)

    Luszczki Jarogniew J.

    2014-06-01

    Full Text Available The aim of this study was to determine the effect of SYM 2206 (a potent non-competitive AMPA receptor antagonist on the threshold for maximal electroshock (MEST-induced seizures in mice. Electroconvulsions were produced in mice by means of a current (sinewave, 50 Hz, maximum 500 V, strength from 4 to 14 mA, 0.2-s stimulus duration, tonic hind limb extension taken as the endpoint delivered via ear-clip electrodes. SYM 2206 administered systemically (i.p., 30 min before the MEST test, at doses of 2.5 and 5 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, SYM 2206 at doses of 10 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (P<0.01 and P<0.001. Linear regression analysis of SYM 2206 doses and their corresponding threshold increases allowed for the determination of threshold increasing doses by 20% and 50% (TID20 and TID50 values that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 and TID50 values for SYM 2206 were 4.25 and 10.56 mg/kg, respectively. SYM 2206 dose-dependently increased the threshold for MEST-induced seizures, suggesting the anticonvulsant action of the compound in this seizure model in mice.

  16. Effect of the Toll-Like Receptor 4 Antagonist Eritoran on Retinochoroidal Inflammatory Damage in a Rat Model of Endotoxin-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Feyzahan Ekici

    2014-01-01

    Full Text Available Purpose. We investigated the effect of eritoran, a Toll-like receptor 4 antagonist, on retinochoroidal inflammatory damage in an endotoxin-induced inflammatory rat model. Methods. Endotoxin-induced inflammatory model was obtained by intraperitoneal injection of 1.5 mg/kg lipopolysaccharide (LPS. Group 1 had control rats; in groups 2-3 LPS and 0.5 mg/kg sterile saline were injected; and in groups 4-5 LPS and 0.5 mg/kg eritoran were injected. Blood samples were taken and eyes were enucleated after 12 hours (h (groups 2 and 4 or 24 hours (Groups 3 and 5. Tumor necrosis factor-α (TNF-α and malondialdehyde (MDA levels in the serum and retinochoroidal tissue and nuclear factor kappa-B (NFκB levels in retinochoroidal tissue were determined. Histopathological examination was performed and retinochoroidal changes were scored. Results. Eritoran treatment resulted in lower levels of TNF-α, MDA, and NFκB after 12 h which became significant after 24 h. Serum TNF-α and retinochoroidal tissue NFκB levels were similar to control animals at the 24th h of the study. Eritoran significantly reversed histopathological damage after 24 h. Conclusions. Eritoran treatment resulted in less inflammatory damage in terms of serum and retinochoroidal tissue parameters.

  17. Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis.

    Science.gov (United States)

    Chang, Yao-Wen; Hsieh, Pei-Wen; Chang, Yu-Tsui; Lu, Meng-Hong; Huang, Tur-Fu; Chong, Kowit-Yu; Liao, Hsiang-Ruei; Cheng, Ju-Chien; Tseng, Ching-Ping

    2015-12-15

    Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCμ were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective. PMID:26528756

  18. CLINICAL COMPARISON OF THE SELECTIVE SEROTONIN3 ANTAGONISTS RAMOSETRON AND GRANISETRON IN TREATING ACUTE CHEMOTHERAPY-INDUCED EMESIS, NAUSEA AND ANOREXIA

    Institute of Scientific and Technical Information of China (English)

    冯奉仪; 张频; 何友兼; 李宇红; 周美珍; 陈刚; 李琳

    2002-01-01

    Objective. The efficacies of the selective 5-hydroxytryptamine3 (5-HT3) antagonists- - ramosetron (0.3 mg) and granisetron (3 mg) in treating acute chemotherapy-induced digestive system dysfunction were compared. Methods. A total of 111 patients were enrolled in a single-blind, randomized crossover study; with data from 98 were used to assess efficacy and data from 110 to assess the safety profile. Ramosetron or granisetron was given intraveneously 15 min before chemotherapy. Results. The ability of ramosetron to prevent emesis, nausea and anorexia was similar to granisetron during the first 6 h following the administration of chemotherapy, cisplatin or doxorubicin. However, during the first 24 h after chemotherapy, significant differences between ramosetron and granisetron appeared: emetic episode (P=0.068), nausea (P=0.006), and anorexia (P=0.048) remained lower in ramosetron-treated patients. The safety profile of ramosetron was similar to that of granisetron and adverse events in both groups were generally mild and transient. Conclusion. Ramosetron is more potent and longer-lasting than granisetron in preventing chemotherapy-induced digestive disturbances.

  19. CLINICAL COMPARISON OF THE SELECTIVE SEROTONIN3 ANTAGONISTS RAMOSETRON AND GRANISETRON IN TREATING ACUTE CHEMOTHERAPY—INDUCED EMESIS,NAUSEA AND ANOREXIA

    Institute of Scientific and Technical Information of China (English)

    冯奉仪; 何友兼; 等

    2002-01-01

    Objective:The efficacies of the selective 5-hydroxytryptamine3 (5-HT3) antagonists-ramosetron (0.3mg) and granisetron (3mg) in treating acute chemotherapy-induced digestive system dysfunction were compared.Methods:A total of 111 patients were enrolled in a single-blind,randomized crossover study;with data from 98 were used to assess efficacy and data from 110 to assess the safety profile.Ramosetron or granisetron was given intraveneously 15 min before chemotherapy.Results:The ability of ramosetron to prevent emesis,nausea and anorexia was similar to granisetron during the first 6h following the administration of chemotherapy,cisplatin or doxorubicin.However,during the first 24h after chemotherapy,significant differences between ramosetron and granisetron appeared:emetic episode (P=0.068),nausea(P=0.006),and anorexia(P=0.048) remained lower in ramosetron-treated patients.The safety profile of ramosetron was similar to that of granisetron and adverse events in both groups were generally mild and transient.Conclusion:Ramosetron is more potent and longer-lasting than granisetron in preventing chemothera py-induced digestive disturbances.

  20. Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity

    Science.gov (United States)

    We studied whether cannabinoid receptor (CB1) blockade with rimonabant has an anti-inflammatory effect in obese mice, and whether this effect depends on weight loss and/or diet consumption. High-fat diet (HFD)-induced obese mice were treated orally with rimonabant (HFD-R) or vehicle (HFD-V) for 4 we...

  1. Compact High Sensitive Laser-Induced Breakdown Spectroscopy Instrument Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Laser induced breakdown spectroscopy (LIBS) is a versatile tool for in situ substance characterization. Existing LIBS instruments are not compact enough for space...

  2. Prophylaxis of Radiation-Induced Nausea and Vomiting Using 5-Hydroxytryptamine-3 Serotonin Receptor Antagonists: A Systematic Review of Randomized Trials

    Energy Technology Data Exchange (ETDEWEB)

    Salvo, Nadia; Doble, Brett [Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario (Canada); Khan, Luluel [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Amirthevasar, Gayathri [Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario (Canada); Dennis, Kristopher [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Pasetka, Mark; DeAngelis, Carlo [Department of Oncology Pharmacy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Tsao, May [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada)

    2012-01-01

    Purpose: To systematically review the effectiveness and safety of 5-hydroxytryptamine-3 receptor antagonists (5-HT3 RAs) compared with other antiemetic medication or placebo for prophylaxis of radiation-induced nausea and vomiting. Methods and Materials: We searched the following electronic databases: MEDLINE, Embase, the Cochrane Central Register of Controlled Clinical Trials, and Web of Science. We also hand-searched reference lists of included studies. Randomized, controlled trials that compared a 5-HT3 RA with another antiemetic medication or placebo for preventing radiation-induced nausea and vomiting were included. We excluded studies recruiting patients receiving concomitant chemotherapy. When appropriate, meta-analysis was conducted using Review Manager (v5) software. Relative risks were calculated using inverse variance as the statistical method under a random-effects model. We assessed the quality of evidence by outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results: Eligibility screening of 47 articles resulted in 9 included in the review. The overall methodologic quality was moderate. Meta-analysis of 5-HT3 RAs vs. placebo showed significant benefit for 5-HT3 RAs (relative risk [RR] 0.70; 95% confidence interval [CI] 0.57-0.86 for emesis; RR 0.84, 95% CI 0.73-0.96 for nausea). Meta-analysis comparing 5-HT3 RAs vs. metoclopramide showed a significant benefit of the 5-HT3 RAs for emetic control (RR 0.27, 95% CI 0.15-0.47). Conclusion: 5-Hydroxytryptamine-3 RAs are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention. 5-Hydroxytryptamine-3 RAs are suggested for prevention of emesis. Limited evidence was found regarding delayed emesis, adverse events, quality of life, or need for rescue medication. Future randomized, controlled trials should evaluate different 5-HT3 antiemetics and new agents with novel mechanisms of action such at the NK

  3. Sensitivity and subsequent "down regulation" of sensitivity induced by chlorocresol in guinea pigs

    DEFF Research Database (Denmark)

    Andersen, Klaus Ejner

    1985-01-01

    Chlorocresol was shown to have great potential for contact sensitization in the guinea-pig maximization test at the Day-21 challenge; 2 weeks later, the reactivity was significantly decreased. Cyclophosphamide (250 mg/kg) was interperitoneally injected and used as a modulator for the immune...... response. When cyclophosphamide was administered 3 days before the first challenge, the decrease in reactivity from Day 21 to Day 35 was reversed. This indicates that the reduction in sensitivity was caused by an immunologic mechanism--probably the formation of suppressor cells. This phenomenon is called...

  4. Chlorine Dioxide Induced Multiple Chemical Sensitivity: MMPI Validity Problems.

    Science.gov (United States)

    Tentoni, Stuart C.

    This paper discusses Minnesota Multiphasic Personality Inventory (MMPI) data obtained from individuals exposed to chlorine dioxide in the workplace who developed Multiple Chemical Sensitivity Syndrome. The paper explores current research on chlorine dioxide exposed persons who were misdiagnosed on the basis of MMPI interpretations. Difficulties…

  5. Comparison and Analysis of Delirium Induced by Histamine H2 Receptor Antagonists and Proton Pump Inhibitors in Cancer Patients

    Directory of Open Access Journals (Sweden)

    Shiro Fujii

    2012-07-01

    Full Text Available Objective: H2 blockers have been reported to be responsible for drug-induced delirium. We compared the incidence of delirium between two groups of patients who were treated with H2 blockers (H2 group or proton pump inhibitors (PPI group for anastomotic ulcer prevention following surgical treatment of esophageal cancer. Method: The incidence and severity of delirium were retrospectively compared in patients of the H2 group (30 cases; age, 65.2 ± 8.1 years and the PPI group (30 cases; 65.2 ± 6.5 years. The diagnosis of delirium was based on the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision. Delirium severity was rated on the Delirium Rating Scale (DRS. Results: The incidence of delirium was significantly lower in the PPI group than in the H2 group (p = 0.047. In the 11 patients from the H2 group who developed delirium, discontinuation of H2 blockers resulted in a significant reduction in the DRS score (p = 0.009. In three patients for whom H2 blockers were discontinued, DRS scores decreased by 50% or more three days after discontinuation compared to the prediscontinuation score. Conclusions: These results suggested that switching antiulcer drugs from H2 blockers to PPIs reduced delirium and thus provided an appropriate coping method for drug-induced delirium from antiulcer drugs.

  6. RF Cavity Induced Sensitivity Limitations on Beam Loss Monitors

    Science.gov (United States)

    Kastriotou, M.; Degiovanni, A.; Sousa, F. S. Domingues; Effinger, E.; Holzer, E. B.; Quirante, J. L. Navarro; del Busto, E. N.; Tecker, F.; Viganò, W.; Welsch, C. P.; Woolley, B. J.

    Due to the secondary showers generated when a particle hits the vacuum chamber, beam losses at an accelerator may be detected via radiation detectors located near the beam line. Several sources of background can limit the sensitivity and reduce the dynamic range of a Beam Loss Monitor (BLM). This document concentrates on potential sources of background generated near high gradient RF cavities due to dark current and voltage breakdowns. An optical fibre has been installed at an experiment of the Compact Linear Collider (CLIC) Test Facility (CTF3), where a dedicated study of the performance of a loaded and unloaded CLIC accelerating structure is undergoing. An analysis of the collected data and a benchmarking simulation are presented to estimate BLM sensitivity limitations. Moreover, the feasibility for the use of BLMs optimised for the diagnostics of RF cavities is discussed.

  7. pH-sensitive liposomes: acid-induced liposome fusion.

    OpenAIRE

    Connor, J.; Yatvin, M B; Huang, L.

    1984-01-01

    Sonicated unilamellar liposomes containing phosphatidylethanolamine and palmitoylhomocysteine fuse rapidly when the medium pH is lowered from 7 to 5. Liposome fusion was demonstrated by (i) mixing of the liposomal lipids as shown by resonance energy transfer, (ii) gel filtration, and (iii) electron microscopy. The pH-sensitive fusion of liposomes was observed only when palmitoylhomocysteine (greater than or equal to 20 mol%) was present in the liposomes. The presence of phosphatidyl-ethanolam...

  8. Does pharmacogenomics account for variability in control of acute chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists?

    Science.gov (United States)

    Trammel, Morgan; Roederer, Mary; Patel, Jai; McLeod, Howard

    2013-06-01

    Chemotherapy-induced nausea and vomiting is one of the most concerning adverse drug effects from cytotoxic chemotherapy. Despite appropriate use of antiemetic guidelines, 20-30 % of patients experience breakthrough nausea and vomiting secondary to chemotherapy. To assess the variability of 5-hydroxytryptamine type 3 receptor antagonist efficacy caused by genetic variation, a review of the available literature was conducted. From the literature, three sources of pharmacogenomic variability were identified: polymorphisms associated with 5-hydroxytryptamine type 3 receptor subunits, drug metabolism via cytochromes P450, and drug transport in the body. Testing for receptor subunit polymorphisms is not applicable to a clinical setting at this time; however, cytochrome P450 2D6 testing is FDA-approved and widely accessible. Cytochrome P450 2D6 ultrarapid metabolizers and poor metabolizers displayed altered antiemetic efficacy when compared with intermediate metabolizers and extensive metabolizers. We postulate that testing for cytochrome P450 2D6 phenotypes may be the most accessible way to provide individualized antiemetic therapy in the future.

  9. Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation

    International Nuclear Information System (INIS)

    Clinicians often experience extrahepatic metastases associated with hepatocellular carcinoma (HCC), even if no evidence of intrahepatic recurrence after treatment is observed. We investigated the pretreatment predictors of extrahepatic metastases in HCC patients. Patients diagnosed with HCC without evidence of extrahepatic metastases were prospectively enrolled. We evaluated the correlation between extrahepatic metastases and pretreatment clinical variables, including serum tumor markers. A total of 354 patients were included. Seventy-six patients (21%) had extrahepatic metastases during the observation period (median, 25.3 months; range, 0.6-51.3 months). Cox regression multivariate analysis showed that serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) production levels, the intrahepatic tumor stage, platelet count, and portal vein thrombosis were independent risk factors for extrahepatic metastases. Patients with a PIVKA-II production ≥ 300 mAU/mL had a 2.7-fold (95% confidence interval; 1.5-4.8; P < 0.001) and 3.7-fold (95% confidence interval; 2.0-6.6; P < 0.001) increased risk for extrahepatic metastases after adjustment for stage, platelet count, alpha-fetoprotein ≥ 400 ng/mL, and portal vein thrombosis according to the AJCC and BCLC staging systems, respectively. PIVKA-II production levels might be a good candidate predictive marker for extrahepatic HCC metastases, especially in patients with smaller and/or fewer tumors in the liver with in stages regardless of serum alpha-fetoprotein

  10. Hepatoid carcinoma of the pancreas producing protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP).

    Science.gov (United States)

    Matsueda, Kazuhiro; Yamamoto, Hiroshi; Yoshida, Yasuo; Notohara, Kenji

    2006-10-01

    We describe a rare case of hepatoid carcinoma of the pancreas with production of protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP). The patient was a 49-year-old woman admitted because of high serum levels of PIVKA-II (1.63 AU/ml) and AFP (623 ng/ml) and abnormal ultrasonographic findings of the pancreas, found incidentally at medical checkup. Both ultrasonography and computed tomography showed swelling of the pancreas with small areas of low density, but no hepatic lesions. The serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were not increased. A PIVKA-II and AFP-producing pancreatic cancer was strongly suspected, and total pancreatectomy was performed. Pathological examination showed that the tumor cells were arranged in trabecular and solid patterns with bile production, and were immunohistochemically positive for PIVKA-II and AFP, resembling hepatocellular carcinoma cells. The tumor was diagnosed as hepatoid carcinoma of the pancreas, and the patient has survived 48 months after initial diagnosis. It is important that hepatoid carcinoma be considered as a possible malignant tumor of the pancreas, and simultaneous measurement of the serum levels of AFP and PIVKA-II will enable earlier diagnosis. This is the first report describing hepatoid carcinoma of the pancreas producing PIVKA-II.

  11. Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation

    Directory of Open Access Journals (Sweden)

    Yoon Jung-Hwan

    2011-10-01

    Full Text Available Abstract Background Clinicians often experience extrahepatic metastases associated with hepatocellular carcinoma (HCC, even if no evidence of intrahepatic recurrence after treatment is observed. We investigated the pretreatment predictors of extrahepatic metastases in HCC patients. Methods Patients diagnosed with HCC without evidence of extrahepatic metastases were prospectively enrolled. We evaluated the correlation between extrahepatic metastases and pretreatment clinical variables, including serum tumor markers. Results A total of 354 patients were included. Seventy-six patients (21% had extrahepatic metastases during the observation period (median, 25.3 months; range, 0.6-51.3 months. Cox regression multivariate analysis showed that serum protein induced by vitamin K absence or antagonist-II (PIVKA-II production levels, the intrahepatic tumor stage, platelet count, and portal vein thrombosis were independent risk factors for extrahepatic metastases. Patients with a PIVKA-II production ≥ 300 mAU/mL had a 2.7-fold (95% confidence interval; 1.5-4.8; P Conclusion PIVKA-II production levels might be a good candidate predictive marker for extrahepatic HCC metastases, especially in patients with smaller and/or fewer tumors in the liver with in stages regardless of serum alpha-fetoprotein.

  12. REM sleep deprivation induces changes of down regulatory antagonist modulator (DREAM) expression in the ventrobasal thalamic nuclei of sprague-dawley rats.

    Science.gov (United States)

    Siran, Rosfaiizah; Ahmad, Asma Hayati; Abdul Aziz, Che Badariah; Ismail, Zalina

    2014-12-01

    REM sleep is a crucial component of sleep. Animal studies indicate that rapid eye movement (REM) sleep deprivation elicits changes in gene expression. Down regulatory antagonist modulator (DREAM) is a protein which downregulates other gene transcriptions by binding to the downstream response element site. The aim of this study is to examine the effect of REM sleep deprivation on DREAM expression in ventrobasal thalamic nuclei (VB) of rats. Seventy-two male Sprague-Dawley rats were divided into four major groups consisting of free-moving control rats (FMC) (n = 18), 72-h REM sleep-deprived rats (REMsd) (n = 18), 72-h REM sleep-deprived rats with 72-h sleep recovery (RG) (n = 18), and tank control rats (TC) (n = 18). REM sleep deprivation was elicited using the inverted flower pot technique. DREAM expression was examined in VB by immunohistochemical, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) studies. The DREAM-positive neuronal cells (DPN) were decreased bilaterally in the VB of rats deprived of REM sleep as well as after sleep recovery. The nuclear DREAM extractions were increased bilaterally in animals deprived of REM sleep. The DREAM messenger RNA (mRNA) levels were decreased after sleep recovery. The results demonstrated a link between DREAM expression and REM sleep deprivation as well as sleep recovery which may indicate potential involvement of DREAM in REM sleep-induced changes in gene expression, specifically in nociceptive processing.

  13. Lipopolysaccharide-induced hyperalgesia of intracranial capsaicin sensitive afferents in conscious rats

    NARCIS (Netherlands)

    Kemper, RHA; Spoelstra, MB; Meijler, WJ; Ter Horst, GJ

    1998-01-01

    Migraineous and non-migraineous headache is reported to be at highest intensity after an infection. This study investigated whether activation of the immune system can induce hyperalgesia in intracranial capsaicin sensitive afferents. The effects of intraperitoneal injected lipopolysaccharides (LPS)

  14. Systemic or intra-amygdala infusion of an endocannabinoid CB1 receptor antagonist AM251 blocked propofol-induced anterograde amnesia.

    Science.gov (United States)

    Ren, Y; Wang, J; Xu, P B; Xu, Y J; Miao, C H

    2015-01-01

    Propofol is well-known for its anterograde amnesic actions. However, a recent experiment showed that propofol can also produce retrograde memory enhancement effects via an interaction with the endocannabinoid CB1 system. Therefore, the authors hypothesized that the regulating effect of propofol on the endocannabinoid CB1 system might also decrease the anterograde amnesic effect of propofol under some conditions, which might be a risk factor for intraoperative awareness. Since, the basolateral amygdala (BLA) has been confirmed to mediate propofol-induced anterograde amnesia and the BLA contains a high concentration of CB1 receptors, the authors investigated whether and how the endocannabinoid system, particularly the CB1 receptor within BLA, influences propofol-induced anterograde amnesia. Male Sprague-Dawley rats trained with inhibitory avoidance (IA) were systematically pre-trained using a memory-impairing dose of propofol (25 mg/kg). Before propofol administration, rats received an intraperitoneal injection of a CB1 receptor antagonist AM251 (1 mg/kg or 2 mg/kg) or a bilateral intra-BLA injection of AM251 (0.6 ng or 6 ng per 0.5 μl). Twenty-four hours after IA training, the IA retention latency was tested. It was found that systemic or intra-BLA injection of a non-regulating dose of AM251 (2 mg/kg or 6 ng per 0.5 μl, respectively) blocked the memory-impairing effect of propofol. These results indicate that the anterograde amnesic effect of propofol is mediated, in part, by activation of the CB1 cannabinoid receptors in the BLA.

  15. The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Michel Alexander Steiner

    2013-12-01

    Full Text Available The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1 in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO associated with metabolic syndrome (MetS. Rats were fed either standard chow (SC or a cafeteria (CAF diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% versus controls and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this

  16. Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: possible implication of serotonergic system.

    Science.gov (United States)

    Gupta, Deepali; Radhakrishnan, Mahesh; Kurhe, Yeshwant

    2014-12-01

    Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes. Experimentally, Swiss albino mice were rendered diabetic by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg). After 8 weeks, diabetic mice received a single dose of vehicle/ondansetron (0.5 and 1 mg/kg, p.o.)/fluoxetine (the positive control, 10 mg/kg p.o.) for 28 days. Thereafter, behavioral studies were conducted to test depression-like behavior using forced swim test (FST) and anxiety-like deficits using hole-board and light-dark tests, followed by biochemical estimation of serotonin content in discrete brain regions. The results demonstrated that, STZ-induced diabetic mice exhibited increased duration of immobility and decreased swimming behavior in FST, reduced exploratory behavior during hole-board test and increased aversion to brightly illuminated light area in light-dark test as compared to non-diabetic mice, while ondansetron (similar to fluoxetine) treatment significantly reversed the same. Biochemical assay revealed that ondansetron administration attenuated diabetes-induced neurochemical impairment of serotonin function, indicated by elevated serotonin levels in discrete brain regions of diabetic mice. Collectively, the data indicate that ondansetron may reverse depression and anxiety-like behavioral deficits associated with diabetes in mice and modulation of serotonergic activity may be a key mechanism of the compound.

  17. Olmesartan, an AT1 Antagonist, Attenuates Oxidative Stress, Endoplasmic Reticulum Stress and Cardiac Inflammatory Mediators in Rats with Heart Failure Induced by Experimental Autoimmune Myocarditis

    Directory of Open Access Journals (Sweden)

    Vijayakumar Sukumaran, Kenichi Watanabe, Punniyakoti T. Veeraveedu, Narasimman Gurusamy, Meilei Ma, Rajarajan A. Thandavarayan, Arun Prasath Lakshmanan, Ken'ichi Yamaguchi, Kenji Suzuki, Makoto Kodama

    2011-01-01

    Full Text Available Studies have demonstrated that angiotensin II has been involved in immune and inflammatory responses which might contribute to the pathogenesis of immune-mediated diseases. Recent evidence suggests that oxidative stress may play a role in myocarditis. Here, we investigated whether olmesartan, an AT1R antagonist protects against experimental autoimmune myocarditis (EAM by suppression of oxidative stress, endoplasmic reticulum (ER stress and inflammatory cytokines. EAM was induced in Lewis rats by immunization with porcine cardiac myosin, were divided into two groups and treated with either olmesartan (10 mg/kg/day or vehicle for a period of 21 days. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Treatment with olmesartan attenuated the myocardial mRNA expressions of proinflammatory cytokines, [Interleukin (IL-1β, monocyte chemoattractant protein-1, tumor necrosis factor-α and interferon-γ] and the protein expression of tumor necrosis factor-α compared with that of vehicle-treated rats. Myocardial protein expressions of AT1R, NADPH oxidase subunits (p47phox, p67phox, gp91phox and the expression of markers of oxidative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal, and the cardiac apoptosis were also significantly decreased by the treatment with olmesartan compared with those of vehicle-treated rats. Furthermore, olmesartan treatment down-regulated the myocardial expressions of glucose regulated protein-78, growth arrest and DNA damage-inducible gene, caspase-12, phospho-p38 mitogen-activated protein kinase (MAPK and phospho-JNK. These findings suggest that olmesartan protects against EAM in rats, at least in part via suppression of oxidative stress, ER stress and inflammatory cytokines.

  18. Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity

    DEFF Research Database (Denmark)

    Holst, Helle; Arendt-Nielsen, Lars; Mosbech, Holger;

    2011-01-01

    in experimental pain models to provoke peripheral and central sensitization. In patients with symptoms elicited by odorous chemicals capsaicin-induced secondary hyperalgesia and temporal summation were assessed as markers for abnormal central nociceptive processing together with neurogenic inflammation (flare).......the underlying cause of pathophysiological mechanisms triggering multiple chemical sensitivity (MCS) remains disputed.Recently, alterations in the central nervous system, for example,central sensitization, similar to various chronic pain disorders, have been suggested. Capsaicin is used...

  19. 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...

  20. Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death.

    Science.gov (United States)

    Burns, Kelly E; Thévenin, Damien

    2015-12-15

    Even though abnormal expression of G protein-coupled receptors (GPCRs) and of their ligands is observed in many cancer cells of various origins, only a few anti-cancer compounds directly act on their signalling. One promising approach to modulate their activity consists of targeting the receptor cytoplasmic surfaces interacting with the associated G-proteins using peptides mimicking the intracellular loops of the receptor. Thus, to be fully effective, the peptide mimics must be selectively targeted to the tumour while sparing healthy tissues, translocated across the cell membrane and stay anchored to the cytoplasmic leaflet of the plasma membrane. In the present study, we introduce a novel way to selectively target and inhibit the activity of a GPCR in cancer cells under acidic conditions, such as those found in solid tumours. We find that the conjugation of a peptide fragment derived from the third intracellular loop (i3) of the protease-activated receptor 1 (PAR1) to a peptide that can selectively target tumours solely based on their acidity [pH(Low) Insertion Peptide (pHLIP)], produces a construct capable of effectively down-regulating PAR1 activity in a concentration- and pH-dependent manner and of inducing a potent cytotoxic effect in a panel of cancer cells that is proportional to the relative level of receptor expression at the cell surface. This strategy not only allows for a more selective targeting and specific intracellular delivery than current approaches, but also offers new possibilities for developing novel anti-cancer drugs targeting GPCRs. PMID:26424552

  1. Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Anna Andrzejewska; Jan W. Dlugosz; Albert Augustynowicz

    2005-01-01

    AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P<0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P<0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P<0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P<0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired

  2. A Randomised Trial Evaluating the Effects of the TRPV1 Antagonist SB705498 on Pruritus Induced by Histamine, and Cowhage Challenge in Healthy Volunteers

    OpenAIRE

    Gibson, Rachel A.; Jon Robertson; Harshna Mistry; Stewart McCallum; Disala Fernando; Melody Wyres; Gil Yosipovitch

    2014-01-01

    BACKGROUND: Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and...

  3. A Randomised Trial Evaluating the Effects of the TRPV1 Antagonist SB705498 on Pruritus Induced by Histamine, and Cowhage Challenge in Healthy Volunteers

    OpenAIRE

    Gibson, Rachel A.; Robertson, Jon; Mistry, Harshna; McCallum, Stewart; Fernando, Disala; Wyres, Melody; Yosipovitch, Gil

    2014-01-01

    Background Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and ...

  4. Complementary roles of neurotrophin 3 and a N-methyl-d-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity

    OpenAIRE

    Duan, Maoli; Agerman, Karin; Ernfors, Patrik; Canlon, Barbara

    2000-01-01

    Recent progress has been made regarding the prevention of hearing loss. However, the complete protection of both hair cells and spiral ganglion neurons, with restored function, has not yet been achieved. It has been shown that spiral ganglion neuronal loss can be prevented by neurotrophin 3 (NT3) and hair cell damage by N-methyl-d-aspartate (NMDA) receptor antagonists. Here we demonstrate that the combined treatment with MK801, a NMDA antagonist, and NT3 protect both cochlear morphology and p...

  5. Intracerebroventricular injection of mu- and delta-opiate receptor antagonists block 60 Hz magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

    Science.gov (United States)

    Lai, H; Carino, M

    1998-01-01

    In previous research, we have found that acute exposure to a 60 Hz magnetic field decreased cholinergic activity in the frontal cortex and hippocampus of the rat as measured by sodium-dependent high-affinity choline uptake activity. We concluded that the effect was mediated by endogenous opioids inside the brain because it could be blocked by pretreatment of rats before magnetic field exposure with the opiate antagonist naltrexone, but not by the peripheral antagonist naloxone methiodide. In the present study, the involvement of opiate receptor subtypes was investigated. Rats were pretreated by intracerebroventricular injection of the mu-opiate receptor antagonist, beta-funaltrexamine, or the delta-opiate receptor antagonist, naltrindole, before exposure to a 60 Hz magnetic field (2 mT, 1 hour). It was found that the effects of magnetic field on high-affinity choline uptake in the frontal cortex and hippocampus were blocked by the drug treatments. These data indicate that both mu- and delta-opiate receptors in the brain are involved in the magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

  6. A new buprenorphine analogy,thenorphine,inhibits morphine-induced behavioral sensitization in mice

    Institute of Scientific and Technical Information of China (English)

    Wen-li ZHAO; Ze-hui GONG; Jian-hui LIANG

    2004-01-01

    AIM: To investigate effects of thenorphine, a new compound of partial agonist of μ-opioid receptor, on the locomotor activity and the behavioral sensitization to morphine in mice. METHODS: Locomotor activity was observed after administration of thenorphine or co-administration of thenorphine and morphine in mice. Mice were induced behavioral sensitization to morphine by intraperitoneal injection of 20 mg/kg morphine once daily for 7 d. Thenorphine was co-administrated with morphine to observe the effects of thenorphine on the development, transfer and expression of morphine-induced behavioral sensitization. RESULTS: A single dose of thenorphine (0.0625, 0.25, and 1.0mg/kg) could dose-dependently inhibit the locomotor activity in mice (P<0.05), repeated administrations of thenorphine, however, were not able to induce locomotor sensitization, but induced tolerance. Pretreatment with thenorphine 30 min prior to morphine effectively inhibited the psychomotor effect of morphine in mice (P<0.01).Co-administration of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the development,transfer, and expression of behavioral sensitization to morphine in mice (P<0.05 or P<0.01). CONCLUSION:Thenorphine inhibited morphine-induced behavioral sensitization in mice, suggesting that thenorphine may be effective against the addiction of opioids.

  7. A new buprenorphine analogy, thenorphine,inhibits morphine-induced behavioral sensitization in mice

    Institute of Scientific and Technical Information of China (English)

    Wen-liZHAO; Ze-huiGONG; Jian-huiLIANG

    2004-01-01

    AIM: To investigate effects of thenorphine, a new compound of partial agonist of μ-opioid receptor, on the locomotor activity and the behavioral sensitization to morphine in mice. METHODS: Locomotor activity was observed after administration of thenorphine or co-administration of thenorphine and morphine in mice. Mice were induced behavioral sensitization to morphine by intraperitoneal injection of 20 mg/kg morphine once daily for 7 d. Thenorphine was co-administrated with morphine to observe the effects of thenorphine on the development, transfer and expression of morphine-induced behavioral sensitization. RESULTS: A single dose of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the locomotor activity in mice (P<0.05), repeated administrations of thenorphine, however, were not able to induce locomotor sensitization, but induced tolerance. Pretreatment with thenorphine 30 min prior to morphine effectively inhibited the psychomotor effect of morphine in mice (P<0.01). Co-administration of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the development,transfer, and expression of behavioral sensitization to morphine in mice (P<0.05 or P<0.01). CONCLUSION:Thenorphine inhibited morphine-induced behavioral sensitization in mice, suggesting that thenorphine may be effective against the addiction of opioids.

  8. Dicentrine is preferentially antagonistic to rat aortic than splenic α1-adrenoceptor stimulation

    Institute of Scientific and Technical Information of China (English)

    MUSTAFA Mohd Rais; ACHIKE Francis Ifejika

    2000-01-01

    AIM: Dicentrine is a known α1-adrenoceptor antagonist, but its α1-adrenoceptor subtype selectivity has not yet been determined. We therefore, investigated the putative α1-adrenoceptor subtype selectivity of this agent. METHODS: Graded isometric contractile responses of rat aortic rings and spleen to phenylephrine were observed in the absence or presence of various concentrations of dicentrine. The pA2 values for dicentrine were determined.RESULTS: Aortic tissues were more sensitive to phenylephrine-induced connaction than the spleen tissues. Dicentrine was approximately 100 times more potent as an antagonist to the aortic contraction, than it was to the splenic contractions. CONCLUSION: Dicenuine is an a1-adrenoceptor antagonist which is more selective towards the putative α1D-adrenoceptor subtype of the rat aorta than the α1s-adrenoceptor of the spleen.

  9. Differential effects of LY235959, a competitive antagonist of the NMDA receptor on kappa-opioid receptor agonist induced responses in mice and rats.

    Science.gov (United States)

    Bhargava, H N; Thorat, S N

    1997-02-01

    The effects of the competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, LY235959, were determined on the analgesic and hypothermic effects as well as on the development of tolerance to these effects of U-50,488H, a kappa-opioid receptor agonist in mice and rats. In the mouse, a single injection of LY235959 given 10 min prior to U-50,488H did not modify the analgesic action of the latter. Similarly, chronic administration of LY235959 twice a day for 4 days did not modify U-50,488H-induced analgesia in mice. Repeated pretreatment of mice with LY235959 dose-dependently attenuated the development of tolerance to the analgesic actions of U-50,488H. In the rat, LY235959 by itself produced a significant analgesia and prior treatment of rats with LY235959 enhanced the analgesic action of U-50,488H. Similar effects were seen with the hypothermic action. Pretreatment of rats with LY235959 attenuated the development of tolerance to the analgesic but not to the hypothermic action of U-50,488H. These results provide evidence that LY235959 produces differential actions on nociception and thermic responses by itself and when given acutely with U-50,488H in mice and rats. However, when the animals are pretreated with LY235959, similar inhibitory effects are observed on the development of tolerance to the analgesic action of U-50,488H in both the species. These studies demonstrate an involvement of the NMDA receptor in the development of kappa-opioid tolerance and suggest that the biochemical consequences of an opioid's interaction with the opioid receptor are not the only factors that contribute to the acute and chronic actions of opioid analgesic drugs. PMID:9045999

  10. CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats.

    Science.gov (United States)

    Arai, Kiyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiroyuki; Homma, Tsuyoshi

    2016-09-01

    The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury. PMID:27384074

  11. The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats.

    Science.gov (United States)

    Khan, Nadia; Saad, Ali; Nurulain, Syed M; Darras, Fouad H; Decker, Michael; Sadek, Bassem

    2016-01-15

    Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual

  12. Geomagnetically induced currents in Uruguay: Sensitivity to modelling parameters

    Science.gov (United States)

    Caraballo, R.

    2016-11-01

    According to the traditional wisdom, geomagnetically induced currents (GIC) should occur rarely at mid-to-low latitudes, but in the last decades a growing number of reports have addressed their effects on high-voltage (HV) power grids at mid-to-low latitudes. The growing trend to interconnect national power grids to meet regional integration objectives, may lead to an increase in the size of the present energy transmission networks to form a sort of super-grid at continental scale. Such a broad and heterogeneous super-grid can be exposed to the effects of large GIC if appropriate mitigation actions are not taken into consideration. In the present study, we present GIC estimates for the Uruguayan HV power grid during severe magnetic storm conditions. The GIC intensities are strongly dependent on the rate of variation of the geomagnetic field, conductivity of the ground, power grid resistances and configuration. Calculated GIC are analysed as functions of these parameters. The results show a reasonable agreement with measured data in Brazil and Argentina, thus confirming the reliability of the model. The expansion of the grid leads to a strong increase in GIC intensities in almost all substations. The power grid response to changes in ground conductivity and resistances shows similar results in a minor extent. This leads us to consider GIC as a non-negligible phenomenon in South America. Consequently, GIC must be taken into account in mid-to-low latitude power grids as well.

  13. Effects of Estrogen Receptor Modulators on Morphine Induced Sensitization in Mice Memory

    Directory of Open Access Journals (Sweden)

    Mahdieh Anoush

    2015-11-01

    Full Text Available  Objective: In this study, the effects of estradiol valerate and raloxifenea selective estrogen receptor modulator; (SERM on morphine induced sensitization were examined in mice memory, according to the step-down passive avoidance task.  Method:The mice received morphine or estradiol and raloxifene for three days alone or in combination with morphine. After a drug free period of 5 days, the subjects received saline or morphine as pre- training treatments followed by a pre-test saline administration. The memory retrieval was evaluated using step-down passive avoidance test both on the training and test day. Results:The results illustrated that the three- day administration of morphine induced sensitization through the enhancement of memory retrieval (morphine induced sensitization in mice memory. Both the three- day administration of estradiol valerate alone and with morphine (5 mg/kg restored memory. On the other hand, the three- day administration of raloxifene had no effect on memory retrieval alone, but declined morphine induced sensitization in mice memory. Conclusion:The results of the study indicated that there is an interaction between estrogen receptor modulators and morphine induced sensitization in mice memory.

  14. Antigen-induced and non-antigen-induced histamine release from rat mast cells sensitized with mouse antiserum.

    Directory of Open Access Journals (Sweden)

    Kurose,Masao

    1981-10-01

    Full Text Available Marked IgE-mediated histamine release from rat mast cells sensitized in vitro with mouse antiserum occurs in the presence of added Ca++ and phosphatidylserine (PS, although a considerable degree of antigen-induced histamine release which may utilize intracellular or cell-bound calcium is also observed. The decay in the responsiveness to Ca++ of the sensitized cells stimulated by antigen in Ca++-free medium in the presence of PS is relatively slow, and maximum release is produced by Ca++ added 1 min after antigen. Histamine release also occurs when Ca++ is added after PS in the absence of antigen to the sensitized cells suspended in Ca++-free medium. Unlike the antigen-induced release, the intensity of this non-antigen-induced release varies depending on both mast-cell and antiserum pools. A heat-labile factor(s, which is different from antigen-specific IgE antibody and is also contained in normal mouse serum, is involved in this reaction. In the antigen-nondependent (PS + Ca++-induced release, no decay in the responsiveness to Ca++ is observed after PS addition. Both the antigen-induced and non-antigen-induced release are completed fairly rapidly and are dependent of temperature, pH and energy.

  15. Attenuation of KATP channel-opener induced shortening of repolarization time by alpha 1-adrenoceptor antagonist during ischemia in canine heart.

    Science.gov (United States)

    Tanabe, T; Aikawa, M; Deguchi, Y; Yoshioka, K; Handa, S

    2000-06-01

    The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and three of the nine dogs in the control group developed VT/VF. These results suggest that the alpha 1-adrenergic blocker bunazosin blunts the shortening effect of KATP channel activator on repolarization time, and that the KATP channel opener Y may be

  16. Inducible nitric oxide synthase after sensitization and allergen challenge of Brown Norway rat lung

    OpenAIRE

    Fang Liu, Shu; Haddad, El-Bdaoui; Adcock, Ian; Salmon, Michael; Koto, Hiro; Gilbey, Tom; Peter J. Barnes; Fan Chung, K

    1997-01-01

    We studied the effects of ovalbumin (OA) sensitization and challenge on inducible nitric oxide synthase (iNOS) gene and protein expression in Brown-Norway rats in vivo.By use of Northern analysis, a 4.4-kb iNOS mRNA transcript was weakly observed in control rat lung but there was a 3 fold increase in lungs sensitized to OA alone (P

  17. Effect of PMD-induced Pulse Broadening on Sensitivity and Frequency Spectrum

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The PMD-induced pulse broadening may cause the degradation of receiver sensitivity and has negative effects on the power spectrum of received signals. The expressions of PMD-induced pulse broadening effects on receiver sensitivity are derived based on the concept of mean square pulse width. The effects of PMD on the spectrum of received power are analyzed in detail. Finally, the scheme is discussed with which the power of a certain frequency component is extracted as a feedback control signal in a PMD compensation system.

  18. Proteomic Alterations in B Lymphocytes of Sensitized Mice in a Model of Chemical-Induced Asthma

    OpenAIRE

    Steven Haenen; Jeroen A.J. Vanoirbeek; Vanessa De Vooght; Liliane Schoofs; Benoit Nemery; Elke Clynen; Hoet, Peter H. M.

    2015-01-01

    Introduction and Aim The role of B-lymphocytes in chemical-induced asthma is largely unknown. Recent work demonstrated that transferring B lymphocytes from toluene diisocyanate (TDI)-sensitized mice into naïve mice, B cell KO mice and SCID mice, triggered an asthma-like response in these mice after a subsequent TDI-challenge. We applied two-dimensional difference gel electrophoresis (2D-DIGE) to describe the “sensitized signature” of B lymphocytes comparing TDI-sensitized mice with control mi...

  19. Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages

    OpenAIRE

    Nagarkar, Deepti R.; Bowman, Emily R.; Schneider, Dina; Wang, Qiong; Shim, Jee; Zhao, Ying; Linn, Marisa J.; McHenry, Christina L.; Gosangi, Babina; Bentley, J. Kelley; Tsai, Wan C.; Sajjan, Umadevi S.; Lukacs, Nicholas W; Hershenson, Marc B.

    2010-01-01

    Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated ovalbumin-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. Compared to sham-infected, ovalbumin-treated mice, virus-infected mice showed increase...

  20. Interactions Between Endocannabinoids and Stress-Induced Decreased Sensitivity to Natural Reward

    OpenAIRE

    Rademacher, David J.; Hillard, Cecilia J.

    2006-01-01

    Since endocannabinoids modulate reward processing and the stress response, we tested the hypothesis that endocannabinoids regulate stress-induced decreased sensitivity to natural reward. Restraint was used to produce stress-induced reductions in sucrose consumption and preference in male mice. Central cannabinoid receptor (CB1) signaling was modulated pharmacologically prior to the application of stress. The preference for sucrose over water was significantly decreased in mice exposed to rest...

  1. Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis.

    Science.gov (United States)

    Kim, Se-Lim; Liu, Yu-Chuan; Park, Young Ran; Seo, Seung Young; Kim, Seong Hun; Kim, In Hee; Lee, Seung Ok; Lee, Soo Teik; Kim, Dae-Ghon; Kim, Sang-Wook

    2015-03-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been evaluated in clinical trials, however, various malignant tumors are resistant to TRAIL. Parthenolide (PT) has recently been demonstrated as a highly effective anticancer agent and has been suggested to be used for combination therapy with other anticancer agents. In this study, we investigate the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. HT-29 (TRAIL-resistant) and HCT116 (TRAIL-sensitive) cells were treated with PT and/or TRAIL. The results demonstrated that combined treatment induced apoptosis which was determined using MTT, cell cycle analysis, Annexin V assay and Hoechst 33258 staining. Interestingly, we confirmed that HCT116 cells have much higher death receptor (DR) 5 than HT-29 cells and PT upregulates DR5 protein level and surface expression in both cell lines. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, p53 cytochrome C release, and caspase cascades. These results suggest that PT sensitizes TRAIL-induced apoptosis via upregulation of DR5 and mitochondria-dependent pathway. Combination treatment using PT and TRAIL may offer an effective strategy to overcome TRAIL resistance of certain CRC cells. PMID:25502339

  2. The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats.

    Science.gov (United States)

    Sadek, Bassem; Khan, Nadia; Darras, Fouad H; Pockes, Steffen; Decker, Michael

    2016-10-15

    Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2mg/kg, i.p.) and DIZ (0.1mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H2R as well as

  3. GENETIC BACKGROUND BUT NOT METALLOTHIONEIN PHENOTYPE DICTATES SENSITIVITY TO CADMIUM-INDUCED TESTICULAR INJURY IN MICE

    Science.gov (United States)

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to Cadmium-Induced Testicular Injury in MiceJie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2 and Curtis D. Klaassen1 ABSTRACTParenteral administrati...

  4. Contact sensitizers induce skin inflammation via ROS production and hyaluronic acid degradation.

    Directory of Open Access Journals (Sweden)

    Philipp R Esser

    Full Text Available BACKGROUND: Allergic contact dermatitis (ACD represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed the role of contact sensitizer induced ROS production and concomitant changes in hyaluronic acid metabolism on CHS responses. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed in vitro and in vivo ROS production using fluorescent ROS detection reagents. HA fragmentation was determined by gel electrophoresis. The influence of blocking ROS production and HA degradation by antioxidants, hyaluronidase-inhibitor or p38 MAPK inhibitor was analyzed in the murine CHS model. Here, we demonstrate that organic contact sensitizers induce production of reactive oxygen species (ROS and a concomitant breakdown of the extracellular matrix (ECM component hyaluronic acid (HA to pro-inflammatory low molecular weight fragments in the skin. Importantly, inhibition of either ROS-mediated or enzymatic HA breakdown prevents sensitization as well as elicitation of CHS. CONCLUSIONS/SIGNIFICANCE: These data identify an indirect mechanism of contact sensitizer induced innate inflammatory signaling involving the breakdown of the ECM and generation of endogenous danger signals. Our findings suggest a beneficial role for anti-oxidants and hyaluronidase inhibitors in prevention and treatment of ACD.

  5. Different effects of valproate on methamphetamine-and cocaine-induced behavioral sensitization in mice

    Institute of Scientific and Technical Information of China (English)

    Jun-XuLi; Jian-HuiLiang

    2004-01-01

    Multiple intermittent administration of psychostimulants induces a behavioral sensitization, which is characterized by the augmentation of locomotor activity and stereotyped behavior, even after their long-term withdrawal. This kind of behavioral effects is thought to serve as a useful animal model that mimics the behavioral responses in drug craving. Dopamine

  6. The pilosebaceous unit—a phthalate-induced pathway to skin sensitization

    Energy Technology Data Exchange (ETDEWEB)

    Simonsson, Carl, E-mail: carl.simonsson@chem.gu.se [Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg (Sweden); Stenfeldt, Anna-Lena; Karlberg, Ann-Therese [Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg (Sweden); Ericson, Marica B., E-mail: marica.ericson@physics.gu.se [Department of Physics, University of Gothenburg, SE-412 96, Gothenburg (Sweden); Jonsson, Charlotte A.M. [Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg (Sweden)

    2012-10-01

    Allergic contact dermatitis (ACD) is caused by low-molecular weight compounds called haptens. It has been shown that the potency of haptens can depend on the formulation in which they are applied on the skin. Specifically the sensitization potency of isothiocyanates, a group of haptens which can be released from e.g. adhesive tapes and neoprene materials, increases with the presence of phthalates; however, the underlying mechanisms are not clear. A better understanding of the mechanisms governing the potency of haptens is important, e.g. to improve the risk assessment and the formulation of chemicals in consumer products. In this study we have explored phthalate-induced effects on the sensitization potency, skin distribution, and reactivity of fluorescent model isothiocyanate haptens using non-invasive two-photon microscopy to provide new insights regarding vehicle effects in ACD. The data presented in this paper indicate that the sensitization potency of isothiocyanates increases when applied in combination with dibutylphthalate due to a specific uptake via the pilosebaceous units. The results highlight the importance of shunt pathways when evaluating the bioavailability of skin sensitizers. The findings also indicate that vehicle-dependent hapten reactivity towards stratum corneum proteins regulates the bioavailability, and thus the potency, of skin sensitizers. -- Highlights: ► Vehicle effects on sensitization potency were investigated in the LLNA. ► In vivo cutaneous absorption of contact sensitizers was visualized using TPM. ► Sensitizing potency of isothiocyanates depends on the presence of a phthalate. ► Phthalate induced cutaneous absorption via the pilosebaceous units. ► Vehicle-dependent reactivity regulates sensitization potency.

  7. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dae-Hee, E-mail: leedneo@gmail.com [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Dong-Wook [Department of Microbiology, Immunology, and Cancer Biology, University of VA (United States); Jung, Chang-Hwa [Division of Metabolism and Functionality Research, Korea Food Research Institute (Korea, Republic of); Lee, Yong J. [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Park, Daeho, E-mail: daehopark@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of)

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  8. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway

  9. Roscovitine sensitizes breast cancer cells to TRAIL-induced apoptosis through a pleiotropic mechanism

    Institute of Scientific and Technical Information of China (English)

    Gustavo Ortiz-Ferrón; Rosario Yerbes; Adriana Eramo; Ana I López-Pérez; Ruggero De Maria; Abelardo López-Rivas

    2008-01-01

    The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2L) is a member of the TNF gene superfamily that induces apoptosis upon engagement of cognate death receptors.While TRAIL is relatively non-toxic to normal cells,it selectively induces apoptosis in many transformed cells.Nevertheless,breast tumor cells are particularly resistant to the effects of TRAIL.Here we report that,in combination with the cyclin-dependent kinase inhibitor roscovitine,exposure to TRAIL induced marked apoptosis in the majority of TRAIL-resistant breast cancer cell Iines examined.Roscovitine facilitated TRAIL death-inducing signaling complex formation and the activation of caspase-8.The cFLIPL and eFLIPs FLICE-inhibitory proteins were significantly down-regulated following exposure to roscovitine and,indeed,the knockdown of cFLIP isoforms by siRNA sensitized breast tumor cells to TRAIL-induced apoptosis.In addition,we demonstrate that roscovitine strongly suppressed Mcl-1 expression and up-regulated E2F1 protein levels in breast tumor cells.Significantly,the silencing of Mcl-1 by siRNA sensitized breast tumor cells to TRAIL-induced apoptosis.Furthermore,the knockdown of E2F1 protein by siRNA reduced the sensitizing effect of roscovitine in TRAIL-induced apoptosis.In summary,our results reveal a pleitropic mechanism for the pro-apoptotic influence of roscovitine,highlighting its potential as an antitumor agent in breast cancer in combination with TRAIL.

  10. Calcium influences sensitivity to growth inhibition induced by a cell surface sialoglycopeptide

    Science.gov (United States)

    Betz, N. A.; Fattaey, H. K.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    While studies concerning mitogenic factors have been an important area of research for many years, much less is understood about the mechanisms of action of cell surface growth inhibitors. We have purified an 18 kDa cell surface sialoglycopeptide growth inhibitor (CeReS-18) which can reversibly inhibit the proliferation of diverse cell types. The studies discussed in this article show that three mouse keratinocyte cell lines exhibit sixty-fold greater sensitivity than other fibroblasts and epithelial-like cells to CeReS-18-induced growth inhibition. Growth inhibition induced by CeReS-18 treatment is a reversible process, and the three mouse keratinocyte cell lines exhibited either single or multiple cell cycle arrest points, although a predominantly G0/G1 cell cycle arrest point was exhibited in Swiss 3T3 fibroblasts. The sensitivity of the mouse keratinocyte cell lines to CeReS-18-induced growth inhibition was not affected by the degree of tumorigenic progression in the cell lines and was not due to differences in CeReS-18 binding affinity or number of cell surface receptors per cell. However, the sensitivity of both murine fibroblasts and keratinocytes could be altered by changing the extracellular calcium concentration, such that increased extracellular calcium concentrations resulted in decreased sensitivity to CeReS-18-induced proliferation inhibition. Thus the increased sensitivity of the murine keratinocyte cell lines to CeReS-18 could be ascribed to the low calcium concentration used in their propagation. Studies are currently under way investigating the role of calcium in CeReS-18-induced growth arrest. The CeReS-18 may serve as a very useful tool to study negative growth control and the signal transduction events associated with cell cycling.

  11. Overexpression of Bax sensitizes prostate cancer cells to TGF-β induced apoptosis

    Institute of Scientific and Technical Information of China (English)

    Pei Hui LIN; Zui PAN; Lin ZHENG; Na LI; David DANIELPOUR; Jian Jie MA

    2005-01-01

    NRP-154 is a tumorigenic epithelial cell line derived from the preneoplastic dorsal-lateral prostate of rats. These cells are exquisitely sensitive to TGF-β induced apoptosis. In contrast, we find that NRP-154 cells can sustain overexpression of exogenous Bax protein, which is different from non-tumor cells where Bax functions as a ubiquitous stimulator of apoptosis. NRP-154 cells stably overexpressing Bax show increased sensitivity to TGF-β induced apoptosis. The degree of TGF-β induced apoptosis displays high correlation with cleavage of Bax at the amino-terminus. Our data indicate that prostate cancer cells can host high levels of latent Bax which can be activated through post-translational modification.

  12. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

    Directory of Open Access Journals (Sweden)

    Mercado Ramon

    2011-01-01

    Full Text Available Abstract Background Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Results Intraplantar Complete Freund's Adjuvant (CFA produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX, an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. Conclusions These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a is transient, (b driven by peripheral input resulting from the injury, (c dependent on TRPV1 positive

  13. Interferon-gamma sensitizes colonic epithelial cell lines to physiological and therapeutic inducers of colonocyte apoptosis.

    LENUS (Irish Health Repository)

    O'Connell, J

    2012-02-03

    Homeostasis in the colonic epithelium is achieved by a continuous cycle of proliferation and apoptosis, in which imbalances are associated with disease. Inflammatory bowel disease (IBD) and colon cancer are associated with either excessive or insufficient apoptosis of colonic epithelial cells, respectively. By using two colonic epithelial cell lines, HT29 and SW620, we investigated how the epithelial cell\\'s sensitivity to apoptosis was regulated by the proinflammatory cytokine interferon-gamma (IFN-gamma). We found that IFN-gamma sensitized HT29 cells, and to a lesser extent SW620, to diverse inducers of apoptosis of physiologic or therapeutic relevance to the colon. These apoptosis inducers included Fas (CD95\\/APO-1) ligand (FasL), short-chain fatty acids, and chemotherapeutic drugs. The extent of IFN-gamma-mediated apoptosis sensitization in these two cell lines correlated well with the degree of IFN-gamma-mediated upregulation of the proapoptotic protease caspase-1. Although IFN-gamma alone effectively sensitized HT29 cells to apoptosis, inclusion of the protein synthesis inhibitor cyclohexamide (CHX) during apoptotic challenge was necessary for maximal sensitization of SW620. The requirement of CHX to sensitize SW620 cells to apoptosis implies a need to inhibit translation of antiapoptotic proteins absent from HT29. In particular, the antiapoptotic protein Bcl-2 was strongly expressed in SW620 cells but absent from HT29. Our results indicate that IFN-gamma increases the sensitivity of colonic epithelial cells to diverse apoptotic stimuli in concert, via upregulation of caspase-1. Our findings implicate caspase-1 and Bcl-2 as important central points of control determining the general sensitivity of colonic epithelial cells to apoptosis.

  14. Development of transdermal therapeutic formulation of CNS5161, a novel NMDA receptor antagonist, by utilizing pressure-sensitive adhesives II: improved transdermal absorption and evaluation of efficacy and safety.

    Science.gov (United States)

    Naruse, Mamoru; Ogawara, Ken-ichi; Kimura, Toshikiro; Konishi, Ryoji; Higaki, Kazutaka

    2014-02-14

    The aim of this study was to prepare a transdermal therapeutic formulation of CNS5161, an NMDA receptor antagonist developed as a drug for neuropathic pain. Since a silicone pressure-sensitive adhesive (PSA) was found to be the best PSA for CNS5161 among six different PSAs examined in our previous study, the effects of the loading concentration of CNS5161 on release and rat skin permeability were investigated using silicone PSAs. The release of CNS5161 was elevated with an increase in the drug concentration from 1% to 14%. The transdermal flux at the steady state reached a plateau at 8% and over, while crystallization of CNS5161 was not observed for any formulation even at high drug concentrations. The drug concentration in rat skin at the steady state was also saturated at 8% and over, which correlated well with the transdermal flux at the steady state. Therefore, skin permeation clearance defined to the skin concentration at the steady state was almost constant at 0.21/h from 2% to 14% of CNS5161, which suggests that drug concentrations in the skin would be a driving force for transport of the drug to the receptor side. Since increasing the concentration of CNS5161 in the PSA patch was not able to elevate the transdermal flux, 12 formulations containing several permeation enhancers were examined to improve the transdermal transport of CNS5161. Among them, the formulation containing propylene glycol, diisopropyl adipate, and polyvinylpyrrolidone significantly increased the transdermal flux by approximately 1.8-fold by improving the diffusivity of CNS5161 in the skin, and also significantly enhanced the analgesic effect of CNS5161. This formulation caused only slight skin irritation, which indicated that it would be a promising transdermal therapeutic system for CNS5161.

  15. Enhanced sensitivity of tumorigenic cells to rapid rounding induced by phenylalaninol.

    Science.gov (United States)

    Mak, W W; Pinteric, L; Wong, J T

    1980-09-01

    This study describes a rounding reaction induced in mammalian cells by the addition of phenylalaninol. In the Chinese hamster ovary tsH1 line the rounding occurred rapidly with a half time of 1 min at 25 mM phenylalaninol. After the removal of phenylalaninol, the rounding was reversed, leading to the reflattening of the cells with a half-time of 3.5 min. Rounding was inhibited by dibutyryl-cAMP and testosterone, and reflattening by cytochalasin B. Either in the case of the tsH1 line and its growth-control revertant GRC+L-73, or in the case of SV40-transformed and untransformed human WI-38 cells, the transformed cells displayed a weakened resistance toward rounding. Likewise rat cells transformed by th highly oncogenic adenovirus-12 were more sensitive to rounding than cells transformed by the poorly oncogenic adenovirus-5, which in turn were more sensitive than untransformed cells. However, drug-resistant cell-surface mutants of the Chinese hamster ovary GAT- line also exhibited an altered sensitivity to rounding. These findings suggest that more than one cellular component determines cellular sensitivity to phenylalaninol-induced rounding. One of these components is specifically altered, giving rise to an enhanced sensitivity, in the course of tumorigenic transformation. PMID:6257353

  16. Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization

    Directory of Open Access Journals (Sweden)

    Meadows Rena M

    2011-03-01

    Full Text Available Abstract Background The GDNF family ligands (GFLs are regulators of neurogenic inflammation and pain. We have previously shown that GFLs increase the release of the sensory neuron neuropeptide, calcitonin gene-related peptide (CGRP from isolated mouse DRG. Results Inhibitors of the mitogen-activated protein kinase (MAPK pathway abolished the enhancement of CGRP release by GDNF. Neurturin-induced enhancement in the stimulated release of CGRP, used as an indication of sensory neuronal sensitization, was abolished by inhibition of the phosphatidylinositol-3 kinase (PI-3K pathway. Reduction in Ret expression abolished the GDNF-induced sensitization, but did not fully inhibit the increase in stimulus-evoked release of CGRP caused by neurturin or artemin, indicating the presence of Ret-independent GFL-induced signaling in sensory neurons. Integrin β-1 and NCAM are involved in a component of Ret-independent GFL signaling in sensory neurons. Conclusions These data demonstrate the distinct and variable Ret-dependent and Ret-independent signaling mechanisms by which GFLs induce sensitization of sensory neurons. Additionally, there is a clear disconnect between intracellular signaling pathway activation and changes in sensory neuronal function.

  17. Prior Multiple Ethanol Withdrawals Enhance Stress-Induced Anxiety-Like Behavior: Inhibition by CRF1- and Benzodiazepine-Receptor Antagonists and a 5-HT1a-Receptor Agonist

    OpenAIRE

    Breese, George R.; Overstreet, David H.; KNAPP, DARIN J.; Navarro, Montserrat

    2005-01-01

    Repeated withdrawals from chronic ethanol induce a persistent adaptive change. Further, stress substitutes for the initial two withdrawals of a multiple-withdrawal protocol to sensitize rats to withdrawal-induced anxiety-like behavior (‘anxiety’). Therefore, it was tested whether the persistent adaptation induced by multiple-withdrawal exposures allows stress to elicit anxiety after a period of abstinence. Social interaction was used to assess the degree of anxiety induced by 45 min of restra...

  18. Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy.

    Science.gov (United States)

    Peng, Chun-Xia; Zhang, Ai-di; Chen, Bing; Yang, Bing-Jian; Wang, Qiu-Hong; Yang, Mo; Wei, Shi-Hui

    2016-03-01

    Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual field loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retinal nerve fiber layer, macular thickness and visual sensitivity loss would be observed in 11 ethambutol-induced optic neuropathy patients (22 eyes) using optical coherence tomography. Twenty-four healthy age- and sex-matched participants (48 eyes) were used as controls. Results demonstrated that the temporal peripapillary retinal nerve fiber layer thickness and average macular thickness were thinner in patients with ethambutol-induced optic neuropathy compared with healthy controls. The average macular thickness was strongly positively correlated with central visual sensitivity loss (r (2) =0.878, P=0.000). These findings suggest that optical coherence tomography can be used to efficiently screen patients. Macular thickness loss could be a potential factor for predicting the onset of ethambutol-induced optic neuropathy. PMID:27127488

  19. Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy

    Directory of Open Access Journals (Sweden)

    Chun-xia Peng

    2016-01-01

    Full Text Available Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual field loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retinal nerve fiber layer, macular thickness and visual sensitivity loss would be observed in 11 ethambutol-induced optic neuropathy patients (22 eyes using optical coherence tomography. Twenty-four healthy age- and sex-matched participants (48 eyes were used as controls. Results demonstrated that the temporal peripapillary retinal nerve fiber layer thickness and average macular thickness were thinner in patients with ethambutol-induced optic neuropathy compared with healthy controls. The average macular thickness was strongly positively correlated with central visual sensitivity loss (r2 =0.878, P=0.000. These findings suggest that optical coherence tomography can be used to efficiently screen patients. Macular thickness loss could be a potential factor for predicting the onset of ethambutol-induced optic neuropathy.

  20. Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy

    Institute of Scientific and Technical Information of China (English)

    Chun-xia Peng; Ai-di Zhang; Bing Chen; Bing-jian Yang; Qiu-hong Wang; Mo Yang; Shi-hui Wei

    2016-01-01

    Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual ifeld loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retinal nerve ifber layer, macular thickness and visual sensitivity loss would be observed in 11 ethambutol-induced optic neuropathy patients (22 eyes) using optical coherence tomography. Twenty-four healthy age- and sex-matched participants (48 eyes) were used as controls. Results demonstrated that the temporal peripapil-lary retinal nerve ifber layer thickness and average macular thickness were thinner in patients with ethambutol-induced optic neuropathy compared with healthy controls. The average macular thickness was strongly positively correlated with central visual sensitivity loss (r2=0.878,P=0.000). These ifndings suggest that optical coherence tomography can be used to efifciently screen patients. Macular thickness loss could be a potential factor for predicting the onset of ethambutol-induced optic neuropathy.

  1. Knockdown of Akt Sensitizes Osteosarcoma Cells to Apoptosis Induced by Cisplatin Treatment

    Directory of Open Access Journals (Sweden)

    Changwei Yang

    2011-05-01

    Full Text Available Akt plays an important role in the inhibition of apoptosis induced by chemotherapy and other stimuli. We therefore investigated if knockdown of Akt2 promoted drug-induced apoptosis in cultured osteosarcoma cells in vitro. SAOS-2 cells were transfected with Akt2 siRNA. The sensitivity of the transformed cell line to the chemotherapeutic drug cisplatin was assessed. Reduced expression of Akt2 did not directly inhibit the growth rate of the transfected cells; however, it significantly increased their sensitivity to cisplatin. Knockdown of Akt2, together with cisplatin treatment, promoted the expression of p53 up-regulated modulator of apoptosis (PUMA. It is possible that the augmentation of cisplatin cytotoxicity may be mediated by PUMA activation. The results of this study suggest that knockdown of Akt2 expression may have therapeutic applications in enhancing the efficacy of chemotherapy in patients with osteosarcoma.

  2. Fast and sensitive detection of indels induced by precise gene targeting

    DEFF Research Database (Denmark)

    Yang, Zhang; Steentoft, Catharina; Hauge, Camilla;

    2015-01-01

    The nuclease-based gene editing tools are rapidly transforming capabilities for altering the genome of cells and organisms with great precision and in high throughput studies. A major limitation in application of precise gene editing lies in lack of sensitive and fast methods to detect...... and characterize the induced DNA changes. Precise gene editing induces double-stranded DNA breaks that are repaired by error-prone non-homologous end joining leading to introduction of insertions and deletions (indels) at the target site. These indels are often small and difficult and laborious to detect...... by traditional methods. Here we present a method for fast, sensitive and simple indel detection that accurately defines indel sizes down to ±1 bp. The method coined IDAA for Indel Detection by Amplicon Analysis is based on tri-primer amplicon labelling and DNA capillary electrophoresis detection, and IDAA...

  3. Allergic skin inflammation induced by chemical sensitizers is controlled by the transcription factor Nrf2.

    Science.gov (United States)

    El Ali, Zeina; Gerbeix, Cédric; Hemon, Patrice; Esser, Philipp R; Martin, Stefan F; Pallardy, Marc; Kerdine-Römer, Saadia

    2013-07-01

    Allergic contact dermatitis (ACD) is induced by low-molecular weight electrophilic chemicals and metal ions. Chemical contact sensitizers trigger reactive oxygen species production and provoke electrophilic stress, leading to the accumulation of the transcription factor nuclear-related factor 2 (Nrf2) in innate immune cell types. The objective of this work was to identify the role of Nrf2 in the regulation of ACD. We used the local lymph node assay (LLNA) and the mouse ear swelling test (MEST) to study the role of Nrf2 in both the sensitization and elicitation phase in nrf2 knockout (nrf2(-/-)) and wild-type (nrf2(+/+)) mice. Five chemicals were used: two compounds known to react with cysteine residues, 2,4-dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA); one sensitizer known to exhibit mixed reactivity to cysteine and lysine residues, isophorone diisocyanate; and one reacting specifically with lysine residues, trimellitic anhydride and croton oil, a well-known irritant. In the MEST assay, DNCB (1 and 2%) induced a significant increase in ear thickness in nrf2(-/-) compared with nrf2(+/+) mice, suggesting a role for Nrf2 in the control of the inflammatory process. When DNCB was used at 0.25 and 0.5% or when mice were treated with CinA, inflammation was found only in nrf2(-/-) mice. In the LLNA, all chemical sensitizers induced an increase of lymphocyte proliferation in nrf2(-/-) compared with nrf2(+/+) mice for the same chemical concentration. These results reveal an important role for Nrf2 in controlling ACD and lymphocyte proliferation in response to sensitizers. PMID:23564646

  4. Effects of Estrogen Receptor Modulators on Morphine Induced Sensitization in Mice Memory

    OpenAIRE

    Mahdieh Anoush; Ali Jani; Moosa Sahebgharani; Mohammad Reza Jafari

    2015-01-01

     Objective: In this study, the effects of estradiol valerate and raloxifenea selective estrogen receptor modulator; (SERM) on morphine induced sensitization were examined in mice memory, according to the step-down passive avoidance task.  Method:The mice received morphine or estradiol and raloxifene for three days alone or in combination with morphine. After a drug free period of 5 days, the subjects received saline or morphine as pre- training treatments followed by a pre-test saline adminis...

  5. Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

    Science.gov (United States)

    Ahmed, Firoj; Toume, Kazufumi; Ohtsuki, Takashi; Rahman, Mahmudur; Sadhu, Samir Kumar; Ishibashi, Masami

    2011-01-01

    Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2-3). Compound 1 showed strong activity in overcoming TRAIL-resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 μm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL-induced apoptosis at the aforementioned concentrations.

  6. Oxygenation-sensitive CMR for assessing vasodilator-induced changes of myocardial oxygenation

    OpenAIRE

    Wang Jiun; Dharmakumar Rohan; Green Jordin D; Flewitt Jacqueline A; Vöhringer Matthias; Tyberg John V; Friedrich Matthias G

    2010-01-01

    Abstract Background As myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation. However, the impact of induced blood flow changes on oxygenation is not well understood. We used oxygenation-sensitive CMR to assess the relations between myocardial oxygenation and coronary sinus blood oxygen saturation (SvO2) and coronary blood flow in a dog model in which hyperemia ...

  7. Inhibitory effects of ginseng total saponins on behavioral sensitization and dopamine release induced by cocaine.

    Science.gov (United States)

    Lee, BomBi; Yang, Chae Ha; Hahm, Dae-Hyun; Lee, Hye-Jung; Han, Seung-Moo; Kim, Kyung-Soo; Shim, Insop

    2008-03-01

    Many studies have suggested that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. It has been shown that repeated injections of cocaine produce an increase in locomotor activity, the expression of the immediate-early gene, c-fos, and the release of dopamine (DA) in the nucleus accumbens (NAc), which is one of the main dopaminergic terminal areas. Several studies have shown that behavioral activation and changes in extracellular dopamine levels in the central nervous system induced by psychomotor stimulants are prevented by ginseng total saponins (GTS). In order to investigate the effects of GTS on the repeated cocaine-induced behavioral and neurochemical alterations, we examined the influence of GTS on the cocaine-induced behavioral sensitization and on c-Fos expression in the brain using immunohistochemistry in rats repeatedly treated with cocaine. We also examined the effect of GTS on cocaine-induced dopamine release in the NAc of freely moving rats repeatedly treated with cocaine using an in vivo microdialysis technique. Pretreatment with GTS (100, 200, 400 mg/kg, i.p.) 30 min before the daily injections of cocaine (15 mg/kg, i.p.) significantly inhibited the repeated cocaine-induced increase in locomotor activity as well as the c-Fos expression in the core and shell in a dose-dependent manner. Also, pretreatment with GTS significantly decreased the repeated cocaine-induced increase in dopamine release in the NAc. Our data demonstrate that the inhibitory effects of GTS on the repeated cocaine-induced behavioral sensitization were closely associated with the reduction of dopamine release and the postsynaptic neuronal activity. The results of the present study suggest that GTS may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. These results also suggest that GTS may prove to be a useful therapeutic agent for cocaine addiction. PMID:18310906

  8. Oxygenation-sensitive CMR for assessing vasodilator-induced changes of myocardial oxygenation

    Directory of Open Access Journals (Sweden)

    Wang Jiun

    2010-03-01

    Full Text Available Abstract Background As myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation. However, the impact of induced blood flow changes on oxygenation is not well understood. We used oxygenation-sensitive CMR to assess the relations between myocardial oxygenation and coronary sinus blood oxygen saturation (SvO2 and coronary blood flow in a dog model in which hyperemia was induced by intracoronary administration of vasodilators. Results During administration of acetylcholine and adenosine, CMR signal intensity correlated linearly with simultaneously measured SvO2 (r2 = 0.74, P 2 and CMR signal intensity were exponentially related to coronary blood flow, with SvO2 approaching 87%. Conclusions Myocardial oxygenation as assessed with oxygenation-sensitive CMR imaging is linearly related to SvO2 and is exponentially related to vasodilator-induced increases of blood flow. Oxygenation-sensitive CMR may be useful to assess ischemia and microvascular function in patients. Its clinical utility should be evaluated.

  9. Phenylephrine induced fixed drug eruption: a rare case of cross sensitivity

    Directory of Open Access Journals (Sweden)

    Mahesh Chander Gupta

    2016-08-01

    Full Text Available Fixed drug eruption (FDE is a type of dermatosis characterized by recurrent lesions at exactly the same sites with each administration of the causative agents. FDEs are common types of drug eruptions amongst all cutaneous drug-induced side effects, mostly by intermittent exposure. Multiple drugs with common chemical structure can cause same type of lesions at same site called as cross sensitivity. There are many causative agents and the incidence of FDEs for a particular drug depends on the frequency of its use. Though usually not severe or fatal, cosmetic embarrassment is main problem, especially when they recur on the previously affected sites leaving behind residual hyperpigmentation. Phenylephrine is a sympathomimetic agent, given orally for the symptomatic relief of nasal congestion. It is also commonly combined with other ingredients in preparations intended for the relief of cough and cold symptoms. Considering the frequent use of Phenylephrine, associated drug eruptions generally appear to be rare, cross sensitivity with pseudoephedrine is even rarer. In our case phenylepherine was self-administered to control cold induced congestion and patient developed FDE on vermillion of upper lip, which healed after 2 weeks leaving hyperpigmentation and reappear on same site after re-challenge also. She has history of FDEs due to pseudoephedrine on same site on lips. This is a rare case of sympathomimetics induced FDE with cross sensitivity between phenylepherine and pseudoephedrine; hence we are reporting it here. [Int J Basic Clin Pharmacol 2016; 5(4.000: 1687-1690

  10. Mutagen sensitivity as measured by induced chromatid breakage as a marker of cancer risk.

    Science.gov (United States)

    Wu, Xifeng; Zheng, Yun-Ling; Hsu, T C

    2014-01-01

    Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in the chromosomes of peripheral blood lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related maladies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by clastogenic agents, such as the γ-radiation mimetic DNA cross-linking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-nitroquinoline and the tobacco smoke constituent benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.

  11. The Geometry of Plasticity-Induced Sensitization in Isoinhibitory Rate Motifs.

    Science.gov (United States)

    Kumar, Gautam; Ching, ShiNung

    2016-09-01

    A well-known phenomenon in sensory perception is desensitization, wherein behavioral responses to persistent stimuli become attenuated over time. In this letter, our focus is on studying mechanisms through which desensitization may be mediated at the network level and, specifically, how sensitivity changes arise as a function of long-term plasticity. Our principal object of study is a generic isoinhibitory motif: a small excitatory-inhibitory network with recurrent inhibition. Such a motif is of interest due to its overrepresentation in laminar sensory network architectures. Here, we introduce a sensitivity analysis derived from control theory in which we characterize the fixed-energy reachable set of the motif. This set describes the regions of the phase-space that are more easily (in terms of stimulus energy) accessed, thus providing a holistic assessment of sensitivity. We specifically focus on how the geometry of this set changes due to repetitive application of a persistent stimulus. We find that for certain motif dynamics, this geometry contracts along the stimulus orientation while expanding in orthogonal directions. In other words, the motif not only desensitizes to the persistent input, but heightens its responsiveness (sensitizes) to those that are orthogonal. We develop a perturbation analysis that links this sensitization to both plasticity-induced changes in synaptic weights and the intrinsic dynamics of the network, highlighting that the effect is not purely due to weight-dependent disinhibition. Instead, this effect depends on the relative neuronal time constants and the consequent stimulus-induced drift that arises in the motif phase-space. For tightly distributed (but random) parameter ranges, sensitization is quite generic and manifests in larger recurrent E-I networks within which the motif is embedded. PMID:27391684

  12. β3-Adrenoceptor Antagonist SR59230A Attenuates the Imbalance of Systemic and Myocardial Oxygen Transport Induced by Dopamine in Newborn Lambs

    OpenAIRE

    Gill, Richdeep S.; Po-Yin Cheung; Xiaoyang Yu; Mohammed Al Aklabi; Jeevan Nagendran; Quinonez, Luis G.; Ying Qian Li; John Miller; Ross, David B.; Rebeyka, Ivan M.; Jia Li

    2012-01-01

    Background In neonates, the increase in O2-delivery (DO2) by dopamine is offset by a greater increase in O2-consumption (VO2). This has been attributed to β3-adrenergic receptors in neonatal brown fat tissue. β3 receptors in the heart have negative inotropic properties. We evaluated the effects of SR59230A, a β3-antagonist, on the balance of systemic and myocardial O2-transport in newborn lambs treated with dopamine. Methods Lambs (2–5 days old, n = 12) were anesthetized and mechanically vent...

  13. Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome

    Directory of Open Access Journals (Sweden)

    Xu Zhao-Hui

    2012-05-01

    Full Text Available Abstract Background Fragile X syndrome (FXS is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP, encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP by D1 receptor is impaired in Fmr1 knockout (KO mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied. Results Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2 in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs at Tyr-1472 (p-NR2B-Tyr1472 in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice. Conclusion The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.

  14. IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide.

    Science.gov (United States)

    Ramcharan, Roger; Aleksic, Tamara; Kamdoum, Wilfride Petnga; Gao, Shan; Pfister, Sophia X; Tanner, Jordan; Bridges, Esther; Asher, Ruth; Watson, Amanda J; Margison, Geoffrey P; Woodcock, Mick; Repapi, Emmanouela; Li, Ji-Liang; Middleton, Mark R; Macaulay, Valentine M

    2015-11-24

    Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage. PMID

  15. TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis

    DEFF Research Database (Denmark)

    Davidsen, Marie Louise; Würts, S.Ø.; Rømer, Maria Unni Koefoed;

    2006-01-01

    in cancer. In this regard, several studies have demonstrated an antiapoptotic effect of TIMP-1 in a number of different cell types. Since chemotherapy works by inducing apoptosis in cancer cells, we raised the hypothesis that TIMP-1 promotes resistance against chemotherapeutic drugs. In order to investigate...... this hypothesis, we have established TIMP-1 gene-deficient and TIMP-1 wild-type fibrosarcoma cells from mouse lung tissue. We have characterised these cells with regard to TIMP-1 genotype, TIMP-1 expression, malignant transformation and sensitivity to chemotherapy-induced apoptosis. We show that TIMP-1 gene...... deficiency increases the response to chemotherapy considerably, confirming that TIMP-1 protects the cells from apoptosis. This is to our knowledge the first study investigating TIMP-1 and chemotherapy-induced apoptosis employing a powerful model system comprising TIMP-1 gene-deficient cells...

  16. β-Sitosterol sensitizes MDA-MB-231 cells to TRAIL-induced apoptosis

    Institute of Scientific and Technical Information of China (English)

    Cheol PARK; Dong-oh MOON; Chung-ho RYU; Byung tae CHOI; Won ho LEE; Gi-young KIM; Yung hyun CHOI

    2008-01-01

    Aim:To investigate whether subtoxic concentration of β-sitosterol (SITO) com-bined with TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in TRAIL-resistant MDA-MB-231 breast cancer cells.Methods:Cell viability and growth were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphnyl-2H-tetrazolim bromide assays,chromatin condensation,release of lactate dehydrogenase (LDH),and Annexin V+ cells.The apoptosis-related proteins were detected by Western blotting.Results:Treatment with TRAIL in combination with subtoxic concen-trations of SITO sensitized MDA-MB-231 breast cancer cells to TRAIL-mediated apoptosis.The synergistic treatment induced chromatin condensation,DNA fragmentation,the release of LDH,and Annexin V cells.The indicators of apoptosis are correlated to the induction of caspase activities,which results in the cleavage ofpoly(ADP-ribose)polymerase.Both the cytotoxic effects and apoptotic characteristics induced by the synergistic treatment were significantly inhibited by a pan-caspase inhibitor z-VAD-fmk,demonstrating the important role of caspases.These results indicate that caspases are crucial regulators of apoptosis induced by the combined treatment of SITO and TRAIL in MDA-MB-231 cells.Conclusion:The synergistic treatment of SITO and TRAIL induces apoptosis,which can serve as a potential preventive and therapeutic agent.

  17. Carbon Disulphide Induced Sensitivity Changes of Rat Anococcygeus Muscle to Noradrenaline(NA)

    Institute of Scientific and Technical Information of China (English)

    D.N.GANDHI; H.VENKATAKRISHNA-BHATT

    1993-01-01

    The sensitivity of rat anococcygeus muscle to noradrenaline(NA)was reduced following carbon disulphide(CS2)pretreatment.Preparations incubated in excess Ca++(4.2mmol·L-1)or Zero Ca++(0.0mmol·L-1)media showed decrease in sensitivity to NA.Reserpinization failed to induce supersensitivity to NA in any Mg++ concentration in the media.Reserpinized tissue in Mg++ free media with EDTA showed increased sensitivity while decreased sensitivity and maximum response to NA in Mg++(1.2mmol·L-1)and excess Mg++(3.6mmol·L-1)concentration of the medium.In the presence of EDTA,the inhibition obsevved with CS2 in excess Mg++(3.6mmol·L-1)medium was comparatively much less in both non-reserpinized and reserpinized preparations.In normal Ca++ and its deficient medium decrease in sensitivity to CS2 and the relevant maximum response to NA were observed.In excess Ca++,the CS2 effect depressed corresponding to its maximal response to NA.Thus CS2 may be inhibiting responss to NA by interfering with Ca++ utilization.

  18. Resistance of UV induced mutants of antagonistic fungi to fungicides%植物土传病害拮抗真菌的抗药性筛选

    Institute of Scientific and Technical Information of China (English)

    黎起秦; 陈永宁

    2000-01-01

    When four antagonistic fungi(Trichoderma koningii, T.pseudokoningii,T.harzianum and Gliocladium spp.)were irradiated with ultrav iolet light for 30 min,mutants of strains were obtained.Mutants did not change t he morphological characters and antagonistic activity to Fusarium oxysporum f. sp.melonis and Sclerotinia minor when compared with the wild type.Resi stance to iprodione and copper oxychloride was found to occur in all mutants.Some of t hem,such as mutants of T.koningii,T.harzianum and Gliocladium spp,resi sted to carbendazim.None of the mutants resisted to propiconazole.%从土壤中分离得到的4种拮抗真菌(Trichoderma koningii、T. pseudokoningii、T.harzianum和Gliocladium spp.)分别用紫外光诱变,得到抗氧氯化铜、扑海因和多菌灵的变异菌株。这些变异菌株对西瓜枯萎病菌(Fusarium oxysporum f. sp.melonis)和生菜菌核病菌(Sclerotinia minor)仍有较强的拮抗性。

  19. Overexpression of Bax induces apoptosis and enhances drug sensitivity of hepatocellular cancer-9204 cells

    Institute of Scientific and Technical Information of China (English)

    Jian-Yong Zheng; Guang-Shun Yang; Wei-Zhong Wang; Jiang Li; Kai-Zong Li; Wen-Xian Guan; Wen-Liang Wang

    2005-01-01

    AIM: To investigate the role of overexpression of Bax in apoptotic pathways and the response of human hepatocellular cancer (HCC)-9204 cells to cell death induced by adriamycin.METHODS: The whole length of Bax cDNA was transfectrd into human HCC-9204 cells by the method of lipofectamine transfection. An inducible MT-Ⅱ regulatory system was constructed, which allowed controlled expression of protein upon addition of ZnSO4 (100 μmol/L) as an external inducer. Stable transfecting inducible expression vector containing Bax gene was performed. Expression of Bax in protein was analyzed by immunohistochemistry and Western blotting. TUNEL and flow cytometry were used to assess the effect of Bax on apoptosis. Colony assay and tetrazolium blue (MTT) assay were used to evaluate the difference in drug sensitivity of HCC-9204 cells after Bax-transfection.RESULTS: Immunohistochemistry and Western blotting demonstrated that the expression of Bax protein markedly increased in Bax-transfected cells 4 h after the addition cytoplasm and perinuclear region of HCC-9404 cells, and there was ectopic expression in cells with marked condensation of chromatin and cytoplasm (apoptotic cells). Apoptotic index significantly increased in Bax-transfected HCC-9204/Bax cells (3.6 vs 27.2, 4.2 vs 32.3, P<0.05).Flow cytometry analysis showed a significant sub-G1 peak and apoptosis in 15.4% HCC-9204/Bax cells 24 h after treatment. Furthermore, colony survival rate decreased from 66% (HCC-9204/pMD) to 45% (HCC-9204/Bax) 2 dafter ADR withdrawal. MTT assay result showed that the effects of Bax on cell viability following ADR exposure were significant as compared to the vehicle-transfected HCC-9204/pMD cells (21% vs 44%, P<0.01).CONCLUSION: Overexpression of Bax not only induces apoptosis, but also sensitizes HCC-9204 cells to cell death induced by adriamycin.

  20. Multiple mechanisms determine the sensitivity of human-induced pluripotent stem cells to the inducible caspase-9 safety switch.

    Science.gov (United States)

    Yagyu, Shigeki; Hoyos, Valentina; Del Bufalo, Francesca; Brenner, Malcolm K

    2016-01-01

    Expression of the inducible caspase-9 (iC9) suicide gene is one of the most appealing safety strategies for cell therapy and has been applied for human-induced pluripotent stem cells (hiPSC) to control the cell fate of hiPSC. iC9 can induce cell death of over 99% of iC9-transduced hiPSC (iC9-hiPSC) in less than 24 hours after exposure to chemical inducer of dimerization (CID). There is, however, a small number of resistant cells that subsequently outgrows. To ensure greater uniformity of the hiPSC response to iC9 activation, we purified a resistant population by culturing iC9-hiPSC with CID and analyzing the mechanisms by which the cells evade killing. We found that iC9-resistant hiPSC have significant heterogeneity in terms of their escape mechanisms from caspase-dependent apoptosis including reduced expression of iC9 by promoter silencing and overexpression of BCL2. As a consequence, modifying a single element alone will be insufficient to ensure sustained susceptibility of iC9 in all cells and prevent the eventual outgrowth of a resistant population. To solve this issue, we propose to isolate an iC9-sensitive population and show that this hiPSC line has sustained a uniform responsiveness to iC9-mediated growth control. PMID:27626039

  1. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  2. Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer.

    Science.gov (United States)

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2016-01-01

    Neuregulin 4 (NRG4), an epidermal growth factor-like signaling molecule, plays an important role in cell-to-cell communication during tissue development. Its function to regulate energy metabolism has recently been reported. This current study was designed to assess the preventive and therapeutic effects of NRG4 overexpression on high fat diet (HFD)-induced obesity. Using the hydrodynamic gene transfer method, we demonstrate that Nrg4 gene transfer in mice suppressed the development of diet-induced obesity, but did not affect pre-existing adiposity and body weight in obese mice. Nrg4 gene transfer curbed HFD-induced hepatic steatosis by inhibiting lipogenesis and PPARγ-mediated lipid storage. Concurrently, overexpression of NRG4 reduced chronic inflammation in both preventive and treatment studies, evidenced by lower mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and macrophage chemokine Mcp1, resulting in improved insulin sensitivity. Collectively, these results demonstrate that overexpression of the Nrg4 gene by hydrodynamic gene delivery prevents HFD-induced weight gain and fatty liver, alleviates obesity-induced chronic inflammation and insulin resistance, and supports the health benefits of NRG4 in managing obesity and obesity-associated metabolic disorders. PMID:27184920

  3. Diuretics Prevent Thiazolidinedione-Induced Cardiac Hypertrophy without Compromising Insulin-Sensitizing Effects in Mice

    Science.gov (United States)

    Chang, Cherng-Shyang; Tsai, Pei-Jane; Sung, Junne-Ming; Chen, Ju-Yi; Ho, Li-Chun; Pandya, Kumar; Maeda, Nobuyo; Tsai, Yau-Sheng

    2015-01-01

    Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg+/−) mice, but not in mice defective for ligand binding (PpargP465L/+). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity. PMID:24287404

  4. Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons

    Directory of Open Access Journals (Sweden)

    Langeslag Michiel

    2011-12-01

    Full Text Available Abstract Oncostatin M (OSM is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/- and gp130 floxed (gp130fl/fl mice. Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo. The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.

  5. Radio frequency radiation-induced hyperthermia using Si nanoparticle-based sensitizers for mild cancer therapy

    Science.gov (United States)

    Tamarov, Konstantin P.; Osminkina, Liubov A.; Zinovyev, Sergey V.; Maximova, Ksenia A.; Kargina, Julia V.; Gongalsky, Maxim B.; Ryabchikov, Yury; Al-Kattan, Ahmed; Sviridov, Andrey P.; Sentis, Marc; Ivanov, Andrey V.; Nikiforov, Vladimir N.; Kabashin, Andrei V.; Timoshenko, Victor Yu

    2014-11-01

    Offering mild, non-invasive and deep cancer therapy modality, radio frequency (RF) radiation-induced hyperthermia lacks for efficient biodegradable RF sensitizers to selectively target cancer cells and thus avoid side effects. Here, we assess crystalline silicon (Si) based nanomaterials as sensitizers for the RF-induced therapy. Using nanoparticles produced by mechanical grinding of porous silicon and ultraclean laser-ablative synthesis, we report efficient RF-induced heating of aqueous suspensions of the nanoparticles to temperatures above 45-50°C under relatively low nanoparticle concentrations (nanoparticles the heating rate was linearly dependent on nanoparticle concentration, while laser-ablated nanoparticles demonstrated a remarkably higher heating rate than porous silicon-based ones for the whole range of the used concentrations from 0.01 to 0.4 mg/mL. The observed effect is explained by the Joule heating due to the generation of electrical currents at the nanoparticle/water interface. Profiting from the nanoparticle-based hyperthermia, we demonstrate an efficient treatment of Lewis lung carcinoma in vivo. Combined with the possibility of involvement of parallel imaging and treatment channels based on unique optical properties of Si-based nanomaterials, the proposed method promises a new landmark in the development of new modalities for mild cancer therapy.

  6. Berberine induces pacemaker potential inhibition via cGMP-dependent ATP-sensitive K+ channels by stimulating mu/delta opioid receptors in cultured interstitial cells of Cajal from mouse small intestine.

    Science.gov (United States)

    Kim, Hyun Jung; Kim, Hyungwoo; Jung, Myeong Ho; Kwon, Young Kyu; Kim, Byung Joo

    2016-10-01

    Berberine is traditionally used to treat gastrointestinal (GI) motility disorders. The interstitial cells of Cajal (ICCs) are the pacemaker cells of the gastrointestinal tract, which are responsible for the production of gut movements. The present study aimed to investigate the effects of berberine on pacemaker potentials (PPs) in cultured ICC clusters from the mouse small intestine, and sought to identify the receptors involved and the underlying mechanisms of action. All experiments were performed on cultured ICCs, and a whole‑cell patch‑clamp configuration was used to record PPs from ICC clusters (current clamp mode). Under current clamp mode, berberine was shown to decrease the amplitude and frequency of PPs. However, these effects were suppressed by treatment with glibenclamide, a specific ATP‑sensitive K+ channel blocker. Nor‑binaltorphimine dihydrochloride (a kappa opioid receptor antagonist) did not suppress berberine‑induced PP inhibition, whereas ICI 174,864 (a delta opioid receptor antagonist) and CTOP (a mu opioid receptor antagonist) did suppress the inhibitory effects of berberine. Pretreatment with SQ‑22536 (an adenylate cyclase inhibitor) or with KT‑5720 (a protein kinase A inhibitor) did not suppress the effects of berberine; however, pretreatment with 1H‑[1,2,4] oxadiazolo [4,3‑a] quinoxalin‑1‑one (a guanylate cyclase inhibitor) or KT‑5823 [a protein kinase G (PKG) inhibitor] did. In addition, berberine stimulated cyclic guanosine monophosphate (cGMP) production in ICCs. These observations indicate that berberine may inhibit the pacemaker activity of ICC clusters via ATP‑sensitive K+ channels and the cGMP‑PKG‑dependent pathway by stimulating mu and delta opioid receptors. Therefore, berberine may provide a basis for the development of novel agents for the treatment of GI motility dysfunction. PMID:27601272

  7. Antagonistic activity of Bacillus sp. obtained from an Algerian oilfield and chemical biocide THPS against sulfate-reducing bacteria consortium inducing corrosion in the oil industry.

    Science.gov (United States)

    Gana, Mohamed Lamine; Kebbouche-Gana, Salima; Touzi, Abdelkader; Zorgani, Mohamed Amine; Pauss, André; Lounici, Hakim; Mameri, Nabil

    2011-03-01

    The present study enlightens the role of the antagonistic potential of nonpathogenic strain B21 against sulfate-reducing bacteria (SRB) consortium. The inhibitor effects of strain B21 were compared with those of the chemical biocide tetrakishydroxymethylphosphonium sulfate (THPS), generally used in the petroleum industry. The biological inhibitor exhibited much better and effective performance. Growth of SRB in coculture with bacteria strain B21 antagonist exhibited decline in SRB growth, reduction in production of sulfides, with consumption of sulfate. The observed effect seems more important in comparison with the effect caused by the tested biocide (THPS). Strain B21, a dominant facultative aerobic species, has salt growth requirement always above 5% (w/v) salts with optimal concentration of 10-15%. Phylogenetic analysis based on partial 16S rRNA gene sequences showed that strain B21 is a member of the genus Bacillus, being most closely related to Bacillus qingdaonensis DQ115802 (94.0% sequence similarity), Bacillus aidingensis DQ504377 (94.0%), and Bacillus salarius AY667494 (92.2%). Comparative analysis of partial 16S rRNA gene sequence data plus physiological, biochemical, and phenotypic features of the novel isolate and related species of Bacillus indicated that strain B21 may represent a novel species within the genus Bacillus, named Bacillus sp. (EMBL, FR671419). The results of this study indicate the application potential of Bacillus strain B21 as a biocontrol agent to fight corrosion in the oil industry.

  8. Development of sensitive analytical technique by Laser-Induced Photoacoustic Spectroscopy

    International Nuclear Information System (INIS)

    A LIPAS (Laser-Induced Photoacoustic Spectroscopy) system has been developed for sensitive and remote analysis of neptunium which diffuse in low concentration range in reprocessing. The correction technique of background which disturbs sensitive analysis has been studied in visible to infrared range. And optical fiber system which is important for light operation has been also investigated for remote analysis in PUREX process. In visible range, the double-cell system, which has two photoacoustic cells in series, has been studied. The detection limit absorptivity was 4.47 x 10-5cm-1, this system has two orders higher sensitivity than that of absorption spectroscopy. This system was applied to measure photoacoustic spectrum of Pr(III), Nd(III), Er(III) and Np(V) in low concentration range in water. On photoacoustic spectrum of Np(V), the absorption peak at 614nm, which was not observed in low pH range, was identified. In near infrared range, analytical system which has parallel cells using alexandrite laser has been investigated. It was obtained that detection limit concentration of Np(V) is one order lower than that in visible range. The optical fiber system for application of LIPAS to reprocessing has been examined. The sensitivity of fiber-PAS is two times higher than that of absorption spectroscopy. However it is necessary to develop a beam operation system and a photoacoustic cell optimized for optical fiber system. (author)

  9. [A Case of Drug-Induced Thrombocytopenia Resulting from Sensitivity to Oxaliplatin].

    Science.gov (United States)

    Masuda, Taiki; Nagai, Kagami; Sanada, Katsuya

    2015-11-01

    A 67-year-old man was diagnosed with pulmonary metastasis from advanced transverse colon cancer. Thus, a local resection was performed. Adjuvant chemotherapy with mFOLFOX6 was started. Sixteen courses were carried out without problems. However, he complained of chills and chest discomfort 2 hours after beginning the 17th course of chemotherapy. Laboratory data showed remarkable thrombocytopenia, and platelet-associated IgG level was high. After administration of steroids and platelet transfusions, the platelet count improved. Therefore, we diagnosed drug-induced thrombocytopenia resulting from sensitivity to oxaliplatin (L-OHP). Since then, sLV5FU2 therapy was started, and the patient received the whole adjuvant chemotherapy without problems. Thrombocytopenia resulting from sensitivity to L-OHP is a relatively rare side effect. We herein report this case with a review of the relevant literature. PMID:26805296

  10. The α1 Antagonist Doxazosin Alters the Behavioral Effects of Cocaine in Rats

    Directory of Open Access Journals (Sweden)

    Colin N. Haile

    2012-11-01

    Full Text Available Medications that target norepinephrine (NE neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX, a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8 were administered saline, cocaine (COC, 10 mg/kg or DOX (0.3 or 1.0 mg/kg alone or in combination for 5 consecutive days (development. Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression. COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg, but not the low dose (0.3 mg/kg of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.

  11. Mucosal exposure to cockroach extract induces allergic sensitization and allergic airway inflammation

    Directory of Open Access Journals (Sweden)

    Arizmendi Narcy G

    2011-12-01

    Full Text Available Abstract Background Allergic sensitization to aeroallergens develops in response to mucosal exposure to these allergens. Allergic sensitization may lead to the development of asthma, which is characterized by chronic airway inflammation. The objective of this study is to describe in detail a model of mucosal exposure to cockroach allergens in the absence of an exogenous adjuvant. Methods Cockroach extract (CE was administered to mice intranasally (i.n. daily for 5 days, and 5 days later mice were challenged with CE for 4 consecutive days. A second group received CE i.n. for 3 weeks. Airway hyperresponsiveness (AHR was assessed 24 h after the last allergen exposure. Allergic airway inflammation was assessed by BAL and lung histology 48 h after the last allergen exposure. Antigen-specific antibodies were assessed in serum. Lungs were excised from mice from measurement of cytokines and chemokines in whole lung lysate. Results Mucosal exposure of Balb/c mice to cockroach extract induced airway eosinophilic inflammation, AHR and cockroach-specific IgG1; however, AHR to methacholine was absent in the long term group. Lung histology showed patchy, multicentric damage with inflammatory infiltrates at the airways in both groups. Lungs from mice from the short term group showed increased IL-4, CCL11, CXCL1 and CCL2 protein levels. IL4 and CXCL1 were also increased in the BAL of cockroach-sensitized mice in the short-term protocol. Conclusions Mucosal exposure to cockroach extract in the absence of adjuvant induces allergic airway sensitization characterized by AHR, the presence of Th2 cytokines in the lung and eosinophils in the airways.

  12. A dual drug sensitive L. major induces protection without lesion in C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Noushin Davoudi

    Full Text Available Leishmaniasis is a major health problem in some endemic areas and yet, no vaccine is available against any form of the disease. Historically, leishmanization (LZ which is an inoculation of individual with live Leishmania, is the most effective control measure at least against cutaneous leishmaniasis (CL. Due to various reasons, LZ is not used today. Several live attenuated Leishmania have been developed but their use is limited. Previously, we developed a transgenic strain of L. major that harbors two suicide genes tk and cd genes (lmtkcd+/+ for use as a challenge strain in vaccine studies. These genes render the parasite susceptible to Ganciclovir (GCV and 5-flurocytosine (5-FC. The dual drug sensitive strain of L. major was developed using gene targeting technology using a modified Herpes Simplex Virus thymidine kinase gene (hsv-tk sensitive to Ganciclovir antibiotic and Saccharomyces cerevisae cytosine deaminase gene (cd sensitive to 5-flurocytosine that were stably introduced into L. major chromosome. BALB/c mice inoculated with lmtkcd+/+ developed lesions which upon treatment with GCV and 5-FC completely healed. In the current study, the transgenic lmtkcd+/+strain was assessed as a live vaccine model to determine the time necessary to develop a protective immune response. C57BL/6 mice were inoculated with the transgenic lmtkcd+/+strain, and treated at the time of inoculation (day 0 or at day 8 after inoculation. Immunized animals were challenged with wild-type L. major, and complete protection was induced in mice that were treated at day 8. The results show that in contrast to leishmanization, in group of mice inoculated with a dual sensitive L. major development and persistence of lesion is not necessary to induce Th1 response and protection.

  13. A large area position-sensitive ionization chamber for heavy-ion-induced reaction studies

    CERN Document Server

    Pant, L M; Dinesh, B V; Thomas, R G; Saxena, A; Sawant, Y S; Choudhury, R K

    2002-01-01

    A large area position-sensitive ionization chamber with a wide dynamic range has been developed to measure the mass, charge and energy of the heavy ions and the fission fragments produced in heavy-ion-induced reactions. The split anode geometry of the detector makes it suitable for both particle identification and energy measurements for heavy ions and fission fragments. The detector has been tested with alpha particles from sup 2 sup 4 sup 1 Am- sup 2 sup 3 sup 9 Pu source, fission fragments from sup 2 sup 5 sup 2 Cf and the heavy-ion beams from the 14UD Mumbai Pelletron accelerator facility. Using this detector, measurements on mass and total kinetic energy distributions in heavy-ion-induced fusion-fission reactions have been carried out for a wide range of excitation energies. Results on deep inelastic collisions and mass-energy correlations on different systems using this detector setup are discussed.

  14. Groomed jets in heavy-ion collisions: sensitivity to medium-induced bremsstrahlung

    CERN Document Server

    Mehtar-Tani, Yacine

    2016-01-01

    We argue that contemporary jet substructure techniques might facilitate a more direct measurement of hard medium-induced gluon bremsstrahlung in heavy-ion collisions, and focus specifically on the "soft drop declustering" procedure that singles out the two leading jet substructures. Assuming coherent jet energy loss, we find an enhancement of the distribution of the energy fractions shared by the two substructures at small subjet energy caused by hard medium-induced gluon radiation. Departures from this approximation are discussed, in particular, the effects of colour decoherence and the contamination of the grooming procedure by soft background. Finally, we propose a complementary observable, that is the ratio of the two-pronged probability in Pb-Pb to proton-proton collisions and discuss its sensitivity to various energy loss mechanisms.

  15. Effect of Herbal-Acupuncture on Repeated Cocaine-induced Behavioral Sensitization in the Rat

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    B.B. Lee

    2004-02-01

    Full Text Available Substantial evidence suggests that behavioral and reinforcing effects of cocaine can be mediated by the mesolimbic dopaminergic system. It has been shown that repeated injections of cocaine produce increase in locomotor activity, expression of the immediate-early gene, c-fos in the nucleus accumbens (NAc, which was one of the main dopaminergic terminal areas. Herbal-acupuncture as a therapeutic intervention has been widely used for the treatment of many functional disorders such as drug abuse. Coptidis Rhizoma (CR and its main component, berberine (BER were selected as herbal medicine of herbal-acupuncture. Both medicines have been known to have the therapeutic effect on the central nervous system. In order to investigate the effects of CR and BER herbal-acupuncture at shenmen (HT7 point (CR/H and BER/H on the cocaine-induced behavioral sensitization, the influence of CR/H and BER/H on repeated cocaine-induced locomotor activity, the change of c-Fos expression in the brain by immunohistochemistry were examined. Male SD rats were given CR/H (0.4 mg/kg and BER/H (0.1 mg/kg 30 min before daily injections of cocaine hydrochloride (15 mg/kg, i.p. 10 days. After 3 days withdrawal, rats received a challenge injection of cocaine (15 mg/kg, i.p.. Systemic challenge with cocaine produced much larger increased locomotor activity, accumbal Fos-like immunoreactivity in the NAc. Pretreatment with CR/H and BER/H significantly inhibited cocaine-induced locomotor activity, the change of c-Fos expression in the rats. Our data demonstrated that the inhibitory effects of cocaine-induced behavioral sensitization by CR/H and BER/H were closely associated with the reduction of presynaptic dopamine release in the NAc. These results suggest that CR/H and BER/H can be effectively applied to cocaine addiction.

  16. Clinical evaluation of serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels in patients with hepatocellular carcinoma following interventional radiology.

    Science.gov (United States)

    Minakuchi, K; Murata, K; Kaminoh, T; Takada, K; Takashima, S; Nakamura, K; Onoyama, Y

    1993-01-01

    Fourteen patients with unrespectable HCC were treated with various interventional radiology (IVR) procedures. The initial therapeutic response was determined using computed tomography (CT) findings, and determinations of serum alpha-fetoprotein (AFP) and protein induced by Vitamin K absence or antagonist-II (PIVKA-II) levels. When CT studies of the initial response to IVR were compared with changes in the serum AFP and PIVKA-II levels, the AFP level was found to correlate more closely than the PIVKA-II levels. The PIVKA-II level correlated more closely than the AFP level in cases with poor response to IVR. Both of these tumor markers should be measured in combination with the diagnostic imagings for follow-up studies of IVR.

  17. Pharmacokinetic interactions with calcium channel antagonists (Part I).

    Science.gov (United States)

    Schlanz, K D; Myre, S A; Bottorff, M B

    1991-11-01

    Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. PMID:1773549

  18. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells.

    Science.gov (United States)

    Crother, Timothy R; Schröder, Nicolas W J; Karlin, Justin; Chen, Shuang; Shimada, Kenichi; Slepenkin, Anatoly; Alsabeh, Randa; Peterson, Ellena; Arditi, Moshe

    2011-01-01

    Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs. PMID:21695198

  19. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Timothy R Crother

    Full Text Available Chlamydia pneumoniae (CP is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate, but not a high dose (severe CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n. with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.

  20. Transcriptomic changes induced by acute ozone in resistant and sensitive Medicago truncatula accessions

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    Mahalingam Ramamurthy

    2008-04-01

    Full Text Available Abstract Background Tropospheric ozone, the most abundant air pollutant is detrimental to plant and animal health including humans. In sensitive plant species even a few hours of exposure to this potent oxidant (200–300 nL. L-1 leads to severe oxidative stress that manifests as visible cell death. In resistant plants usually no visible symptoms are observed on exposure to similar ozone concentrations. Naturally occurring variability to acute ozone in plants provides a valuable resource for examining molecular basis of the differences in responses to ozone. From our earlier study in Medicago truncatula, we have identified cultivar Jemalong is ozone sensitive and PI 464815 (JE154 is an ozone-resistant accession. Analyses of transcriptome changes in ozone-sensitive and resistant accession will provide important clues for understanding the molecular changes governing the plant responses to ozone. Results Acute ozone treatment (300 nL L-1 for six hours led to a reactive oxygen species (ROS burst in sensitive Jemalong six hours post-fumigation. In resistant JE154 increase in ROS levels was much reduced compared to Jemalong. Based on the results of ROS profiling, time points for microarray analysis were one hour into the ozone treatment, end of treatment and onset of an ozone-induced ROS burst at 12 hours. Replicated temporal transcriptome analysis in these two accessions using 17 K oligonucleotide arrays revealed more than 2000 genes were differentially expressed. Significantly enriched gene ontologies (GOs were identified using the Cluster Enrichment analysis program. A striking finding was the alacrity of JE154 in altering its gene expression patterns in response to ozone, in stark contrast to delayed transcriptional response of Jemalong. GOs involved in signaling, hormonal pathways, antioxidants and secondary metabolism were altered in both accessions. However, the repertoire of genes responding in each of these categories was different between

  1. Whole body vibration induces forepaw and hind paw behavioral sensitivity in the rat.

    Science.gov (United States)

    Baig, Hassam A; Guarino, Benjamin B; Lipschutz, Daniel; Winkelstein, Beth A

    2013-11-01

    Whole body vibration (WBV) has been linked to neck and back pain, but the biomechanical and physiological mechanisms responsible for its development and maintenance are unknown. A rodent model of WBV was developed in which rats were exposed to different WBV paradigms, either daily for 7 consecutive days (repeated WBV) or two single exposures at Day 0 and 7 (intermittent WBV). Each WBV session lasted for 30 min and was imposed at a frequency of 15 Hz and RMS platform acceleration of 0.56 ± 0.07 g. Changes in the withdrawal response of the forepaw and hind paw were measured, and were used to characterize the onset and maintenance of behavioral sensitivity. Accelerations and displacements of the rat and deformations in the cervical and lumbar spines were measured during WBV to provide mechanical context for the exposures. A decrease in withdrawal threshold was induced at 1 day after the first exposure in both the hind paw and forepaw. Repeated WBV exhibited a sustained reduction in withdrawal threshold in both paws and intermittent WBV induced a sustained response only in the forepaw. Cervical deformations were significantly elevated which may explain the more robust forepaw response. Findings suggest that a WBV exposure leads to behavioral sensitivity.

  2. Silver nanocrystals sensitize magnetic-nanoparticle-mediated thermo-induced killing of cancer cells

    Institute of Scientific and Technical Information of China (English)

    Lianke Liu; Fang Ni; Jianchao Zhang; Xiaoli Jiang; Xiang Lu; Zhirui Guo; Ruizhi Xu

    2011-01-01

    Magnetic nanoparticles (MNPs) can heat up tumor tissues and induce killing of cancer cells under external AC magnetic field. However, magnetic nanoparticles hyperthermia (MNPH) requires high concentration of MNPs that are injected into the tumor in order to obtain clinically needed thermal dose because of the complicated heat transfer in v/vo and the limited heat quality of MNPs. To cut down the dose of MNPs and enhance the effect of this Nanotherapy, we prepared silver nanoparticles (AgNPs) with different sizes and investigated the effects of these AgNPs on cancer cells in MNPH treatment. It was found that AgNPs could enhance thermo-sensitivity of glioma cells and this effect was size dependent. AgNPs could induce cell cycles arrested in G2/M phase and enhanced the apoptosis rate of cancer cells after hyperthermia. In glioma bearing rats model, MNPH combined with AgNPs could enhance Bax expression in cancer cells. Our results suggested that AgNPs could be a potential thermo-sensitizer and could be further developed for the design of Ag nanostructurebased thermal seeds for MNPH therapy.

  3. Research of resistance of grape fruits induced by antagonistic yeast under normal temperature%常温条件下拮抗酵母菌对葡萄果实的抗性诱导研究

    Institute of Scientific and Technical Information of China (English)

    索娜; 周海莲; 王雪强; 肖红梅

    2012-01-01

    The antagonistic yeast,Hanseniaspora uvarum,isolated from strawberry fruit and foundeffective against Botrytis cinerea was tested to the experiment to assay the antagonism in Jufeng grape fruits.Grape fruits were divided into groups.In some of the fruits two holes(one injected antagonistic yeast at the concentration of 1×108cfu/mL,another one injected B.cinerea at the concentration of 1×105spore/mL) were punched,and H.uvarum were sprayed across some of the whole fruits.Organoleptic quality of grape fruits was observed and enzyme activity of enzymes that related to resistance was measured under normal storage temperature.The result showed that antagonistic yeast had no influence on organoleptic quality of fruits,and could maintain the organoleptic quality of fruits.For the fruits punching two holes(one injected antagonistic yeast,another one injected B.cinerea),H.uvarum can be significant induced the activity of peroxidase(POD),phenylalanine ammonia lyase(PAL),ascorbate peroxidase(APX),catalase(CAT) and polyphenol oxidase(PPO).For the whole fruits which sprayed H.uvarum,H.uvarum could be significant induced the activity of POD,PAL,SOD and APX.Taken as a whole,antagonism yeast could trigger stress reaction of fruits,and induce resistance of host.%以从草莓果实上筛选的、对由灰葡萄孢(Botrytis cinerea)引起的灰霉病具有较好抑制作用的葡萄有孢汉逊酵母(Hanseniaspora uvarum)菌株为供试拮抗酵母菌,研究其对"巨峰"葡萄果实抗性的诱导。将葡萄果实分组,并分别进行喷洒和人工接入浓度为1×108cfu/mL的拮抗酵母菌悬液,常温条件下贮藏,观察果实感官品质变化,并测定抗性相关酶酶活变化。结果表明,拮抗酵母菌处理不影响果实感官品质,甚至可以较好地维持果实的感官品质;人工接入的拮抗酵母菌可以较好的诱导果实的POD、PAL、CAT、PPO及APX的酶活,而对喷洒拮抗酵母菌的整个果实可以较好的诱导POD、SOD

  4. Visible light induced photoelectrochemical biosensing based on oxygen-sensitive quantum dots.

    Science.gov (United States)

    Wang, Wenjing; Bao, Lei; Lei, Jianping; Tu, Wenwen; Ju, Huangxian

    2012-09-26

    A visible light induced photoelectrochemical biosensing platform based on oxygen-sensitive near-infrared quantum dots (NIR QDs) was developed for detection of glucose. The NIR QDs were synthesized in an aqueous solution, and characterized with scanning electron microscopy and X-ray photoelectron spectroscopy. The as-prepared NIR QDs were employed to construct oxygen-sensitive photoelectrochemical biosensor on a fluorine-doped tin oxide (FTO) electrode. The oxygen dependency of the photocurrent was investigated at as-prepared electrode, which demonstrated the signal of photocurrent is suppressed with the decreasing of oxygen. Coupling with the consumption of oxygen during enzymatic reaction, a photoelectrochemical strategy was proposed for the detection of substrate. Using glucose oxidase (GOx) as a model enzyme, that is, GOx was covalently attached to the surface of CdTe QDs, the resulting biosensor showed the sensitive response to glucose. Under the irradiation of visible light of a wavelength at 505 nm, the proposed photoelectrochemical method could detect glucose ranging from 0.1 mM to 11 mM with a detection limit of 0.04 mM. The photoelectrochemical biosensor showed a good performance with high upper detection limit, acceptable stability and accuracy, providing an alternative method for monitoring biomolecules and extending the application of near-infrared QDs. PMID:22935371

  5. Caveolin-1 sensitizes rat pituitary adenoma GH3 cells to bromocriptine induced apoptosis

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    Huang Mu-Chiou

    2007-03-01

    Full Text Available Abstract Background Prolactinoma is the most frequent pituitary tumor in humans. The dopamine D2 receptor agonist bromocriptine has been widely used clinically to treat human breast tumor and prolactinoma through inhibition of hyperprolactinemia and induction of tumor cell apoptosis, respectively, but the molecular mechanism of bromocriptine induction of pituitary tumor apoptosis remains unclear. Caveolin-1 is a membrane-anchored protein enriched on caveolae, inverted flask-shaped invaginations on plasma membranes where signal transduction molecules are concentrated. Currently, caveolin-1 is thought to be a negative regulator of cellular proliferation and an enhancer of apoptosis by blocking signal transduction between cell surface membrane receptors and intracellular signaling protein cascades. Rat pituitary adenoma GH3 cells, which express endogenous caveolin-1, exhibit increased apoptosis and shrinkage after exposure to bromocriptine. Hence, the GH3 cell line is an ideal model for studying the molecular action of bromocriptine on prolactinoma. Results The expression of endogenous caveolin-1 in GH3 cells was elevated after bromocriptine treatment. Transiently expressed mouse recombinant caveolin-1 induced apoptosis in GH3 cells by enhancing the activity of caspase 8. Significantly, caveolin-1 induction of GH3 cell apoptosis was sensitized by the administration of bromocriptine. Phosphorylation of caveolin-1 at tyrosine 14 was enhanced after bromocriptine treatment, suggesting that bromocriptine-induced phosphorylation of caveolin-1 may contribute to sensitization of apoptosis in GH3 cells exposed to bromocriptine. Conclusion Our results reveal that caveolin-1 increases sensitivity for apoptosis induction in pituitary adenoma GH3 cells and may contribute to tumor shrinkage after clinical bromocriptine treatment.

  6. Quercetin sensitizes fluconazole-resistant candida albicans to induce apoptotic cell death by modulating quorum sensing.

    Science.gov (United States)

    Singh, B N; Upreti, D K; Singh, B R; Pandey, G; Verma, S; Roy, S; Naqvi, A H; Rawat, A K S

    2015-04-01

    Quorum sensing (QS) regulates group behaviors of Candida albicans such as biofilm, hyphal growth, and virulence factors. The sesquiterpene alcohol farnesol, a QS molecule produced by C. albicans, is known to regulate the expression of virulence weapons of this fungus. Fluconazole (FCZ) is a broad-spectrum antifungal drug that is used for the treatment of C. albicans infections. While FCZ can be cytotoxic at high concentrations, our results show that at much lower concentrations, quercetin (QC), a dietary flavonoid isolated from an edible lichen (Usnea longissima), can be implemented as a sensitizing agent for FCZ-resistant C. albicans NBC099, enhancing the efficacy of FCZ. QC enhanced FCZ-mediated cell killing of NBC099 and also induced cell death. These experiments indicated that the combined application of both drugs was FCZ dose dependent rather than QC dose dependent. In addition, we found that QC strongly suppressed the production of virulence weapons-biofilm formation, hyphal development, phospholipase, proteinase, esterase, and hemolytic activity. Treatment with QC also increased FCZ-mediated cell death in NBC099 biofilms. Interestingly, we also found that QC enhances the anticandidal activity of FCZ by inducing apoptotic cell death. We have also established that this sensitization is reliant on the farnesol response generated by QC. Molecular docking studies also support this conclusion and suggest that QC can form hydrogen bonds with Gln969, Thr1105, Ser1108, Arg1109, Asn1110, and Gly1061 in the ATP binding pocket of adenylate cyclase. Thus, this QS-mediated combined sensitizer (QC)-anticandidal agent (FCZ) strategy may be a novel way to enhance the efficacy of FCZ-based therapy of C. albicans infections. PMID:25645848

  7. Visible light induced photoelectrochemical biosensing based on oxygen-sensitive quantum dots

    Energy Technology Data Exchange (ETDEWEB)

    Wang Wenjing; Bao Lei [State Key Laboratory of Analytical Chemistry for Life Science, Department of Chemistry, Nanjing University, Nanjing 210093 (China); Lei Jianping, E-mail: jpl@nju.edu.cn [State Key Laboratory of Analytical Chemistry for Life Science, Department of Chemistry, Nanjing University, Nanjing 210093 (China); Tu Wenwen [State Key Laboratory of Analytical Chemistry for Life Science, Department of Chemistry, Nanjing University, Nanjing 210093 (China); Ju Huangxian, E-mail: hxju@nju.edu.cn [State Key Laboratory of Analytical Chemistry for Life Science, Department of Chemistry, Nanjing University, Nanjing 210093 (China)

    2012-09-26

    Highlights: Black-Right-Pointing-Pointer The near-infrared QDs are synthesized in an aqueous solution. Black-Right-Pointing-Pointer QDs-based biosensor exhibits visible-light induced cathodic photocurrent. Black-Right-Pointing-Pointer The oxygen dependency of the photocurrent is verified. Black-Right-Pointing-Pointer A photoelectrochemical strategy is established by coupling with enzymatic reaction. Black-Right-Pointing-Pointer Photoelectrochemical sensor shows high upper detection limit, acceptable stability and accuracy. - Abstract: A visible light induced photoelectrochemical biosensing platform based on oxygen-sensitive near-infrared quantum dots (NIR QDs) was developed for detection of glucose. The NIR QDs were synthesized in an aqueous solution, and characterized with scanning electron microscopy and X-ray photoelectron spectroscopy. The as-prepared NIR QDs were employed to construct oxygen-sensitive photoelectrochemical biosensor on a fluorine-doped tin oxide (FTO) electrode. The oxygen dependency of the photocurrent was investigated at as-prepared electrode, which demonstrated the signal of photocurrent is suppressed with the decreasing of oxygen. Coupling with the consumption of oxygen during enzymatic reaction, a photoelectrochemical strategy was proposed for the detection of substrate. Using glucose oxidase (GOx) as a model enzyme, that is, GOx was covalently attached to the surface of CdTe QDs, the resulting biosensor showed the sensitive response to glucose. Under the irradiation of visible light of a wavelength at 505 nm, the proposed photoelectrochemical method could detect glucose ranging from 0.1 mM to 11 mM with a detection limit of 0.04 mM. The photoelectrochemical biosensor showed a good performance with high upper detection limit, acceptable stability and accuracy, providing an alternative method for monitoring biomolecules and extending the application of near-infrared QDs.

  8. Thioridazine Sensitizes Esophageal Carcinoma Cell Lines to Radiotherapy-Induced Apoptosis In Vitro and In Vivo

    Science.gov (United States)

    Li, Hongxia; Juan, Li; Xia, Leiming; Wang, Yi; Bao, Yangyi; Sun, Guoping

    2016-01-01

    Background Radiotherapy is one of the primary treatments for esophageal squamous cell carcinoma (ESCC). Identification of novel radio-sensitizing agents will improve the therapeutic outcome of radiotherapy. This study aimed to determine the radio-sensitizing effect of the antipsychotic agent thioridazine in ESCC and explored the underlying mechanisms. Material/Methods ECA-109 and TE-1 ESCC cells were treated with thioridazine and radiotherapy alone and in combination. Cell survival was measured by MTT assay. Cell cycle and apoptosis were monitored by flow cytometry. Western blot analysis was used to analyze the expression of phospho-PI3K, phosphor-AKT, phospho-mTOR, Caspase-3, Caspase-9, Bax, Bcl-2, Bal-xl, Bak, and p53. The xenograft mouse model was used to study the in vivo anticancer effect of thioridazine and irradiation. Results Combined treatment with thioridazine and irradiation significantly reduced viability of ESCC cells compared with thioridazine or irradiation treatment alone. Thioridazine and irradiation treatment induced G0/G1 phases cell cycle arrest through down-regulation of CDK4 and cyclinD1. In addition, thioridazine and irradiation treatment induced apoptosis through up-regulation of cleaved capase-3 and 9, as well as an increase in the expression of Bax and Bak and a decrease in the expression of Bcl-2 and Bcl-xl. Furthermore, thioridazine and irradiation treatment inhibited the PI3K-AKT-mTOR pathway and up-regulated the expression of p53. In xenograft mice, thioridazine and irradiation reduced ESCC tumor growth. Conclusions Thioridazine sensitizes ESCC cells to radiotherapy. Thioridazine may play a role in ESCC radiation therapy as a promising radiosensitizer. PMID:27453171

  9. Neonatal Treatment with a Pegylated Leptin Antagonist Induces Sexually Dimorphic Effects on Neurones and Glial Cells, and on Markers of Synaptic Plasticity in the Developing Rat Hippocampal Formation.

    Science.gov (United States)

    López-Gallardo, M; Antón-Fernández, A; Llorente, R; Mela, V; Llorente-Berzal, A; Prada, C; Viveros, M P

    2015-08-01

    The present study aimed to better understand the role of the neonatal leptin surge, which peaks on postnatal day (PND)9-10, on the development of the hippocampal formation. Accordingly, male and female rats were administered with a pegylated leptin antagonist on PND9 and the expression of neurones, glial cells and diverse markers of synaptic plasticity was then analysed by immunohistochemistry in the hippocampal formation. Antagonism of the actions of leptin at this specific postnatal stage altered the number of glial fibrillary acidic protein positive cells, and also affected type 1 cannabinoid receptors, synaptophysin and brain-derived neurotrophic factor (BDNF), with the latter effect being sexually dimorphic. The results indicate that the physiological leptin surge occurring around PND 9-10 is critical for hippocampal formation development and that the dynamics of leptin activity might be different in males and females. The data obtained also suggest that some but not all the previously reported effects of maternal deprivation on hippocampal formation development (which markedly reduces leptin levels at PND 9-10) might be mediated by leptin deficiency in these animals.

  10. Memantine, an antagonist of the NMDA glutamate receptor, affects cell proliferation, differentiation and the intracellular cycle and induces apoptosis in Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Flávia Silva Damasceno

    2014-02-01

    Full Text Available Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico and Central and South America. Currently available chemotherapies are limited to two compounds: Nifurtimox and Benznidazole. Both drugs reduce the symptoms of the disease and mortality among infected individuals when used during the acute phase, but their efficacy during the chronic phase (during which the majority of cases are diagnosed remains controversial. Moreover, these drugs have several side effects. The aim of this study was to evaluate the effect of Memantine, an antagonist of the glutamate receptor in the CNS of mammals, on the life cycle of T. cruzi. Memantine exhibited a trypanocidal effect, inhibiting the proliferation of epimastigotes (IC50 172.6 µM. Furthermore, this compound interfered with metacyclogenesis (approximately 30% reduction and affected the energy metabolism of the parasite. In addition, Memantine triggered mechanisms that led to the apoptosis-like cell death of epimastigotes, with extracellular exposure of phosphatidylserine, increased production of reactive oxygen species, decreased ATP levels, increased intracellular Ca(2+ and morphological changes. Moreover, Memantine interfered with the intracellular cycle of the parasite, specifically the amastigote stage (IC50 31 µM. Interestingly, the stages of the parasite life cycle that require more energy (epimastigote and amastigote were more affected as were the processes of differentiation and cell invasion.

  11. Establishment of a novel CCR5 and CXCR4 expressing CD4+ cell line which is highly sensitive to HIV and suitable for high-throughput evaluation of CCR5 and CXCR4 antagonists

    Directory of Open Access Journals (Sweden)

    De Clercq Erik

    2004-03-01

    Full Text Available Abstract Background CCR5 and CXCR4 are the two main coreceptors essential for HIV entry. Therefore, these chemokine receptors have become important targets in the search for anti-HIV agents. Here, we describe the establishment of a novel CD4+ cell line, U87.CD4.CCR5.CXCR4, stably expressing both CCR5 and CXCR4 at the cell surface. Results In these cells, intracellular calcium signalling through both receptors can be measured in a single experiment upon the sequential addition of CXCR4- and CCR5-directed chemokines. The U87.CD4.CCR5.CXCR4 cell line reliably supported HIV-1 infection of diverse laboratory-adapted strains and primary isolates with varying coreceptor usage (R5, X4 and R5/X4 and allows to investigate the antiviral efficacy of combined CCR5 and CXCR4 blockade. The antiviral effects recorded in these cells with the CCR5 antagonist SCH-C and the CXCR4 antagonist AMD3100 were similar to those noted in the single CCR5- or CXCR4-transfected U87.CD4 cells. Furthermore, the combination of both inhibitors blocked the infection of all evaluated HIV-1 strains and isolates. Conclusions Thus, the U87.CD4.CCR5.CXCR4 cell line should be useful in the evaluation of CCR5 and CXCR4 antagonists with therapeutic potential and combinations thereof.

  12. Migfilin sensitizes cisplatin-induced apoptosis in human glioma cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Jing FAN; Yun-wei OU; Chuan-yue WU; Chun-jiang YU; Yong-mei SONG; Qi-min ZHAN

    2012-01-01

    Aim:Filamin binding LIM protein 1,also known as migfilin,is a skeleton organization protein that binds to mitogen-inducible gene 2 at cell-extracellular matrix adhesions.The aim of this study was to investigate the role of migfilin in cisplatin-induced apoptosis in human glioma cells,to determine the functional domains of migfilin,and to elucidate the molecular mechanisms underlying the regulation of cisplatin-related chemosensitivity.Methods:The human glioma cell lines Hs683,H4,and U-87 MG were transfected with pEGFP-C2-migfilin to elevate the expression level of migfilin.RNA interference was used to reduce the expression of migfilin.To determine the functional domains of migfilin,U-87 MG cells were transfected with plasmids of migfilin deletion mutants.After treatment with cisplatin (40 μmol/L) for 24 h,the cell viability was assessed using the MTS assay,and the cell apoptotic was examined using the DAPI staining assay and TUNEL analysis.Expression levels of apoptosis-related proteins were detected by Western blot analysis.Results:Overexpression of migfilin significantly enhanced cisplatin-induced apoptosis in Hs683,H4,and U-87 MG cells,whereas downregulation of migfilin expression inhibited the chemosensitivity of these cell lines.The N-terminal region of migfilin alone was able to enhance the cisplatin-induced apoptosis.However,despite the existence of the N-terminal region,mutants of migfilin with any one of three LIM domains deleted led to a function loss.Furthermore,apoptotic proteins (PARP and caspase-3) and the anti-apoptotic protein Bcl-xL were modulated by the expression level of migfilin in combination with cisplatin.Conclusion:The LIM1-3 domains of migfilin play a key role in sensitizing glioma cells to cisplatin-induced apoptosis through regulation of apoptosis-related proteins.

  13. Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei

    International Nuclear Information System (INIS)

    Folic acid deficiency can lead to uracil incorporation into DNA, hypomethylation of DNA, inefficient DNA repair and increase chromosome malsegregation and breakage. Because ionising radiation increases demand for efficient DNA repair and also causes chromosome breaks we hypothesised that folic acid deficiency may increase sensitivity to radiation-induced chromosome breakage. We tested this hypothesis by using the cytokinesis-block micronucleus assay in 10 day WIL2-NS cell cultures at four different folic acid concentrations (0.2, 2, 20, and 200 nM) that span the 'normal' physiological range in humans. The study showed a significant dose-dependent increase in frequency of binucleated cells with micronuclei and/or nucleoplasmic bridges with decreasing folic acid concentration (P < 0.0001, P = 0.028, respectively). These biomarkers of chromosomal instability were also increased in cells irradiated (1.5 Gy γ-rays) on day 9 relative to un-irradiated controls (P < 0.05). Folic acid deficiency and γ-irradiation were shown to have a significant interactive effect on frequency of cells containing micronuclei (two-way ANOVA, interaction P 0.0039) such that the frequency of radiation-induced micronucleated cells (i.e. after subtracting base-line frequency of un-irradiated controls) increased with decreasing folic acid concentration (P-trend < 0.0001). Aneuploidy of chromosome 21, apoptosis and necrosis were increased by folic acid deficiency but not by ionising radiation. The results of this study show that folate status has an important impact on chromosomal stability and is an important modifying factor of cellular sensitivity to radiation-induced genome damage

  14. Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth

    International Nuclear Information System (INIS)

    cultures were more sensitive to neurite outgrowth inhibitors, they also had a lower dynamic range for detecting chemical-induced neurite outgrowth inhibition and greater variability from culture-to-culture as compared to rat primary cortical cultures.

  15. Effects of anesthesia-induced modest hypothermia on cellular radiation sensitivity

    Institute of Scientific and Technical Information of China (English)

    XIANG; Yingsong(项莺松); TANG; Gusheng(唐古生); XU; Xiongfei(许熊飞); YANG; Rujun(杨如俊); CAI; Jianming(蔡建明); ZHANG; Minghui(张明辉); CAO; Xuetao(曹雪涛)

    2002-01-01

    To assess the mechanisms of modest hypothermia(MH) and its effects on cellular radiation response, a model of anesthesia-induced modest hypothermia(AIMH) in the adult mice and a model of pure MH in the newborn mice were established. The survival rate of lethally irradiated mice was increased to 72% through AIMH before irradiation. Both apoptosis and necrosis of human fetal bone marrow CD34+ hematopoietic stem cells cultured under MH were significantly decreased as detected by MTT and flow cytometry, with three-color labeled by PE-CD34+/ FITC-AnnexinV /7AAD. The survival and proliferation of mouse bone marrow MNC treated with MH after irradiation were also increased. The MH exerted similar protective effects on the leukemia cell lines A20, HL60, K562 to the normal bone marrow cells, but it enhanced the radiation sensitivity of leukemia cell line FBL3 and mouse melanoma B16F10. No effects have been found on the radiation sensitivity of those cells treated with MH before irradiation. The results also showed that MH mediated the effects on radiation sensitivity, in addition to increasing the oxygen tension. These results show different effects of MH on different cells:(i) AIMH exerts a protective effect on the normal hematopoietic stem cells, some leukemia cell lines A20, HL60, K562, and some neoplasma 3LL, LOVO. And MH exhibits a synthetic effect with anesthetic.(ii) MH enhances the radiation sensitivity of another leukemia and neoplasma cell lines FBL3, B16F10 and CT26. Therefore, AIMH has a potential to enhance the effects of radiation-therapy and decrease side effects on some tumors.

  16. Effect of low-level laser therapy on tooth sensitivity induced by in-office bleaching.

    Science.gov (United States)

    Moosavi, Horieh; Arjmand, Nooshin; Ahrari, Farzaneh; Zakeri, Majid; Maleknejad, Fatemeh

    2016-05-01

    This study aimed to investigate the effect of low-level laser therapy (LLLT) on tooth sensitivity induced by in-office bleaching. Sixty-six patients enrolled in this randomized clinical trial. Following the in-office procedure with 40 % hydrogen peroxide, the participants were randomly divided into three groups. The patients in group 1 received irradiation from a low-level red laser (LLRL; 660 nm, 200 mW, 15 s, 12 J/cm(2)), whereas participants in group 2 were subjected to a low-level infrared laser (LLIL; 810 nm) under similar conditions as in group 1. In group 3 (placebo), the laser treatment was the same as that in groups 1 and 2, but without energy output. The degree of tooth sensitivity was recorded at 1, 24, and 48 h after bleaching using a visual analog scale (VAS). The change in tooth shade was measured 30 days after tooth whitening. The intensity of tooth sensitivity was not significantly different between groups at 1 h after bleaching (p > 0.05). At 24 h after therapy, pain level was significantly lower in the LLIL group compared to the LLRL and placebo groups (p  0.05) and both were significantly lower than that of the placebo group (p  0.05). LLLT with an infrared diode laser could be recommended as a suitable strategy to reduce the intensity of tooth sensitivity after in-office bleaching. PMID:26964798

  17. Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth

    Energy Technology Data Exchange (ETDEWEB)

    Harrill, Joshua A.; Freudenrich, Theresa M.; Robinette, Brian L.; Mundy, William R., E-mail: mundy.william@epa.gov

    2011-11-15

    cultures were more sensitive to neurite outgrowth inhibitors, they also had a lower dynamic range for detecting chemical-induced neurite outgrowth inhibition and greater variability from culture-to-culture as compared to rat primary cortical cultures.

  18. Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Mu Dezhi

    2010-11-01

    Full Text Available Abstract Background Glucocorticoid (GC resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL. In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex treatment. Methods Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl- 2,5-diphenyltetrazolium bromide (MTT assay. Fluorescence-activated cell sorting (FACS analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR, the cell cycle regulatory proteins, and apoptosis associated proteins. Results 10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G1-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1. Conclusion Our data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G0/G1 phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting

  19. Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice

    Directory of Open Access Journals (Sweden)

    Shvetank Bhatt

    2014-01-01

    Full Text Available Aim: The aim of the study was to evaluate a novel 5 HT 3 receptor antagonist (6g on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body′s reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants. Materials and Methods: In the present study, a novel and potential 5-HT 3 receptor antagonist (4-benzylpiperazin-1-yl(3-methoxyquinoxalin-2-yl methanone (6g with good Log P (3.08 value and pA 2 (7.5 values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour. Results: The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05 decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05 increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. ′6g′ (1 and 2 mg/kg, p.o., 21 days and fluoxetine treatment (20 mg/kg, p.o., 21 days significantly (P < 0.05 reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities. However fluoxetine treatment (20 mg/kg, p.o., 21 days significantly decreased the nitrite level in the brain while ′6g′ (1 and 2 mg/kg, p.o., 21 days did not show significant (P < 0

  20. Wheat-dependent exercise-induced anaphylaxis sensitized with hydrolyzed wheat protein in soap.

    Science.gov (United States)

    Chinuki, Yuko; Morita, Eishin

    2012-12-01

    Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy typically induced by exercise after ingestion of wheat products. Wheat ω-5 gliadin is a major allergen associated with conventional WDEIA, and detection of serum immunoglobulin E (IgE) specific to recombinant ω-5 gliadin is a reliable method for its diagnosis. Recently, an increased incidence of a new subtype of WDEIA, which is likely to be sensitized via a percutaneous and/or rhinoconjunctival route to hydrolyzed wheat protein (HWP), has been observed. All of the patients with this new subtype had used the same brand of soap, which contained HWP. Approximately half of these patients developed contact allergy several months later and subsequently developed WDEIA. In each of these patients, contact allergy with soap exposure preceded food ingestion-induced reactions. Other patients directly developed generalized symptoms upon ingestion of wheat products. The predominant observed symptom of the new WDEIA subtype was angioedema of the eyelids; a number of patients developed anaphylaxis. This new subtype of WDEIA has little serum ω-5 gliadin-specific serum IgE.

  1. Wheat-Dependent Exercise-Induced Anaphylaxis Sensitized with Hydrolyzed Wheat Protein in Soap

    Directory of Open Access Journals (Sweden)

    Yuko Chinuki

    2012-01-01

    Full Text Available Wheat-dependent exercise-induced anaphylaxis (WDEIA is a specific form of wheat allergy typically induced by exercise after ingestion of wheat products. Wheat ω-5 gliadin is a major allergen associated with conventional WDEIA, and detection of serum immunoglobulin E (IgE specific to recombinant ω-5 gliadin is a reliable method for its diagnosis. Recently, an increased incidence of a new subtype of WDEIA, which is likely to be sensitized via a percutaneous and/or rhinoconjunctival route to hydrolyzed wheat protein (HWP, has been observed. All of the patients with this new subtype had used the same brand of soap, which contained HWP. Approximately half of these patients developed contact allergy several months later and subsequently developed WDEIA. In each of these patients, contact allergy with soap exposure preceded food ingestion-induced reactions. Other patients directly developed generalized symptoms upon ingestion of wheat products. The predominant observed symptom of the new WDEIA subtype was angioedema of the eyelids; a number of patients developed anaphylaxis. This new subtype of WDEIA has little serum ω-5 gliadin-specific serum IgE.

  2. Long-day photoperiod induced unhealthy development of chloroplasts in the photoperiod-sensitive genie male-sterile rice

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    By measurement of photochemical activities of chloroplasts and observation on supramolecular archi tecture of thylakoids in chloroplasts, it was found that compared with the effects of short-day photoperiod, long-day pho toperiod could induce normal development of chloroplasts in seedlings of NK58S (photoperiod-sensitive genie male-sterile rice) and NK58 (original line) which do not enter the photoperiod sensitive phase and in seedlings of NK58 just enter the photoperiod-sensitive phase. However, it could induce unhealthy development of chloroplasts in seedlings of NK58S which also just enter the photoperiod sensitive phase. This special effect of long-day photoperiod on the development of chloroplasts in NK58S is probably one of main reasons why long-day photoperiod induces rale-sterility in NK58S and normal fertility in NK58.

  3. Chronic exposure to MDMA (Ecstasy elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants

    Directory of Open Access Journals (Sweden)

    Swann Alan C

    2006-01-01

    Full Text Available Abstract Background The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. Methods The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg and a saline control group (N = 9/group. All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13. Rats were then given an additional 25-day washout period, and re-challenged (day 38 with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39. Open-field locomotor activity was recorded using a computerized automated activity monitoring system. Results Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group, while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change

  4. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

  5. IFN-γ Mediates Enhancement of HIV Replication in Astrocytes by Inducing an Antagonist of the β-Catenin Pathway (DKK1) in a STAT 3-Dependent Manner

    OpenAIRE

    Li, Wei; Henderson, Lisa J.; Major, Eugene O.; Al-Harthi, Lena

    2011-01-01

    Typically, IFN-γ is an antiviral cytokine that inhibits the replication of many viruses, including HIV. However, in the CNS, IFN-γ induces HIV-productive replication in astrocytes. Although astrocytes in vitro are refractory to HIV replication, recent in vivo evidence demonstrated that astrocytes are infected by HIV, and their degree of infection is correlated with proximity to activated macrophages/microglia. The ability of IFN-γ to induce HIV replication in astrocytes suggests that the envi...

  6. Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking

    OpenAIRE

    Kumaresan, Vidhya; Yuan, Menglu; Yee, Judy; Famous, Katie R.; Anderson, Sharon M.; Schmidt, Heath D.; Pierce, R Christopher

    2009-01-01

    Accumulating evidence suggests that metabotropic glutamate receptors (mGluRs) are involved in both cocaine reinforcement and the reinstatement of cocaine-seeking behavior. In the present experiments, rats were trained to self-administer cocaine under fixed ratio (for cocaine priming-induced reinstatement) or second order (for cocaine cue-induced reinstatement) schedules of reinforcement. Lever pressing was then extinguished followed by a reinstatement phase where operant responding was promot...

  7. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E;

    2007-01-01

    with parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment.......Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance...... for future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells...

  8. Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

    Science.gov (United States)

    Sharma, Aruna; Muresanu, Dafin F; Lafuente, José V; Patnaik, Ranjana; Tian, Z Ryan; Buzoianu, Anca D; Sharma, Hari S

    2015-10-01

    Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB

  9. H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K(+) restriction.

    Science.gov (United States)

    Walter, Christine; Tanfous, Mariem Ben; Igoudjil, Katia; Salhi, Amel; Escher, Geneviève; Crambert, Gilles

    2016-10-01

    In industrialized countries, a large part of the population is daily exposed to low K(+) intake, a situation correlated with the development of salt-sensitive hypertension. Among many processes, adaptation to K(+)-restriction involves the stimulation of H,K-ATPase type 2 (HKA2) in the kidney and colon and, in this study, we have investigated whether HKA2 also contributes to the determination of blood pressure (BP). By using wild-type (WT) and HKA2-null mice (HKA2 KO), we showed that after 4 days of K(+) restriction, WT remain normokalemic and normotensive (112 ± 3 mmHg) whereas HKA2 KO mice exhibit hypokalemia and hypotension (104 ± 2 mmHg). The decrease of BP in HKA2 KO is due to the absence of NaCl-cotransporter (NCC) stimulation, leading to renal loss of salt and decreased extracellular volume (by 20 %). These effects are likely related to the renal resistance to vasopressin observed in HKA2 KO that may be explained, in part by the increased production of prostaglandin E2 (PGE2). In WT, the stimulation of NCC induced by K(+)-restriction is responsible for the elevation in BP when salt intake increases, an effect blunted in HKA2-null mice. The presence of an activated HKA2 is therefore required to limit the decrease in plasma [K(+)] but also contributes to the development of salt-sensitive hypertension.

  10. Heavy Ion Induced SEU Sensitivity Evaluation of 3D Integrated SRAMs

    CERN Document Server

    Cao, Xuebing; Huo, Mingxue; Wang, Tianqi; Li, Anlong; Qi, Chunhua; Wang, Jinxiang

    2016-01-01

    Heavy ions induced single event upset (SEU) sensitivity of three-dimensional integrated SRAMs are evaluated by using Monte Carlo sumulation methods based on Geant4. The cross sections of SEUs and Multi Cell Upsets (MCUs) for 3D SRAM are simulated by using heavy ions with different energies and LETs. The results show that the sensitivity of different die of 3D SRAM has obvious discrepancies at low LET. Average percentage of MCUs of 3D SRAMs rises from 17.2% to 32.95% when LET increases from 42.19 MeV cm2/mg to 58.57MeV cm2/mg. As for a certain LET, the percentage of MCUs shows a notable distinction between face-to-face structure and back-to-face structure. For back-to-face structure, the percentage of MCUs increases with the deeper die. However, the face-to-face die presents the relatively low percentage of MCUs. The comparison of SEU cross sections for planar SRAMs and experiment data are conducted to indicate the effectiveness of our simulation method. Finally, we compare the upset cross sections of planar p...

  11. Sensitivity Jump of Micro Accelerometer Induced by Micro-fabrication Defects of Micro Folded Beams

    Science.gov (United States)

    Zhou, Wu; Chen, Lili; Yu, Huijun; Peng, Bei; Chen, Yu

    2016-08-01

    The abnormal phenomenon occurring in sensor calibration is an obstacle to product development but a useful guideline to product improvement. The sensitivity jump of micro accelerometers in the calibrating process is recognized as an important abnormal behavior and investigated in this paper. The characteristics of jumping output in the centrifuge test are theoretically and experimentally analyzed and their underlying mechanism is found to be related to the varied stiffness of supporting beam induced by the convex defect on it. The convex defect is normally formed by the lithography deviation and/or etching error and can result in a jumping stiffness of folded microbeams and further influence the sensitivity when a part of the bending beams is stopped from moving by two surfaces contacting. The jumping level depends on the location of convex and has nothing to do with the contacting properties of beam and defects. Then the location of defect is predicted by theoretical model and simulation and verified by the observation of micro structures under microscopy. The results indicate that the tested micro accelerometer has its defect on the beam with a distance of about 290μm from the border of proof mass block.

  12. Increased sensitivity to cocaine-induced analgesia in Spontaneously Hypertensive Rats (SHR

    Directory of Open Access Journals (Sweden)

    Takahashi Reinaldo N

    2007-02-01

    Full Text Available Abstract This study examined the analgesic effect of cocaine in Spontaneously Hypertensive Rats (SHR, which are considered a suitable model for the study of attention deficit hyperactivity disorder (ADHD, and in Wistar (WIS rats of both sexes using the hot-plate test. In addition, we tested whether habituation to the unheated hot-plate apparatus, that "normalizes" the basal hypoalgesic phenotype of SHR, alters the subsequent cocaine-induced analgesia (CIA in this strain. SHR of both sexes were hypoalgesic compared to WIS rats in the hot-plate test and showed higher sensitivity to CIA. Habituation to the unheated hot-plate reduced the basal nociceptive latency of SHR, suggesting cognitive/emotional modulation of pain in this strain, but did not alter the magnitude of CIA. The present study shows increased sensitivity to CIA in SHR, which may be related to abnormalities in the mesocorticolimbic dopaminergic system. Further studies using SHR strain may reveal new information on the neurobiological mechanisms underlying ADHD and its co-morbidity with drug addiction.

  13. Tramadol—induced physical dependence and its effects on behavioral sensitization to methamphetamine in mice

    Institute of Scientific and Technical Information of China (English)

    LiangJH; WangK

    2002-01-01

    Tramadol is a widely used and non-controlled analgesic,which stimulates both centrally opiatergic and monoaminergic systems.The epidemiological data indicate that tramadol possesses relatively high poly-drug abuse potential.Therefore,the present study was designed to assess the physical dependence of tramadol and investigate the effects of tramadol on behavioral sensitization to methamphetamine (MA) and its toxicity.Mice were made acute dependence on tramadol by injection (sc) of tramadol.After 3h,naloxone was given (ip) to precipitate withdrawal symptoms.The results showed that tramadol displayed marked naloxoneprecipitated withdrawal symptoms.5-HTP,a precursor of 5-HT,attenuated tramadol withdrawal symptoms,but parachlorophenylalanine,a tryptophan hydroxylase inhibitor,aggravated them.In the open field test,tramadol enhanced the development and expression of behavioral sensitization to MA in mice.In addition,co-administration of tramadol (120mg·kg-1,a non-lethal dose) and MA reduced the LD50 for MA from 63.4mg·kg-1 to 32.3mg·kg-1.Our findings suggest that tramadol produce physical dependence in itself and potentiate MA-induced addictive behavior and toxicity.

  14. Highly sensitive SnO2 sensor via reactive laser-induced transfer

    Science.gov (United States)

    Palla Papavlu, Alexandra; Mattle, Thomas; Temmel, Sandra; Lehmann, Ulrike; Hintennach, Andreas; Grisel, Alain; Wokaun, Alexander; Lippert, Thomas

    2016-04-01

    Gas sensors based on tin oxide (SnO2) and palladium doped SnO2 (Pd:SnO2) active materials are fabricated by a laser printing method, i.e. reactive laser-induced forward transfer (rLIFT). Thin films from tin based metal-complex precursors are prepared by spin coating and then laser transferred with high resolution onto sensor structures. The devices fabricated by rLIFT exhibit low ppm sensitivity towards ethanol and methane as well as good stability with respect to air, moisture, and time. Promising results are obtained by applying rLIFT to transfer metal-complex precursors onto uncoated commercial gas sensors. We could show that rLIFT onto commercial sensors is possible if the sensor structures are reinforced prior to printing. The rLIFT fabricated sensors show up to 4 times higher sensitivities then the commercial sensors (with inkjet printed SnO2). In addition, the selectivity towards CH4 of the Pd:SnO2 sensors is significantly enhanced compared to the pure SnO2 sensors. Our results indicate that the reactive laser transfer technique applied here represents an important technical step for the realization of improved gas detection systems with wide-ranging applications in environmental and health monitoring control.

  15. The relationship between cocaine-induced increases in NAC1 and behavioral sensitization.

    Science.gov (United States)

    Wang, P J; Stromberg, Michael; Replenski, Stephen; Snyder-Mackler, Alexander; Mackler, Scott A

    2003-04-01

    Repeated exposure to cocaine can cause long-term behavioral changes in mammals, including an augmented locomotor response known as behavioral sensitization. A major goal of research is the identification of molecules associated with these behaviors. NAC1, a member of the POZ/BTB transcription factor family, exhibited increased mRNA levels in the nucleus accumbens of the rat weeks after cocaine use. NAC1 exists as two isoforms, each demonstrating the ability to inhibit transcription, but to different extents. The present experiments examined the time course for both NAC1 isoforms after five consecutive days of systemic cocaine administration in male rats. Tissues were collected from several central nervous system regions and underwent Western blot analysis. There was significantly greater expression of the long isoform, lNAC1 (cocaine 1.341+/-0.641; saline 1+/-0.321; P=.044), and the short isoform, sNAC1 (cocaine 3.038+/-2.816; saline 1+/-0.720; P=.001), in the nucleus accumbens of cocaine-treated rats. The olfactory tubercle also showed a significant increase, but only in sNAC1 expression and at only one time period. No other significant differences were observed for either isoform of NAC1 in any other brain region. The expression of lNAC1 exhibited an inverse relationship with behavioral sensitization in rats 1-3 months following repeated cocaine injections predicting approximately 40% of the variance in the behavior variables (R(2)=.387; and P=.031 for distance and P=.025 for ambulatory count). These results indicate that NAC1 expression is increased for a period of several months after chronic cocaine exposure. Furthermore, these data suggest that NAC1 may function as an endogenous inhibitor of behavioral sensitization. NAC1 represents a target for future studies examining cocaine-induced behavioral changes.

  16. Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants

    OpenAIRE

    Swann Alan C; Yang Pamela B; Modi Gunjan M; Dafny Nachum

    2006-01-01

    Abstract Background The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. Methods The objectives of this study were to examine the dose-response characteristics o...

  17. Blood flow in histamine- and allergen-induced weal and flare responses, effects of an H1 antagonist, alpha-adrenoceptor agonist and a topical glucocorticoid.

    Science.gov (United States)

    Hammarlund, A; Olsson, P; Pipkorn, U

    1990-01-01

    Allergen has previously been shown to induce a continuous increase in local dermal blood flow after a prick test in allergic subjects, whereas histamine induced, initially, similar peak increases in blood flow of much shorter duration. Blood flow changes induced by histamine and allergen have now been evaluated (i) after pretreatment with a local corticosteroid cream, clobetasole-17-propionate; (ii) after oral administration of the H1-antihistamine loratadine; and (iii) after oral pretreatment with the alpha 1-adrenoceptor agonist pseudoephedrine. Blinded placebo-controlled designs were used in the substudies. Laser doppler flowmetry was used for non-invasive recording of changes in local blood flow intermittently for 24 h after the topical corticosteroid, 6 h for the substudies on loratadine and pseudoephedrine. The size of the immediate weal and flare reactions, as well as late phase reactions, were also determined. Pretreatment with clobetasole-17-propionate cream on the skin for 1 week prior to prick tests did not affect the blood flow response elicited by histamine or allergen, in either the initial part (up to 1 h) or the protracted 24 h determinations. The size of the weal and flare reactions decreased. Loratadine and pseudoephedrine did not reduce the initial allergen-induced increase in blood flow, while lower blood flow compared with placebo pretreatment was noted for the protracted (1-6 h) determinations. Blood flow changes after histamine were unaffected. The histamine-induced weal and flare was inhibited by loratadine more effectively than the corresponding allergen-induced reaction. The weal and flare reactions after histamine and allergen were not changed after pseudoephedrine.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Monitoring drug induced apoptosis and treatment sensitivity in non-small cell lung carcinoma using dielectrophoresis.

    Science.gov (United States)

    Taruvai Kalyana Kumar, Rajeshwari; Liu, Shanshan; Minna, John D; Prasad, Shalini

    2016-09-01

    Non-invasive real time methods for characterizing biomolecular events that contribute towards apoptotic kinetics would be of significant importance in the field of cancer biology. Effective drug-induced apoptosis is an important factor for establishing the relationship between cancer genetics and treatment sensitivity. The objective of this study was to develop a non-invasive technique to characterize cancer cells that are undergoing drug-induced apoptosis. We used dielectrophoresis to determine apoptotic cells as early as 2h post drug treatment as compared to 24h with standard flow cytometry method using non-small cell lung cancer (NSCLC) adenocarcinoma cell line (HCC1833) as a study model. Our studies have shown significant differences in apoptotic cells by chromatin condensation, formation of apoptotic bodies and exposure of phosphatidylserine (PS) on the extracellular surface when the cells where treated with a potent Bcl-2 family inhibitor drug (ABT-263). Time lapse dielectrophoretic studies were performed over 24h period after exposure to ABT-263 at clinically relevant concentrations. The dielectrophoretic studies were compared to Annexin-V FITC flow assay for the detection of PS in mid-stage apoptosis using flow cytometry. As a result of physical and biochemical changes, inherent dielectric properties of cells undergoing varying stages of apoptosis showed amplified changes in their cytoplasmic and membrane capacitance. In addition, zeta potential of these fixed isolated cells was measured to obtain direct correlation to biomolecular events. PMID:27262539

  19. Using ultra-sensitive next generation sequencing to dissect DNA damage-induced mutagenesis.

    Science.gov (United States)

    Wang, Kaile; Ma, Xiaolu; Zhang, Xue; Wu, Dafei; Sun, Chenyi; Sun, Yazhou; Lu, Xuemei; Wu, Chung-I; Guo, Caixia; Ruan, Jue

    2016-01-01

    Next generation sequencing (NGS) technologies have dramatically improved studies in biology and biomedical science. However, no optimal NGS approach is available to conveniently analyze low frequency mutations caused by DNA damage treatments. Here, by developing an exquisite ultra-sensitive NGS (USNGS) platform "EasyMF" and incorporating it with a widely used supF shuttle vector-based mutagenesis system, we can conveniently dissect roles of lesion bypass polymerases in damage-induced mutagenesis. In this improved mutagenesis analysis pipeline, the initial steps are the same as in the supF mutation assay, involving damaging the pSP189 plasmid followed by its transfection into human 293T cells to allow replication to occur. Then "EasyMF" is employed to replace downstream MBM7070 bacterial transformation and other steps for analyzing damage-induced mutation frequencies and spectra. This pipeline was validated by using UV damaged plasmid after its replication in lesion bypass polymerase-deficient 293T cells. The increased throughput and reduced cost of this system will allow us to conveniently screen regulators of translesion DNA synthesis pathway and monitor environmental genotoxic substances, which can ultimately provide insight into the mechanisms of genome stability and mutagenesis. PMID:27122023

  20. Sarcolemmal ATP-sensitive potassium channel protects cardiac myocytes against lipopolysaccharide-induced apoptosis.

    Science.gov (United States)

    Zhang, Xiaohui; Zhang, Xiaohua; Xiong, Yiqun; Xu, Chaoying; Liu, Xinliang; Lin, Jian; Mu, Guiping; Xu, Shaogang; Liu, Wenhe

    2016-09-01

    The sarcolemmal ATP-sensitive K+ (sarcKATP) channel plays a cardioprotective role during stress. However, the role of the sarcKATP channel in the apoptosis of cardiomyocytes and association with mitochondrial calcium remains unclear. For this purpose, we developed a model of LPS-induced sepsis in neonatal rat cardiomyocytes (NRCs). The TUNEL assay was performed in order to detect the apoptosis of cardiac myocytes and the MTT assay was performed to determine cellular viability. Exposure to LPS significantly decreased the viability of the NRCs as well as the expression of Bcl-2, whereas it enhanced the activity and expression of the apoptosis-related proteins caspase-3 and Bax, respectively. The sarcKATP channel blocker, HMR-1098, increased the apoptosis of NRCs, whereas the specific sarcKATP channel opener, P-1075, reduced the apoptosis of NRCs. The mitochondrial calcium uniporter inhibitor ruthenium red (RR) partially inhibited the pro-apoptotic effect of HMR-1098. In order to confirm the role of the sarcKATP channel, we constructed a recombinant adenovirus vector carrying the sarcKATP channel mutant subunit Kir6.2AAA to inhibit the channel activity. Kir6.2AAA adenovirus infection in NRCs significantly aggravated the apoptosis of myocytes induced by LPS. Elucidating the regulatory mechanisms of the sarcKATP channel in apoptosis may facilitate the development of novel therapeutic targets and strategies for the management of sepsis and cardiac dysfunction. PMID:27430376

  1. Antagonistic effects of black tea against gamma radiation-induced oxidative damage to normal lymphocytes in comparison with cancerous K562 cells.

    Science.gov (United States)

    Ghosh, Debjani; Dey, Subrata Kumar; Saha, Chabita

    2014-11-01

    The potential of naturally occurring antioxidants to reduce the cellular oxidative damage induced by ionizing radiation has been studied for more than a decade for their pharmacological application during cancer treatment. It is already known that radioprotective efficacy of phytochemicals might influence various end points of radiation damage. Flavonoids are well-known natural radioprotectors, and their biological effects depend upon their chemical structure. In the present study, radioprotective effect of black tea rich in flavonoids was evaluated against gamma radiation-induced oxidative damage on normal lymphocytes and compared with erythroleukemic K562 cells. Pre-treatment with black tea extract (BTE) significantly reduced radiation-induced loss of cell viability, generation of reactive oxygen species, mitochondrial dysfunction, activation of caspase-3 and apoptosis in normal lymphocytes compared to K562 cells. BTE also regulates the activity of endogenous antioxidant enzymes. The changes in the mRNA expression of bax, bcl2, p53 and Nrf2 were also followed to evaluate regulation of radiation-induced apoptosis by BTE. These findings suggest that black tea may have the potential of a natural radioprotective agent which can be used as adjunct with radiation during cancer treatment.

  2. Luteolin inhibits behavioral sensitization by blocking methamphetamine-induced MAPK pathway activation in the caudate putamen in mice.

    Directory of Open Access Journals (Sweden)

    Tinglin Yan

    Full Text Available GOAL: To investigate the effect of luteolin on methamphetamine (MA-induced behavioral sensitization and mitogen-activated protein kinase (MAPK signal transduction pathway activation in mice. METHODS: Mice received a single dose of MA to induce hyperactivity or repeated intermittent intraperitoneal injections of MA to establish an MA-induced behavioral sensitization mouse model. The effect of luteolin on the development and expression of MA-induced hyperactivity and behavioral sensitization was examined. The expression and activity of ΔFosB and the levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2, phosphorylated c-Jun N-terminal kinase (pJNK, and phosphorylated p38 mitogen-activated protein kinase (pp38 in the caudate putamen (CPu were measured by western blot. RESULTS: Luteolin significantly decreased hyperactivity as well as the development and expression of MA-induced behavioral sensitization in mice. ΔFosB, pERK1/2, and pJNK levels in the CPu were higher in MA-treated mice than in control mice, whereas the pp38 level did not change. Injection of luteolin inhibited the MA-induced increase in ΔFosB, pERK1/2, and pJNK levels, but did not affect the pp38 level. CONCLUSIONS: Luteolin inhibits MA-induced hyperactivity and behavioral sensitization in mice through the ERK1/2/ΔFosB pathway. Furthermore, the JNK signaling pathway might be involved in MA-induced neurodegeneration in the CPu, and luteolin inhibits this process.

  3. Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy.

    Science.gov (United States)

    de Theije, C C; Langen, R C J; Lamers, W H; Gosker, H R; Schols, A M W J; Köhler, S E

    2015-01-15

    Hypoxia as a consequence of acute and chronic respiratory disease has been associated with muscle atrophy. This study investigated the sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. Male mice were exposed to 8% normobaric oxygen for up to 21 days. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were isolated, weighed, and assayed for expression profiles of the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF1α) signaling. Fiber-type composition and the capillary network were investigated. Hypoxia-induced muscle atrophy was more prominent in the EDL than the soleus muscle. Although increased expression of HIF1α target genes showed that both muscle types sensed hypoxia, their adaptive responses differed. Atrophy consistently involved a hypoxia-specific effect (i.e., not attributable to a hypoxia-mediated reduction of food intake) in the EDL only. Hypoxia-specific activation of the UPS and ALP and increased expression of the glucocorticoid receptor (Gr) and its target genes were also mainly observed in the EDL. In the soleus, stimulation of gene expression of those pathways could be mimicked to a large extent by food restriction alone. Hypoxia increased the number of capillary contacts per fiber cross-sectional area in both muscles. In the EDL, this was due to type II fiber atrophy, whereas in the soleus the absolute number of capillary contacts increased. These responses represent two distinct modes to improve oxygen supply to muscle fibers, but may aggravate muscle atrophy in chronic obstructive pulmonary disease patients who have a predominance of type II fibers.

  4. Modelling the sensitivity of soil mercury storage to climate-induced changes in soil carbon pools

    Directory of Open Access Journals (Sweden)

    O. Hararuk

    2013-04-01

    Full Text Available Substantial amounts of mercury (Hg in the terrestrial environment reside in soils and are associated with soil organic carbon (C pools, where they accumulated due to increased atmospheric deposition resulting from anthropogenic activities. The purpose of this study was to examine potential sensitivity of surface soil Hg pools to global change variables, particularly affected by predicted changes in soil C pools, in the contiguous US. To investigate, we included a soil Hg component in the Community Land Model based on empirical statistical relationships between soil Hg / C ratios and precipitation, latitude, and clay; and subsequently explored the sensitivity of soil C and soil Hg densities (i.e., areal-mass to climate scenarios in which we altered annual precipitation, carbon dioxide (CO2 concentrations and temperature. Our model simulations showed that current sequestration of Hg in the contiguous US accounted for 15 230 metric tons of Hg in the top 0–40 cm of soils, or for over 300 000 metric tons when extrapolated globally. In the simulations, US soil Hg pools were most sensitive to changes in precipitation because of strong effects on soil C pools, plus a direct effect of precipitation on soil Hg / C ratios. Soil Hg pools were predicted to increase beyond present-day values following an increase in precipitation amounts and decrease following a reduction in precipitation. We found pronounced regional differences in sensitivity of soil Hg to precipitation, which were particularly high along high-precipitation areas along the West and East Coasts. Modelled increases in CO2 concentrations to 700 ppm stimulated soil C and Hg accrual, while increased air temperatures had small negative effects on soil C and Hg densities. The combined effects of increased CO2, increased temperature and increased or decreased precipitation were strongly governed by precipitation and CO2 showing pronounced regional patterns. Based on these results, we conclude

  5. Modeling the sensitivity of soil mercury storage to climate-induced changes in soil carbon pools

    Directory of Open Access Journals (Sweden)

    O. Hararuk

    2012-08-01

    Full Text Available Substantial amounts of mercury (Hg in the terrestrial environment reside in soils and are associated with soil organic carbon (C pools, where they accumulated due to increased atmospheric deposition due to anthropogenic activities. The purpose of this study was to examine potential sensitivity of surface soil Hg pools to global change variables, particularly affected by predicted changes in soil C pools, in the contiguous US. To investigate, we included a soil Hg component in the Community Land Model based on empirical statistical relationships between soil Hg / C ratios and precipitation, latitude and clay; and subsequently explored the sensitivity of soil C and soil Hg densities (i.e. areal-mass to climate scenarios in which we altered annual precipitation, carbon dioxide (CO2 concentrations, and temperature.

    Our model simulations showed that current sequestration of Hg in the contiguous US accounted for 15 230 metric tons of Hg in the top 0–40 cm of soils. In the simulations, these soil Hg pools were most sensitive to changes in precipitation because of strong effects on soil C pools plus a direct effect of precipitation on soil Hg / C ratios. Soil Hg pools were predicted to increase beyond present-day values following an increase in precipitation amounts and decrease following a reduction in precipitation. We found pronounced regional differences in sensitivity of soil Hg to precipitation, which were particularly high along high-precipitation areas along the West and East Coasts. Modeled increases in CO2 concentrations to 700 ppm stimulated soil C and Hg densities, while increased air temperatures had small negative effects on soil C and Hg. The combined effects of increased CO2, increased temperature, and increased or decreased precipitation were strongly governed by precipitation and CO2 showing pronounced regional patterns. Based on these results, we conclude that the combination of

  6. Reversal of ethanol-seeking behavior by D1 and D2 antagonists in an animal model of relapse: differences in antagonist potency in previously ethanol-dependent versus nondependent rats.

    Science.gov (United States)

    Liu, Xiu; Weiss, Friedbert

    2002-03-01

    Mesocorticolimbic dopamine (DA) transmission has been implicated in the consummatory and, more recently, the incentive-motivational aspect of ethanol's actions. The purpose of this study was to test whether ethanol-seeking behavior induced by an ethanol-associated contextual stimulus is sensitive to antagonism of DA transmission. Male Wistar rats were trained to orally self-administer 10% ethanol and to associate olfactory discriminative stimuli with the availability of ethanol (S(+)) versus nonreward (S(-)). Ethanol-reinforced operant responding then was extinguished by withholding ethanol and the associated S(+). After reaching a predetermined extinction criterion, reinstatement tests were conducted in which the animals were presented noncontingently with only the S(+) or S(-). Exposure to the S(+) but not the S(-) reinstated responding at the previously active lever. The D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 5, 10, 50 microg/kg s.c.) and the D2 antagonist eticlopride (5, 10, 50 microg/kg s.c.) dose dependently decreased the number of S(+)-induced responses and increased response latency. During a second test, conducted in the same rats, 3 weeks after withdrawal from a 12-day ethanol vapor inhalation procedure, the response-reinstating efficacy of the S(+) remained unaltered. However, the potency of both DA antagonists to inhibit the S(+)-induced drug-seeking response was significantly increased. The results confirm that ethanol-related contextual stimuli reliably elicit drug-seeking behavior and suggest that this effect requires activation of DA neurotransmission. The results also indicate that chronic ethanol exposure produces changes in D1 and D2 receptor function that lead to enhanced sensitivity to the behavioral effects of antagonists for these receptors. PMID:11861794

  7. Cohort Removal Induces Changes in Body Temperature, Pain Sensitivity, and Anxiety-Like Behavior.

    Science.gov (United States)

    Takao, Keizo; Shoji, Hirotaka; Hattori, Satoko; Miyakawa, Tsuyoshi

    2016-01-01

    Mouse behavior is analyzed to elucidate the effects of various experimental manipulations, including gene mutation and drug administration. When the effect of a factor of interest is assessed, other factors, such as age, sex, temperature, apparatus, and housing, are controlled in experiments by matching, counterbalancing, and/or randomizing. One such factor that has not attracted much attention is the effect of sequential removal of animals from a common cage (cohort removal). Here we evaluated the effects of cohort removal on rectal temperature, pain sensitivity, and anxiety-like behavior by analyzing the combined data of a large number of C57BL/6J mice that we collected using a comprehensive behavioral test battery. Rectal temperature increased in a stepwise manner according to the position of sequential removal from the cage, consistent with previous reports. In the hot plate test, the mice that were removed first from the cage had a significantly longer latency to show the first paw response than the mice removed later. In the elevated plus maze, the mice removed first spent significantly less time on the open arms compared to the mice removed later. The results of the present study demonstrated that cohort removal induces changes in body temperature, pain sensitivity, and anxiety-like behavior in mice. Cohort removal also increased the plasma corticosterone concentration in mice. Thus, the ordinal position in the sequence of removal from the cage should be carefully counterbalanced between groups when the effect of experimental manipulations, including gene manipulation and drug administration, are examined using behavioral tests. PMID:27375443

  8. Cohort removal induces changes in body temperature, pain sensitivity, and anxiety-like behavior

    Directory of Open Access Journals (Sweden)

    Keizo eTakao

    2016-06-01

    Full Text Available Mouse behavior is analyzed to elucidate the effects of various experimental manipulations, including gene mutation and drug administration. When the effect of a factor of interest is assessed, other factors, such as age, sex, temperature, apparatus, and housing, are controlled in experiments by matching, counterbalancing, and/or randomizing. One such factor that has not attracted much attention is the effect of sequential removal of animals from a common cage (cohort removal. Here we evaluated the effects of cohort removal on rectal temperature, pain sensitivity, and anxiety-like behavior by analyzing the combined data of a large number of C57BL/6J mice that we collected using a comprehensive behavioral test battery. Rectal temperature increased in a stepwise manner according to the position of sequential removal from the cage, consistent with previous reports. In the hot plate test, the mice that were removed first from the cage had a significantly longer latency to show the first paw response than the mice removed later. In the elevated plus maze, the mice removed first spent significantly less time on the open arms compared to the mice removed later. The results of the present study demonstrated that cohort removal induces changes in body temperature, pain sensitivity, and anxiety-like behavior in mice. Cohort removal also increased the plasma corticosterone concentration in mice. Thus, the ordinal position in the sequence of removal from the cage should be carefully counterbalanced between groups when the effect of experimental manipulations, including gene manipulation and drug administration, are examined using behavioral tests.

  9. Cohort Removal Induces Changes in Body Temperature, Pain Sensitivity, and Anxiety-Like Behavior.

    Science.gov (United States)

    Takao, Keizo; Shoji, Hirotaka; Hattori, Satoko; Miyakawa, Tsuyoshi

    2016-01-01

    Mouse behavior is analyzed to elucidate the effects of various experimental manipulations, including gene mutation and drug administration. When the effect of a factor of interest is assessed, other factors, such as age, sex, temperature, apparatus, and housing, are controlled in experiments by matching, counterbalancing, and/or randomizing. One such factor that has not attracted much attention is the effect of sequential removal of animals from a common cage (cohort removal). Here we evaluated the effects of cohort removal on rectal temperature, pain sensitivity, and anxiety-like behavior by analyzing the combined data of a large number of C57BL/6J mice that we collected using a comprehensive behavioral test battery. Rectal temperature increased in a stepwise manner according to the position of sequential removal from the cage, consistent with previous reports. In the hot plate test, the mice that were removed first from the cage had a significantly longer latency to show the first paw response than the mice removed later. In the elevated plus maze, the mice removed first spent significantly less time on the open arms compared to the mice removed later. The results of the present study demonstrated that cohort removal induces changes in body temperature, pain sensitivity, and anxiety-like behavior in mice. Cohort removal also increased the plasma corticosterone concentration in mice. Thus, the ordinal position in the sequence of removal from the cage should be carefully counterbalanced between groups when the effect of experimental manipulations, including gene manipulation and drug administration, are examined using behavioral tests.

  10. Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction.

    Science.gov (United States)

    Tennant, B R; Vanderkruk, B; Dhillon, J; Dai, D; Verchere, C B; Hoffman, B G

    2016-01-01

    Diabetes is a chronic disease that results from the body's inability to properly control circulating blood glucose levels. The loss of glucose homoeostasis can arise from a loss of β-cell mass because of immune-cell-mediated attack, as in type 1 diabetes, and/or from dysfunction of individual β-cells (in conjunction with target organ insulin resistance), as in type 2 diabetes. A better understanding of the transcriptional pathways regulating islet-cell survival is of great importance for the development of therapeutic strategies that target β-cells for diabetes. To this end, we previously identified the transcription factor Myt3 as a pro-survival factor in islets following acute suppression of Myt3 in vitro. To determine the effects of Myt3 suppression on islet-cell survival in vivo, we used an adenovirus to express an shRNA targeting Myt3 in syngeneic optimal and marginal mass islet transplants, and demonstrate that suppression of Myt3 impairs the function of marginal mass grafts. Analysis of grafts 5 weeks post-transplant revealed that grafts transduced with the shMyt3 adenovirus contained ~20% the number of transduced cells as grafts transduced with a control adenovirus. In fact, increased apoptosis and significant cell loss in the shMyt3-transduced grafts was evident after only 5 days, suggesting that Myt3 suppression sensitizes islet cells to stresses present in the early post-transplant period. Specifically, we find that Myt3 suppression sensitizes islet cells to high glucose-induced cell death via upregulation of the pro-apoptotic Bcl2 family member Bim. Taken together these data suggest that Myt3 may be an important link between glucotoxic and immune signalling pathways. PMID:27195679

  11. Effects of thermal sensitization on radiation-induced segregation in type 304 stainless steel irradiated with He-ions

    International Nuclear Information System (INIS)

    Type 304 stainless steels, solution-annealed and thermally sensitized at 923 K for 0.5 to 24 h, were He-ion-irradiated up to about 4 dpa at 723 K and radiation-induced segregation (RIS) at grain boundaries was measured by EDS analysis using a FEG-TEM. Ni, Si and P were enriched, and Cr was depleted at the grain boundaries by irradiation. However, although the irradiation dose was the same for the specimens, the RIS of the elements linearly increased with the logarithm of the thermally sensitizing time, except for Cr in the specimen thermally sensitized for 24 h. The enhancement of RIS was attributed to the radiation-induced point defects having large mobility in thermally sensitized stainless steels, because of an expected decrease in C near the grain boundaries and in the matrix after the sensitization heat treatments. It was clarified by the electrochemical potentiokinetic reactivation test (EPR) that the degree of sensitization increased with the progress of Cr depletion at grain boundaries. The Cr concentration at grain boundaries in the heavily sensitized specimen was not changed, and the width of the depleted area was slightly narrowed by the irradiation. This result could be explained that the diffusion of Cr due to initial Cr concentration gradient near grain boundaries exceeded the inverse Kirkendall effect. (orig.)

  12. Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: Involvement of Ca2+ influx

    International Nuclear Information System (INIS)

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation. Highlights: ► Capsaicin sensitizes TRAIL-induced apoptosis through activation of caspases. ► Capsaicin induces expression of DR5 through Sp1 activation. ► Capsaicin activates calcium signaling pathway.

  13. SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis

    International Nuclear Information System (INIS)

    Highlights: ► Up-regulation of SIRT1 protein and activity sensitizes Hep3B-HBX cells to oxidative stress-induced apoptosis. ► Nuclear localization of SIRT1 is not required for oxidation-induced apoptosis. ► Ectopic expression and enhanced activity of SIRT1 attenuate JNK phosphorylation. ► Inhibition of SIRT1 activity restores resistance to oxidation-induced apoptosis through JNK activation. -- Abstract: We previously showed that SIRT1 deacetylase inhibits proliferation of hepatocellular carcinoma cells expressing hepatitis B virus (HBV) X protein (HBX), by destabilization of β-catenin. Here, we report another role for SIRT1 in HBX-mediated resistance to oxidative stress. Ectopic expression and enhanced activity of SIRT1 sensitize Hep3B cells stably expressing HBX to oxidative stress-induced apoptosis. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for sensitization of oxidation-mediated apoptosis. Furthermore, ectopic expression of SIRT1 and treatment with resveratrol (a SIRT1 activator) attenuated JNK phosphorylation, which is a prerequisite for resistance to oxidative stress-induced apoptosis. Conversely, suppression of SIRT1 activity with nicotinamide inhibited the effect of resveratrol on JNK phosphorylation, leading to restoration of resistance to oxidation-induced apoptosis. Taken together, these results suggest that up-regulation of SIRT1 under oxidative stress may be a therapeutic strategy for treatment of hepatocellular carcinoma cells related to HBV through inhibition of JNK activation.

  14. The improvement effects of edible bird’s nest on proliferation and activation of B lymphocyte and its antagonistic effects on immunosuppression induced by cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Zhao R

    2016-01-01

    Full Text Available Ran Zhao,1,* Geng Li,1,* Xiu-juan Kong,1 Xiu-yan Huang,2 Wei Li,1 Yao-ying Zeng,2 Xiao-ping Lai31Traditional Chinese Medicinal College, Guangzhou University of Chinese Medicine, 2Life Science College, Jinan University, Guangzhou, 3Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, People’s Republic of China*These authors contributed equally to this workAbstract: Edible bird’s nest (EBN is regarded as an immune-enhancing food in the People’s Republic of China. The aim of this study is to demonstrate the efficiency of EBN in improving the immunity of mouse both in vivo and in vitro. We observed the effects of EBN on spleen lymphocytes proliferation and activation, as well as immunoglobulin isotypes as indicators. In addition, we evaluated the content of total sIgA in the intestinal juice to assess mucosal immunity. The results showed that EBN could promote the proliferation and activation of B-cells and increase IgE, IgA, IgM, and IgG3 levels. We also found that EBN extract can promote the secretion of sIgA in the small intestine. Using cyclophosphamide (CY, we established an immunosuppressed mouse model in which we identified a reversal influence on the ratio of CD3+/CD19+ cells, which indicates that EBN also protects B-cells from the damage induced by CY. We also applied polymyxin B to exclude the interference of lipopolysaccharide throughout the experiment. In conclusion, we found that EBN can reduce the intestinal immune injury induced by CY by accelerating the proliferation and activation of B-cells and enhancing antibody secretion of B-cells.Keywords: chemotherapy, immunological enhancement, intestinal mucosal immune, EBN

  15. Quantitative and sensitive analysis of CN molecules using laser induced low pressure He plasma

    International Nuclear Information System (INIS)

    We report the results of experimental study on CN 388.3 nm and C I 247.8 nm emission characteristics using 40 mJ laser irradiation with He and N2 ambient gases. The results obtained with N2 ambient gas show undesirable interference effect between the native CN emission and the emission of CN molecules arising from the recombination of native C ablated from the sample with the N dissociated from the ambient gas. This problem is overcome by the use of He ambient gas at low pressure of 2 kPa, which also offers the additional advantages of cleaner and stronger emission lines. The result of applying this favorable experimental condition to emission spectrochemical measurement of milk sample having various protein concentrations is shown to yield a close to linear calibration curve with near zero extrapolated intercept. Additionally, a low detection limit of 5 μg/g is found in this experiment, making it potentially applicable for quantitative and sensitive CN analysis. The visibility of laser induced breakdown spectroscopy with low pressure He gas is also demonstrated by the result of its application to spectrochemical analysis of fossil samples. Furthermore, with the use of CO2 ambient gas at 600 Pa mimicking the Mars atmosphere, this technique also shows promising applications to exploration in Mars

  16. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    Science.gov (United States)

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. PMID:27284107

  17. High temperature, drought and their interaction induced protein alterations in sensitive and tolerant wheat varieties

    Directory of Open Access Journals (Sweden)

    Vikender Kaur, Reena Mahla And R.K.Behl

    2014-12-01

    Full Text Available Two contrasting wheat (Triticum aestivum L. cultivars WH730 (high temperature tolerant and UP2565 (high temperature sensitive were tested for differential response to combined and individually applied high temperature (HT and drought (D stress at seedling stage for peptide profile. Initial profile of the stress induced peptides was outlined via SDS electrophoresis of leaf extracts. Electrophoretic pattern of proteins revealed expression of new bands as well as disappearance of certain others in HT, D and interactive HT+D stress treated and revived samples in both wheat varieties relative to untreated control samples. Some of the bands that appeared in stress treated seedlings were also present after revival indicating their protective role, while some new peptides synthesized after stress but disappeared after revival period may be designated true stress proteins. However, all the plants from heat, drought and their interactive stress treatments continued to grow during recovery period. This suggests that these proteins and other newly synthesized proteins may have protective effects at high temperature (40°C and water scarcity and provide plants for healthy growth during the recovery period. Furthermore, elucidating the functions of proteins expressed by genes in stress tolerant and susceptible plants may provide important information for designing new strategies for crop improvement.

  18. Higher sensitivity of LEC strain rat in radiation-induced acute intestinal death.

    Science.gov (United States)

    Hayashi, M; Endoh, D; Kon, Y; Yamashita, T; Hashimoto, N; Sato, F; Kasai, N; Namioka, S

    1992-04-01

    LEC strain rats (LEC rats), which have been known to develop hereditarily spontaneous fulminant hepatitis 4-5 months after birth, were highly sensitive to whole-body X-irradiation as compared to WKAH strain rats (WKAH rats). Radiation-induced acute intestinal death occurred at doses higher than 6.5 Gy in LEC rats, and at doses higher than 12.8 Gy in WKAH rats, respectively. By the probit analysis of survival data, it was shown that the LD50/7 value of LEC rats was estimated to be 7.03 Gy which was significantly lower than that (12.99 Gy) of WKAH rats. Histopathological examinations of small intestines from LEC rats 2 days after irradiation at the dose of 8.5 Gy showed severe epithelial death together with edema, whereas little or no significant changes were noted in intestinal epithelium of 8.5 Gy-irradiated WKAH rats. These results suggest that the radiosensitivity of LEC rats to ionizing radiation appears to be higher than that of other strains of rats.

  19. Quantitative and sensitive analysis of CN molecules using laser induced low pressure He plasma

    Energy Technology Data Exchange (ETDEWEB)

    Pardede, Marincan [Department of Electrical Engineering, University of Pelita Harapan, 1100 M.H. Thamrin Boulevard, Lippo Village, Tangerang 15811 (Indonesia); Hedwig, Rinda [Department of Computer Engineering, Bina Nusantara University, 9 K.H. Syahdan, Jakarta 14810 (Indonesia); Abdulmadjid, Syahrun Nur; Lahna, Kurnia; Idris, Nasrullah; Ramli, Muliadi [Department of Physics, Faculty of Mathematics and Natural Sciences, Syiah Kuala University, Darussalam, Banda Aceh 23111, NAD (Indonesia); Jobiliong, Eric [Department of Industrial Engineering, University of Pelita Harapan, 1100 M.H. Thamrin Boulevard, Lippo Village, Tangerang 15811 (Indonesia); Suyanto, Hery [Department of Physics, Faculty of Mathematics and Natural Sciences, Udayana University, Kampus Bukit Jimbaran, Denpasar 80361, Bali (Indonesia); Marpaung, Alion Mangasi [Department of Physics, Faculty of Mathematics and Natural Sciences, Jakarta State University, 10 Rawamangun, Jakarta 13220 (Indonesia); Suliyanti, Maria Margaretha [Research Center for Physics, Indonesia Institute of Sciences, Kawasan Puspiptek, Serpong, Tangerang Selatan, 15314 Banten (Indonesia); Tjia, May On [Physics of Magnetism and Photonics Group, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology, 10 Ganesha, Bandung 40132 (Indonesia); Research Center of Maju Makmur Mandiri Foundation, 40/80 Srengseng Raya, Jakarta 11630 (Indonesia); Lie, Tjung Jie; Lie, Zener Sukra; Kurniawan, Davy Putra; Kurniawan, Koo Hendrik, E-mail: kurnia18@cbn.net.id [Research Center of Maju Makmur Mandiri Foundation, 40/80 Srengseng Raya, Jakarta 11630 (Indonesia); Kagawa, Kiichiro [Research Center of Maju Makmur Mandiri Foundation, 40/80 Srengseng Raya, Jakarta 11630 (Indonesia); Fukui Science Education Academy, Takagi Chuou 2 choume, Fukui 910-0804 (Japan)

    2015-03-21

    We report the results of experimental study on CN 388.3 nm and C I 247.8 nm emission characteristics using 40 mJ laser irradiation with He and N{sub 2} ambient gases. The results obtained with N{sub 2} ambient gas show undesirable interference effect between the native CN emission and the emission of CN molecules arising from the recombination of native C ablated from the sample with the N dissociated from the ambient gas. This problem is overcome by the use of He ambient gas at low pressure of 2 kPa, which also offers the additional advantages of cleaner and stronger emission lines. The result of applying this favorable experimental condition to emission spectrochemical measurement of milk sample having various protein concentrations is shown to yield a close to linear calibration curve with near zero extrapolated intercept. Additionally, a low detection limit of 5 μg/g is found in this experiment, making it potentially applicable for quantitative and sensitive CN analysis. The visibility of laser induced breakdown spectroscopy with low pressure He gas is also demonstrated by the result of its application to spectrochemical analysis of fossil samples. Furthermore, with the use of CO{sub 2} ambient gas at 600 Pa mimicking the Mars atmosphere, this technique also shows promising applications to exploration in Mars.

  20. Si nanoparticles as sensitizers for radio frequency-induced cancer hyperthermia

    Science.gov (United States)

    Kabashin, A. V.; Tamarov, K. P.; Ryabchikov, Yu. V.; Osminkina, L. A.; Zinovyev, S. V.; Kargina, J. V.; Gongalsky, M. B.; Al-Kattan, A.; Yakunin, V. G.; Sentis, M. L.; Ivanov, A. V.; Nikiforov, V. N.; Kanavin, A. P.; Zavestovskaya, I. N.; Timoshenko, V. Y.

    2016-03-01

    We review our recently obtained data on the employment of Si nanoparticles as sensitizers of radiofrequency (RF) - induced hyperthermia for mild cancer therapy tasks. Such an approach makes possible the heating of aqueous suspensions of Si nanoparticles by tens of degrees Celsius under relatively low intensities (1-5 W/cm2) of 27 MHz RF radiation. The heating effect is demonstrated for nanoparticles synthesized by laser ablation in water and mechanical grinding of porous silicon, while laser-ablated nanoparticles demonstrate a remarkably higher heating rate than porous silicon-based ones for the whole range of the used concentrations. The observed RF heating effect can be explained in the frame of a model considering the polarization of Si NPs and electrolyte in the external oscillating electromagnetic field and the corresponding release of heat by electric currents around the nanoparticles. Our tests evidence relative safety of Si nanostructures and their efficient dissolution in physiological solutions, suggesting potential clearance of nanoparticles from a living organism without any side effects. Profiting from Si nanoparticle-based heating, we finally demonstrate an efficient treatment of Lewis Lung carcinoma in vivo. The obtained data promise a breakthrough in the development of mild, non-invasive methods for cancer therapy.

  1. Simple and sensitive method for monitoring drug-induced cell injury in cultured cells

    Energy Technology Data Exchange (ETDEWEB)

    Shirhatti, V.; Krishna, G.

    1985-06-01

    A simple, sensitive method has been developed for evaluating cell injury noninvasively in monolayer cells in culture. The cell ATP pool was radiolabeled by incubating the cells with (/sup 14/C)adenine. The uptake and incorporation of (/sup 14/C)adenine was shown to proportional to the number of cells. As determined by HPLC, about 65-70% of the incorporated /sup 14/C label was in the ATP pool, 15-20% was in the ADP pool, and the rest was in the 5'-AMP pool. When prelabeled cells were exposed to toxic drugs (acetaminophen, calcium ionophore A-23187, or daunomycin) there was a marked decrease in cell ATP with a concomitant increase in leakage of labeled nucleotides, mainly 5'-AMP and 5'IMP. The authors have shown that leakage of /sup 14/C label into the medium from the prelabeled cells may be employed for quantitation of cell injury. This new measure of toxicity was shown to correlate very well with LDH leakage from the cells, which is a well accepted measure of cell injury. The leakage of 5'-(/sup 14/C)AMP also correlated very well with the reduction of cell ATP in cardiac myocytes. This method has been used for monitoring drug-induced toxicity in liver cells, cardiac myocytes, and LB cells.

  2. Studies on antagonistic marine streptomycetes

    Digital Repository Service at National Institute of Oceanography (India)

    Chandramohan, D.; Nair, S.

    Sixty nine strains of Streptomyces sp. isolated from the sediments of Andaman and Nicobar islands (Bay of Bengal) were screened for their antagonistic property against a number of test cultures (Vibrio sp., Klebsiella sp., Escherichia coli, Shigella...

  3. Increased visceral sensitivity to capsaicin after DSS-induced colitis in mice : spinal cord c-Fos expression and behavior

    NARCIS (Netherlands)

    Eijkelkamp, Niels; Kavelaars, Annemieke; Elsenbruch, Sigrid; Schedlowski, Manfred; Holtmann, Gerald; Heijnen, Cobi J.

    2007-01-01

    Increased visceral sensitivity to capsaicin after DSS-induced colitis in mice: spinal cord c-Fos expression and behavior. Am J Physiol Gastrointest Liver Physiol 293: G749-G757, 2007. First published July 26, 2007; doi:10.1152/ajpgi.00114.2007.During acute and chronic inflammation visceral pain perc

  4. Effects of angiotensin Ⅱ receptor antagonist olmesartan on renal hemodynamic variables and vascular structural properties in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    SONG Hui-fen; CHEN Jian-fei; SUN Ning-ling; LI Hong-wei

    2011-01-01

    Background Diabetic nephropathy is a major cause of renal failure in diabetes mellitus (DM). It has been known that renin-angiotensin system (RAS) blockers have a renal protective effect. This study aimed to investigate whether treatment with angiotensin Ⅱ receptor blocker, olmesartan, could modify renal hemodynamic variables and vascular structural properties, then attenuate renal injury in streptozotocin (STZ)-induced DM rats.Methods DM was induced in male Wistar rats by intraperitoneal administration of STZ. The rats were then randomized to a DM group and an olmesartan treatment (OLM+DM) group. The normal group (non-DM) were administered only citrate buffer. At the end of the 14th week, blood glucose, kidney weight/body weight and urinary protein-to-creatinine ratio were determined. Further, the flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated, perfused kidneys. From the relationship, 3 indices of vascular structural properties were estimated: slope of flow-pressure (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of pressure-GFR (glomerular filtration capacity against pressure)and threshold pressure for beginning filtration at pressure-GFR (preglomerular to postglomerular vascular resistance ratio). Kidneys were then perfusion fixed for histological analysis. The renal histopathology was observed by light microscopy.Results The body weight of DM rats was lower than that of non-DM rats. Blood glucose, kidney weight/body weight,urinary protein-to-creatinine ratio were significantly greater in DM rats than in non-DM rats. The parameters such as kidney weight/body weight, urinary protein-to-creatinine ratio in OLM+DM rats had dramatically decreased compared with those in DM rats. However, the treatment with olmesartan had no effect on blood glucose levels. The slope of flow-pressure relationship was greater in DM rats

  5. Mediation of a glutamate antagonist, a NOS inhibitor and antioxidants with – SH groups on striatal dopamine release induced by clothianidin

    Directory of Open Access Journals (Sweden)

    M. Alfonso

    2015-01-01

    Full Text Available La clotianidina es un insecticida neonicotinoide con actividad selectiva sobre los receptores de acetilcolina. El ob jetivo de este estudio es comprobar si un inhibidor de los receptores glutamatérgicvos (APV, un inhibidor de la óxido nítrico sintet asa (L-NAME y dos antioxidantes como el glutatión y el dithiotreit ol previene la liberación de dopamina inducida por la clotianidina , usando la técnica de microdiálisis en ratas conscientes y en li bre movimiento. La administración intraestriatal de clothianidina ( 3.5 mM produce un aumento de 2462 ± 627%, de los niveles estriatal es de dopamina respecto a los nivele s basales. La coadministracion de 0.65 mM de APV y 3.5 mM d clothianidina genera un a aumento de 1089 ± 243.5% de los niveles estr iatales de dopamina, siendo es te incremento 55.7% más bajo que el generado por la clotianidina sola. La Coadministration de.0,1 mM de L-NAME y3.5 mM de clotianidina genera un aumento de 836.5 ± 150.6% de los niveles extracelulares de dopamina, siendo este aumento un 55.7% más ba jo que el generado por la clotianidi na sola. La coadministracion of 3.5 mM clothianidina en combinación con 0.4 mM de glutatión induce un aumento de 465.6 ± 126.8% de los niveles estriatales de dopamina, indicando que la administración de glutatión provoca una inhibición del 81% del efecto generado por la infusión de clotianidina sola. La administración de 3.5 mM de clothianidina junto con 0.005 mM de diithiothreitol induce un aumento de 693. 8 ± 117.8% en los niveles extracelulares de dopamina en el estria do, siendo este incremento 72% más bajo que el generado por la clotianidina sola. Nue stros resultados sugieren que el efecto d e la clotianidina sobre la liberación estriatal de dopamina pueden s er reducidos por la administración de un antagonista glutamatérgic o, un ihibibidor de la NOS o por antioxidantes con grupo –SH, lo cual supone un simple mecanismo de pr otección contra el daño causado

  6. The α9α10 nicotinic receptor antagonist α-conotoxin RgIA prevents neuropathic pain induced by oxaliplatin treatment.

    Science.gov (United States)

    Pacini, Alessandra; Micheli, Laura; Maresca, Mario; Branca, Jacopo Juno Valerio; McIntosh, J Michael; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo

    2016-08-01

    Oxaliplatin, a third-generation diaminocyclohexane platinum drug, is widely used alone or in combination with 5-fluorouracil and leucovorin to treat metastatic colorectal, ovarian, and pancreatic cancers. Oxaliplatin long-term treatment is associated with the development of a dose-limiting painful neuropathy that dramatically impairs the patient's quality of life and therapy possibility. To study novel strategies to treat oxaliplatin-induced neuropathy, we evaluated α-conotoxin RgIA, a peptide that potently blocks the α9α10 nicotinic acetylcholine receptor (nAChR) subtype in a rat model of oxaliplatin-dependent neurotoxicity (2.4mgkg(-1) oxaliplatin intraperitoneally daily for 21days). The administration of RgIA (2 and 10nmol injected intramuscularly once a day concomitantly with oxaliplatin treatment), reduced the oxaliplatin-dependent hypersensitivity to mechanical and thermal noxious and non-noxious stimuli. Moreover, morphological modifications of L4-L5 dorsal root ganglia were significantly prevented. In the spinal cord the numerical increase of astrocyte cell density present in oxaliplatin-treated rats is partially prevented by RgIA treatment. Nevertheless, the administration of the α-conotoxin is able per se to elicit a numerical increase and a morphological activation of microglia and astrocytes in specific brain areas. PMID:27132993

  7. A role for b-cell-depleting agents in treating psoriatic skin lesions induced by tumor necrosis factor-alpha antagonists: A case report and literature review

    Directory of Open Access Journals (Sweden)

    Ancuta Codrina Mihaela

    2014-01-01

    Full Text Available Despite recent advances in understanding the pathological pathways, clinical pattern and management opportunities for new-onset psoriasis as a paradoxical adverse event in patients receiving TNF inhibitors for their immune-mediated disorder, there is a subset of patients who are either partial responders or non-responders, whatever the therapeutic scenario. We present the case of new-onset psoriasis and severe alopecia development in a case study of long-standing rheumatoid arthritis (RA treated with adalimumab (ADA and leflunomide. Since skin lesions and alopecia are resistant to the classic protocol (topical treatment, ADA discontinuation and RA becomes highly active, rituximab (RTX was started. Dramatic improvement in joint disease, total remission of alopecia and partial remission of pustular psoriasis were described after the first RTX cycle. Although B-cell-depleting agents result in controversial effects on psoriatic skin lesions, this is the first case of ADA-induced psoriasis and alopecia that improved under RTX, suggesting a possible role in treating such a patient population.

  8. Inducing Expectations for Health: Effects of Verbal Suggestion and Imagery on Pain, Itch, and Fatigue as Indicators of Physical Sensitivity.

    Directory of Open Access Journals (Sweden)

    Kaya J Peerdeman

    Full Text Available Research into placebo effects has convincingly shown that inducing positive outcome expectations can reduce pain and other physical sensations. However, the comparative effects of different expectation inductions, such as verbal suggestion or mental imagery, and their generic effects on physical sensitivity, to different sensations such as pain, itch, and fatigue, are still largely unknown. In the current study, we assessed the individual and combined effects of verbal suggestion and imagery on pain, itch, and fatigue as indicators of physical sensitivity in a randomized study design. Healthy participants (n = 116 were given an inert (placebo capsule that was said to be effective for reducing physical sensitivity in either the majority (positive verbal suggestion or the minority (control verbal suggestion of users. Subsequently, they imagined either their best possible health (positive imagery or a typical day (control imagery. Sensitivity to pain, itch, and fatigue was tested using a cold pressor test, histamine iontophoresis, and a bicycle test, respectively. Heart rate and skin conductance were recorded continuously. Results showed that positive verbal suggestion and imagery successfully induced positive expectations, but they did not affect physical sensitivity, as indicated by sensitivity to pain, itch, or fatigue, or concurrent physiological responses. These results could indicate that the specificity and concreteness of expectation inductions might be important for their applicability in the treatment of physical symptoms.Nederlands Trial Register NTR3641.

  9. Critical features of acute stress-induced cross-sensitization identified through the hypothalamic-pituitary-adrenal axis output.

    Science.gov (United States)

    Belda, Xavier; Nadal, Roser; Armario, Antonio

    2016-01-01

    Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors. PMID:27511270

  10. Optogenetics reveals a role for accumbal medium spiny neurons expressing dopamine D2 receptors in cocaine-induced behavioral sensitization.

    Science.gov (United States)

    Song, Shelly Sooyun; Kang, Byeong Jun; Wen, Lei; Lee, Hyo Jin; Sim, Hye-Ri; Kim, Tae Hyong; Yoon, Sehyoun; Yoon, Bong-June; Augustine, George J; Baik, Ja-Hyun

    2014-01-01

    Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc) have been proposed to contribute to drug-mediated addictive behaviors. Here we have used an optogenetic approach to examine the role of NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs) in cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding channelrhodopsin-2 (ChR2) were delivered into the NAc of D2R-Cre transgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2R-MSNs form local inhibitory circuits, because photostimulation of D2R-MSN evoked inhibitory postsynaptic currents (IPSCs) in neighboring MSNs. Photostimulation of NAc D2R-MSN in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. However, photostimulation during the drug withdrawal period attenuated expression of cocaine-induced behavioral sensitization. These results show that D2R-MSNs of NAc play a key role in withdrawal-induced plasticity and may contribute to relapse after cessation of drug abuse. PMID:25352792

  11. Optogenetics reveals a role for accumbal medium spiny neurons expressing dopamine D2 receptors in cocaine-induced behavioral sensitization.

    Science.gov (United States)

    Song, Shelly Sooyun; Kang, Byeong Jun; Wen, Lei; Lee, Hyo Jin; Sim, Hye-Ri; Kim, Tae Hyong; Yoon, Sehyoun; Yoon, Bong-June; Augustine, George J; Baik, Ja-Hyun

    2014-01-01

    Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc) have been proposed to contribute to drug-mediated addictive behaviors. Here we have used an optogenetic approach to examine the role of NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs) in cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding channelrhodopsin-2 (ChR2) were delivered into the NAc of D2R-Cre transgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2R-MSNs form local inhibitory circuits, because photostimulation of D2R-MSN evoked inhibitory postsynaptic currents (IPSCs) in neighboring MSNs. Photostimulation of NAc D2R-MSN in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. However, photostimulation during the drug withdrawal period attenuated expression of cocaine-induced behavioral sensitization. These results show that D2R-MSNs of NAc play a key role in withdrawal-induced plasticity and may contribute to relapse after cessation of drug abuse.

  12. Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis

    DEFF Research Database (Denmark)

    Zhuang, Hongqin; Jiang, Weiwei; Cheng, Wei;

    2010-01-01

    Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL...... siRNA on drug sensitization of A549 cells to TRAIL treatment. The results showed that treatment of A549 cells with HSP27 siRNA down-regulated HSP27 expression but did not induce significant apoptosis. However, combination of HSP27 siRNA with TRAIL-induced significant apoptosis in TRAIL-resistant A549...... cells. In addition to inducing caspases activation and apoptosis, combined treatment with HSP27 siRNA and TRAIL also increased JNK and p53 expression and activity. Collectively, these findings provide a conclusion that siRNA targeting of the HSP27 gene specifically down-regulated HSP27 expression in A...

  13. Smoking, calcium, calcium antagonists, and aging.

    Science.gov (United States)

    Nicita-Mauro, V

    1990-01-01

    Aging is characterized, besides other changes, by a progressive increase in calcium content in the arterial wall, which is enhanced by diabetes mellitus, osteoporosis, arterial hypertension, and tabagism. As to tabagism, experiments in animals have shown that nicotine can increase calcium content of the arterial wall, and clinical studies have demonstrated that cigarette smoking induces peripheral vasoconstriction, with consequent increase in blood pressure levels. In order to study the role of calcium ions in the pathogenesis of the vasoconstrictive lesions caused by "acute" smoking, the author has studied the peripheral vascular effects of the calcium-channel antagonist nifedipine, a dihydropyridine derivative, and calcitonin, a hypocalcemizing hormone which possess vasoactive actions on 12 elderly regular smokers (mean age 65.8 years). The results demonstrated that both nifedipine (10 mg sublingually 20 min before smoking) and salmon calcitonin (100 MRC U/daily intramuscularly for three days) are able to prevent peripheral vasoconstriction evaluated by Doppler velocimetry, as well as the increase of blood pressure induced by smoking. On the basis of our results, the author proposes that cigarette smoking-induced vasoconstriction is a calcium-mediated process, which can be hindered by drugs with calcium antagonist action. PMID:2226675

  14. Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension.

    Science.gov (United States)

    Xue, Baojian; Thunhorst, Robert L; Yu, Yang; Guo, Fang; Beltz, Terry G; Felder, Robert B; Johnson, Alan Kim

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-α synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-α, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines.

  15. Laser ablation laser induced fluorescence for sensitive detection of heavy metals in water

    Science.gov (United States)

    Godwal, Yogesh

    Laser Induced Breakdown Spectroscopy LIBS is a fast non-contact technique for the analysis of the elemental composition using spectral information of the emission from a laser-induced plasma. For the LIBS studies in this thesis the focus has been in using very low energy, microjoule pulses in order to give high spatial resolution and minimize the laser system requirements. This is a regime that we refer to as microLIBS. Under such conditions it is important to maximize the signal detected to give the lowest limit of detection LOD possible. One technique to improve the signal to noise ratios is by coupling LIBS with Laser Induced Fluorescence. This is a technique where the first pulse creates a vapor plume and the second pulse tuned to a resonant absorption line of the species of interest re-excites the plume. We term this technique as Laser ablation Laser Induced Fluorescence LA-LIF. We have been investigating the performance of LA-LIF at low pulse energies (≤ 1 mJ for both pulses) for the detection of elemental contaminants in water. This technique allows reasonable performance compared to high energy single-pulse LIBS, but at a much reduced total energy expenditure. This allows LODs in the parts per billion range ppb range which typically cannot be obtained with low energy single pulse probing of the systems. This approach or exceeds the sensitivities which can be obtained with many shots using much larger energy systems. In this thesis we investigated the performance of LIBS at low pulse energies for the detection of Pb as a contaminant in water. An LOD of 70 ppb was obtained for an accumulation of 100 shots with the ablation laser pulse energy of 250 muJ and an excitation laser pulse energy of 8 muJ. A systematic study of the detector conditions was made for the system for the detection of Pb. Scaling laws for the LOD in terms of the pump and probe energies were measured and also the effect of detector gain, the gate delay and the gate width were studied. In

  16. Quercetin sensitizes pancreatic cancer cells to TRAIL-induced apoptosis through JNK-mediated cFLIP turnover.

    Science.gov (United States)

    Kim, Ji Hye; Kim, Min Joo; Choi, Kyung-Chul; Son, Jaekyoung

    2016-09-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that can selectively kill cancer cells. Nonetheless, many cancers are resistant to TRAIL, and the molecular mechanisms of TRAIL resistance in cancer, particularly pancreatic cancer, are still unclear. In this study, we tested the hypothesis that quercetin, a flavonoid, induces apoptosis in TRAIL-resistant pancreatic cancer cells. Although quercetin alone had no significant cytotoxic effect, when combined with TRAIL, it promoted TRAIL-induced apoptosis that required mitochondrial outer membrane permeabilization. A BH3-only protein BID knockdown dramatically attenuated TRAIL/quercetin-induced apoptosis. The expression levels of cellular FLICE-like inhibitory protein (cFLIP) decreased in a dose-dependent manner in the presence of quercetin, and overexpression of cFLIP was able to robustly rescue pancreatic cancer cells from TRAIL/quercetin-induced apoptosis. Additionally, quercetin activated c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which in turn induced the proteasomal degradation of cFLIP, and JNK activation also sensitized pancreatic cancer cells to TRAIL-induced apoptosis. Thus, our results suggest that quercetin induces TRAIL-induced apoptosis via JNK activation-mediated cFLIP turnover. PMID:27477310

  17. Increased salt sensitivity induced by sensory denervation:role of superoxide

    Institute of Scientific and Technical Information of China (English)

    Wei-zhong SONG; Alex F CHEN; Donna H WANG

    2004-01-01

    AIM: To test the hypothesis that production of superoxide in mesenteric resistance arteries is increased and contributes to the development of hypertension induced by sensory denervation plus high salt intake. METHODS:Newborn Wistar rats were given capsaicin 50mg/kg sc on the 1st and 2nd d of life. After weaning, male rats were grouped as follows and treated for 3 weeks with: capsaicin pretreatment plus normal sodium diet (0.5%, CAP-NS),CAP plus high sodium diet (4%, CAP-HS), control plus NS (CON-NS), or CON-HS. Both tail-cuff systolic blood pressure and mean arterial pressure (MAP) were measured in each of the groups. Western blot analysis was used for measurement of manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) in the mesenteric resistance arteries. Lucigenin chemiluminescence assay was used for superoxide production in the mesenteric resistance arteries. The Griess method was used for measurement of nitrite/nitrate levels in plasma.RESULTS: Both tail-cuff pressure and MAP were higher in CAP-HS compared with CAP-NS, CON-HS, and CONNS rats (P<0.05). Both MnSOD and eNOS in the mesenteric resistance arteries were increased in CAP-HS compared with CAP-NS, CON-HS, and CON-NS (P<0.05). However, nitrite/nitrate levels in plasma were not different among 4 groups. Acute iv administration of tempol, a membrane-permeable superoxide scavenger, decreased MAP in both CAP-HS and CON-HS when compared with their respective controls. However, the decreases of MAP between these two groups were not different. Chronic treatment with tempol failed to prevent the development of hypertension in CAP-HS rats. Superoxide production in the mesenteric resistance arteries was increased in CAP-HS compared with CAP-NS, CON-HS, and CON-NS (P<0.05). However, chronic treatment with tempol did not prevent the increase of mesenteric superoxide production in CAP-HS rats. CONCLUSIONS:Regardless of increased vascular MnSOD levels, salt sensitive hypertension

  18. Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis.

    Science.gov (United States)

    Storm, P; Aits, S; Puthia, M K; Urbano, A; Northen, T; Powers, S; Bowen, B; Chao, Y; Reindl, W; Lee, D Y; Sullivan, N L; Zhang, J; Trulsson, M; Yang, H; Watson, J D; Svanborg, C

    2011-12-01

    HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1α modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing ∼8000 targets, and HK activity decreased within 15 min of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 min. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.

  19. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  20. Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

    Science.gov (United States)

    Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

    2016-06-01

    Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. PMID:27016579

  1. Punishment sensitivity modulates the processing of negative feedback but not error-induced learning

    OpenAIRE

    Unger, Kerstin; Heintz, Sonja; Kray, Jutta

    2012-01-01

    Accumulating evidence suggests that individual differences in punishment and reward sensitivity are associated with functional alterations in neural systems underlying error and feedback processing. In particular, individuals highly sensitive to punishment have been found to be characterized by larger mediofrontal error signals as reflected in the error negativity/error-related negativity (Ne/ERN) and the feedback-related negativity (FRN). By contrast, reward sensitivity has been shown to rel...

  2. Sensitivity of different areas of the flexor aspect of the human forearm to corticosteroid-induced skin blanching.

    Science.gov (United States)

    Meyer, E; Smith, E W; Haigh, J M

    1992-10-01

    The intensity of corticosteroid-induced blanching has been found to vary at different areas of the flexor aspect of the human forearm. A retrospective analysis of 38,880 observations of skin blanching in 56 volunteers was conducted to assess the sensitivity of forearm skin to betamethasone 17-valerate. The mid-forearm appears to be more sensitive to the blanching response than do the areas close to the wrist or elbow. These results indicate that each preparation under evaluation should be applied to several sites along the forearm when using the human skin blanching assay in order to obtain an accurate comparative assessment of corticosteroid release from topical delivery vehicles.

  3. [Wheat dependent exercise induced anaphylaxis possibly sensitized by the hydrolyzed wheat proteins in a facial cleansing soap].

    Science.gov (United States)

    Kobayashi, Miwa; Okura, Risa; Yoshioka, Haruna; Hiromasa, Kana; Yoshioka, Manabu; Nakamura, Motonobu

    2012-03-01

    There are increasing cases of wheat dependent exercise-induced anaphylaxis (WDEIA) with transcutaneous or transmucosal sensitization. Hydrolyzed wheat included in a certain brand of soap was identified as a cause of sensitization. The useful clues to detect this disorder consist of the patient's past usage of a soap containing hydrolyzed wheat, the appearance of cutaneous or mucosal symptoms after the intake of wheat or washing with this soap, and a high level of specific IgE for wheat gluten. Because hydrolyzed wheat is used as an additive in a wide variety of cosmetics, we should pay careful attention to the ingredients of cosmetics when observing WDEIA.

  4. Inhibition of SNL-induced upregulation of CGRP and NPY in the spinal cord and dorsal root ganglia by the 5-HT(2A) receptor antagonist ketanserin in rats.

    Science.gov (United States)

    Wang, Dongmei; Chen, Tingjun; Gao, Yun; Quirion, Rémi; Hong, Yanguo

    2012-05-01

    Our previous study has demonstrated that topical and systemic administration of the 5-HT(2A) receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3 mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT(2A) receptors in neuropathic pain and (3) the blockade of 5-HT(2A) receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain.

  5. The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization.

    Science.gov (United States)

    Todtenkopf, M S; Carreiras, T; Melloni, R H; Stellar, J R

    2002-04-01

    The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral

  6. Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis - treatment effects of neuromuscular exercise and total joint replacement

    DEFF Research Database (Denmark)

    Kosek, E; Roos, Ewa M.; Ageberg, E;

    2013-01-01

    To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters.......To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters....

  7. SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Srisuttee, Ratakorn [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Moon, Jeong; Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Jhun, Byung Hak [Department of Applied Nanoscience, Pusan National University, Busan 609-735 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sapporo 060-8556 (Japan); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of)

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer Up-regulation of SIRT1 protein and activity sensitizes Hep3B-HBX cells to oxidative stress-induced apoptosis. Black-Right-Pointing-Pointer Nuclear localization of SIRT1 is not required for oxidation-induced apoptosis. Black-Right-Pointing-Pointer Ectopic expression and enhanced activity of SIRT1 attenuate JNK phosphorylation. Black-Right-Pointing-Pointer Inhibition of SIRT1 activity restores resistance to oxidation-induced apoptosis through JNK activation. -- Abstract: We previously showed that SIRT1 deacetylase inhibits proliferation of hepatocellular carcinoma cells expressing hepatitis B virus (HBV) X protein (HBX), by destabilization of {beta}-catenin. Here, we report another role for SIRT1 in HBX-mediated resistance to oxidative stress. Ectopic expression and enhanced activity of SIRT1 sensitize Hep3B cells stably expressing HBX to oxidative stress-induced apoptosis. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for sensitization of oxidation-mediated apoptosis. Furthermore, ectopic expression of SIRT1 and treatment with resveratrol (a SIRT1 activator) attenuated JNK phosphorylation, which is a prerequisite for resistance to oxidative stress-induced apoptosis. Conversely, suppression of SIRT1 activity with nicotinamide inhibited the effect of resveratrol on JNK phosphorylation, leading to restoration of resistance to oxidation-induced apoptosis. Taken together, these results suggest that up-regulation of SIRT1 under oxidative stress may be a therapeutic strategy for treatment of hepatocellular carcinoma cells related to HBV through inhibition of JNK activation.

  8. Optogenetics reveals a role for accumbal medium spiny neurons expressingdopamine D2 receptors in cocaine-induced behavioral sensitization

    Directory of Open Access Journals (Sweden)

    Shelly Sooyun eSong

    2014-10-01

    Full Text Available Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc have beenproposed to contribute to drug-mediated addictive behaviors. Here we have used anoptogenetic approach to examine the role of NAc medium spiny neurons (MSNs expressingdopamine D2 receptors (D2R in cocaine-induced behavioral sensitization. Adeno-associatedviral vectors coding channelrhodopsin-2 (ChR2 were delivered into the NAc of D2R-Cretransgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2RMSNsform local inhibitory circuits, because photostimulation of D2R-MSN evokedinhibitory postsynaptic currents in neighboring MSNs. Photostimulation of NAc D2R-MSNin vivo affected neither the initiation nor the expression of cocaine-induced behavioralsensitization. However, photostimulation during the drug withdrawal period attenuatedexpression of cocaine-induced behavioral sensitization. These results show that D2R-MSNsof NAc play a key role in withdrawal-induced plasticity and may contribute to relapse aftercessation of drug abuse.

  9. Connecting Model Species to Nature: Predator-Induced Long-Term Sensitization in "Aplysia Californica"

    Science.gov (United States)

    Mason, Maria J.; Watkins, Amanda J.; Wakabayashi, Jordann; Buechler, Jennifer; Pepino, Christine; Brown, Michelle; Wright, William G.

    2014-01-01

    Previous research on sensitization in "Aplysia" was based entirely on unnatural noxious stimuli, usually electric shock, until our laboratory found that a natural noxious stimulus, a single sublethal lobster attack, causes short-term sensitization. We here extend that finding by demonstrating that multiple lobster attacks induce…

  10. Background odour induces adaptation and sensitization of olfactory receptors in the antennae of houseflies

    NARCIS (Netherlands)

    Kelling, F.J; Ialenti, F.; den Otter, C.J

    2002-01-01

    The presence of background odour was found to have a small but significant effect on the sensitivity of the antennal olfactory system of houseflies, Musca domestica Linnaeus (Diptera: Muscidae), to new pulses of odour. We show that cross-adaptation and cross-sensitization between a background odour

  11. Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

    Directory of Open Access Journals (Sweden)

    Tomoko Asagami

    2011-01-01

    Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

  12. 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...

  13. Punishment sensitivity modulates the processing of negative feedback but not error-induced learning

    Directory of Open Access Journals (Sweden)

    Kerstin eUnger

    2012-06-01

    Full Text Available Accumulating evidence suggests that individual differences in punishment and reward sensitivity are associated with functional alterations in neural systems underlying error and feedback processing. In particular, individuals highly sensitive to punishment have been found to be characterized by larger midfrontal error signals as reflected in the error negativity (Ne/ERN and the FRN (feedback-related negativity. By contrast, reward sensitivity has been shown to relate to the error positivity (Pe. Given that Ne/ERN, FRN, and Pe have been functionally linked to flexible behavioral adaptation, the aim of the present research was to examine how these electrophysiological reflections of error and feedback processing vary as a function of punishment and reward sensitivity during reinforcement learning. We applied a probabilistic learning task that involved three different conditions of feedback validity (100%, 80%, and 50%. In contrast to prior studies using response competition tasks, we did not find reliable correlations between punishment sensitivity and the Ne/ERN. Instead, higher punishment sensitivity predicted larger FRN amplitudes, irrespective of feedback validity. Moreover, higher reward sensitivity was associated with a larger Pe. However, only reward sensitivity was related to better overall learning performance and higher post-error accuracy, whereas highly punishment sensitive participants showed impaired learning performance, suggesting that larger negative feedback-related error signals were not beneficial for learning or even reflected maladaptive information processing in these individuals. Thus, although our findings indicate that individual differences in reward and punishment sensitivity are related to electrophysiological correlates of error and feedback processing, we found less evidence for influences of these personality characteristics on the relation between performance monitoring and feedback-based learning.

  14. 4-nitroquinoline-1-oxide-induced mutagen sensitivity and risk of cutaneous melanoma: a case-control analysis.

    Science.gov (United States)

    Wang, Li-E; Li, Chunying; Xiong, Ping; Gershenwald, Jeffrey E; Prieto, Victor G; Duvic, Madeleine; Lee, Jeffrey E; Grimm, Elizabeth A; Hsu, Tao C; Wei, Qingyi

    2016-04-01

    Mutagen sensitivity assay, which measures the enhanced cellular response to DNA damage induced in vitro by mutagens/carcinogens, has been used in the study of cancer susceptibility. 4-Nitroquinoline-1-oxide (4-NQO), an ultraviolet (UV) radiation-mimetic chemical, can produce chromosomal breaks in mammalian cells and induce cancer. Given the potential role of 4-NQO as the experimental mutagen substituting for UV as the etiological carcinogen of cutaneous melanoma (CM), we tested the hypothesis that cellular sensitivity to 4-NQO is associated with the risk of developing CM in a case-control study of 133 patients with primary CM and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 μmol/l for 24 h and scored chromatid breaks in 50 well-spread metaphases. Multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals. We found that the log-transformed frequency of chromatid breaks was significantly higher in 133 patients than in 176 controls (P=0.004) and was associated with an increased risk for CM (adjusted odds ratio=1.78, 95% confidence interval: 1.12-2.84) after adjustment for age and sex. Moreover, as the chromatid break values increased, the risk for CM increased in a dose-dependent manner (P(trend)=0.003). Further analysis explored a multiplicative interaction between the sensitivity to 4-NQO and a family history of skin cancer (P(interaction)=0.004) on the risk of CM. Therefore, our findings suggest that sensitivity to 4-NQO may be a risk factor for the risk of CM, which is more sensitive than UV-induced chromotid breaks.

  15. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  16. NAC Attenuates LPS-Induced Toxicity in Aspirin-Sensitized Mouse Macrophages via Suppression of Oxidative Stress and Mitochondrial Dysfunction

    OpenAIRE

    Raza, Haider; John, Annie; Shafarin, Jasmin

    2014-01-01

    Bacterial endotoxin lipopolysaccharide (LPS) induces the production of inflammatory cytokines and reactive oxygen species (ROS) under in vivo and in vitro conditions. Acetylsalicylic acid (ASA, aspirin) is a commonly used anti-inflammatory drug. Our aim was to study the effects of N-acetyl cysteine (NAC), an antioxidant precursor of GSH synthesis, on aspirin-sensitized macrophages treated with LPS. We investigated the effects of LPS alone and in conjunction with a sub-toxic concentration of A...

  17. 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.

  18. Read Power Sensitivity in Energy-Gap-Induced Super-Resolution Read-Only-Memory Disc with Germanium Reflective Film

    Science.gov (United States)

    Yamamoto, Masaki; Yamada, Hirohisa; Harada, Yasuhiro; Mori, Go; Tajima, Hideharu; Takamori, Nobuyuki; Murakami, Yoshiteru; Kojima, Kunio; Takahashi, Akira

    2007-01-01

    Energy-gap-induced super-resolution (EG-SR) read-only-memory (ROM) discs have already been reported as high-density media. However, the read power of EG-SR ROM discs is higher than that of conventional (non-super-resolution) ROM discs. In this paper, we suggest that a germanium (Ge) reflective film can improve the read power sensitivity of the EG-SR effect. Two materials, silicon (Si) and Ge, were compared as reflective films. Si was previously reported to be suitable for high read power sensitivity. For an EG-SR ROM disc with a Ge reflective film, the reflectance change with temperature was larger and the read power sensitivity was higher than those for an EG-SR ROM disc with a Si film.

  19. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

    Energy Technology Data Exchange (ETDEWEB)

    Mota, Alba, E-mail: amota@iib.uam.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Jiménez-Garcia, Lidia, E-mail: ljimenez@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Herránz, Sandra, E-mail: sherranz@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Heras, Beatriz de las, E-mail: lasheras@ucm.es [Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid (Spain); Hortelano, Sonsoles, E-mail: shortelano@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain)

    2015-08-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced

  20. Nitric oxide decreases the sensitivity of pulmonary endothelial cells to LPS-induced apoptosis in a zinc-dependent fashion.

    Science.gov (United States)

    Tang, Zi-Lue; Wasserloos, Karla J; Liu, Xianghong; Stitt, Molly S; Reynolds, Ian J; Pitt, Bruce R; St Croix, Claudette M

    2002-01-01

    We hypothesized that: (a) S-nitrosylation of metallothionein (MT) is a component of pulmonary endothelial cell nitric oxide (NO) signaling that is associated with an increase in labile zinc; and (b) NO mediated increases in labile zinc in turn reduce the sensitivity of pulmonary endothelium to LPS-induced apoptosis. We used microspectrofluorometric techniques to show that exposing mouse lung endothelial cells (MLEC) to the NO-donor, S-nitrosocysteine, resulted in a 45% increase in fluorescence of the Zn2+-specific fluorophore, Zinquin, that was rapidly reversed by exposure to the Zn2+ chelator, NNN'N'-tetrakis-(2-pyridylmethyl)ethylenediamine; TPEN). The absence of a NO-mediated increase in labile Zn2+ in MLEC from MT-I and -II knockout mice inferred a critical role for MT in the regulation of Zn2+ homeostasis by NO. Furthermore, we found that prior exposure of cultured endothelial cells from sheep pulmonary artery (SPAEC), to the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP) reduced their sensitivity to lipopolysaccharide (LPS) induced apoptosis. The anti-apoptotic effects of NO were significantly inhibited by Zn2+ chelation with low doses of TPEN (10 microM). Collectively, these data suggest that S-nitrosylation of MT is associated with an increase in labile (TPEN chelatable) zinc and NO-mediated MT dependent zinc release is associated with reduced sensitivity to LPS-induced apoptosis in pulmonary endothelium. PMID:12162436

  1. Sensitization by wortmannin of heat- or X-ray induced cell death in cultured Chinese hamster V79 cells

    International Nuclear Information System (INIS)

    Here we found that wortmannin sensitized Chinese hamster V79 cells to hyperthermic treatment at 44.0 deg C as determined either by colony formation assay or by dye exclusion assay. Wortmannin enhanced heat-induced cell death accompanying cleavage of poly (ADP-ribose) polymerases (PARP). Additionally, the induction of heat shock protein HSP70 was suppressed and delayed in wortmannin-treated cells. Heat sensitizing effect of wortmannin was obvious at more than 5 or 10 μM of final concentrations, while radiosensitization was apparent at 5 μM. Requirement for high concentration of wortmannin, i.e., order of μM, suggests a possible role of certain protein kinases, such as DNA-PK and/or ATM among PI3-kinase family. The sensitization was minimal when wortmannin was added at the end of heat treatment. This was similar to the case of X-ray. Since heat-induced cell death and PARP cleavage preceded HSP70 induction phenomenon, the sensitization to the hyperthermic treatment was considered mainly caused by enhanced apoptotic cell death rather than secondary to suppression or delay by wortmannin of HSP70 induction. Further, in the present system radiosensitization by wortmannin was also at least partly mediated through enhancement of apoptotic cell death. (author)

  2. High Salt Intake Increases Copeptin but Salt Sensitivity Is Associated with Fluid Induced Reduction of Copeptin in Women

    Directory of Open Access Journals (Sweden)

    Irina Tasevska

    2014-01-01

    Full Text Available This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P = 0,02. Copeptin correlated inversely with urinary volume, at both low (r = −0,42; P = 0,001 and high (r = −0,60; P < 0,001 salt consumption, as well as with the change in body weight (r = −0,53; P < 0,001. Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r = −0,58; P = 0,017. As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity.

  3. Mental stress-induced increase in blood pressure is not related to baroreflex sensitivity in middle-aged healthy men.

    Science.gov (United States)

    Fauvel, J P; Cerutti, C; Quelin, P; Laville, M; Gustin, M P; Paultre, C Z; Ducher, M

    2000-04-01

    The baroreflex that acts to blunt blood pressure (BP) variations through opposite variations in heart rate should limit the BP increase produced by an emotional challenge. However, relations between baroreflex sensitivity and BP reactivity induced by a psychological stress in a large group of adults have never been firmly established. In 280 healthy men, rest (10 minutes) and stress (5 minutes) BP and heart rate were recorded beat to beat by a blood pressure monitor. The mental stress was elicited by a well-standardized computerized version of a word color conflict stress test (Stroop Color Test). Rest and stress baroreflex sensitivity was assessed by the cross-spectral analysis of BP and heart rate and by the sequence method. The stress-induced increase in systolic BP (22.4+/-0.1 mm Hg) was not correlated with resting baroreflex sensitivity but was slightly correlated (r=0.2, P<0.001) with BP variability assessed either by standard deviation or by mid-frequency band spectral power. Our results suggested that a centrally mediated sympathetic stimulation overcame cardiac autonomic regulation and emphasized the role of the sympathetic vasoconstriction in the pressure response at the onset of the stressing stimulation. During the sustained sympathoexcitatory phase, the cardiac baroreflex blunts BP variations but at a lower sensitivity.

  4. Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells

    DEFF Research Database (Denmark)

    Edvinsson, Lars; Alm, Rikard; Shaw, Duncan;

    2002-01-01

    , coronary, and omental arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation that was antagonized by both CGRP-(8-37) and BIBN4096BS in a competitive manner. CGRP was a weaker agonist on coronary arteries as compared to intracranial arteries; however......, BIBN4096BS was an equally effective antagonist. In human omental arteries, CGRP did not induce relaxation. BIBN4096 had a pA(2) value of 10.1 in cerebral and 10.4 in coronary arteries. The results of clinical trials with BIBN4096BS for acute migraine attacks are awaited with great interest....

  5. Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.

    Science.gov (United States)

    Henrich, C J; Brooks, A D; Erickson, K L; Thomas, C L; Bokesch, H R; Tewary, P; Thompson, C R; Pompei, R J; Gustafson, K R; McMahon, J B; Sayers, T J

    2015-01-01

    Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects. PMID:25719250

  6. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    OpenAIRE

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J.; Park, Daeho

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol ...

  7. Raman and loss induced quantum noise in a depleted phase-sensitive parametric amplifier

    DEFF Research Database (Denmark)

    Friis, Søren Michael Mørk; Rottwitt, Karsten

    We study the quantum noise properties of phase-sensitive fiber optical parametric amplifiers in deep pump depletion using a semiclassical approach. Amplified spontaneous emission and spontaneous Raman scattering are included in the analysis.......We study the quantum noise properties of phase-sensitive fiber optical parametric amplifiers in deep pump depletion using a semiclassical approach. Amplified spontaneous emission and spontaneous Raman scattering are included in the analysis....

  8. ATP-sensitive K+ channels that are blocked by hypoglycemia-inducing sulfonylureas in insulin-secreting cells are activated by galanin, a hyperglycemia-inducing hormone

    International Nuclear Information System (INIS)

    The action of the hyperglycemia-inducing hormone galanin, a 29-amino acid peptide names from its N-terminal glycine and C-terminal amidated alanine, was studied in rat insulinoma (RINm5F) cells using electrophysiological and 86Rb+ flux techniques. Galanin hyperpolarizes and reduces spontaneous electrical activity by activating a population of APT-sensitive K+ channels with a single-channel conductance of 30 pS (at -60 mV). Galanin-induced hyperpolarization and reduction of spike activity are reversed by the hypoglycemia-inducing sulfonylurea glibenclamine. Glibenclamide blocks the galanin-activated ATP-sensitive K+ channel. 86Rb+ efflux from insulinoma cells is stimulated by galanin in a dose-dependent manner. The half-maximum value of activation is found at 1.6 nM. Galanin-induced 86Rb+ efflux is abolished by glibenclamide. The half-maximum value of inhibition is found at 0.3 nM, which is close to the half-maximum value of inhibition of the ATP-dependent K+ channel reported earlier. 86Rb+ efflux studies confirm the electrophysiological demonstration that galanin activates and ATP-dependent K+ channel

  9. NOXA-induced alterations in the Bax/Smac axis enhance sensitivity of ovarian cancer cells to cisplatin.

    Directory of Open Access Journals (Sweden)

    Chao Lin

    Full Text Available Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy.

  10. 5-Fluorouracil preferentially sensitizes mutant KRAS non-small cell lung carcinoma cells to TRAIL-induced apoptosis.

    Science.gov (United States)

    Wang, Haizhen; Yang, Tao; Wu, Xiangwei

    2015-11-01

    Mutations in the KRAS gene are very common in non-small cell lung cancer (NSCLC), but effective therapies targeting KRAS have yet to be developed. Interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of cell death, has increased following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and in xenograft models. However, results from clinical trials of TRAIL-based therapy are disappointingly modest at best and many have demonstrated a lack of therapeutic benefit. Current research has focused on selecting a subpopulation of cancer patients who may benefit from TRAIL-based therapy and identifying best drugs to work with TRAIL. In the current study, we found that NSCLC cells with a KRAS mutation were highly sensitive to treatment with TRAIL and 5-fluorouracil (5FU). Compared with other chemotherapeutic agents, 5FU displayed the highest synergy with TRAIL in inducing apoptosis in mutant KRAS NSCLC cells. We also found that, on a mechanistic level, 5FU preferentially repressed survivin expression and induced expression of TRAIL death receptor 5 to sensitize NSCLC cells to TRAIL. The combination of low-dose 5FU and TRAIL strongly inhibited xenograft tumor growth in mice. Our results suggest that the combination of TRAIL and 5FU may be beneficial for patients with mutant KRAS NSCLC.

  11. Circulating intercellular adhesion molecule-1 (ICAM-1) as an early and sensitive marker for virus-induced T cell activation

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Johansen, J; Marker, O;

    1995-01-01

    The effect of systemic virus infection on the level of circulating ICAM-1 (cICAM-1) in serum, and the role of virus-activated T cells in this context, were studied using the murine lymphocytic choriomeningitis virus infection as primary model system. A marked virus-induced elevation in cICAM-1...... in serum was revealed, the presence of which coincided with the phase of virus-induced T cell activation. However, high levels of cICAM-1 in serum were observed well before maximal T cell activation could be demonstrated. No increase in cICAM-1 was observed in the serum of infected T cell-deficient nude...... induce shedding of ICAM-1 into the circulation, and this parameter may be used as an early and sensitive marker for immune activation....

  12. Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization

    OpenAIRE

    Alves, Vinicius M.; Muratov, Eugene; Fourches, Denis; Strickland, Judy; Kleinstreuer, Nicole; Carolina H. Andrade; Tropsha, Alexander

    2015-01-01

    Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop ...

  13. Antagonistic Interfa(e)ces

    DEFF Research Database (Denmark)

    Cox, Geoff; Jackson, Robert

    2011-01-01

    "lingering stink" so that it became purer and closer to authority. The paper will further link the purification of code to the structure of ideology inherent in Zizek’s psychoanalytical model between Symbolic reality, the antagonistic Real and ideological concealment. The purification is technical in so far...

  14. Fractionated irradiation induced radio-resistant esophageal cancer EC109 cells seem to be more sensitive to chemotherapeutic drugs

    Directory of Open Access Journals (Sweden)

    Wang Xingwu

    2009-05-01

    Full Text Available Abstract Background Chemo-radiotherapy, a combination of chemotherapy and radiotherapy, is the most frequent treatment for patients with esophageal cancer. In the process of radiotherapy, the radiosensitive cancer will become a radio-resistant one. Methods In order to detect the chemotherapeutic drug sensitivity in radio-resistant cancer cells and improve the therapy efficiency, we firstly established a radio-resistant esophageal cancer cell model (referred to as EC109/R from the human esophageal squamous cell carcinoma cell line EC109 through fractionated irradiation using X-rays. The radio-sensitivity of EC109/R cells was measured by clonogenic assay. To detect the drug sensitivity for EC109/R compared to its parent cells, we employed MTT method to screen the effectiveness of five different drugs commonly used in clinical therapy. The ratio of apoptosis was examined by flow cytometry. Results EC109/R cells were more sensitive to 5-fluorouracil, doxorubicin, paclitaxel and etoposide, but tolerant to cisplatin compared to its original cells. Conclusion Our study implies that fractionated irradiation induced radio-resistant esophageal cancer cell is more sensitive to certain kind of chemotherapeutic drugs. It provides evidence for choosing the sequence of radiotherapy and chemotherapy in esophageal cancer.

  15. Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions.

    Directory of Open Access Journals (Sweden)

    Gary B Kaplan

    Full Text Available Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/ΔFosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12 with either subcutaneous morphine (10 mg/kg or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1, consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/ΔFosB, measured on day 16, in multiple brain regions including prelimbic (PL and infralimbic (IL cortex, nucleus accumbens (NAc core, dorsomedial caudate-putamen (CPU, basolateral amygdala (BLA and central nucleus of the amygdala (CNA but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/ΔFosB plasticity in motivational pathways (NAc, motor outputs (CPU, and associative learning (PL, IL, BLA and stress pathways (CNA.

  16. PKCδ sensitizes neuroblastoma cells to L-buthionine-sulfoximine and etoposide inducing reactive oxygen species overproduction and DNA damage.

    Directory of Open Access Journals (Sweden)

    Barbara Marengo

    Full Text Available Neuroblastoma is a type of pediatric cancer. The sensitivity of neuroblastoma (NB cancer cells to chemotherapy and radiation is inhibited by the presence of antioxidants, such as glutathione (GSH, which is crucial in counteracting the endogenous production of reactive oxygen species (ROS. We have previously demonstrated that cells depleted of GSH undergo apoptosis via oxidative stress and Protein kinase C (PKC δ activation. In the present study, we transfected PKCδ in NB cells resistant to oxidative death induced by L-buthionine-S,R-sulfoximine (BSO, a GSH-depleting agent. Cell responses, in terms of ROS production, apoptosis and DNA damage were evaluated. Moreover, PKCδ activation was monitored by analyzing the phosphorylation status of threonine 505 residue, carrying out PKC activity assay and investigating the subcellular localization of the kinase. The cell responses obtained in BSO-resistant cells were also compared with those obtained in BSO-sensitive cells subjected to the same experimental protocol. Our results demonstrate, for the first time, that PKCδ induces DNA oxidation and ROS overproduction leading to apoptosis of BSO-resistant NB cells and potentiates the cytotoxic effects induced by BSO in sensitive cells. Moreover, PKCδ overexpression enhances the sensitivity of NB cells to etoposide, a well-characterised drug, commonly used in neuroblastoma therapy. Altogether our data provide evidence of a pro-oxidant role of PKCδ that might be exploited to design new therapeutic strategies aimed at selective killing of cancer cells and overcoming drug resistance. However, it becomes evident that a more detailed understanding of ROS-mediated signaling in cancer cells is necessary for the development of redox-modulated therapeutic approaches.

  17. Mutually-antagonistic interactions in baseball networks

    Science.gov (United States)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  18. Repeated patch testing to nickel during childhood do not induce nickel sensitization

    DEFF Research Database (Denmark)

    Søgaard Christiansen, Elisabeth

    2014-01-01

    Background: Previously, patch test reactivity to nickel sulphate in a cohort of unselected infants tested repeatedly at 3-72 months of age has been reported. A reproducible positive reaction at 12 and 18 months was selected as a sign of nickel sensitivity, provided a patch test with an empty Finn...... chamber was negative. The objective of this study is to follow-up on infants with suspected nickel sensitivity. Methods: A total of 562 infants were included in the cohort and patch tested with nickel sulphate. The 26 children with a positive patch test to nickel sulphate at 12 and 18 months were offered...... repeated patch test to nickel sulphate at 3 (36 months), 6 (72 months) and 14 years of age. Results: At 3 years, 24 of 26 nickel sensitive children were retested and a positive reaction was seen in 7 children, a negative reaction in 16 and 1 child was excluded due to reaction to both nickel and the empty...

  19. Pancreatic beta-cell lipotoxicity induced by overexpression of hormone-sensitive lipase

    DEFF Research Database (Denmark)

    Winzell, Maria Sörhede; Svensson, Håkan; Enerbäck, Sven;

    2003-01-01

    Lipid perturbations associated with triglyceride overstorage in beta-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in beta-cells, in the development of lipotoxicity, we generated transgenic...... mice overexpressing hormone-sensitive lipase specifically in beta-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased...... results highlight the importance of mobilization of the islet triglyceride pool in the development of beta-cell lipotoxicity. We propose that hormone-sensitive lipase is involved in mediating beta-cell lipotoxicity by providing ligands for peroxisome proliferator-activated receptors and other lipid...

  20. Spectral sensitivity of light induced respiratory activity of photoreceptor mitochondria in the intact fly

    NARCIS (Netherlands)

    Tinbergen, J.; Stavenga, D.G.

    1987-01-01

    Fly Calliphora erythrocephala (white eyed) photoreceptors were investigated in intact, living animals by microspectrofluorometry in vivo. The fluorescence of mitochondrial flavoproteins was used to monitor transient changes in oxidative metabolism, which were induced by a test light following a stim

  1. Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy

    OpenAIRE

    Chun-xia Peng; Ai-di Zhang; Bing Chen; Bing-jian Yang; Qiu-hong Wang; Mo Yang; Shi-hui Wei

    2016-01-01

    Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual field loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retina...

  2. Laser irradiation-induced Au-ZnO nanospheres with enhanced sensitivity and stability for ethanol sensing.

    Science.gov (United States)

    Zhang, Hao; Wu, Shouliang; Liu, Jun; Cai, Yunyu; Liang, Changhao

    2016-08-10

    Incorporating noble metal nanoparticles on the surface or the inner side of semiconductors to form a hybrid nanostructure is an effective route for improving the gas sensing performance of the semiconductors. In this study, we present novel Au-decorated ZnO nanospheres (Au-ZnO NSs) obtained by the laser irradiation of liquids. Structural characterization indicated that the Au-ZnO NSs consisted of single crystalline ZnO NSs with a few Au nanoparticles decorated on their surfaces and abundant encapsulated Au nanoparticles with relatively small sizes. Laser irradiation-induced heating-melting-evaporating processes are responsible for the formation of unique Au-ZnO NSs. The gas sensing properties of the Au-ZnO NSs, as gas sensing materials, were investigated and compared with those of pure ZnO NSs. The former showed a lower working temperature, higher sensitivity, better selectivity, and good reproducibility. The response values of the Au-ZnO NS and pure ZnO NS sensors to ethanol of 100 ppm were 252 and 75 at a working temperature of 320 °C and 360 °C, respectively. Significant enhancements in gas sensing performance should be attributed to the electronic sensitization induced by the depleted layers between the encapsulated Au nanoparticles and ZnO and chemical sensitization originating from the catalytic effects of Au nanoparticles decorated on the surfaces that dissociated molecular oxygen. PMID:27465699

  3. Surface stress-induced deflection of a microcantilever with various widths and overall microcantilever sensitivity enhancement via geometry modification

    International Nuclear Information System (INIS)

    The issues of surface stress-induced deflection of a microcantilever with various widths and overall microcantilever sensitivity enhancement of microcantilever-based biosensors are investigated in this paper. A remarkably precise and simple analytical formula for calculating surface stress-induced deflection of a microcantilever with various widths is deduced. Particularly, the effect of surface stress on the location of the microcantilever's neutral axis is considered. This explicit analytical formula is validated by the finite element method simulation. An analytical equation for computing the fundamental resonant frequency of a microcantilever with various widths is also derived. This paper explores the deflections and resonant frequencies of the microcantilevers having basic and modified shapes. It is found that minimizing the effective mass near the microcantilever's free end and the clamping width at the fixed end significantly enhances the overall microcantilever sensitivity. A novel microcantilever, which is expected to have much more excellent performance and overall sensitivity than the simple rectangular-shaped microcantilever, is proposed as sensor element in biological detection.

  4. Vasopressin induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule

    DEFF Research Database (Denmark)

    Pedersen, Nis Borbye; Hofmeister, Marlene Vind; Rosenbaek, Lena L;

    2010-01-01

    The thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) is important for renal electrolyte balance and its phosphorylation causes an increase in its transport activity and cellular localization. Here, we generated phospho-specific antibodies against two conserved N-terminal phosphorylation sites...

  5. 3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Qin, J.-Z.; Xin, H. [Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University of Chicago Medical Center (United States); Nickoloff, B.J., E-mail: bnickol@lumc.edu [Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University of Chicago Medical Center (United States)

    2010-05-28

    Clinicians successfully utilize high uptake of radiolabeled glucose via PET scanning to localize metastases in melanoma patients. To take advantage of this altered metabolome, 3-bromopyruvate (BrPA) was used to overcome the notorious resistance of melanoma to cell death. Using four melanoma cell lines, BrPA triggered caspase independent necrosis in two lines, whilst the other two lines were resistant to killing. Mechanistically, sensitive cells differed from resistant cells by; constitutively lower levels of glutathione, reduction of glutathione by BrPA only in sensitive cells; increased superoxide anion reactive oxygen species, loss of outer mitochondrial membrane permeability, and rapid ATP depletion. Sensitive cell killing was blocked by N-acetylcysteine or glutathione. When glutathione levels were reduced in resistant cell lines, they became sensitive to killing by BrPA. Taken together, these results identify a metabolic-based Achilles' heel in melanoma cells to be exploited by use of BrPA. Future pre-clinical and clinical trials are warranted to translate these results into improved patient care for individuals suffering from metastatic melanoma.

  6. Skin irritants and contact sensitizers induce Langerhans cell migration and maturation at irritant concentration

    NARCIS (Netherlands)

    Jacobs, J.J.L.; Lehé, C.L.; Hasegawa, H.; Elliott, G.R.; Das, P.K.

    2006-01-01

    Skin irritants and contact allergens reduce the number of Langerhans cells (LCs). It has been assumed that this reduction is due their migration to the draining lymph node (LN) for initiating immune sensitization in a host. Skin irritation, however, as opposed to contact allergy is not considered to

  7. The attractive Achilles heel of germ cell tumours : an inherent sensitivity to apoptosis-inducing stimuli

    NARCIS (Netherlands)

    Spierings, DCJ; de Vries, EGE; Vellenga, E; de Jong, S

    2003-01-01

    Testicular germ cell tumours (TGCTs) are extremely sensitive to cisplatin-containing chemotherapy. The rapid time course of apoptosis induction after exposure to cisplatin suggests that TGCT cells are primed to undergo programmed cell death as an inherent property of the cell of origin. In fact, apo

  8. ET-66ER-STRESS INDUCING DRUGS SENSITIZES GBM TO TEMOZOLOMIDE THROUGH DOWNREGULATION OF MGMT AND INDUCTION OF REGULATED NECROSIS

    Science.gov (United States)

    Xipell, Enric; Martínez-Velez, Naiara; Vera-Cano, Beatriz; Idoate, Miguel Angel; Garzón, Antonia García; Acanda, Arlet M.; Fueyo, Juan; Gomez-Manzano, Candelaria; Alonso, Marta M

    2014-01-01

    Termozolamide (TMZ) is the standard treatment against GBM, unfortunately its therapeutic effect is limited due to the expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Therefore, approaches that overcome the resistance to TMZ could be feasible therapeutic alternatives for this deadly disease. Endoplasmic reticulum (ER) stress suppresses several DNA damage proteins through the unfolding protein response. In this work we sought to evaluate whether ER-stress inducing drugs were able to downmodulate MGMT and sensitize GBM cells to TMZ treatment. Salinomycin (SLM) is a potassium ionophore that has proven effective against cancer stem cells and a possible candidate to induce ER stress. Our data showed that SLM triggered ER stress that was accompanied by the downregulation of MGMT. We obtained the same results with other ER stress inducing drugs (thapsigergin, tunicamycin) suggesting that this is a general mechanism. Chemical inhibition of ER stress reverted the abrogation of MGMT downregulation. Of importance, SLM induced an aberrant autophagic flux that led to regulated necrosis cell death mediated by the action of AIF protein, which induces DNA damage when localized in the nucleus. Combination of TMZ and SLM displayed a potent antitumor effect in vitro and in vivo in mice bearing a GBM stem cell model. Combination treatment induced a significant increase in DNA damage as shown by H2AX activation and PARP. Moreover, we observed AIF in the nucleus, as a result of the regulated necrosis, furthering favoring the DNA damage. Combination treatment showed an increment of the median survival and of long term survivors. Moreover tissue analysis confirmed a dramatic increase in the level of DNA damage. Altogether our results showed that combination treatment induces a potent antiglioma effect in vitro and in vivo. Our data uncover the possibility to exploit ER stress and regulated necrosis as therapeutic strategies for GBM treatment.

  9. Chromatin condensation and differential sensitivity of mammalian and insect cells to DNA strand breaks induced by bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Larraza, Daniel M. [IMBICE, C.C. 403, 1900 La Plata (Argentina)]. E-mail: danielop@imbice.org.ar; Padron, Juan [IMBICE, C.C. 403, 1900 La Plata (Argentina); Ronci, Natalia E. [IMBICE, C.C. 403, 1900 La Plata (Argentina); Vidal Rioja, Lidia A. [IMBICE, C.C. 403, 1900 La Plata (Argentina)

    2006-08-30

    Bleomycin (BLM) induces DNA damage in living cells. In this report we analyzed the role of chromatin compactness in the differential response of mosquito (ATC-15) and mammalian (CHO) cells to DNA strand breaks induced by BLM. We used cells unexposed and exposed to sodium butyrate (NaB), which induces chromatin decondensation. By nucleoid sedimentation assay and digestions of nuclei with DNAse I, untreated mosquito cells (no BLM; no NaB) were shown to have more chromatin condensation than untreated CHO cells. By alkaline unwinding ATC-15 cells treated with NaB showed more BLM-induced DNA strand breaks than NaB-untreated CHO cells. The time-course of BLM-induced DNA damage to nuclear DNA was similar for NaB-untreated mammalian and insect cells, but with mosquito cells showing less DNA strand breaks, both at physiological temperatures and at 4 {sup o}C. However, when DNA repair was inhibited by low temperatures and chromatin was decondensed by NaB treatments, differences in BLM-induced DNA damage between these cells lines were no longer observed. In both cell lines, NaB did not affect BLM action on cell growth and viability. On the other hand, the low sensitivity of ATC-15 cells to BLM was reflected in their better growth efficiency. These cells exhibited a satisfactory growth at BLM doses that produced a permanent arrest of growth in CHO cells. The data suggest that mosquito cells might have linker DNAs shorter than those of mammalian cells, which would result in the observed both greater chromatin condensation and greater resistance to DNA damage induced by BLM as compared to CHO cells.

  10. Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.

    Directory of Open Access Journals (Sweden)

    Vinay K Tripathi

    Full Text Available The expression and metabolic profile of cytochrome P450s (CYPs is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y and glial (U373-MG cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC, cyclophosphamide (CPA, ethanol and known neurotoxicant- monocrotophos (MCP, a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against

  11. Highly sensitive visual detection of Avian Influenza A (H7N9) virus based on the enzyme-induced metallization.

    Science.gov (United States)

    Zhang, Huifang; Ma, Xiaoming; Hu, Shuisheng; Lin, Yue; Guo, Longhua; Qiu, Bin; Lin, Zhenyu; Chen, Guonan

    2016-05-15

    Development of convenient but sensitive method for influenza detection is highly important in immediate and effective clinical treatment. In this study, an ultrasensitive colorimetric approach combining the advantages of the convenience of the enzyme-induced metallization and the high specificity of enzyme-linked immunosorbent assay for the detection of influenza virus A (H7N9 as model) has been developed. Two rounds of amplification are utilized to enhance the detection sensitivity. The amplification of enzymatic reaction combines with the specific optical properties of gold nanoparticles causing the enhancing of the optical signal immensely. In addition, the increased surface area and the magnetic enrichment effect also enable the magnetic bead (MB) to catch a large number of alkaline phosphatase (ALP) and detection antibody (Ab2), thus very small amounts of the virus can be easily detected. Compared with conventional method, this approach exhibits outstanding sensitivity for ALP detection, 0.2U/L of ALP can be distinguished with a spectrometer and 2U/L with the naked eye. And as low as 25 pg/mL of H7N9 can be detected by the naked eye. This approach shows an extensive horizon for bioassays and is available in clinical diagnosis with the advances of simplification, effectiveness, low cost and sensitive readout. PMID:26797249

  12. 灵芝孢子粉对亚硝酸钠致果蝇畸变效应的抑制作用研究%Antagonistic Effects of Ganoderma Spore on Mutation Induced by Sodium Nitrite in Drosophila melanogaster

    Institute of Scientific and Technical Information of China (English)

    王鑫; 卢路; 叶敬波; 刘志杰; 伍嘉明; 何炎明

    2009-01-01

    Objective To study the antagonistic effects of Ganoderma spore on mutation induced by NaNO_2 in Drosophila melanogaster. Methods After 24 hours of starvation, male Drosophila melanogaster were transferred to the culture bottles with medium with NaNO_2 of 0,0.001,0.01,0.05 and 0.1 g/L for 24 hours and then cultured with female Drosophila melanogaster for 7 days. Male Drosophila melanogaster were treated with NaNO_2 at the doses of 0,0.01,0.001 g/L for 24 hours and then transferred to the medium with Ganoderma spores at the dose of 0.2%, 1% ,2% , cultured with female Drosophila melanogaster for 7 days. The distilled water was used as the negative control. The amount of F1 generation and the mutation of the F1 generation were calculated. Results The mutation Drosophila melanogaster were mainly vestigial, some had malformation with white body and strange eyes. Compared with the negative control group,the count of offspring decreased, the rate of mutation proved positively correlated to the concentration of NaNO_2. High dose of sporoderm-unbroken spores could cause a decrease of number of offspring. Compared with the negative control group,the mutation in the group of 0.1,0.01 g/L NaNO_2 with 0.2% sporoderm-unbroken spores was much higher (P<0.01 or P<0.05). Compared with the negative group, number of offspring in the group of 0.01 g/L NaNO_2 with 1%, 2% sporoderm-broken and the group of 0.1 g/L NaNO_2 with 0.2% sporoderm-broken increased(P<0.01 or P<0.05). The rate of mutation proved negatively correlated to the concentration of sporoderm-broken spores. Conclusion Ganoderma spore has a significant antagonistic effects on mutation induced by NaNO_2 in Drosophila melanogaster.%目的 研究灵芝孢子粉对亚硝酸钠诱发的黑腹果蝇畸变效应的抑制作用.方法 将野生型雄性黑腹果蝇饥饿处理24 h,接着转移到0、0.001、0.01、0.05和0.1g/L的亚硝酸钠培养基里培养24 h,再加入雌果蝇培养7 d.以0、0.2%、1%、2%的去壁和未

  13. Increased sensitivity of DNA damage response-deficient cells to stimulated microgravity-induced DNA lesions.

    Directory of Open Access Journals (Sweden)

    Nan Li

    Full Text Available Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG. In this study we used mouse embryonic stem (MES and mouse embryonic fibroblast (MEF cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9-deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs in Rad9-/- MES and Mdc1-/- MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9-/- MES. As the exposure to SMG was prolonged, Rad9-/- MES cells adapted to the SMG disturbance by reducing the induced DNA lesions. The induced DNA lesions in Rad9-/- MES were due to SMG-induced reactive oxygen species (ROS. Interestingly, Mdc1-/- MEF cells were only partially adapted to the SMG disturbance. That is, the induced DNA lesions were reduced over time, but did not return to the control level while ROS returned to a control level. In addition, ROS was only partially responsible for the induced DNA lesions in Mdc1-/- MEF cells. Taken together, these data suggest that SMG is a weak genomic DNA stress and can aggravate genomic instability in cells with DNA damage response (DDR defects.

  14. Olodaterol attenuates citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs.

    Science.gov (United States)

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the cough reflex, the mechanism underlying the pro-tussive property of indacaterol is not known.

  15. Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

    Science.gov (United States)

    Perrine, Shane A; Ghoddoussi, Farhad; Desai, Kirtan; Kohler, Robert J; Eapen, Ajay T; Lisieski, Michael J; Angoa-Perez, Mariana; Kuhn, Donald M; Bosse, Kelly E; Conti, Alana C; Bissig, David; Berkowitz, Bruce A

    2015-11-01

    A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence. PMID:26411897

  16. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  17. Effective use of TNF antagonists

    OpenAIRE

    Yocum, David

    2004-01-01

    Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined...

  18. Several observables sensitive to the symmetry energy in heavy-ion collisions induced by high energy radioactive beams

    Institute of Scientific and Technical Information of China (English)

    Yong Gao-Chan; Li Bao-An; Zuo Wei

    2005-01-01

    Using an isospin- and momentum-dependent hadronic transport model, effects of the symmetry energy on several observables in heavy-ion collisions induced by radioactive beams at intermediate energies are studied. It is found that rapidity distribution of the isospin asymmetry of nucleon emissions, transverse momentum distribution of the ratio of free neutrons to protons at mid-rapidity, kinetic energy distribution of the ratio of π-/π+ as well as evolution of the isospin fractionation are all sensitive to the symmetry energy.

  19. Clinical features of panic patients sensitive to hyperventilation or breath-holding methods for inducing panic attacks

    OpenAIRE

    A.E. Nardi; A.M. Valença; F.L. Lopes; Nascimento, I.; M.A. Mezzasalma; W.A. Zin

    2004-01-01

    Our aim was to compare the clinical features of panic disorder (PD) patients sensitive to hyperventilation or breath-holding methods of inducing panic attacks. Eighty-five PD patients were submitted to both a hyperventilation challenge test and a breath-holding test. They were asked to hyperventilate (30 breaths/min) for 4 min and a week later to hold their breath for as long as possible, four times with a 2-min interval. Anxiety scales were applied before and after the tests. We selected the...

  20. Improving the sensitivity of protein microarray by evanescent-field-induced fluorescence

    Institute of Scientific and Technical Information of China (English)

    WANG Li-qiang; LU Zu-kang

    2005-01-01

    To improve the sensitivity of protein microarray, a prism surface replaces the surface of the common microscope slide.The protein targets arrayed on the surface are hybridized and labelled by fluorescent probes. Evanescent excitation occurs when the convergent laser reaches the surface, and a photomultiplier tube detects the emitted fluorescent signal. A two-dimensional actuator scans the whole surface to achieve planar laser excitation and fluorescence collection. The penetration depth of the evanescent field into the protein targets is only some hundred nanometers and can be controlled by different incident angle of the laser beam, so the undesired background signals are reduced dramatically and the detection sensitivity is improved by a factor of 50 to 100 comparing to confocal excitation. This approach can detect low abundance analytes without signal amplification.

  1. Sensitivity Analysis for Reactor Period Induced by Positive Reactivity Using One-point Adjoint Kinetic Equation

    Science.gov (United States)

    Chiba, G.; Tsuji, M.; Narabayashi, T.

    2014-04-01

    In order to better predict a kinetic behavior of a nuclear fission reactor, an improvement of the delayed neutron parameters is essential. The present paper specifies important nuclear data for a reactor kinetics: Fission yield and decay constant data of 86Ge, some bromine isotopes, 94Rb, 98mY and some iodine isotopes. Their importance is quantified as sensitivities with a help of the adjoint kinetic equation, and it is found that they are dependent on an inserted reactivity (or a reactor period). Moreover, dependence of sensitivities on nuclear data files is also quantified using the latest files. Even though the currently evaluated data are used, there are large differences among different data files from a view point of the delayed neutrons.

  2. AMPA receptor trafficking in inflammation-induced dorsal horn central sensitization

    Institute of Scientific and Technical Information of China (English)

    Yuan-Xiang Tao

    2012-01-01

    Activity-dependent postsynaptic receptor trafficking is critical for long-term synaptic plasticity in the brain,but it is unclear whether this mechanism actually mediates the spinal cord dorsal horn central sensitization (a specific form of synaptic plasticity) that is associated with persistent pain.Recent studies have shown that peripheral inflammation drives changes in α-amino-3-hydroxy-5-methy1-4-isoxazolepropionic acid receptor (AMPAR) subunit trafficking in the dorsal horn and that such changes contribute to the hypersensitivity that underlies persistent pain.Here,we review current evidence to illustrate how spinal cord AMPARs participate in the dorsal horn central sensitization associated with persistent pain.Understanding these mechanisms may allow the development of novel therapeutic strategies for treating persistent pain.

  3. Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Satoshi Tanida

    2012-01-01

    Full Text Available Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1, thereby releasing poly(ADP-ribosepolymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity.

  4. Identification of neutron irradiation induced strain rate sensitivity change using inverse FEM analysis of Charpy test

    International Nuclear Information System (INIS)

    A simple methodology how to obtain additional information about the mechanical behaviour of neutron-irradiated WWER 440 reactor pressure vessel steel was developed. Using inverse identification, the instrumented Charpy test data records were compared with the finite element computations in order to estimate the strain rate sensitivity of 15Ch2MFA steel irradiated with different neutron fluences. The results are interpreted in terms of activation volume change

  5. Total adiponectin and adiponectin multimeric complexes in relation to weight loss-induced improvements in insulin sensitivity in obese women

    DEFF Research Database (Denmark)

    Polak, J.; Kovacova, Z.; Holst, C.;

    2008-01-01

    diet induced changes in insulin sensitivity (responders and non-responders respectively), matched for weight loss (body mass index (BMI)=34.5 (s.d. 2.9) resp. 36.5 kg/m(2) (s.d. 4.0) for responders and non-responders), were selected from 292 women who underwent a 10-week low-caloric diet (LCD; 600 kcal....../d less than energy requirements). Plasma HMW, MMW, and LMW forms of adiponectin were quantified using Western blot method. RESULTS: LCD induced comparable weight reduction in responders and non-responders by 8.2 and 7.6 kg. Homeostasis model assessment insulin resistance index decreased by 48......, and LMW were negatively associated with fasting insulin levels at baseline. CONCLUSION: No differences in total plasma adiponectin, HMW, MMW, and LMW forms were observed between responders and non-responders following 10-week LCD, suggesting that adiponectin is not a major determinant of weight loss...

  6. A highly-sensitive automatic transient laser-induced breakdown spectroscopy system with high temporal and spatial resolution

    Institute of Scientific and Technical Information of China (English)

    Liu Qiao-Jun; S.K.Fong; Andrew Y.S.Cheng; Luo Shi-Rong; K.S.Tam; Zhu Jian-Hua; A.Viseu

    2012-01-01

    A highly-sensitive automatic transient laser-induced breakdown spectroscopy (LIBS) system is designed and integrated.It successfully avoids the delay time selecting problem in the conventional LIBS system,and realizes the LIBS data acquisition with high spatiotemporal resolution automatically.Multiple transient spectra can be obtained in each measurement,which will provide more information for spectral research.The water-vapour and liquid-water Raman scattering spectra are captured by this system,and the comparison of experimental water-vapour Raman scattering spectrum with theoretical data verifies the reliability of the LIBS system.Based on this system,the air laser induced air breakdown spectra are captured and analysed.The system is also useful for the research on water-vapour Raman Lidar remote sensing.

  7. Prevention of Antigen-Induced Bronchial Hyperreactivity and Airway Inflammation in Sensitized Guinea-Pigs by Tacrolimus

    Directory of Open Access Journals (Sweden)

    J. R. Lapa e Silva

    1999-01-01

    Full Text Available We examined the effect of the immunosuppressive agent, tacrolimus (FK506, on antigen-induced bronchial hyperreactivity to acetylcholine and leukocyte infiltration into the airways of ovalbumin-challenged guinea-pigs. Subcutaneous injection of 0.5 mg/kg of FK506, 1 h before and 5 h after intra-nasal antigen challenge prevented bronchial hyperreactivity to aerosolized acetylcholine, eosinophilia in bronchoalveolar lavage (BAL fluid and bronchial tissue and the invasion of the bronchial wall by CD4+ T-lymphocytes. FK506 also suppressed ovalbumininduced increase in the number of leukocytes adhering to the pulmonary vascular endothelium and expressing α4-integrins. Inhibition by FK506 of antigen-induced bronchial hyperreactivity in sensitized guinea-pigs may thus relate to its ability to prevent the emergence of important inflammatory components of airway inflammation, such as eosinophil accumulation, as well as CD4+ T-lymphocyte infiltration into the bronchial tissue.

  8. Driving p53 Response to Bax Activation Greatly Enhances Sensitivity to Taxol by Inducing Massive Apoptosis

    Directory of Open Access Journals (Sweden)

    Paola De Feudis

    2000-05-01

    Full Text Available The proapoptotic gene bax is one of the downstream effectors of p53. The p53 binding site in the bax promoter is less responsive to p53 than the one in the growth arrest mediating gene p21. We introduced the bax gene under the control of 13 copies of a strong p53 responsive element into two ovarian cancer cell lines. The clones expressing bax under the control of p53 obtained from the wild-type (wt p53-expressing cell line A2780 were much more sensitive (500- to 1000-fold to the anticancer agent taxol than the parent cell line, with a higher percentage of cells undergoing apoptosis after drug treatment that was clearly p53-dependent and bax-mediated. Xenografts established in nude mice from one selected clone (A2780/C3 were more responsive to taxol than the parental line and the apoptotic response of A2780/C3 tumors was also increased after treatment. Introduction of the same plasmid into the p53 null SKOV3 cell line did not alter the sensitivity to taxol or the induction of apoptosis. In conclusion, driving the p53 response (after taxol treatment by activating the bax gene rather than the p21 gene results in induction of massive apoptosis, in vitro and in vivo, and greatly enhances sensitivity to the drug.

  9. Voltage surges induced in transformer secondaries with loads characterized by sensitive electronic equipment

    Energy Technology Data Exchange (ETDEWEB)

    Cogo, Joao Roberto [GSI Engenharia e Consultoria Ltda., Taubate, SP (Brazil)], Email: gsi@gsiconsultoria.com.br; Dommel, Hermann Wilhelm [University of British Columbia, Vancouver (Canada)], Email: hermannd@ece.ubc.ca

    2007-07-01

    The grounding of sensitive electronic equipment such as computers, programmable logic controllers (PLC), process control systems, and other electronic equipment is one of the most important considerations towards obtaining an efficient operation of such systems. Such equipment, which for the purposes of this work is called 'Sensitive Electronic Equipment - SEE' is very sensitive to faults and low intensity random voltages which have no effect upon the electrical power equipment and upon human beings. In this work, the grounding problem is evaluated, to guide the user on the proper installation of SEEs, so as to prevent them from being damaged. The following items will be discussed: voltages which SEEs are subject to during incidence of atmospheric surges in the distribution overhead lines to which they are connected; sustained voltage that the high voltage supply of SEEs must be able to withstand during line-to-ground faults that originate from atmospheric surges that reach the transmission lines which are connected to the electrical power self producers (or electrical power independent producers). (author)

  10. A missense mutation in CHS1, a TIR-NB protein, induces chilling sensitivity in Arabidopsis.

    Science.gov (United States)

    Wang, Yuancong; Zhang, Yao; Wang, Zheng; Zhang, Xiaoyan; Yang, Shuhua

    2013-08-01

    Low temperature is an environmental factor that affects plant growth and development and plant-pathogen interactions. How temperature regulates plant defense responses is not well understood. In this study, we characterized chilling-sensitive mutant 1 (chs1), and functionally analyzed the role of the CHS1 gene in plant responses to chilling stress. The chs1 mutant displayed a chilling-sensitive phenotype, and also displayed defense-associated phenotypes, including extensive cell death, the accumulation of hydrogen peroxide and salicylic acid, and an increased expression of PR genes: these phenotypes indicated that the mutation in chs1 activates the defense responses under chilling stress. A map-based cloning analysis revealed that CHS1 encodes a TIR-NB-type protein. The chilling sensitivity of chs1 was fully rescued by pad4 and eds1, but not by ndr1. The overexpression of the TIR and NB domains can suppress the chs1-conferred phenotypes. Interestingly, the stability of the CHS1 protein was positively regulated by low temperatures independently of the 26S proteasome pathway. This study revealed the role of a TIR-NB-type gene in plant growth and cell death under chilling stress, and suggests that temperature modulates the stability of the TIR-NB protein in Arabidopsis.

  11. Strain-dependent susceptibility to radiation-induced mammary cancer is a result of differences in epithelial cell sensitivity to transformation.

    Science.gov (United States)

    Ullrich, R L; Bowles, N D; Satterfield, L C; Davis, C M

    1996-09-01

    Variations in sensitivity to radiation-induced mammary cancer among different strains of mice are well known. However, the reasons for these variations have not been determined. In the present study, the cell dissociation assay was used to determine the radiation-induced transformation frequencies in sensitive BALB/c mice and resistant C57BL mice as well as the resistant hybrid B6CF1 independent of host environment. The influence of host environment on the progression of transformed cells to the neoplastic phenotype was also examined. Results demonstrated that the variations in sensitivity among these sensitive and resistant mice are a result of inherent differences in the sensitivity of the mammary epithelial cells to radiation-induced transformation. Under the conditions used, host environment played no role in the initiation of transformed cells by radiation or in the progression of these cells to the neoplastic phenotype.

  12. Strain-dependent susceptibiltiy to radiation-induced mammary cancer is a result of differences in epithelial cell sensitivity to transformation

    Energy Technology Data Exchange (ETDEWEB)

    Ullrich, R.L.; Davis, C.M. [Univ. of Texas Medical Branch, Galveston, TX (United States); Bowles, N.D.; Satterfield, L.C. [Oak Ridge National Lab., Oak Ridge, TN (United States)

    1996-09-01

    Variations in sensitivity to radiation-induced mammary cancer among different strains of mice are well known. However, the reasons for these variations have not been determined. In the present study, the cell dissociation assay was used to determine the radiation-induced transformation frequencies in sensitive BALB/c mice and resistant C57BL mice as well as the resistant hybrid B6Cf{sub 1} independent of host environment. The influence of host environment on the progression of transformed cells to the neoplastic phenotype was also examined. Results demonstrated that the variations in sensitivity among these sensitive and resistant mice are a result of inherent differences in the sensitivity of the mammary epithelial cells to radiation-induced transformation. Under the conditions used, host environment played no role in the initiation of transformed cells by radiation or in the progression of these cells to the neoplastic phenotype. 19 refs., 1 tab.

  13. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia

    DEFF Research Database (Denmark)

    Imel, Erik A; Peacock, Munro; Pitukcheewanont, Pisit;

    2006-01-01

    Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors...

  14. BCL-XS adenovirus-mediated gene therapy approach sensitizes cancer cells to radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Purpose: Apoptosis, a process in which a genetic program is activated ultimately leading to programmed cell death, has been shown to play a role in radiation therapy (RT)-induced cell death. We and others have previously shown that members of the bcl-2 family (including bcl-xl) protect cells from RT-induced apoptosis through p53-dependent and -independent pathways. Therefore, we postulated that inactivation of bcl-2 family members by overexpression of bcl-xs (a functional inhibitor of the bcl-2 family) would enhance RT-induced apoptosis. Overexpression of bcl-xs was achieved using two strategies: stable transfection and transient infection using an adenovirus (AV) vector. Methods: An expression plasmid encodingbcl-xs (pSFFVneo-bcl-xs) or a control plasmid (pSFFVneo) was stably transfected into MCF-7 (breast cancer), K562 (human leukemia), and FL512 (pro B-cell) cells and clonogenic survival was determined following RT. The second method used to overexpress bcl-xs involved construction of an AV vector that expresses bcl-xs by inserting the bcl-xs coding sequence into the pADRSV vector. Immunoblotting using a rabbit polyclonal antibody raised against the bcl-x protein revealed that K562 cells infected with the bcl-xs AV, but not the control AV that contains the β-galactosidase gene, expressed the 21 kDA bcl-xs protein. K562 cells were infected with the bcl-xs AV or the control AV at titres to achieve 90-95% infection. Various doses of RT were given 24 hrs following infection since maximal expression of bcl-xs was achieved at this time. Colony forming ability following RT was performed. Apoptotic death at 24 and 48 hrs following RT was assayed by flow cytometry using propidium iodide which quantitates DNA damage. Results: Bcl-xs overexpression by stable transfection in all three cell lines tested induced a marked increase in radiosensitivity. Bcl-xs overexpressing K562, FL512, and MCF-7 cells were more sensitive to RT-induced clonogenic death than their neo

  15. Sensitivity of neuroprogenitor cells to chemical-induced apoptosis using a multiplexed assay suitable for high-throughput screening

    International Nuclear Information System (INIS)

    High-throughput methods are useful for rapidly screening large numbers of chemicals for biological activity, including the perturbation of pathways that may lead to adverse cellular effects. In vitro assays for the key events of neurodevelopment, including apoptosis, may be used in a battery of tests for detecting chemicals that could result in developmental neurotoxicity. Apoptosis contributes to nervous system development by regulating the size of the neuroprogenitor cell pool, and the balance between cellular proliferation and apoptosis during neuroprogenitor cell proliferation helps to determine the size and shape of the nervous system. Therefore, chemicals that affect apoptosis during neuronal development can have deleterious effects on the developing brain. The present study examined the utility of a high-throughput assay to detect chemical-induced apoptosis in mouse or human neuroprogenitor cells, as well as differentiated human neurons derived from induced pluripotent stem cells. Apoptosis was assessed using an assay that measures enzymatic activity of caspase-3/7 in a rapid and cost efficient manner. The results show that all three commercially available models generated a robust source of proliferating neuroprogenitor cells, and that the assay was sensitive and reproducible when used in a multi-well plate format. There were differences in the response of rodent and human neuroprogenitor cells to a set of chemicals previously shown to induce apoptosis in vitro. Neuroprogenitor cells were more sensitive to chemical-induced apoptosis than differentiated neurons, suggesting that neuroprogenitor cells are one of the cell models that should be considered for use in a developmental neurotoxicity screening battery

  16. NAC attenuates LPS-induced toxicity in aspirin-sensitized mouse macrophages via suppression of oxidative stress and mitochondrial dysfunction.

    Directory of Open Access Journals (Sweden)

    Haider Raza

    Full Text Available Bacterial endotoxin lipopolysaccharide (LPS induces the production of inflammatory cytokines and reactive oxygen species (ROS under in vivo and in vitro conditions. Acetylsalicylic acid (ASA, aspirin is a commonly used anti-inflammatory drug. Our aim was to study the effects of N-acetyl cysteine (NAC, an antioxidant precursor of GSH synthesis, on aspirin-sensitized macrophages treated with LPS. We investigated the effects of LPS alone and in conjunction with a sub-toxic concentration of ASA, on metabolic and oxidative stress, apoptosis, and mitochondrial function using J774.2 mouse macrophage cell line. Protection from LPS-induced toxicity by NAC was also studied. LPS alone markedly induced ROS production and oxidative stress in macrophage cells. When ASA was added to LPS-treated macrophages, the increase in oxidative stress was significantly higher than that with LPS alone. Similarly, alteration in glutathione-dependent redox metabolism was also observed in macrophages after treatment with LPS and ASA. The combination of LPS and ASA selectively altered the CYP 3A4, CYP 2E1 and CYP 1A1 catalytic activities. Mitochondrial respiratory complexes and ATP production were also inhibited by LPS-ASA treatment. Furthermore a higher apoptotic cell death was also observed in LPS-ASA treated macrophages. NAC pre-treatment showed protection against oxidative stress induced apoptosis and mitochondrial dysfunction. These effects are presumed, at least in part, to be associated with alterations in NF-κB/Nrf-2 mediated cell signaling. These results suggest that macrophages are more sensitive to LPS when challenged with ASA and that NAC pre-treatment protects the macrophages from these deleterious effects.

  17. Relationships between Phosphatidylglycerol Molecular Species of Thylakoid Membrane Lipids and Sensitivities to Chilling-induced Photoinhibition in Rice

    Institute of Scientific and Technical Information of China (English)

    Su-Qin Zhu; Hua Zhao; Jian-Sheng Liang; Ben-Hua Ji; De-Mao Jiao

    2008-01-01

    In an attempt to explore the relationships between phosphatidylglycerol (PG) molecular species of thylakoid membrane lipids and sensitivities to chilling-induced photoinhibition, PG molecular species, D1 protein, electron transport activities of thylakoid membrane and the potential quantum yield (Fv/Fm) in rice treated under middle and low photon flux density (PFD) at 11℃ were analyzed by high performance liquid chromatography, enzyme hydrolysis, gas phase chromatography (GC) and so on. Results showed that the major molecular species of PGs in rice thylakoid membrane were 18:3/16:0, 18:3/16:1(3t), 18:2/16:0, 18:2/16:1(3t), 18:1/16:0, 18:1116:1(3t), 16:0/16:0, 16:0116:1(3t). There were large differences in the contents of unsaturated PG molecular species such as 18:1-3/16:0-16:1(3t) and saturated PG molecular species like 16:0116:0-16:1(3t) among japonica cv 9516 (j-9516),japonica-indica hybrid F1 j-951611-SY63 (ji-95SY) and indica cv Shanyou 63 (i-SY63). J-9516 containing higher contents of unsaturated PG molecular species was manifest in stable DI protein contents under chill and tolerant to chill-induced photoinhibition. In contrast to j-9516, i-SY63 with lower contents of unsaturated PG molecular species, exhibited unstable D1 protein contents under chill and was sensitive to chill-induced photoinhibition, ji-g5SY containing middle contents of unsaturated PG molecular species between those of j-9516 and i-SY63, exhibited mid extent of sensitivity to chill-induced photoinhibition. The losses in D1 protein also account for the inhibition in electron transport activity of thylakoid membrane and the observed decline in FvlFm. The PG molecular species that is efficient in raising chilling-resistant capacity were those containing unsaturated fatty acids, namely, unsaturated PG molecular species. These results implied that the substrate selectivity of the glycerol-3-phosphate acyltransferase In chloroplasts towards 16:0 or 18:1 displayed greatly the difference

  18. Sensitivity and specificity of different staining methods to monitor apoptosis induced by oxidative stress in adherent cells

    Institute of Scientific and Technical Information of China (English)

    ZHAO Jinshun 赵进顺; Alexandra Schmid-Kotsas; Hans-Juergen Gross; Adolf Gruenert; Max G. Bachem

    2003-01-01

    Objective To study the sensitivity and specificity of different staining methods to monitor apoptosis induced by oxidative stress in adherent cells.Methods Sensitivity and specificity of several common methods for apoptosis determination were evaluated (Apo2.7-expression, Annexin V-binding, TUNEL-reaction, poly-(ADP-ribose)-polymerase-(PARP) cleavage and single-stranded-DNA (ssDNA) staining). Apoptosis was induced by oxidative stress generated by hydrogen peroxide in 3 cultured cells types growing as adherent monolayer (MiaPaCa-2, Hep-G2 and human skin fibroblasts), necrosis was induced by depletion of cellular ATP using sodium azide. Cells positively stained by the respective apoptosis assay were quantified and alterations of cell morphology were monitored by fluorescence microscopy. The date was analyzed by one-way analysis of variance and significance test of correlation coefficient.Results One hour after apoptosis induction significant cell fractions were positively stained for ssDNA (33% with MiaPaCa-2 cells, 35% with Hep-G2 cells, 56% with human skin fibroblasts). PARP-cleavage was less sensitive compared to the ssDNA-staining. Apo2.7-expression, Annexin V-binding and TUNEL-reaction were not applicable to detect early apoptosis induced by oxidative stress (below 2 hours), but were efficiently monitoring late apoptosis.Specificity of ssDNA-staining was complete with each cell type even 4 hs after induction of necrosis by the highest sodium azide concentration. In contrast, the same experimental conditions resulted in 50%-90% positively stained necrotic cells by using Apo2.7-expression, TUNEL-reaction or AnnexinV-binding. Surprisingly, specificity of PARP-cleavage was highly depending on the respective cell type.Conclusions Our study prove that among the five methods investigated only ssDNA-staining allowed to completely differentiate apoptosis from necrosis, and is thus suitable to reliably detect early as well as late apoptosis. Therefore, the ss

  19. Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

    Directory of Open Access Journals (Sweden)

    Guan Yifu

    2009-02-01

    Full Text Available Abstract Background The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. Methods Proteasome activity, intracellular glutathione (GSH and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR. Results At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death. Conclusion GSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis.

  20. Role of oxidative stress in ERK and p38 MAPK activation induced by the chemical sensitizer DNFB in a fetal skin dendritic cell line

    OpenAIRE

    Matos, MT; Duarte, CB; Gonçalo, Margarida; Lopes, MC

    2005-01-01

    The intracellular mechanisms involved in the early phase of dendritic cell (DC) activation upon contact with chemical sensitizers are not well known. The strong skin sensitizer 2,4-dinitrofluorobenzene (DNFB) was shown to induce the activation of mitogen-activated protein kinases (MAPK) in DC. In the present study, we investigated a putative role for oxidative stress in DNFB-induced MAPK activation and upregulation of the costimulatory molecule CD40. In a DC line generated from fetal mouse sk...

  1. Development and characterization of high affinity leptins and leptin antagonists.

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  2. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  3. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers.

    Science.gov (United States)

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  4. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    Directory of Open Access Journals (Sweden)

    Mallory Batty

    2016-08-01

    Full Text Available This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa. Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.

  5. Influence of Nitric Oxide in the Central Amygdala on the Acquisition and Expression of Morphine-Induced Place Preference in Morphine Sensitized Rats

    Directory of Open Access Journals (Sweden)

    Hedayat Sahraei

    2011-08-01

    Full Text Available Effects of intra-central amygdala administration of L-arginine, a nitric oxide precursor, and NG-nitro-L-arginine methyl-ester (L NAME, a nitric oxide synthase inhibitor, on the morphine-induced sensitization and also on the expression of morphine-induced place conditioning in rats were studied. Subcutaneous (s.c. administration of morphine (2.5, 5 and 7.5 mg/kg induced place conditioning. Repeated pretreatment of morphine (5 mg/kg, i.p. followed by 5 days no drug treatment, increased place conditioning induced by morphine (0.5 mg/kg. Repeated intra-central amygdala administration of L-arginine (0.3, 1 and 3 μg/ rat, with morphine during acquisition of sensitization, significantly increased or reduced morphine place conditioning in sensitized rats. The drug administration before testing also increased and reduced the expression of morphine place conditioning in sensitized animals. Repeated intra-central amygdala injections of L-NAME (0.3, 1 and 3 μg/rat with morphine during acquisition of sensitization, reduced the acquisition of morphine place conditioning in the sensitized animals. The drug injection before testing also reduced morphine-induced conditioning. The results indicate that nitric oxide (NO within the central amygdala may be involved in the acquisition and expression of morphine place conditioning in morphine-sensitized rats.

  6. Sensitive detection of PDT-induced cell damages with luminescent oxygen nanosensors

    Science.gov (United States)

    Ma, Hong-Ru; Peng, Hong-shang; You, Fang-tian; Ping, Jian-tao; Zhou, Chao; Guo, Lan-ying

    2016-09-01

    In this work luminescent nanosensors specifically created for intracellular oxygen (ic-O2) were utilized to assess photodynamic therapy (PDT) -induced cell damages. Firstly, ic-O2 was demonstrated to be consumed much faster than extracellular O2 with respective O2 nanosensors. Using the ic-O2 nanosensors, PDT-treated cells with different degree of impairment were then resolved according to the oxygen consumption rate (OCR). The evolving trend of cytotoxicity derived from OCRs was in agreement with cell viability obtained from 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Moreover, the direct damage of PDT on cell mitochondria was successfully detected by monitoring respiration instantly after PDT treatment, which is actually beyond the scope of MTT assay. These results suggest that fluorescence sensing of ic-O2-associated cell respiration is promising and even may become a standardized method, complementary to MTT assay, to evaluate PDT-induced cytotoxicity.

  7. Higher sensitivity to cadmium induced cell death of basal forebrain cholinergic neurons: A cholinesterase dependent mechanism

    International Nuclear Information System (INIS)

    Cadmium is an environmental pollutant, which is a cause of concern because it can be greatly concentrated in the organism causing severe damage to a variety of organs including the nervous system which is one of the most affected. Cadmium has been reported to produce learning and memory dysfunctions and Alzheimer like symptoms, though the mechanism is unknown. On the other hand, cholinergic system in central nervous system (CNS) is implicated on learning and memory regulation, and it has been reported that cadmium can affect cholinergic transmission and it can also induce selective toxicity on cholinergic system at peripheral level, producing cholinergic neurons loss, which may explain cadmium effects on learning and memory processes if produced on central level. The present study is aimed at researching the selective neurotoxicity induced by cadmium on cholinergic system in CNS. For this purpose we evaluated, in basal forebrain region, the cadmium toxic effects on neuronal viability and the cholinergic mechanisms related to it on NS56 cholinergic mourine septal cell line. This study proves that cadmium induces a more pronounced, but not selective, cell death on acetylcholinesterase (AChE) on cholinergic neurons. Moreover, MTT and LDH assays showed a dose dependent decrease of cell viability in NS56 cells. The ACh treatment of SN56 cells did not revert cell viability reduction induced by cadmium, but siRNA transfection against AChE partially reduced it. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on the function and viability of neurons, and the possible relevance of cadmium in the pathogenesis of neurodegenerative diseases

  8. Inhibitory Effects of Coptidis rhizoma and Berberine on Cocaine-Induced Sensitization

    Directory of Open Access Journals (Sweden)

    Bombi Lee

    2009-01-01

    Full Text Available Substantial evidence suggests that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. Repeated injections of cocaine produce an increase in locomotor activity and the expression of tyrosine hydroxylase (TH in the main dopaminergic areas. Protoberberine alkaloids affect neuronal functions. Coptidis rhizoma (CR and its main compound, berberine (BER reduced the dopamine content in the central nervous system. In order to investigate the effects of CR or BER on the repeated cocaine-induced neuronal and behavioral alterations, we examined the influence of CR or BER on the repeated cocaine-induced locomotor activity and the expression of TH in the brain by using immunohistochemistry. Male SD rats were given repeated injections of saline or cocaine hydrochloride (15 mg/kg, i.p. for 10 consecutive days followed by one challenge injection on the 4th day after the last daily injection. Cocaine challenge (15 mg/kg, i.p produced a larger increase in locomotor activity and expression of TH in the central dopaminergic areas. Pretreatment with CR (50, 100, 200 and 400 mg/kg, p.o. and BER (200 mg/kg, p.o. 30 min before the daily injections of cocaine significantly inhibited the cocaine-induced locomotor activity as well as TH expression in the central dopaminergic areas. Our data demonstrate that the inhibitory effects of CR and BER on the repeated cocaine-induced locomotor activity were closely associated with the reduction of dopamine biosynthesis and post-synaptic neuronal activity. These results suggest that CR and BER may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system.

  9. Inhibitory Effects of Coptidis rhizoma and Berberine on Cocaine-induced Sensitization.

    Science.gov (United States)

    Lee, Bombi; Yang, Chae Ha; Hahm, Dae-Hyun; Choe, Eun Sang; Lee, Hye-Jung; Pyun, Kwang-Ho; Shim, Insop

    2009-03-01

    Substantial evidence suggests that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. Repeated injections of cocaine produce an increase in locomotor activity and the expression of tyrosine hydroxylase (TH) in the main dopaminergic areas. Protoberberine alkaloids affect neuronal functions. Coptidis rhizoma (CR) and its main compound, berberine (BER) reduced the dopamine content in the central nervous system. In order to investigate the effects of CR or BER on the repeated cocaine-induced neuronal and behavioral alterations, we examined the influence of CR or BER on the repeated cocaine-induced locomotor activity and the expression of TH in the brain by using immunohistochemistry. Male SD rats were given repeated injections of saline or cocaine hydrochloride (15 mg/kg, i.p. for 10 consecutive days) followed by one challenge injection on the 4th day after the last daily injection. Cocaine challenge (15 mg/kg, i.p) produced a larger increase in locomotor activity and expression of TH in the central dopaminergic areas. Pretreatment with CR (50, 100, 200 and 400 mg/kg, p.o.) and BER (200 mg/kg, p.o.) 30 min before the daily injections of cocaine significantly inhibited the cocaine-induced locomotor activity as well as TH expression in the central dopaminergic areas. Our data demonstrate that the inhibitory effects of CR and BER on the repeated cocaine-induced locomotor activity were closely associated with the reduction of dopamine biosynthesis and post-synaptic neuronal activity. These results suggest that CR and BER may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. PMID:18955248

  10. Contact Sensitizers Induce Skin Inflammation via ROS Production and Hyaluronic Acid Degradation

    OpenAIRE

    Esser, Philipp R.; Ute Wölfle; Christoph Dürr; Friederike D von Loewenich; Schempp, Christoph M.; Freudenberg, Marina A.; Thilo Jakob; Martin, Stefan F.

    2012-01-01

    BACKGROUND: Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS) model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed ...

  11. Contact Sensitizers Induce Skin Inflammation via ROS Production and Hyaluronic Acid Degradation

    OpenAIRE

    Philipp R Esser; Wölfle, Ute; Dürr, Christoph; Friederike D von Loewenich; Schempp, Christoph M.; Freudenberg, Marina A.; Jakob, Thilo; Martin, Stefan F

    2012-01-01

    Background Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS) model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed t...

  12. Performance Degradation of Dye-Sensitized Solar Cells Induced by Electrolytes

    OpenAIRE

    Ru-Yuan Yang; Huang-Yu Chen; Fu-Der Lai

    2012-01-01

    We investigated the change of the electric characteristics in dye-sensitized solar cell (DSSC) when the electrolyte has been injected and measured initially and lately for a period of time. It was found that the short-circuit current density decreased from 9.799 mA/cm2 to 7.056 mA/cm2 and the fill factor increased from 0.406 to 0.559 when the cell had stood for an hour, while the open-circuit photovoltage did not change due to fixed difference between the Fermi level of TiO2 and the oxidation...

  13. A fission-fragment-sensitive target for X-ray spectroscopy in neutron-induced fission

    CERN Document Server

    Ethvignot, T; Giot, L; Casoli, P; Nelson, R O

    2002-01-01

    A fission-fragment-sensitive detector built for low-energy photon spectroscopy applications at the WNR 'white' neutron source at Los Alamos is described. The detector consists of eight layers of thin photovoltaic cells, onto which 1 mg/cm sup 2 of pure sup 2 sup 3 sup 8 U is deposited. The detector serves as an active target to select fission events from background and other reaction channels. The fairly small thickness of the detector with respect to transmission of 20-50 keV photons permits the measurement of prompt fission-fragment X-rays. Results with the GEANIE photon spectrometer are presented.

  14. CTEN/tensin 4 expression induces sensitivity to paclitaxel in prostate cancer

    OpenAIRE

    Li, You Qiang; Mizokami, Atsushi; Izumi, Kouji; Narimoto, Kazutaka; Shima, Takashi; Zhang, Jian; Dai, Jinlu; Keller, Evan T.; Namiki, Mikio

    2010-01-01

    BACKGROUND. Recently, we established paclitaxel-resistant prostate cancer cell lines (PC-3-TxR and DU145-TxR). To determine the mechanisms of paclitaxel resistance in PC-3-TxR cells, we compared the gene expression profiles between PC-3 and PC-3-TxR cells. Our results indicated that expression of the C-terminal tensin like protein (CTEN, tensin 4) gene was down-regulated by 10-fold in PC-3-TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity. MET...

  15. Effects of irritant gas induced damage of bronchial epithelium (SO sub 2 , NO sub 2 , ozone, cigarette smoke) on sensitization by inhaled allergens. Lokale bronchiale Sensibilisierung mit inhalativen Antigenen nach vorausgegangener Schaedigung durch Reizgasinhalation (SO sub 2 , NO sub 2 , Ozon und Tabakrauch)

    Energy Technology Data Exchange (ETDEWEB)

    Riedel, F.; Rieger, C.H.L. (Marburg Univ. (Germany, F.R.). Zentrum fuer Kinderheilkunde)

    1989-04-01

    This report concerns results of ozone- and tobacco smoke exposure: 5 days of exposure (6 hours per day) with 1.0 ppm O{sub 3}, but not with 0.5 ppm O{sub 3}, enhance bronchial sensitization compared to an air-exposed control group. The combination of 1.0 ppm SO{sub 2} (not effective on its own) with 0.5 ppm O{sub 3} has the same effect. Exposure with tobacco smoke (mixture of main- and sidestream smoke), leading to serum Cotinine levels of 87 ng/ml in the mean at the end of the 5th exposure day, enhances sensitization to inhaled Ovalbumin as well. During a 5-day exposure with 5 ppm SO{sub 2} groups of 6 animals were treated prophylactically with anti-inflammatory drugs and the influence on the sensitization by inhaled Ovalbumin was studied. Inhalation of Nedocromil-Sodium and high-dose oral Methylprednisolone (8 mg/kg/d) could completely inhibit inhalative sensitization. Indomethacin was only partly effective, whereas no effect was seen on treatment with low-dose steroids and PAF-antagonist WEB 2170 BS. Inflammatory reactions as the leading pathogenetic mechanism of air pollution induced inhalative sensitization is discussed. (orig./MG).

  16. Increased sensitivity of apolipoprotein E knockout mice to copper-induced oxidative injury to the liver.

    Science.gov (United States)

    Chen, Yuan; Li, Bin; Zhao, Ran-ran; Zhang, Hui-feng; Zhen, Chao; Guo, Li

    2015-04-10

    Apolipoprotein E (ApoE) genotypes are related to clinical presentations in patients with Wilson's disease, indicating that ApoE may play an important role in the disease. However, our understanding of the role of ApoE in Wilson's disease is limited. High copper concentration in Wilson's disease induces excessive generation of free oxygen radicals. Meanwhile, ApoE proteins possess antioxidant effects. We therefore determined whether copper-induced oxidative damage differ in the liver of wild-type and ApoE knockout (ApoE(-/-)) mice. Both wild-type and ApoE(-/-) mice were intragastrically administered with 0.2 mL of copper sulfate pentahydrate (200 mg/kg; a total dose of 4 mg/d) or the same volume of saline daily for 12 weeks, respectively. Copper and oxidative stress markers in the liver tissue and in the serum were assessed. Our results showed that, compared with the wild-type mice administered with copper, TBARS as a marker of lipid peroxidation, the expression of oxygenase-1 (HO-1), NAD(P)H dehydrogenase, and quinone 1 (NQO1) significantly increased in the ApoE(-/-) mice administered with copper, meanwhile superoxide dismutase (SOD) activity significantly decreased. Thus, it is concluded that ApoE may protect the liver from copper-induced oxidative damage in Wilson's disease.

  17. Screening of antagonistic bacteria for biological control of nursery wilt of black pepper (Piper nigrum).

    Science.gov (United States)

    Anith, K N; Radhakrishnan, N V; Manomohandas, T P

    2003-01-01

    Bacterial antagonists of Phytophthora capsici were isolated from underground shoot portions of rooted cuttings of black pepper. Initially isolates were screened by dual culture on potato dextrose agar and carrot agar. Further, a screening was done on black pepper shoots for supression of lesion caused by the pathogen. Most of the antagonists showed varying levels of antagonism in the dual culture and the shoot assay. Isolate PN-026, showing the highest suppression of lesion development in the shoot assay was found to be the most efficient antagonist in reducing Phytophthora capsici induced nursery wilt of black pepper. This screening involving the host, pathogen, and the antagonist, performed on black pepper shoot (the planting material for this vegetatively propagated crop), could be used as a rapid and reliable method for the isolation of efficient bacterial antagonists of P. capsici.

  18. Epicutaneous immunotherapy (EPIT blocks the allergic esophago-gastro-enteropathy induced by sustained oral exposure to peanuts in sensitized mice.

    Directory of Open Access Journals (Sweden)

    Lucie Mondoulet

    Full Text Available BACKGROUND: Food allergy may affect the gastrointestinal tract and eosinophilia is often associated with allergic gastrointestinal disorders. Allergy to peanuts is a life-threatening condition and effective and safe treatments still need to be developed. The present study aimed to evaluate the effects of sustained oral exposure to peanuts on the esophageal and jejunal mucosa in sensitized mice. We also evaluated the effects of desensitization with epicutaneous immunotherapy (EPIT on these processes. METHODS: Mice were sensitized by gavages with whole peanut protein extract (PPE given with cholera toxin. Sensitized mice were subsequently exposed to peanuts via a specific regimen and were then analysed for eosinophilia in the esophagus and gut. We also assessed mRNA expression in the esophagus, antibody levels, and peripheral T-cell response. The effects of EPIT were tested when intercalated with sensitization and sustained oral peanut exposure. RESULTS: Sustained oral exposure to peanuts in sensitized mice led to severe esophageal eosinophilia and intestinal villus sub-atrophia, i.e. significantly increased influx of eosinophils into the esophageal mucosa (136 eosinophils/mm(2 and reduced villus/crypt ratios (1.6±0.15. In the sera, specific IgE levels significantly increased as did secretion of Th2 cytokines by peanut-reactivated splenocytes. EPIT of sensitized mice significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines as well as esophageal eosinophilia (50 eosinophils/mm(2, p<0.05, mRNA expression of Th2 cytokines in tissue--eotaxin (p<0.05, IL-5 (p<0.05, and IL-13 (p<0.05--GATA-3 (p<0.05, and intestinal villus sub-atrophia (2.3±0.15. EPIT also increased specific IgG2a (p<0.05 and mRNA expression of Foxp3 (p<0.05 in the esophageal mucosa. CONCLUSIONS: Gastro-intestinal lesions induced by sustained oral exposure in sensitized mice are efficaciously treated by allergen specific EPIT.

  19. The BH3 Only Protein Mimetic Obatoclax Sensitizes Cholangiocarcinoma Cells to Apo2L/TRAIL-Induced Apoptosis

    Science.gov (United States)

    Mott, Justin L.; Bronk, Steve F.; Mesa, Ruben A.; Kaufmann, Scott H.; Gores, Gregory J.

    2008-01-01

    Human cholangiocarcinomas evade apoptosis by overexpression of Mcl-1. The drug obatoclax (GX15–070) inhibits anti-apoptotic members of the Bcl-2 family including Mcl-1. Purpose To determine if obatoclax sensitizes human cholangiocarcinoma cells to apoptosis. Experimental Design The human cholangiocarcinoma cell lines, KMCH, KMBC, and TFK, were employed for these studies. Protein expression was assessed by immunoblot, and protein-protein interactions detected by co-precipitation of the polypeptide of interest with S-tagged Mcl-1. Activation of Bak and Bax was observed by immunocytochemistry with conformation specific antisera. Results Obatoclax induced minimal apoptosis alone; however, it increased apoptosis 3- to 13-fold in all three cancer cell lines when combined with Apo2L/TRAIL. Obatoclax did not alter cellular expression of Bid, Bim, Puma, Noxa, Bak, Bax, Mcl-1 or cFLIP. Mcl-1 binding to Bak was readily identified in untreated cells, and this association was disrupted by treating the cells with obatoclax. Additionally, Bim binding to Mcl-1 was markedly decreased by obatoclax treatment. We also identified alterations in Bak and Bax conformation following treatment with obatoclax plus Apo2L/TRAIL, but not with either Apo2L/TRAIL or obatoclax alone. Conclusions In conclusion, obatoclax releases Bak and Bim from Mcl-1 and sensitizes human cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Obatoclax is a potentially promising adjunctive agent for the treatment of this cancer. PMID:18723481

  20. Study on effect of optical wavelength on photo induced strain sensitivity in carbon nanotubes using fiber Bragg grating

    International Nuclear Information System (INIS)

    In this work, the role of optical wavelength on the photo induced strain in carbon nanotubes (CNT) is probed using a Fiber Bragg Grating (FBG), upon exposure to infrared (IR) (21 με mW−1) and visible (9 με mW−1) radiations. The strain sensitivity in CNT is monitored over a smaller range (10−3 to 10−9 ε) by exposing to a low optical power varying in the range 10−3 to 10−6 W. In addition, the wavelength dependent response and recovery periods of CNT under IR (τrise = 150 ms, τfall = 280 ms) and visible (τrise = 1.07 s, τfall = 1.18 s) radiations are evaluated in detail. This study can be further extended to measure the sensitivity of nano–scale photo induced strains in nano materials and opens avenues to control mechanical actuation using various optical wavelengths. (paper)

  1. Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Y.; Mu, J.J.; Liu, F.Q.; Ren, K.Y.; Xiao, H.Y. [Xi' an Jiaotong University, Medical College, First Affiliated Hospital, Cardiovascular Department, Xi' an, China, Cardiovascular Department, First Affiliated Hospital, Medical College, Xi' an Jiaotong University, Xi' an (China); Ministry of Education, Key Laboratory of Environment and Genes Related to Diseases, Xi' an, China, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi' an (China); Yang, Z. [Xi' an Jiaotong University, Medical College, First Affiliated Hospital, Department of Pathology, Xi' an, China, Department of Pathology, First Affiliated Hospital, Medical College, Xi' an Jiaotong University, Xi' an (China); Yuan, Z.Y. [Xi' an Jiaotong University, Medical College, First Affiliated Hospital, Cardiovascular Department, Xi' an, China, Cardiovascular Department, First Affiliated Hospital, Medical College, Xi' an Jiaotong University, Xi' an (China); Ministry of Education, Key Laboratory of Environment and Genes Related to Diseases, Xi' an, China, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi' an (China)

    2014-03-03

    Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13{sup BN} rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure.

  2. Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure

    International Nuclear Information System (INIS)

    Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13BN rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure

  3. The Comparison of Antagonistic Effects of Normal Vaginal Lactobacilli and Some Commonly used Antibiotics on Isolated Bacteria of Uterine Infections in Dairy Cows

    Directory of Open Access Journals (Sweden)

    Pouya Dini

    2012-12-01

    Full Text Available Uterine infections are one of the major reproductive complications during postpartum. The antibiotics and antiseptic agents used in the treatment of postpartum infections have residues in food, induce bacterial resistance, increase the financial costs and cause failure in defense mechanism of host. On the other hand, nowadays the administration of probiotics is considered as an alternative method for the prevention and treatment of infections. Therefore, preventive treatment with probiotic product could decrease the usage of antibiotic and bring advantages in dairy farm systems. The objective of this study was screening of the antagonistic properties of isolated vaginal Lactic Acid Bacteria (LAB against the most prevalent bacteria in uterine infections in order to investigate their probiotic potentials as an alternative approach for prevention of uterine infections. LAB were isolated from sampling of cranial part of vagina during estrus phase and luteal phase of Holstein dairy cattle and pathogens bacteria were isolated from merits and endometritis specimens which referred to our veterinary laboratory. The antagonistic activity of isolated LAB against uterine pathogens was tested by Agar spot test. Antibiotic susceptibilities of pathogenic strains to commonly used antibiotics were investigated by using disc diffusion method. Inhibition zones around both the probiotic spots and the antibiotic discs were classified to weak, moderate and strong categories and their antagonistic efficacies were compared. Isolated LAB had antagonistic effects against all the pathogenic strains including both gram negative and gram positive, Arcanobacterium pyogenes and Pseudomonas aeroginosa were the most sensitive bacteria (with 12.60 and 14 mm an average inhibition zone, respectively. LAB had the least antagonistic effects on Clostridium perfringens (3.6 mm of an average inhibition zone. Comparing the antagonistic efficacies, the percentages of overall

  4. Differential sensitivity to aphidicolin of replicative DNA synthesis and ultraviolet-induced unscheduled DNA synthesis in vivo in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Seki,Shuji

    1984-06-01

    Full Text Available In vivo in mammalian cells, ultraviolet-induced unscheduled DNA synthesis was less sensitive to aphidicolin than was replicative DNA synthesis. Replicative DNA synthesis in HeLa, HEp-2, WI-38 VA-13 and CV-1 cells was inhibited more than 97% by aphidicolin at 10 micrograms/ml, whereas aphidicolin inhibition of DNA synthesis in ultraviolet-irradiated cells varied between 30% and 90% depending on cell types and assay conditions. Aphidicolin inhibition of unscheduled DNA synthesis (UDS in HeLa cells increased gradually with increasing aphidicolin concentration and reached approximately 90% at 100 micrograms/ml aphidicolin. A significant fraction of UDS in ultraviolet-irradiated HEp-2 cells was resistant to aphidicolin even at 300 micrograms/ml. Considered along with related information reported previously, the present results suggest that both aphidicolin-sensitive and insensitive DNA polymerases, DNA polymerase alpha and a non-alpha DNA polymerase (possibly DNA polymerase beta, are involved in in situ UDS in these ultraviolet-irradiated cells. Comparison of staphylococcal nuclease sensitivity between DNAs repaired in the presence and in the absence of aphidicolin in HEp-2 cells suggested that the involvement of DNA polymerase alpha in UDS favored DNA synthesis in the intranucleosomal region.

  5. Near-ultraviolet radiation-induced damage using an actinic reticuloid strain as a possible sensitive model

    Energy Technology Data Exchange (ETDEWEB)

    Kralli, A.

    1987-01-01

    The introduction to this thesis consists of a review of current concepts regarding the effects of ultraviolet radiation on living cells. Actinic reticuloid, a disease condition for which a near-ultraviolet radiation cellular sensitivity has been proposed as an underlying cause, is described. The experimental work, the broad aim of which is to expand existing knowledge of the effects of near-ultraviolet radiation that may lead to cell lethality, has centred upon the irradiation of a normal human skin fibroblast strain, GM730, and a strain derived from an actinic reticuloid patient, AR6LO. Parts 1 and 2 examine the effects of the irradiation on both normal and actinic fibroblast sensitivities to a range of ultraviolet wavelengths. The next two sections include observations on the protective effect of Trolox-C, a vitamin E analogue and the sensitization resulting from the replacement of the irradiation medium by a deuterated one, using both normal and actinic reticuloid fibroblasts. The final part examines broad-band near- and far-ultraviolet radiation induced membrane damage by the use of radioactively labelled rubidium as a potassium analogue.

  6. Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents.

    Directory of Open Access Journals (Sweden)

    Ryan J Mailloux

    Full Text Available Uncoupling protein-2 (UCP2 is known to suppress mitochondrial reactive oxygen species (ROS production and is employed by drug-resistant cancer cells to mitigate oxidative stress. Using the drug-sensitive HL-60 cells and the drug-resistant MX2 subline as model systems, we show that genipin, a UCP2 inhibitor, sensitizes drug-resistant cells to cytotoxic agents. Increased MX2 cell death was observed upon co-treatment with genipin and different doses of menadione, doxorubicin, and epirubicin. DCFH-DA fluorimetry revealed that the increase in MX2 cell death was accompanied by enhanced cellular ROS levels. The drug-induced increase in ROS was linked to genipin-mediated inhibition of mitochondrial proton leak. State 4 and resting cellular respiratory rates were higher in the MX2 cells in comparison to the HL-60 cells, and the increased respiration was readily suppressed by genipin in the MX2 cells. UCP2 accounted for a remarkable 37% of the resting cellular oxygen consumption indicating that the MX2 cells are functionally reliant on this protein. Higher amounts of UCP2 protein were detected in the MX2 versus the HL-60 mitochondria. The observed effects of genipin were absent in the HL-60 cells pointing to the selectivity of this natural product for drug-resistant cells. The specificity of genipin for UCP2 was confirmed using CHO cells stably expressing UCP2 in which genipin induced an ∼22% decrease in state 4 respiration. These effects were absent in empty vector CHO cells expressing no UCP2. Thus, the chemical inhibition of UCP2 with genipin sensitizes multidrug-resistant cancer cells to cytotoxic agents.

  7. Atorvastatin improves insulin sensitivity in mice with obesity induced by monosodium glutamate

    OpenAIRE

    Zhang, Ning; Huan, Yi; Huang, Hui; Song, Guang-ming; Sun, Su-juan; Shen, Zhu-fang

    2009-01-01

    Aim: To examine the mechanisms underlying the effects of atorvastatin on glucose and lipid metabolism. Methods: Mice with insulin resistance and obesity induced by monosodium glutamate (MSG) were used. Atorvastatin (80 mg·kg−1·d−1) or vehicle control treatment was given orally once a day for 30 days. Plasma levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and free fatty acids were monitored. Serum insulin an...

  8. Serotonin (2C) receptor regulation of cocaine-induced conditioned place preference and locomotor sensitization

    OpenAIRE

    Craige, Caryne P.; Unterwald, Ellen M.

    2012-01-01

    Previous studies have identified an inhibitory regulatory role of the 5-HT2C receptor in serotonin and dopamine neurotransmission. As cocaine is known to enhance serotonin and dopamine transmission, the ability of 5-HT2C receptors to modulate cocaine-induced behaviors was investigated. Alterations in cocaine reward behavior were assessed in the conditioned place preference (CPP) paradigm. Mice were injected with a selective 5-HT2C receptor agonist, Ro 60-0175 (0, 1, 3, 10 mg/kg, i.p.) prior t...

  9. Down-regulation of ATM Protein Sensitizes Human Prostate Cancer Cells to Radiation-induced Apoptosis*

    OpenAIRE

    Truman, Jean-Philip; Gueven, Nuri; Lavin, Martin; Leibel, Steven; Kolesnick, Richard; Fuks, Zvi; Haimovitz-Friedman, Adriana

    2005-01-01

    Treatment with the protein kinase C activator 12-O tetradecanoylphorbol 12-acetate (TPA) enables radiation-resistant LNCaP human prostate cancer cells to undergo radiation-induced apoptosis, mediated via activation of the enzyme ceramide synthase (CS) and de novo synthesis of the sphingolipid ceramide (Garzotto, M., Haimovitz-Friedman, A., Liao, W. C., White-Jones, M., Huryk, R., Heston, D. W. W., Cardon-Cardo, C., Kolesnick, R., and Fuks, Z. (1999) Cancer Res. 59, 5194-5201). Here, we show t...

  10. Selective enzymatic cleavage and labeling for sensitive capillary electrophoresis laser-induced fluorescence analysis of oxidized DNA bases.

    Science.gov (United States)

    Li, Cuiping; Wang, Hailin

    2015-08-01

    Oxidatively generated DNA damage is considered to be a significant contributing factor to cancer, aging, and age-related human diseases. It is important to detect oxidatively generated DNA damage to understand and clinically diagnosis diseases caused by oxidative damage. In this study, using selective enzymatic cleavage and quantum dot (QD) labeling, we developed a novel capillary electrophoresis-laser induced fluorescence method for the sensitive detection of oxidized DNA bases. First, oxidized DNA bases are recognized and removed by one DNA base excision repair glycosylase, leaving apurinic and apyrimidinic sites (AP sites) at the oxidized positions. The AP sites are further excised by the AP nicking activity of the chosen glycosylase, generating a nucleotide gap with 5'- and 3'- phosphate groups. After dephosphorylation with one alkaline phosphatase, a biotinylated ddNTP is introduced into the nucleotide space within the DNA strand by DNA polymerase I. The biotin-tagged DNA is further labeled with a QD-streptavidin conjugate via non-covalent interactions. The DNA-bound QD is well-separated from excess DNA-unbound QD by highly efficient capillary electrophoresis and is sensitively detected by online coupled laser-induced fluorescence analysis. Using this method, we can assess the trace levels of oxidized DNA bases induced by the Fenton reaction and UV irradiation. Interestingly, the use of the formamidopyrimidine glycosylase (FPG) protein and endonuclease VIII enables the detection of oxidized purine and pyrimidine bases, respectively. Using the synthesized standard DNA, the approach has low limits of detection of 1.1×10(-19)mol in mass and 2.9pM in concentration. PMID:26105778

  11. Performance Degradation of Dye-Sensitized Solar Cells Induced by Electrolytes

    Directory of Open Access Journals (Sweden)

    Ru-Yuan Yang

    2012-01-01

    Full Text Available We investigated the change of the electric characteristics in dye-sensitized solar cell (DSSC when the electrolyte has been injected and measured initially and lately for a period of time. It was found that the short-circuit current density decreased from 9.799 mA/cm2 to 7.056 mA/cm2 and the fill factor increased from 0.406 to 0.559 when the cell had stood for an hour, while the open-circuit photovoltage did not change due to fixed difference between the Fermi level of TiO2 and the oxidation-reduction potential of electrolyte. The results can be explained by using the variation of the series resistance in the equivalent circuit of the DSSC.

  12. Contractions induce phosphorylation of the AMPK site Ser565 in hormone-sensitive lipase in muscle

    DEFF Research Database (Denmark)

    Donsmark, Morten; Langfort, Jozef; Holm, Cecilia;

    2004-01-01

    Intramyocellular triglyceride is an important energy store which is related to insulin resistance. Mobilization of fatty acids from this pool is probably regulated by hormone-sensitive lipase (HSL), which has recently been shown to exist in muscle and to be activated by epinephrine via PKA...... and by contractions via PKC and ERK. 5' AMP-activated protein kinase (AMPK) is an intracellular fuel gauge which regulates metabolism. In this study we incubated rat soleus muscle to investigate if AMPK influences HSL during 5min of repeated tetanic contractions. An eightfold increase in AMPK activity was accompanied...... by a 2.5-fold increase in phosphorylation of the AMPK-site Ser(565) in HSL (pHSL activation while HSL-Ser(565) phosphorylation was not reduced. The study indicates that during contractions AMPK phosphorylates HSL in Ser(565...

  13. LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small cell lung cancer (NSCLC) cells

    OpenAIRE

    Whang, Young Mi; Park, Serk In; Trenary, Irina A.; Egnatchik, Robert A.; Fessel, Joshua P.; Kaufman, Jacob M.; Carbone, David P.; Young, Jamey D.

    2015-01-01

    The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20–30% of non-small cell lung cancer (NSCLC) patient tumors. Loss of LKB1-AMPK signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations...

  14. Down-Regulation of Bcl-2 Protein Sensitizes NCI 460 Cells to Radiotherapy-Induced Apoptosis

    Institute of Scientific and Technical Information of China (English)

    Dongmei He; Yuan Zhang; Gexiu Liu

    2006-01-01

    OBJECTIVE To determine whether Bcl-2 protein down-regulation can render NCI-460 cells more susceptible to gamma radiation-induced apoptosis by treatment with antisense oligonucleotide (ASODN) against the coding region of Bcl-2 mRNA.METHODS Cell survival was determined using the trypan blue dye exclusion. Expression of the Bcl-2 protein was assayed using immunofluorescence labeling with fluoresce isothiocyanate. Apoptosis was determined by Giemsa staining and flow cytomertry.RESULTS It was found that Bcl-2 ASODN combined with radiation significantly reduced the number of viable cells (P<0.05). There was no difference in cell survival between a nonsense oligodeoxynucleotide/radiation combination and cells treated with radiation alone. Bcl-2 ASODN combined with radiation significantly inhibited expression of the Bcl-2protein in the NCI-H460 cells (P<0.05). Using Giemsa staining, cells treated with Bcl-2 ASODN combined with radiation at 72 h displayed classic apoptotic changes. Apoptotic rates of the NCI-H460 cells treated with Bcl-2 ASODN combined with radiation significantly increased (P<0.05), compared with either a nonsense oligodeoxynucleotide/radiation combination or radiation-treatment cells alone.CONCLUSION ASODN against the coding region of Bcl-2 mRNA increases radiation-induced apoptosis in NCI-H460 cells.

  15. Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Georg T. Wondrak

    2013-02-01

    Full Text Available Repurposing approved and abandoned non-oncological drugs is an alternative developmental strategy for the identification of anticancer therapeutics that has recently attracted considerable attention. Due to the essential role of the cellular heat shock response in cytoprotection through the maintenance of proteostasis and suppression of apoptosis, small molecule heat shock response antagonists can be harnessed for targeted induction of cytotoxic effects in cancer cells. Guided by gene expression array analysis and a phenotypic screen interrogating a collection of 3,7-diamino-phenothiazinium derivatives, we have identified the redox-drug methylene blue (MB, used clinically for the infusional treatment of methemoglobinemia, as a negative modulator of heat shock response gene expression in human metastatic melanoma cells. MB-treatment blocked thermal (43 °C and pharmacological (celastrol, geldanamycin induction of heat shock response gene expression, suppressing Hsp70 (HSPA1A and Hsp27 (HSPB1 upregulation at the mRNA and protein level. MB sensitized melanoma cells to the apoptogenic activity of geldanamycin, an Hsp90 antagonist known to induce the counter-regulatory upregulation of Hsp70 expression underlying cancer cell resistance to geldanamycin chemotherapy. Similarly, MB-cotreatment sensitized melanoma cells to other chemotherapeutics (etoposide, doxorubicin. Taken together, these data suggest feasibility of repurposing the non-oncological redox drug MB as a therapeutic heat shock response antagonist for cancer cell chemosensitization.

  16. Seasonal trends in reduced leaf gas exchange and ozone-induced foliar injury in three ozone sensitive woody plant species

    Energy Technology Data Exchange (ETDEWEB)

    Novak, K. [Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zuercherstrasse 111, 8903 Birmensdorf (Switzerland)]. E-mail: kristopher.novak@wsl.ch; Schaub, M. [Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zuercherstrasse 111, 8903 Birmensdorf (Switzerland); Fuhrer, J. [Swiss Federal Research Station for Agroecology and Agriculture FAL, 8046 Zurich (Switzerland); Skelly, J.M. [Department of Plant Pathology, The Pennsylvania State University, University Park, PA 16802 (United States); Hug, C. [Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zuercherstrasse 111, 8903 Birmensdorf (Switzerland); Landolt, W. [Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zuercherstrasse 111, 8903 Birmensdorf (Switzerland); Bleuler, P. [Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zuercherstrasse 111, 8903 Birmensdorf (Switzerland); Kraeuchi, N. [Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zuercherstrasse 111, 8903 Birmensdorf (Switzerland)

    2005-07-15

    Seasonal trends in leaf gas exchange and ozone-induced visible foliar injury were investigated for three ozone sensitive woody plant species. Seedlings of Populus nigra L., Viburnum lantana L., and Fraxinus excelsior L. were grown in charcoal-filtered chambers, non-filtered chambers and open plots. Injury assessments and leaf gas exchange measurements were conducted from June to October during 2002. All species developed typical ozone-induced foliar injury. For plants exposed to non-filtered air as compared to the charcoal-filtered air, mean net photosynthesis was reduced by 25%, 21%, and 18% and mean stomatal conductance was reduced by 25%, 16%, and 8% for P. nigra, V. lantana, and F. excelsior, respectively. The timing and severity of the reductions in leaf gas exchange were species specific and corresponded to the onset of visible foliar injury. - Reductions in leaf gas exchange corresponded to the onset of ozone-induced visible foliar injury for seedlings exposed to ambient ozone exposures.

  17. Ultra-fast and sensitive photo-induced phase switching in (EDO-TTF)2PF6

    International Nuclear Information System (INIS)

    Organic conductor (EDO-TTF)2PF6 crystal having 14 filled band shows a metal (M)-insulator (I) transition accompanied with Peierls transition, charge ordering, and anion ordering at transition temperature, TC=280K. This crystal is an important and fascinating candidate for photo-induced M-I transition because the multi-instability will afford sensitivity to the tiny stimulation. We make the report of the reflectivity change in (EDO-TTF)2PF6 crystal induced by the irradiation of femto-second (fs) pulsed laser (pulse width: 120fs, main wavelength: 800nm, repetition rate: 1kHz). The obtained results indicate that the highly efficient I-to-M transition occurs within 3ps in this material. Based on these results, the strong electron-lattice cooperative interaction is proved to play an essential role in the driving process of this M-I transition. Also, 14 filled materials, which show M-I transition, accompanied with the charge ordering, can be classified as fascinating candidates not only for superconductivity but also for photo-induced cooperative phenomena and application in phase switching devices

  18. Evaluation of γ-radiation-induced DNA damage in two species of bivalves and their relative sensitivity using comet assay

    Energy Technology Data Exchange (ETDEWEB)

    Praveen Kumar, M.K., E-mail: here.praveen@gmail.com [Department of Zoology, Goa University, Goa 403206 (India); Shyama, S.K., E-mail: skshyama@gmail.com [Department of Zoology, Goa University, Goa 403206 (India); Sonaye, B.S. [Department of Radiation Oncology, Goa Medical College, Goa (India); Naik, U Roshini; Kadam, S.B.; Bipin, P.D.; D’costa, A. [Department of Zoology, Goa University, Goa 403206 (India); Chaubey, R.C. [Radiation Biology and Health Science Division, Bhabha Atomic Research Centre, Mumbai (India)

    2014-05-01

    Highlights: • Possible genotoxic effect of accidental exposure of aquatic fauna to γ radiation. • Relative sensitivity of bivalves to γ radiation is also analyzed using comet assay. • γ radiation induced significant genetic damage in both the species of bivalves. • P. malabarica and M. casta exhibited a similar level of sensitivity to γ radiation. • Comet assay may be used as a biomarker for the environmental biomonitoring. - Abstract: Ionizing radiation is known to induce genetic damage in diverse groups of organisms. Under accidental situations, large quantities of radioactive elements get released into the environment and radiation emitted from these radionuclides may adversely affect both the man and the non-human biota. The present study is aimed (a) to know the genotoxic effect of gamma radiation on aquatic fauna employing two species of selected bivalves, (b) to evaluate the possible use of ‘Comet assay’ for detecting genetic damage in haemocytes of bivalves as a biomarker for environmental biomonitoring and also (c) to compare the relative sensitivity of two species of bivalves viz. Paphia malabarica and Meretrix casta to gamma radiation. The comet assays was optimized and validated using different concentrations (18, 32 and 56 mg/L) of ethyl methanesulfonate (EMS), a direct-acting reference genotoxic agent, to which the bivalves were exposed for various times (24, 48 and 72 h). Bivalves were irradiated (single acute exposure) with 5 different doses (viz. 2, 4, 6, 8 and 10 Gy) of gamma radiation and their genotoxic effects on the haemocytes were studied using the comet assay. Haemolymph was collected from the adductor muscle at 24, 48 and 72 h of both EMS-exposed and irradiated bivalves and comet assay was carried out using standard protocol. A significant increase in DNA damage was observed as indicated by an increase in % tail DNA damage at different concentrations of EMS and all the doses of gamma radiation as compared to controls in

  19. Evaluation of γ-radiation-induced DNA damage in two species of bivalves and their relative sensitivity using comet assay

    International Nuclear Information System (INIS)

    Highlights: • Possible genotoxic effect of accidental exposure of aquatic fauna to γ radiation. • Relative sensitivity of bivalves to γ radiation is also analyzed using comet assay. • γ radiation induced significant genetic damage in both the species of bivalves. • P. malabarica and M. casta exhibited a similar level of sensitivity to γ radiation. • Comet assay may be used as a biomarker for the environmental biomonitoring. - Abstract: Ionizing radiation is known to induce genetic damage in diverse groups of organisms. Under accidental situations, large quantities of radioactive elements get released into the environment and radiation emitted from these radionuclides may adversely affect both the man and the non-human biota. The present study is aimed (a) to know the genotoxic effect of gamma radiation on aquatic fauna employing two species of selected bivalves, (b) to evaluate the possible use of ‘Comet assay’ for detecting genetic damage in haemocytes of bivalves as a biomarker for environmental biomonitoring and also (c) to compare the relative sensitivity of two species of bivalves viz. Paphia malabarica and Meretrix casta to gamma radiation. The comet assays was optimized and validated using different concentrations (18, 32 and 56 mg/L) of ethyl methanesulfonate (EMS), a direct-acting reference genotoxic agent, to which the bivalves were exposed for various times (24, 48 and 72 h). Bivalves were irradiated (single acute exposure) with 5 different doses (viz. 2, 4, 6, 8 and 10 Gy) of gamma radiation and their genotoxic effects on the haemocytes were studied using the comet assay. Haemolymph was collected from the adductor muscle at 24, 48 and 72 h of both EMS-exposed and irradiated bivalves and comet assay was carried out using standard protocol. A significant increase in DNA damage was observed as indicated by an increase in % tail DNA damage at different concentrations of EMS and all the doses of gamma radiation as compared to controls in

  20. The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

    Science.gov (United States)

    Lochner, Martin; Thompson, Andrew J

    2016-09-01

    Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects. PMID:27108935

  1. 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.

  2. Position sensitive anodes for MCP read-out using induced charge measurement

    CERN Document Server

    Jagutzki, O; Mergel, V; Schmidt-Böcking, H; Spillmann, U; Worth, L B C

    2002-01-01

    We investigate the method of an indirect detection of a MCP charge avalanche projected onto a resistive layer (G. Battistoni, et al., Nucl. Instr. and Meth., 202 (1982) 459). If the sheet resistance is favourable one can detect the charge cloud by the capacitive coupling to an anode structure a few millimetres behind the layer. The anode structure can be, for example, a wedge-and-strip electrode pattern (M. Unverzagt, Diplomarbeit, Universitaet Frankfurt 1992, private communication) as it is used for directly collecting the electron avalanche from a MCP. Detection of the induced charge is beneficial in several respects. Firstly, image distortions produced by secondary electron mediated charge redistribution are eliminated. Secondly, the noise component due to quantized charge collection, commonly referred to as partition noise, is not present. In addition, the dielectric substrate can function both as an element of the vacuum enclosure and HV insulator, making the electrical connections easily accessible and ...

  3. Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?

    International Nuclear Information System (INIS)

    Drug resistance is a fundamental problem in the treatment of most common human cancers. Our understanding of the cellular mechanisms underlying death and survival has allowed the development of rational approaches to overcoming drug resistance. The mitogen activated protein kinase family of protein serine/threonine kinases has been implicated in this complex web of signalling, with some members acting to enhance death and other members to prevent it. A recent publication by MacKeigan et al is the first to demonstrate an enhancement of drug-induced cell death by simultaneous blockade of MEK-mediated survival signalling, and offers the potential for targeted adjuvant therapy as a means of overcoming drug resistance

  4. Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.

    Directory of Open Access Journals (Sweden)

    Mihajlo Bosnjak

    Full Text Available The present study investigated the role of autophagy, a cellular self-digestion process, in the cytotoxicity of antileukemic drug cytarabine towards human leukemic cell lines (REH, HL-60, MOLT-4 and peripheral blood mononuclear cells from leukemic patients. The induction of autophagy was confirmed by acridine orange staining of intracellular acidic vesicles, electron microscopy visualization of autophagic vacuoles, as well as by the increase in autophagic proteolysis and autophagic flux, demonstrated by immunoblot analysis of p62 downregulation and LC3-I conversion to autophagosome-associated LC3-II in the presence of proteolysis inhibitors, respectively. Moreover, the expression of autophagy-related genes Atg4, Atg5 and Atg7 was stimulated by cytarabine in REH cells. Cytarabine reduced the phosphorylation of the major negative regulator of autophagy, mammalian target of rapamycin (mTOR, and its downstream target p70S6 kinase in REH cells, which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase. Cytarabine had no effect on the activation of mTOR inhibitor AMP-activated protein kinase. Leucine, an mTOR activator, reduced both cytarabine-induced autophagy and cytotoxicity. Accordingly, pharmacological downregulation of autophagy with bafilomycin A1 and chloroquine, or RNA interference-mediated knockdown of LC3β or p62, markedly increased oxidative stress, mitochondrial depolarization, caspase activation and subsequent DNA fragmentation and apoptotic death in cytarabine-treated REH cells. Cytarabine also induced mTOR-dependent cytoprotective autophagy in HL-60 and MOLT-4 leukemic cell lines, as well as primary leukemic cells, but not normal leukocytes. These data suggest that the therapeutic efficiency of cytarabine in leukemic patients could be increased by the inhibition of the mTOR-dependent autophagic response.

  5. Effect of calmodulin antagonists on the growth and graviresponsiveness of primary roots of maize

    Science.gov (United States)

    Stinemetz, C. L.; Hasenstein, K. H.; Young, L. M.; Evans, M. L.

    1992-01-01

    We examined the effect of calmodulin (CaM) antagonists applied at the root tip on root growth, gravity-induced root curvature, and the movement of calcium across the root tip and auxin (IAA) across the elongation zone of gravistimulated roots. All of the CaM antagonists used in these studies delayed gravity-induced curvature at a concentration (1 micromole) that did not affect root growth. Calmodulin antagonists (> or = 1 micromole) inhibited downward transport of label from 45Ca2+ across the caps of gravistimulated roots relative to the downward transport of 45Ca2+ in gravistimulated roots which were not treated with CaM antagonists. Application of CaM antagonists at the root tip (> or = 1 micromole) also decreased the relative downward movement of label from 3H-IAA applied to the upper side of the elongation zone of gravistimulated roots. In general, tip application of antagonists inhibited neither the upward transport of 45Ca2+ in the root tip nor the upward movement of label from 3H-IAA in the elongation zone of gravistimulated roots. Thus, roots treated with CaM antagonists > or = 1 micromole become less graviresponsive and exhibit reduced or even a reversal of downward polarity of calcium transport across the root tip and IAA transport across the elongation zone. The results indicate that calmodulin-regulated events play a role in root gravitropism.

  6. A sensitive HIV-1 envelope induced fusion assay identifies fusion enhancement of thrombin

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, De-Chun; Zhong, Guo-Cai; Su, Ju-Xiang [Department of Microbiology, Harbin Medical University, 194 Xuefu Road, Harbin, Heilongjiang 150081 (China); Liu, Yan-Hong [Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150081 (China); Li, Yan; Wang, Jia-Ye [Department of Microbiology, Harbin Medical University, 194 Xuefu Road, Harbin, Heilongjiang 150081 (China); Hattori, Toshio [Department of Emerging Infectious Diseases, Division of Internal Medicine, Graduate School of Medicine, Tohoku University, Sendai 9808574 (Japan); Ling, Hong, E-mail: lingh@ems.hrbmu.edu.cn [Department of Microbiology, Harbin Medical University, 194 Xuefu Road, Harbin, Heilongjiang 150081 (China); Department of Parasitology, Harbin Medical University, 194 Xuefu Road, Harbin, Heilongjiang 150081 (China); Key Lab of Heilongjiang Province for Infection and Immunity, Key Lab of Heilongjiang Province Education Bureau for Etiology, Harbin, Heilongjiang 150081 (China); Zhang, Feng-Min, E-mail: fengminzhang@yahoo.com.cn [Department of Microbiology, Harbin Medical University, 194 Xuefu Road, Harbin, Heilongjiang 150081 (China); Key Lab of Heilongjiang Province for Infection and Immunity, Key Lab of Heilongjiang Province Education Bureau for Etiology, Harbin, Heilongjiang 150081 (China)

    2010-01-22

    To evaluate the interaction between HIV-1 envelope glycoprotein (Env) and target cell receptors, various cell-cell-fusion assays have been developed. In the present study, we established a novel fusion system. In this system, the expression of the sensitive reporter gene, firefly luciferase (FL) gene, in the target cells was used to evaluate cell fusion event. Simultaneously, constitutively expressed Renilla luciferase (RL) gene was used to monitor effector cell number and viability. FL gave a wider dynamic range than other known reporters and the introduction of RL made the assay accurate and reproducible. This system is especially beneficial for investigation of potential entry-influencing agents, for its power of ruling out the false inhibition or enhancement caused by the artificial cell-number variation. As a case study, we applied this fusion system to observe the effect of a serine protease, thrombin, on HIV Env-mediated cell-cell fusion and have found the fusion enhancement activity of thrombin over two R5-tropic HIV strains.

  7. CHEF induced highly selective and sensitive turn-on fluorogenic and colorimetric sensor for Fe3+.

    Science.gov (United States)

    Goswami, Shyamaprosad; Das, Sangita; Aich, Krishnendu; Sarkar, Deblina; Mondal, Tapan Kumar; Quah, Ching Kheng; Fun, Hoong-Kun

    2013-11-14

    A new fluorescent probe was synthesized from rhodamine-6G and 6-(hydroxymethyl) picolinohydrazide for the sensing of Fe(3+) in an aqueous environment. The structure of the sensor was confirmed through its single crystal X-ray study. It exhibit