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Sample records for agonist diminishes acute

  1. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility.

  2. Diminished natriuretic response to dopamine D1 receptor agonist, SKF-38393 in obese Zucker rats.

    PubMed

    Marwaha, Aditi; Lokhandwala, Mustafa F

    2003-11-01

    Dopamine causes natriuresis and diuresis via activation of D1 receptors located on the renal proximal tubules and subsequent inhibition of the sodium transporters, Na-H exchanger and Na+/K+ ATPase. We have reported that dopamine fails to inhibit the activities of these two transporters in the obese Zucker rats (OZR). The present study was designed to examine the functional consequence of this phenomenon by determining the natriuretic and diuretic response to D1 receptor activation in lean Zucker rats (LZR) and OZR. In 11-12 week-old OZR and LZR, natriuretic and diuretic responses to intravenously administered D1 receptor agonist, SKF 38393 (3 microg/kg/min for 30 min) were measured under Inactin anesthesia. Plasma insulin and glucose levels were significantly higher in the obese rats as compared to the lean rats. Intravenous infusion of SKF 38393 caused significant increases in urine flow, urinary sodium excretion (U(Na)V), fractional excretion of sodium (FE(Na)), and glomerular filtration rate (GFR) in the lean rats. However, the natriuretic and diuretic response to SKF 38393 was markedly blunted in OZR. Infusion of SKF 38393 did not cause significant changes in the mean blood pressure and heart rate in either of the two groups. We suggest that the diminished natriuretic response to D1 receptor activation in OZR is the consequence of the previously reported defect in the D1 receptor-G-protein coupling and the failure of dopamine to inhibit the sodium transporters in these animals.

  3. 14-Alkoxy- and 14-acyloxypyridomorphinans: μ agonist/δ antagonist opioid analgesics with diminished tolerance and dependence side effects.

    PubMed

    Ananthan, Subramaniam; Saini, Surendra K; Dersch, Christina M; Xu, Heng; McGlinchey, Nicholas; Giuvelis, Denise; Bilsky, Edward J; Rothman, Richard B

    2012-10-11

    In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

  4. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

    PubMed

    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

  5. Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice

    PubMed Central

    Ringelstetter, Ashley; Khatib, Hasan; Abbott, David H.; Salih, Sana M.

    2015-01-01

    Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2–24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the “infertility index” (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse

  6. Diminishing willingness to pay per quality-adjusted life year: valuing acute foodborne illness.

    PubMed

    Haninger, Kevin; Hammitt, James K

    2011-09-01

    We design and conduct a stated-preference survey to estimate willingness to pay (WTP) to reduce foodborne risk of acute illness and to test whether WTP is proportional to the corresponding gain in expected quality-adjusted life years (QALYs). If QALYs measure utility for health, then economic theory requires WTP to be nearly proportional to changes in both health quality and duration of illness and WTP could be estimated by multiplying the expected change in QALYs by an appropriate monetary value. WTP is elicited using double-bounded, dichotomous-choice questions in which respondents (randomly selected from the U.S. general adult population, n = 2,858) decide whether to purchase a more expensive food to reduce the risk of foodborne illness. Health risks vary by baseline probability of illness, reduction in probability, duration and severity of illness, and conditional probability of mortality. The expected gain in QALYs is calculated using respondent-assessed decrements in health-related quality of life if ill combined with the duration of illness and reduction in probability specified in the survey. We find sharply diminishing marginal WTP for severity and duration of illness prevented. Our results suggest that individuals do not have a constant rate of WTP per QALY, which implies that WTP cannot be accurately estimated by multiplying the change in QALYs by an appropriate monetary value.

  7. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists.

    PubMed

    Miller, Dennis K; Lever, John R; Rodvelt, Kelli R; Baskett, James A; Will, Matthew J; Kracke, George R

    2007-07-10

    Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced (K(i)=0.74 microM) the binding of [(3)H]DAMGO [(D-Ala(2), N-ME-Phe(4), Gly(5)-ol)-enkephalin]. In a functional assay system comprised of MOR-1 mu opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC(50)=1.1 microM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1-0.3 microM) that did not have intrinsic activity attenuated ( approximately 50%) morphine-evoked [(3)H]overflow. Overall, the results suggest that lobeline functions as a mu opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction.

  8. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

    PubMed Central

    Iepsen, E W; Lundgren, J; Dirksen, C; Jensen, J-EB; Pedersen, O; Hansen, T; Madsbad, S; Holst, J J; Torekov, S S

    2015-01-01

    Background: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. Methods: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. Results: Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml−1 (−3.0 (95% confidence interval (CI)=−0.5 to −5.5)), P<0.001 and free leptin index decrease was 43% smaller; −62±15 vs −109±20 (−47 (95% CI=−11 to −83)), P<0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI=−0.6 to −4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=−0.6 to −1)), P<0.001. Fasting glucose was decreased by an additional −0.2±0.1 mmol l−1 in the GLP-1RA group in contrast to the control group, where glucose increased 0.3±0.1 mmol l−1 to the level before weight loss (−0.5mmol l−1 (95% CI=−0.1 to −0.9)), P<0.005. Meal response of peptide

  9. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. I. Acute effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of gamma-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0 degrees C. Similarly, in vitro exposure to pentobarbital (200 microM) or flunitrazepam (1 microM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)(1,4)BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity gamma-aminobutyric acidA receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter (3H)flumazenil (Ro15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift).

  10. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats#

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats ...

  11. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wis...

  12. beta2 adrenergic agonists in acute lung injury? The heart of the matter.

    PubMed

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  13. Acute and chronic head-down tail suspension diminishes cerebral perfusion in rats

    NASA Technical Reports Server (NTRS)

    Wilkerson, M. Keith; Colleran, Patrick N.; Delp, Michael D.

    2002-01-01

    The purpose of this study was to test the hypothesis that regional brain blood flow and vascular resistance are altered by acute and chronic head-down tail suspension (HDT). Regional cerebral blood flow, arterial pressure, heart rate, and vascular resistance were measured in a group of control rats during normal standing and following 10 min of HDT and in two other groups of rats after 7 and 28 days of HDT. Heart rate was not different among conditions, whereas mean arterial pressure was elevated at 10 min of HDT relative to the other conditions. Total brain blood flow was reduced from that during standing by 48, 24, and 27% following 10 min and 7 and 28 days of HDT, respectively. Regional blood flows to all cerebral tissues and the eyes were reduced with 10 min of HDT and remained lower in the eye, olfactory bulbs, left and right cerebrum, thalamic region, and the midbrain with 7 and 28 days of HDT. Total brain vascular resistance was 116, 44, and 38% greater following 10 min and 7 and 28 days of HDT, respectively, relative to that during control standing. Vascular resistance was elevated in all cerebral regions with 10 min of HDT and remained higher than control levels in most brain regions. These results demonstrate that HDT results in chronic elevations in total and regional cerebral vascular resistance, and this may be the underlying stimulus for the HDT-induced smooth muscle hypertrophy of cerebral resistance arteries.

  14. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats.

    PubMed

    Miller, Desinia B; Snow, Samantha J; Schladweiler, Mette C; Richards, Judy E; Ghio, Andrew J; Ledbetter, Allen D; Kodavanti, Urmila P

    2016-04-01

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosterone tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (P = .15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX > DEMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not observed in DEMED and ADREX rats. We demonstrate that ozone-induced peripheral metabolic effects and lung injury/inflammation are mediated through adrenal-derived stress hormones likely via the activation of stress response pathway.

  15. Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents

    PubMed Central

    Yasuda, Shin-ichiro; Tsuchida, Takuma; Oguma, Takahiro; Marley, Anna; Wennberg-Huldt, Charlotte; Hovdal, Daniel; Fukuda, Hajime; Yoneyama, Yukimi; Sasaki, Kazuyo; Johansson, Anders; Lundqvist, Sara; Brengdahl, Johan; Isaacs, Richard J.; Brown, Daniel; Geschwindner, Stefan; Benthem, Lambertus; Priest, Claire; Turnbull, Andrew

    2015-01-01

    Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents. PMID:26720709

  16. Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to β2-agonist Treatment.

    PubMed

    Koumbourlis, Anastassios C; Mastropietro, Christopher

    2015-01-01

    To present the case of a patient with persistent bronchospasm, refractory to treatment with β2-agonists, that resolved promptly with continuous inhalation of large dose (1000 mcg/hr) ipratropium bromide, and to discuss the possibility of tolerance to β2-agonists as the cause for his failure to respond to adrenergic medications. The patient had received multiple doses of albuterol, as well as subcutaneous terbutaline (0.3 mg), intravenous magnesium sulfate (1 g) and intravenous dexamethasone (10 mg) prior to his admission to the intensive care unit. He remained symptomatic despite systemic intravenous steroids, continuous intravenous terbutaline (up to 0.6 mcg/kg/min), and continuous nebulized albuterol (up to 20 mg/hr for 57 hr) followed by 49 hours of continuous levalbuterol (7 mg/hr). Due to the lack of response, all β2-agonists were discontinued at 106 hours post-admission, and he was started on large dose ipratropium bromide (1000 mcg/hr) by continuous nebulization. Clinical improvement was evident within 1 hour and complete resolution of his symptoms within 4 hours. Continuous inhalation of large dose ipratropium bromide may be an effective regimen for the treatment of patients hospitalized with acute asthma who are deemed to be nonresponsive and/or tolerant to β2-agonist therapy.

  17. Acute hypoxia diminishes the relationship between blood pressure and subarachnoid space width oscillations at the human cardiac frequency

    PubMed Central

    Wszedybyl-Winklewska, Magdalena; Wolf, Jacek; Swierblewska, Ewa; Kunicka, Katarzyna; Gruszecka, Agnieszka; Gruszecki, Marcin; Kucharska, Wieslawa; Winklewski, Pawel J.; Zabulewicz, Joanna; Guminski, Wojciech; Pietrewicz, Michal; Frydrychowski, Andrzej F.; Bieniaszewski, Leszek; Narkiewicz, Krzysztof

    2017-01-01

    Background Acute hypoxia exerts strong effects on the cardiovascular system. Heart-generated pulsatile cerebrospinal fluid motion is recognised as a key factor ensuring brain homeostasis. We aimed to assess changes in heart-generated coupling between blood pressure (BP) and subarachnoid space width (SAS) oscillations during hypoxic exposure. Methods Twenty participants were subjected to a controlled decrease in oxygen saturation (SaO2 = 80%) for five minutes. BP and heart rate (HR) were measured using continuous finger-pulse photoplethysmography, oxyhaemoglobin saturation with an ear-clip sensor, end-tidal CO2 with a gas analyser, and cerebral blood flow velocity (CBFV), pulsatility and resistive indices with Doppler ultrasound. Changes in SAS were recorded with a recently-developed method called near-infrared transillumination/backscattering sounding. Wavelet transform analysis was used to assess the relationship between BP and SAS oscillations. Results Gradual increases in systolic, diastolic BP and HR were observed immediately after the initiation of hypoxic challenge (at fifth minute +20.1%, +10.2%, +16.5% vs. baseline, respectively; all P<0.01), whereas SAS remained intact (P = NS). Concurrently, the CBFV was stable throughout the procedure, with the only increase observed in the last two minutes of deoxygenation (at the fifth minute +6.8% vs. baseline, P<0.05). The cardiac contribution to the relationship between BP and SAS oscillations diminished immediately after exposure to hypoxia (at the fifth minute, right hemisphere -27.7% and left hemisphere -26.3% vs. baseline; both P<0.05). Wavelet phase coherence did not change throughout the experiment (P = NS). Conclusions Cerebral haemodynamics seem to be relatively stable during short exposure to normobaric hypoxia. Hypoxia attenuates heart-generated BP SAS coupling. PMID:28241026

  18. [Cardiogenic pulmonary edema following β2 agonist infusion for acute, severe asthma].

    PubMed

    Bahloul, M; Chaari, A; Dammak, H; Medhioub, F; Abid, L; Chtourou, K; Rekik, N; Chelly, H; Kallel, H; Bouaziz, M

    2015-09-01

    We report the case of a severe acute pulmonary edema secondary to the administration of salbutamol to a patient admitted for severe asthma. The diagnosis of acute pulmonary edema was suspected on the clinical examination, chest radiography, biological (plasmatic Pro-BNP rate) and echocardiographic findings. Rapid improvement under dobutamine and mechanical ventilation argue in favour of cardiogenic pulmonary edema. The young age of our patient, the absence of history of cardiovascular disease and the chronology of this complication onset regarded to salbutamol infusion could suggest β2 agonist involvement in this event. The improvement of cardiac function on echocardiography and the normal results obtained with myocardial perfusion scintigraphy performed 35 days later show the left ventricular reversible dysfunction.

  19. Preclinical toxicology studies with the new dopamine agonist pergolide. Acute, subchronic, and chronic evaluations.

    PubMed

    Francis, P C; Carlson, K H; Owen, N V; Adams, E R

    1994-03-01

    Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the treatment of Parkinson's disease, was evaluated for toxicity in acute, subchronic, and chronic studies. Acute toxicity tests using oral, intravenous and intraperitoneal routes were conducted in rats, mice, rabbits, and dogs. The acute oral median lethal doses (MLD) ranged from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to 87.2 mg/kg in ICR mice. Oral doses of 20 and 25 mg/kg produced no mortality in rabbits or dogs, respectively. The MLD by the iv route ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to 37.1 mg/kg for ICR mice. The predominant signs of toxicity in the acute studies included hyperactivity, poor grooming, ptosis, aggressive behavior, increased gnawing activity, tremors, convulsions, and emesis. In the subchronic and chronic studies, Fischer 344 rats, B6C3F1 mice, and beagle dogs were administered pergolide either by gavage or in the diet for up to 1 year. Daily doses in these studies ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for dogs. The predominant treatment-related effects seen in these studies were attributable to the pharmacologic activity of pergolide. These consisted primarily of CNS-mediated clinical signs in rats and dogs, weight loss or decreased weight gain, emesis in dogs, and inhibition of lysis of corpora lutea with a corresponding increase in the weight of the uterus and ovaries. Pergolide treatment was not associated with any specific target organ toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

    PubMed Central

    2015-01-01

    Herein, the synthesis and biological evaluation of dual opioid agonists–neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds. PMID:26713106

  1. Diminished acute phase response and increased hepatic inflammation of aged rats in response to intraperitoneal injection of lipopolysaccharide.

    PubMed

    Gomez, Christian R; Acuña-Castillo, Claudio; Pérez, Claudio; Leiva-Salcedo, Elías; Riquelme, Denise M; Ordenes, Gamaliel; Oshima, Kiyoko; Aravena, Mauricio; Pérez, Viviana I; Nishimura, Sumiyo; Sabaj, Valeria; Walter, Robin; Sierra, Felipe

    2008-12-01

    Aging is associated with a deterioration of the acute phase response to inflammatory challenges. However, the nature of these defects remains poorly defined. We analyzed the hepatic inflammatory response after intraperitoneal administration of lipopolysaccharide (LPS) given to Fisher 344 rats aged 6, 15, and 22-23 months. Induction of the acute phase proteins (APPs), haptoglobin, alpha-1-acid glycoprotein, and T-kininogen was reduced and/or retarded with aging. Initial induction of interleukin-6 in aged rats was normal, but the later response was increased relative to younger counterparts. An exacerbated hepatic injury was observed in aged rats receiving LPS, as evidenced by the presence of multiple microabscesses in portal tracts, confluent necrosis, higher neutrophil accumulation, and elevated serum levels of alanine aminotransferase, relative to younger animals. Our results suggest that aged rats displayed a reduced expression of APPs and increased hepatic injury in response to the inflammatory insult.

  2. The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, does not require functional leptin receptor, serotonin, and hypothalamic POMC and CART activities in mice.

    PubMed

    Nonogaki, Katsunori; Kaji, Takao

    2016-10-01

    The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, did not require functional leptin receptor, serotonin, and hypothalamic proopiomelanocortin and cocaine amphetamine regulated transcript activities in mice, although decrease in functional hypothalamic orexin activity might be involved in the acute anorexic effect of liraglutide.

  3. Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys.

    PubMed

    Neale, R; Gerhardt, S; Liebman, J M

    1984-01-01

    It has been suggested that the neuroleptic-induced acute dyskinetic syndrome in monkeys may be a useful model of extrapyramidal dysfunction. Various drugs that have well-characterized effects on clinical extrapyramidal syndromes and on catecholaminergic, cholinergic, or GABAergic neurotransmission were assessed in dyskinesia-susceptible squirrel monkeys. Catecholamine depletors (alpha-methyl-p-tyrosine, tetrabenazine) induced the syndrome, as do dopamine (DA) receptor antagonists, and d-amphetamine reversed the effects of tetrabenazine. The haloperidol-induced syndrome was reversed by the indirectly acting DA agonists amantadine and L-dopa. Neither of the DA autoreceptor agonist TL-99 or 3-PPP elicited this syndrome, suggesting that these agents lack extrapyramidal involvement. Anticholinergics reversed haloperidol-induced dyskinesias and the cholinomimetic arecoline was capable of inducing dyskinesias. When coadministered repeatedly with haloperidol, benztropine suppressed the emergence of susceptibility to neuroleptic-induced dyskinesias. These results confirm that the acute dyskinetic syndrome in the monkey is characterized by DA deficiency and acetylcholine excess. Diazepam and baclofen, which have been reported to have some clinical benefit in tardive dyskinesia, suppressed haloperidol-induced acute dyskinesias without causing gross motor depression. Pharmacological manipulation of GABAergic pathways from striatum may constitute a fruitful approach to the treatment of dyskinetic motor disorders.

  4. Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats.

    PubMed

    Micheli, Laura; Di Cesare Mannelli, Lorenzo; Guerrini, Remo; Trapella, Claudio; Zanardelli, Matteo; Ciccocioppo, Roberto; Rizzi, Anna; Ghelardini, Carla; Calò, Girolamo

    2015-05-05

    Severe pain occurs in the context of many diseases and conditions and is a leading cause of disability. Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOP) receptor. This peptidergic system controls pain transmission and in particular spinally administered N/OFQ has robust antinociceptive properties. The aim of this study was to investigate the spinal antinociceptive properties of NOP peptide agonists after acute and subchronic treatment in rats. Doses unable to alter motor coordination were selected. UFP-112 (full NOP agonist) and UFP-113 (partial NOP agonist) were administered intrathecally (i.t.) by spinal catheterization. Acute injection of UFP-112 induced antinociceptive response at lower dosages (0.03-1nmol i.t.) compared to morphine and similar to N/OFQ. UFP-113 was effective in a 0.001-1nmol i.t. dose range. The antinociceptive effects of NOP ligands were no longer evident in rats knockout for the NOP gene, while those of morphine were maintained. The continuous spinal infusion (by osmotic pumps) of 0.1nmol/h UFP-112 and UFP-113 showed antinociceptive action comparable to 1-3nmol/h morphine or N/OFQ. The antinociceptive effect of morphine progressively decreased and was no longer significant after 6 days of treatment. Similar results were obtained with N/OFQ, UFP-112, and UFP-113. The acute i.t. injection of morphine in animals tolerant to N/OFQ and UFP-112 evoked analgesic effects. Neither morphine nor N/OFQ induced antinociceptive effects in morphine- and UFP-113-tolerant rats. In conclusion this study highlights the analgesic efficacy and potency of UFP-112 and UFP-113 underlining the relevance of NOP system in analgesia.

  5. Capitals diminished, denied, mustered and deployed. A qualitative longitudinal study of women's four year trajectories after acute health crisis, Burkina Faso

    PubMed Central

    Murray, Susan F.; Akoum, Mélanie S.; Storeng, Katerini T.

    2012-01-01

    Accumulating evidence indicates that health crises can play a key role in precipitating or exacerbating poverty. For women of reproductive age in low-income countries, the complications of pregnancy are a common cause of acute health crisis, yet investigation of longer-term dynamics set in motion by such events, and their interactions with other aspects of social life, is rare. This article presents findings from longitudinal qualitative research conducted in Burkina Faso over 2004–2010. Guided by an analytic focus on patterns of continuity and change, and drawing on recent discussions on the notion of ‘resilience’, and the concepts of ‘social capital’ and ‘bodily capital’, we explore the trajectories of 16 women in the aftermath of costly acute healthcare episodes. The synthesis of case studies shows that, in conditions of structural inequity and great insecurity, an individual's social capital ebbs and flow over time, resulting in a trajectory of multiple adaptations. Women's capacity to harness or exploit bodily capital in its various forms (beauty, youthfulness, physical strength, fertility) to some extent determines their ability to confront and overcome adversities. With this, they are able to further mobilise social capital without incurring excessive debt, or to access and accumulate significant new social capital. Temporary self-displacement, often to the parental home, is also used as a weapon of negotiation in intra-household conflict and to remind others of the value of one's productive and domestic labour. Conversely, diminished bodily capital due to the physiological impact of an obstetric event or its complications can lead to reduced opportunities, and to further disadvantage. PMID:23063215

  6. The effects of the adenosine A3 receptor agonist IB-MECA on sodium taurocholate-induced experimental acute pancreatitis.

    PubMed

    Prozorow-Krol, Beata; Korolczuk, Agnieszka; Czechowska, Grazyna; Slomka, Maria; Madro, Agnieszka; Celinski, Krzysztof

    2013-09-01

    The role of adenosine A3 receptors and their distribution in the gastrointestinal tract have been widely investigated. Most of the reports discuss their role in intestinal inflammations. However, the role of adenosine A3 receptor agonist in pancreatitis has not been well established. The aim of this study is [corrected] to evaluate the effects of the adenosine A3 receptor agonist on the course of sodium taurocholate-induced experimental acute pancreatitis (EAP). The experiments were performed on 80 male Wistar rats, 58 of which survived, subdivided into 3 groups: C--control rats, I--EAP group, and II--EAP group treated with the adenosine A3 receptor agonist IB-MECA (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide at a dose of 0.75 mg/kg b.w. i.p. at 48, 24, 12 and 1 h before and 1 h after the injection of 5% sodium taurocholate solution into the biliary-pancreatic duct. Serum for α-amylase and lipase determinations and tissue samples for morphological examinations were collected at 2, 6, and 24 h of the experiment. In the IB-MECA group, α-amylase activity was decreased with statistically high significance compared to group I. The activity of lipase was not significantly different among the experimental groups but higher than in the control group. The administration of IB-MECA attenuated the histological parameters of inflammation as compared to untreated animals. The use of A3 receptor agonist IB-MECA attenuates EAP. Our findings suggest that stimulation of adenosine A3 receptors plays a positive role in the sodium taurocholate-induced EAP in rats.

  7. Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of ...

  8. Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists.

    PubMed

    Farzin, Davood; Asghari, Ladan; Nowrouzi, Mahvash

    2002-06-01

    The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.

  9. Effects of μ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of μ-agonist efficacy and noxious stimulus intensity.

    PubMed

    Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens

    2015-02-01

    Pain is associated with stimulation of some behaviors and depression of others, and μ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six μ-agonists that varied in efficacy at μ-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All μ-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All μ-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy μ-agonist nalbuphine, but not the high-efficacy μ-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective μ-opioid analgesics and reveal distinctions between opioids based on efficacy at the μ-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.

  10. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

    PubMed Central

    Montgomery, Megan D.; Chan, Trevor; Swigart, Philip M.; Myagmar, Bat-erdene; Dash, Rajesh; Simpson, Paul C.

    2017-01-01

    Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID:28081170

  11. Differences in agonist dissociation constant estimates for 5-HT at 5-HT2-receptors: a problem of acute desensitization?

    PubMed Central

    Leff, P.; Martin, G. R.

    1988-01-01

    1. The agonist dissociation constant for 5-hydroxytryptamine (5-HT) was estimated in the guinea-pig isolated trachea by the method of receptor inactivation. The value obtained (pKA = 6.45) was significantly lower than estimates previously obtained in the rabbit aorta and rat jugular vein, although all three tissues are supposed to contain the same 5-HT2 class of receptor. 2. The antagonist dissociation constant for alpha,alpha-dimethyltryptamine was also estimated in the guinea-pig trachea. The pKB value (5.43) was not significantly different from previous estimates in the rabbit aorta and rat jugular vein, consistent with receptor homogeneity between the three tissues. 3. The effect-time profiles corresponding to individual 5-HT applications were more transient in the guinea-pig trachea than in the rabbit aorta. This difference could be accounted for using a simple model of acute receptor desensitization (Leff, 1986), assuming that the conversion of active agonist-receptor complexes into inactive ones was faster in the guinea-pig trachea than in the rabbit aorta. 4. Computer simulation of the desensitization model showed that the discrepancy of pKA estimates for 5-HT between the rabbit aorta and guinea-pig trachea could also be explained using the same rate constant difference that accounted for the difference in effect-time profiles. This analysis indicated that the estimate made in the trachea was erroneously low, whereas that made in the aorta was concluded to be correct. 5. The apparent association between transience of response and pKA estimates is discussed with particular attention to the reliability of agonist affinity estimates in receptor classification. PMID:3228675

  12. Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain

    PubMed Central

    Podolsky, Alexander T.; Sandweiss, Alexander; Hu, Jackie; Bilsky, Edward J; Cain, Jim P; Kumirov, Vlad K.; Lee, Yeon Sun; Hruby, Victor J; Vardanyan, Ruben S.; Vanderah, Todd W.

    2014-01-01

    Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids has highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Aims Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main Methods Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findings RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. Significance This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists. PMID:24084045

  13. Effects of the PPAR-α agonist fenofibrate on acute and short-term consequences of brain ischemia

    PubMed Central

    Ouk, Thavarak; Gautier, Sophie; Pétrault, Maud; Montaigne, David; Maréchal, Xavier; Masse, Isabelle; Devedjian, Jean-Christophe; Deplanque, Dominique; Bastide, Michèle; Nevière, Rémi; Duriez, Patrick; Staels, Bart; Pasquier, Florence; Leys, Didier; Bordet, Régis

    2014-01-01

    In stroke, there is an imperative need to develop disease-modifying drugs able to (1) induce neuroprotection and vasculoprotection, (2) modulate recovery and brain plasticity, and (3) limit the short-term motor and cognitive consequences. We hypothesized that fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, could exert a beneficial effect on immediate and short-term poststroke consequences related to its pleiotropic mechanisms. Rats or mice were subjected to focal ischemia to determine the effects of acute treatment by fenofibrate on (i) motor and memory impairment, (2) both cerebral and vascular compartments, (3) inflammation, (4) neurogenesis, and (5) amyloid cascade. We show that fenofibrate administration results in both neuronal and vascular protection and prevents the short-term motor and cognitive poststroke consequences by interaction with several mechanisms. Modulation of PPAR-α generates beneficial effects in the immediate poststroke consequences by mechanisms involving the interactions between polynuclear neutrophils and the vessel wall, and microglial activation. Fenofibrate modulates mechanisms involved in neurorepair and amyloid cascade. Our results suggest that PPAR-α agonists could check the key points of a potential disease-modifying effect in stroke. PMID:24398933

  14. Acute fatigue impairs neuromuscular activity of anterior cruciate ligament-agonist muscles in female team handball players.

    PubMed

    Zebis, M K; Bencke, J; Andersen, L L; Alkjaer, T; Suetta, C; Mortensen, P; Kjaer, M; Aagaard, P

    2011-12-01

    In sports, like team handball, fatigue has been associated with an increased risk of anterior cruciate ligament (ACL) injury. While effects of fatigue on muscle function are commonly assessed during maximal isometric voluntary contraction (MVC), such measurements may not relate to the muscle function during match play. The purpose of this study was to investigate the effect of muscle fatigue induced by a simulated handball match on neuromuscular strategy during a functional sidecutting movement, associated with the incidence of ACL injury. Fourteen female team handball players were tested for neuromuscular activity [electromyography (EMG)] during a sidecutting maneuver on a force plate, pre and post a simulated handball match. MVC was obtained during maximal isometric quadriceps and hamstring contraction. The simulated handball match consisted of exercises mimicking handball match activity. Whereas the simulated handball match induced a decrease in MVC strength for both the quadriceps and hamstring muscles (P<0.05), a selective decrease in hamstring neuromuscular activity was seen during sidecutting (P<0.05). This study shows impaired ACL-agonist muscle (i.e. hamstring) activity during sidecutting in response to acute fatigue induced by handball match play. Thus, screening procedures should involve functional movements to reveal specific fatigue-induced deficits in ACL-agonist muscle activation during high-risk phases of match play.

  15. The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury

    PubMed Central

    Rübig, Eva; Stypmann, Jörg; Van Slyke, Paul; Dumont, Daniel J; Spieker, Tilmann; Buscher, Konrad; Reuter, Stefan; Goerge, Tobias; Pavenstädt, Hermann; Kümpers, Philipp

    2016-01-01

    Microvascular barrier dysfunction plays a major role in the pathophysiology of acute kidney injury (AKI). Angiopoietin-1, the natural agonist ligand for the endothelial-specific Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor. Here we evaluate the efficacy of a polyethylene glycol-clustered Tie2 agonist peptide, vasculotide (VT), to protect against endothelial-cell activation with subsequent microvascular dysfunction in a murine model of ischemic AKI. Renal ischemia reperfusion injury (IRI) was induced by clamping of the renal arteries for 35 minutes. Mice were treated with VT or PEGylated cysteine before IRI. Sham-operated animals served as time-matched controls. Treatment with VT significantly reduced transcapillary albumin flux and renal tissue edema after IRI. The protective effects of VT were associated with activation of Tie2 and stabilization of its downstream effector, VE-cadherin in renal vasculature. VT abolished the decline in renal tissue blood flow, attenuated the increase of serum creatinine and blood urea nitrogen after IRI, improved recovery of renal function and markedly reduced mortality compared to PEG [HR 0.14 (95% CI 0.05–0.78) P < 0.05]. VT is inexpensive to produce, chemically stable and unrelated to any Tie2 ligands. Thus, VT may represent a novel therapy to prevent AKI in patients. PMID:26911791

  16. Acute Effects of Different Agonist and Antagonist Stretching Arrangements on Static and Dynamic Range of Motion

    PubMed Central

    Amiri-Khorasani, Mohammadtaghi; Kellis, Eleftherios

    2015-01-01

    Background: Traditionally, stretching exercises are considered as basic components of warm up aiming to prepare the musculoskeletal system for performance and to prevent injuries. Objectives: The purpose of this study was to examine the effects of different agonist and antagonist stretching arrangements within a pre-exercise warm-up on hip static (SROM) and dynamic range of motion (DROM). Materials and Methods: Sixty trained male subjects (Mean ± SD: height, 177.38 ± 6.92 cm; body mass, 68.4 ± 10.22 kg; age, 21.52 ± 1.17 years) volunteered to participate in this study. SROM was measured by V-sit test and DROM captured by a motion analysis system before and after (i) static stretching for both hip flexor and extensor muscles (SFSE), (ii) dynamic stretching for both hip flexor and extensor muscles (DFDE), (iii) static stretching for the hip flexors and dynamic stretching for hip extensors (SFDE), and (iv) dynamic stretching for the hip flexors and static stretching for hip extensors (DFSE). Results: DFSE showed a significantly higher increase in DROM and SROM than the remainder of the stretching protocols (P < 0.05). There were significant differences between DFDE with SFSE and SFDE (P < 0.05) and SFSE showed significant increase as compared to SFDE (P < 0.05). Conclusions: In conclusion, DFSE is probably the best stretching arrangement due to producing more post activation potentiation on agonist muscles and less muscle stiffness in antagonist muscles. PMID:26715975

  17. Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.

    PubMed

    Patil, Renukadevi; Szabó, Erzsébet; Fells, James I; Balogh, Andrea; Lim, Keng G; Fujiwara, Yuko; Norman, Derek D; Lee, Sue-Chin; Balazs, Louisa; Thomas, Fridtjof; Patil, Shivaputra; Emmons-Thompson, Karin; Boler, Alyssa; Strobos, Jur; McCool, Shannon W; Yates, C Ryan; Stabenow, Jennifer; Byrne, Gerrald I; Miller, Duane D; Tigyi, Gábor J

    2015-02-19

    Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.

  18. Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

    PubMed Central

    2010-01-01

    Background Liver × receptor α (LXRα) and β (LXRβ) are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), tumor necrosis factor-α, (TNF-α) and interleukin-1β (IL-1β). Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression) in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases. PMID:20175894

  19. The effect of intra-articular vanilloid receptor agonists on pain behavior measures in a murine model of acute monoarthritis

    PubMed Central

    Abdullah, Mishal; Mahowald, Maren L; Frizelle, Sandra P; Dorman, Christopher W; Funkenbusch, Sonia C; Krug, Hollis E

    2016-01-01

    Arthritis is the most common cause of disability in the US, and the primary manifestation of arthritis is joint pain that leads to progressive physical limitation, disability, morbidity, and increased health care utilization. Capsaicin (CAP) is a vanilloid agonist that causes substance P depletion by interacting with vanilloid receptor transient receptor potential V1 on small unmyelinated C fibers. It has been used topically for analgesia in osteoarthritis with variable success. Resiniferatoxin (RTX) is an ultra potent CAP analog. The aim of this study was to measure the analgesic effects of intra-articular (IA) administration of CAP and RTX in experimental acute inflammatory arthritis in mice. Evoked pain score (EPS) and a dynamic weight bearing (DWB) device were used to measure nociceptive behaviors in a murine model of acute inflammatory monoarthritis. A total of 56 C57B16 male mice underwent EPS and DWB testing – 24 nonarthritic controls and 32 mice with carrageenan-induced arthritis. The effects of pretreatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX were measured. Nociception was reproducibly demonstrated by increased EPS and reduced DWB measures in the affected limb of arthritic mice. Pretreatment with 0.001% RTX resulted in statistically significant improvement in EPS and DWB measures when compared with those observed in carrageenan-induced arthritis animals. Pretreatment with IA 0.0003% RTX and IA 0.01% CAP resulted in improvement in some but not all of these measures. The remaining 24 mice underwent evaluation following treatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX, and the results obtained were similar to that of naïve, nonarthritic mice. PMID:27574462

  20. Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

    PubMed

    Jin, Shunying; Merchant, Michael L; Ritzenthaler, Jeffrey D; McLeish, Kenneth R; Lederer, Eleanor D; Torres-Gonzalez, Edilson; Fraig, Mostafa; Barati, Michelle T; Lentsch, Alex B; Roman, Jesse; Klein, Jon B; Rane, Madhavi J

    2015-01-01

    Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a

  1. The Diminishing Apple.

    ERIC Educational Resources Information Center

    Kelly, Catherine

    2002-01-01

    Introduces the Apple Ocean activity which teaches about the diminishing natural resources of the earth including drinkable water, habitable land, and productive areas while working with fractions, ratios, and proportions. (YDS)

  2. Acute central administration of immepip, a histamine H3 receptor agonist, suppresses hypothalamic histamine release and elicits feeding behavior in rats.

    PubMed

    Chiba, Seiichi; Itateyama, Emi; Sakata, Toshiie; Yoshimatsu, Hironobu

    2009-04-06

    Histamine suppresses feeding behavior via histamine H1 receptors in the hypothalamus. This study was performed to examine whether the acute reduction of histamine release in the hypothalamus caused by immepip, a histamine H3 agonist, modulates the feeding behavior of rats. Rats had a catheter implanted in the third cerebral ventricle (i3v) and were given central injections of phosphate-buffered-saline or immepip (100-300 pmol/rat). Following the i3v administration of immepip, the rats developed dose-dependent hypokinesia within 10 min of administration. Next to hypokinesia, the rats showed significant dose-dependent feeding behavior. High-performance liquid chromatography (HPLC) confirmed the reduction in histamine release in the hypothalamus of rats following i3v administration of immepip. These results suggest that i3v administration of immepip, an H3 receptor agonist, suppresses hypothalamic histamine release and elicits feeding behavior in rats.

  3. Osthole ameliorates acute myocardial infarction in rats by decreasing the expression of inflammatory-related cytokines, diminishing MMP-2 expression and activating p-ERK.

    PubMed

    Duan, Juan; Yang, Yu; Liu, Hong; Dou, Peng-Cheng; Tan, Sheng-Yu

    2016-01-01

    Osthole, the active constituent of Cnidium monnieri extracts, has been shown to have a diverse range of pharmacological properties. In the present study, we aimed to evaluate the cardioprotective effects of osthole in a rat model of acute myocardial infarction (AMI). The rats with AMI were treated with 1, 3 and 10 mg/kg of osthole or the vehicle for 4 weeks. The infarct size of the rats with AMI was measured, and casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) activities in the rats with AMI were analyzed using commercially available kits. The nuclear factor-κB (NF-κB), tumor necrosis factor‑α (TNF-α), interleukin (IL)-1β and IL-6 levels in whole blood from rats with AMI were also detected using commercially available kits. The levels of Toll-like receptors 2/4 (TLR2/4) and nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) were also detected by RT-qPCR. Moreover, the protein expression levels of endothelial nitric oxide synthase (eNOS) and mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, cyclooxygenase-2 (COX-2), as well as matrix metalloproteinase-2 (MMP-2) were all assayed by western blot analysis. Our results revealed that osthole markedly reduced the infarct size, and the levels of CK, CK-MB, LDH and cTnT in the rats with AMI, and that these cardioprotective effects may be associated with the inhibition of inflammatory reactions, the reduction in MMP-2 activity and the activation of MAPK cascades.

  4. Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise.

    PubMed

    Sato, Shogo; Shirato, Ken; Mitsuhashi, Ryosuke; Inoue, Daisuke; Kizaki, Takako; Ohno, Hideki; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

    2013-05-01

    The aim of this study was to clarify the intracellular β2-adrenergic receptor signaling specificity in mouse slow-twitch soleus and fast-twitch tibialis anterior (TA) muscles, resulting from single-dose β2-agonist clenbuterol treatment and acute exercise. At 1, 4, and 24 h after single-dose treatment with clenbuterol or after acute running exercise, the soleus and TA muscles were isolated and subjected to analysis. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased after single-dose clenbuterol treatment and acute exercise in the soleus muscle but not in the TA muscle. Although there was no change in the phosphorylation of Akt after acute exercise in either muscle, phosphorylation of Akt in the soleus muscle increased after single-dose clenbuterol treatment, whereas that in the TA muscle remained unchanged. These results suggest that p38 MAPK and Akt pathways play a functional role in the adaptation to clenbuterol treatment and exercise, particularly in slow-twitch muscles.

  5. The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

    PubMed Central

    Israel, Heike; Neeb, Lars

    2015-01-01

    More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50–400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient. PMID:25584073

  6. PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.

    PubMed

    Nakamura, Taichi; Ito, Tetsuhide; Uchida, Masahiko; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Suzuki, Koichi; Jensen, Robert T; Takayanagi, Ryoichi

    2014-01-01

    There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation

  7. Antidepressant-like activity of EMD 386088, a 5-HT6 receptor partial agonist, following systemic acute and chronic administration to rats.

    PubMed

    Jastrzębska-Więsek, Magdalena; Siwek, Agata; Partyka, Anna; Szewczyk, Bernadeta; Sowa-Kućma, Magdalena; Wasik, Anna; Kołaczkowski, Marcin; Wesołowska, Anna

    2015-10-01

    The study was designed to examine the potency of EMD 386088, a 5-HT6 receptor partial agonist, to exert antidepressant-like properties in animal models following acute and chronic intraperitoneal administration to rats. The modified rat forced swim test (FST) was utilized to examine a potential antidepressant effect of EMD 386088 after acute treatment (30 min before the test) and three times in a 24-h administration scheme (24 h, 5 h, and 30 min prior to the FST). The olfactory bulbectomy (OB) model was used to assess its antidepressant-like properties after chronic treatment (the drug was administered once daily for 14 days). EMD 386088 showed an antidepressant-like effect in all conducted tests. Its activity in FST after its acute administration (5 mg/kg) was blocked by the selective 5-HT6 receptor antagonist SB 271046. The obtained results seem to be specific, as there was no observed locomotor stimulation by the drug given at a lower/antidepressant dose. In the three times in the 24-h treatment scheme, EMD 386088 (2.5 mg/kg) exerted antidepressant properties in FST as well as increased locomotor activity in the open field test. Chronic administration of EMD 386088 (2.5 mg/kg) significantly improved the learning deficit in OB rats without affecting performance in Sham-operated (SH) animals in the passive avoidance test, and reduced OB-related rats' locomotor hyperactivity, but did not change the number of rearing + peeping episodes. The obtained findings suggest that EMD 386088 produces antidepressant-like activity after systemic acute and chronic administration which may result from direct stimulation of 5-HT6 receptors.

  8. Differentiation syndrome in non-M3 acute myeloid leukemia treated with the retinoid X receptor agonist bexarotene.

    PubMed

    DiNardo, Courtney D; Ky, Bonnie; Vogl, Dan T; Forfia, Paul; Loren, Alison; Luger, Selina; Mato, Anthony; Tsai, Donald E

    2008-01-01

    Differentiation Syndrome, also known as all-trans retinoic acid (ATRA) syndrome, is a well-described clinical phenomenon occurring in patients with the M3 subtype of acute myeloid leukemia receiving ATRA chemotherapy. Bexarotene is a novel synthetic compound that selectively binds and activates retinoic X receptors, a subclass of retinoid receptors not targeted by ATRA. We report a patient with refractory non-M3 acute promyelocytic leukemia (AML) who developed differentiation syndrome during bexarotene monotherapy. This case emphasizes the importance of monitoring for differentiation syndrome among patients receiving retinoid therapies and demonstrates the ability of bexarotene to stimulate differentiation of leukemic blasts.

  9. Combined Mitigation of the Gastrointestinal and Hematopoietic Acute Radiation Syndromes by a Novel LPA2 Receptor-specific Non-lipid Agonist

    PubMed Central

    Patil, Renukadevi; Szabó, Erzsébet; Fells, James I.; Balogh, Andrea; Lim, Keng G.; Fujiwara, Yuko; Norman, Derek B.; Lee, Sue-Chin; Balazs, Louisa; Thomas, Fridtjof; Patil, Shivaputra; Emmons-Thompson, Karin; Boler, Alyssa; Strobos, Jur; McCool, Shannon W.; Yates, C. Ryan; Stabenow, Jennifer; Byrne, Gerrald I.; Miller, Duane D.; Tigyi, Gábor J.

    2015-01-01

    Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonists of the type 2 GPCR for lysophosphatidic acid (LPA2) 2-[4-(1,3-Dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay up to 72 hours reduced mortality of C57BL/6 mice but not in LPA2 KO mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ–H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34+ hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering of the hematopoietic acute radiation syndrome after total body irradiation. DBIBB represents the first drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system. PMID:25619933

  10. Acute repeated intracerebroventricular injections of angiotensin II reduce agonist and antagonist radioligand binding in the paraventricular nucleus of the hypothalamus and median preoptic nucleus in the rat brain.

    PubMed

    Speth, Robert C; Vento, Peter J; Carrera, Eduardo J; Gonzalez-Reily, Luz; Linares, Andrea; Santos, Kira; Swindle, Jamala D; Daniels, Derek

    2014-10-02

    Angiotensin II (Ang II) stimulates water and saline intakes when injected into the brain of rats. This arises from activation of the AT1 Ang II receptor subtype. Acute repeated injections, however, decrease the water intake response to Ang II without affecting saline intake. Previous studies provide evidence that Ang II-induced water intake is mediated via the classical G protein coupling pathway, whereas the saline intake caused by Ang II is mediated by an ERK 1/2 MAP kinase signaling pathway. Accordingly, the different behavioral response to repeated injections of Ang II may reflect a selective effect on G protein coupling. To test this hypothesis, we examined the binding of a radiolabeled agonist ((125)I-sarcosine(1) Ang II) and a radiolabeled antagonist ((125)I-sarcosine(1), isoleucine(8) Ang II) in brain homogenates and tissue sections prepared from rats given repeated injections of Ang II or vehicle. Although no treatment-related differences were found in hypothalamic homogenates, a focus on specific brain structures using receptor autoradiography, found that the desensitization treatment reduced binding of both radioligands in the paraventricular nucleus of the hypothalamus (PVN) and median preoptic nucleus (MnPO), but not in the subfornical organ (SFO). Because G protein coupling is reported to have a selective effect on agonist binding without affecting antagonist binding, these findings do not support a G protein uncoupling treatment effect. This suggests that receptor number is more critical to the water intake response than the saline intake response, or that pathways downstream from the G protein mediate desensitization of the water intake response.

  11. Effect of PPAR-β/δ agonist GW0742 treatment in the acute phase response and blood-brain barrier permeability following brain injury.

    PubMed

    Chehaibi, Khouloud; le Maire, Laura; Bradoni, Sarah; Escola, Joan Carles; Blanco-Vaca, Francisco; Slimane, Mohamed Naceur

    2017-04-01

    The systemic response to ischemic stroke is associated with the hepatic acute phase response (APR) that modulates leukocytes recruitment to the injured brain. The inappropriate recruitment of leukocytes to the brain parenchyma can result in blood-brain barrier (BBB) breakdown. Emerging data suggest that peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ) activation has a potential neuroprotective role in ischemic stroke. However, mechanisms of PPAR-β/δ mediated protection in ischemic insults remain unclear. In the present study, we determined for the first time, the effects of GW0742, a PPAR-β/δ agonist on the APR following brain injury and assessed the effects on BBB permeability and tight junction integrity via claudin-5, occludin, and zona occludens-1 expression. C57/BL6 mice were exposed to 1 hour of ischemia and received 10 minutes before reperfusion either a vehicle solution or GW0742. Hepatic expression of chemokines (C-X-C motif ligand: CXCL1, CXCL2, and CXCL10), serum amyloid A-1, tumor necrosis factor alpha, interleukin-1β, and interleukin-6 was measured, and the extent of brain and hepatic neutrophil infiltration was determined. The results showed that GW0742 treatment decreased infarct volume and edema, reactant production and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. GW0742 significantly reduced BBB leakage and metalloproteinase 9 expression and upregulated the expression of tight junction proteins. These findings may help to guide the experimental and clinical therapeutic use of PPAR-β/δ agonists against brain injury.

  12. Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists.

    PubMed

    Zhong, RuiKun; Li, Hongying; Messer, Karen; Lane, Thomas A; Zhou, Jiehua; Ball, Edward D

    2015-06-01

    This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLA-DR and CD86 expression of AML cells was observed by addition of TNF-α, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-α, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-γ release than the medium control in response to autologous AML cells. IFN-γ release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients.

  13. Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes

    PubMed Central

    Belfort-DeAguiar, Renata D.; Naik, Sarita; Hwang, Janice; Szepietowska, Barbara

    2015-01-01

    OBJECTIVE Hypoglycemia is one of the major factors limiting implementation of tight glycemic control in patients with type 1 diabetes and is associated with increased morbidity and mortality during intensive insulin treatment. β-2 Adrenergic receptor (AR) agonists have been reported to diminish nocturnal hypoglycemia; however, whether long-acting inhaled β-2 AR agonists could potentially be used to treat or prevent hypoglycemia has not been established. RESEARCH DESIGN AND METHODS Seven patients with type 1 diabetes and seven healthy control subjects received inhaled formoterol (48 μg), a highly specific β-2 AR agonist, or a placebo during a hyperinsulinemic-hypoglycemic clamp study to evaluate its capacity to antagonize the effect of insulin. In a second set of studies, five subjects with type 1 diabetes received inhaled formoterol to assess its effect as a preventive therapy for insulin-induced hypoglycemia. RESULTS During a hyperinsulinemic-hypoglycemic clamp, compared with placebo, inhaled formoterol decreased the glucose infusion rate required to maintain plasma glucose at a target level by 45–50% (P < 0.05). There was no significant effect on glucagon, epinephrine, cortisol, or growth hormone release (P = NS). Furthermore, in volunteers with type 1 diabetes 1 h after increasing basal insulin delivery twofold, glucose levels dropped to 58 ± 5 mg/dL, whereas hypoglycemia was prevented by inhaled formoterol (P < 0.001). CONCLUSIONS Inhalation of the β-2 AR–specific agonist formoterol may be useful in the prevention or treatment of acute hypoglycemia and thus may help patients with type 1 diabetes achieve optimal glucose control more safely. PMID:26153273

  14. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    SciTech Connect

    Zgoda-Pols, Joanna R.; Chowdhury, Swapan; Wirth, Mark; Milburn, Michael V.; Alexander, Danny C.; Alton, Kevin B.

    2011-08-15

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research Highlights: > Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. > MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. > 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than creatinine

  15. The PPAR-γ agonist, darglitazone, restores acute inflammatory responses to cerebral hypoxia–ischemia in the diabetic ob/ob mouse

    PubMed Central

    Kumari, Rashmi; Willing, Lisa B; Patel, Shyama D; Krady, J Kyle; Zavadoski, William J; Gibbs, E Michael; Vannucci, Susan J; Simpson, Ian A

    2010-01-01

    Diabetes is an increased risk factor for stroke and results in increased brain damage in experimental animals and humans. The precise mechanisms are unclear, but our earlier studies in the db/db mice suggested that the cerebral inflammatory response initiating recovery was both delayed and diminished in the diabetic mice compared with the nondiabetic db/+ mice. In this study, we investigated the actions of the peroxisome proliferator-activated receptor (PPAR)-γ agonist darglitazone in treating diabetes and promoting recovery after a hypoxic-ischemic (H/I) insult in the diabetic ob/ob mouse. Male ob/+ and ob/ob mice received darglitazone (1 mg/kg) for 7 days before induction of H/I. Darglitazone restored euglycemia and normalized elevated corticosterone, triglycerides, and very-low-density lipoprotein levels. Darglitazone dramatically reduced the infarct size in the ob/ob mice at 24 h of recovery compared with the untreated group (30±13% to 3.3±1.6%, n=6 to 8) but did not show any significant effect in the ob/+ mice. Microglial and astrocytic activation monitored by cytokine expression (interleukin-1β and tumor necrosis factor-α) and in situ hybridization studies (bfl1 and glial fibrillary acidic protein) suggest a biphasic inflammatory response, with darglitazone restoring the compromised proinflammatory response(s) in the diabetic mouse at 4 h but suppressing subsequent inflammatory responses at 8 and 24 h in both control and diabetic mice. PMID:19861974

  16. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates

    PubMed Central

    Krivokrysenko, Vadim I.; Toshkov, Ilia A.; Gleiberman, Anatoli S.; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K.; Narizhneva, Natalya V.; Singh, Vijay K.; Whitnall, Mark H.; Purmal, Andrei A.; Shakhov, Alexander N.; Gudkov, Andrei V.; Feinstein, Elena

    2015-01-01

    There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1–48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40–60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters. PMID:26367124

  17. The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

    PubMed

    Krivokrysenko, Vadim I; Toshkov, Ilia A; Gleiberman, Anatoli S; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K; Narizhneva, Natalya V; Singh, Vijay K; Whitnall, Mark H; Purmal, Andrei A; Shakhov, Alexander N; Gudkov, Andrei V; Feinstein, Elena

    2015-01-01

    There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

  18. TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells

    PubMed Central

    Bam, Rujuta A.; Hansen, Derek; Irrinki, Alivelu; Mulato, Andrew; Jones, Gregg S.; Hesselgesser, Joseph; Frey, Christian R.; Cihlar, Tomas

    2016-01-01

    ABSTRACT GS-9620 is a potent and selective oral Toll-like receptor 7 (TLR7) agonist that directly activates plasmacytoid dendritic cells (pDCs). GS-9620 suppressed hepatitis B virus (HBV) in animal models of chronic infection and transiently activated HIV expression ex vivo in latently infected peripheral blood mononuclear cells (PBMCs) from virally suppressed patients. Currently, GS-9620 is under clinical evaluation for treating chronic HBV infection and for reducing latent reservoirs in virally suppressed HIV-infected patients. Here, we investigated the in vitro anti-HIV-1 activity of GS-9620. GS-9620 potently inhibited viral replication in PBMCs, particularly when it was added 24 to 48 h prior to HIV infection (50% effective concentration = 27 nM). Depletion of pDCs but not other immune cell subsets from PBMC cultures suppressed GS-9620 antiviral activity. Although GS-9620 was inactive against HIV in purified CD4+ T cells and macrophages, HIV replication was potently inhibited by conditioned medium derived from GS-9620-treated pDC cultures when added to CD4+ T cells prior to infection. This suggests that GS-9620-mediated stimulation of PBMCs induced the production of a soluble factor(s) inhibiting HIV replication in trans. GS-9620-treated PBMCs primarily showed increased production of interferon alpha (IFN-α), and cotreatment with IFN-α-blocking antibodies reversed the HIV-1-inhibitory effect of GS-9620. Additional studies demonstrated that GS-9620 inhibited a postentry event in HIV replication at a step coincident with or prior to reverse transcription. The simultaneous activation of HIV-1 expression and inhibition of HIV-1 replication are important considerations for the clinical evaluation of GS-9620 since these antiviral effects may help restrict potential local HIV spread upon in vivo latency reversal. PMID:27799218

  19. The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice

    PubMed Central

    Kamens, Helen M.; Andersen, Jimena; Picciotto, Marina R.

    2010-01-01

    Background The costs associated with alcohol abuse are staggering, therefore much effort has been put into developing new pharmacological strategies to decrease alcohol abuse. Recently, the nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to decrease ethanol consumption in both humans and animal models. Methods We examined the effects of varenicline on the ataxic and sedative-hypnotic effects of ethanol. First, varenicline was administered prior to placement in a locomotor activity chamber to determine if varenicline influenced baseline locomotor activity. To determine the effect of nicotinic modulation on ethanol-induced motor incoordination, varenicline was administered 30 min prior to an acute ethanol injection and then mice were tested on the balance beam, dowel test or fixed-speed rotarod. To examine ethanol's sedative-hypnotic effects, varenicline was administered 30 min prior to 4 g/kg ethanol and the duration of loss of righting reflex (LORR) was measured. Results Varenicline markedly reduced baseline locomotor activity in C57BL/6J mice. Varenicline increased ethanol-induced ataxia when measured on the balance beam and dowel test, but had no effect when measured on the fixed-speed rotarod. Pretreatment with varenicline increased the duration of LORR. Conclusions These data provide evidence that nAChRs may be involved in the ataxic and sedative effects of ethanol. It is possible that one mechanism which could contribute to the ability of varenicline to decrease ethanol consumption may be through increasing negative behavioral effects of alcohol. PMID:20946306

  20. Dehydroepiandrosterone and a beta-agonist, energy transducers, alter antioxidant enzyme systems: influence of chronic training and acute exercise in rats.

    PubMed

    Schauer, J E; Schelin, A; Hanson, P; Stratman, F W

    1990-12-01

    We examined the influence of dehydroepiandrosterone (DHEA), a beta-agonist, and exercise training on enzymes that detoxify toxic oxygen species. Feeding 0.4% DHEA decreased hepatic cytosolic (c) selenium-dependent glutathione peroxidase (GPX), (-26%, P less than 0.0001) and increased hepatic mitochondrial (m) Mn superoxide dismutase (SOD), (+38%, P less than 0.001). DHEA decreased myocardial c-GPX (-21%, P less than 0.05) when compared to a beta-agonist (beta A; L644969 Merck and Co.) fed at 5 ppm but neither differed from the Control (C). In contrast, the beta A increased hepatic m-GPX (+25%, P less than 0.05). In skeletal muscle, DHEA and beta A decreased muscle c-GPX by 20 and 12%, respectively (P less than 0.0009). DHEA increased both muscle (+20%, P less than 0.01) and myocardial (+20%, P less than 0.05) c-glutathione S-transferase (GST) over beta A (+20%, P less than 0.01) but neither was significantly different from C. Similar to DHEA, chronic training (Tr) (1 h/day, 5 days/week at 27 m/min, 15% grade on treadmill) decreased hepatic c-GPX (-16%, P less than 0.003). Tr elevates muscle c-GPX (+36%, P less than 0.05) in C. Tr increased myocardial c-GPX by 28% in the beta A-treated rats, whereas Tr decreased myocardial c-GPX by 22% in the C (P less than 0.05, interaction). One hour of acute exercise (Ex) (70% VO2 max relative work load) decreased hepatic homogenate catalase (-12%, P less than 0.02) and increased hepatic m-Mn SOD (+28%, P less than 0.03). Ex decreased myocardial c-GST (P less than 0.05) only in the DHEA-treated rats. DHEA and Tr may improve efficiency of oxygen utilization at the tissue level with lower antioxidant enzyme activity in liver and locally protective up-regulation in muscle. beta A stresses oxygen utilization systems and liver responds by up-regulation of antioxidant enzymes. The increase in myocardial c-GPX activity in the beta A-treated group may be a protective effect against indirect catecholamine-induced myocardial necrosis which

  1. Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2).

    PubMed

    Shakhov, Alexander N; Singh, Vijay K; Bone, Frederick; Cheney, Alec; Kononov, Yevgeniy; Krasnov, Peter; Bratanova-Toshkova, Troitza K; Shakhova, Vera V; Young, Jason; Weil, Michael M; Panoskaltsis-Mortari, Angela; Orschell, Christie M; Baker, Patricia S; Gudkov, Andrei; Feinstein, Elena

    2012-01-01

    Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios.

  2. Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

    PubMed Central

    Shakhov, Alexander N.; Singh, Vijay K.; Bone, Frederick; Cheney, Alec; Kononov, Yevgeniy; Krasnov, Peter; Bratanova-Toshkova, Troitza K.; Shakhova, Vera V.; Young, Jason; Weil, Michael M.; Panoskaltsis-Mortari, Angela; Orschell, Christie M.; Baker, Patricia S.; Gudkov, Andrei; Feinstein, Elena

    2012-01-01

    Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios. PMID:22479357

  3. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial

    PubMed Central

    Smith, Fang Gao; Perkins, Gavin D; Gates, Simon; Young, Duncan; McAuley, Daniel F; Tunnicliffe, William; Khan, Zahid; Lamb, Sarah E

    2012-01-01

    Summary Background In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. Methods We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FIO2) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. Findings We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03–2·08). Interpretation Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended. Funding UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation. PMID:22166903

  4. Anxiogenic-like action of caerulein, a CCK-8 receptor agonist, in the mouse: influence of acute and subchronic diazepam treatment.

    PubMed

    Harro, J; Põld, M; Vasar, E

    1990-01-01

    Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at non-sedative doses (100 ng/kg-1 micrograms/kg i.p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 receptor. Acute treatment with low doses (0.1-0.75 mg/kg i.p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i.p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i.p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers.

  5. Social crowding stress diminishes the pituitary-adrenocortical and hypothalamic histamine response to adrenergic stimulation.

    PubMed

    Bugajski, J; Gadek-Michalska, A; Borycz, J

    1993-12-01

    Social stress of crowding almost totally reduced the rise in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a beta-adrenergic receptor agonist, after 3 and 7 day of crowding and substantially diminished that response after 14 and 21 days. Crowding stress totally abolished the increase in hypothalamic histamine induced by isoprenaline in control rats. Crowding also significantly diminished the increase in serum corticosterone evoked by clonidine, an alpha 2-adrenergic agonist, and abolished the clonidine-induced elevation in hypothalamic histamine levels. The stimulatory effect of phenylephrine, an alpha 1-adrenergic agonist, on corticosterone secretion was only moderately diminished in crowded rats. Neither phenylephrine nor crowding stress changed significantly the hypothalamic histamine levels. These results indicate that social stress of crowding considerably impairs the hypothalamic-pituitary-adrenocortical responsiveness to central beta- and alpha 2-adrenergic receptor stimulation. Crowding also abolishes the rise in hypothalamic histamine induced by beta- and alpha 2-adrenergic agonist, suggesting a role of hypothalamic histamine in the HPA adaptation to the social stress of crowding.

  6. Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats.

    PubMed

    Monti, J M; Jantos, H; Ponzoni, A; Monti, D

    1996-07-01

    The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings. BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS. It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.

  7. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas, acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist

    PubMed Central

    Uchida, Masahiko; Ito, Tetsuhide; Nakamura, Taichi; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Suzuki, Koichi; Takayanagi, Ryoichi; Jensen, Robert T.

    2014-01-01

    Objectives Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1) in acute/chronic pancreatitis, however the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues, and the effects of CX3CL1 on activated-PSCs. Methods CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues were evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated-PSCs were examined with realtime-PCR, BrdU assays and Western Blotting. Results In normal pancreas, acinar cells expressed CX3CR1 within granule-like-formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal and activated-PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1, did not induce inflammatory-genes expression in activated-PSCs, but induced proliferation. Conclusions CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis and the CX3CR1s are activated. CX3CL1 induces proliferation of activated-PSCs without increasing release of inflammatory-mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSCs proliferation in pancreatitis where CX3CL1 levels are elevated. PMID:24681877

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

    PubMed

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

    2007-03-01

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

  9. Topical application of a platelet activating factor receptor agonist suppresses phorbol ester-induced acute and chronic inflammation and has cancer chemopreventive activity in mouse skin.

    PubMed

    Sahu, Ravi P; Rezania, Samin; Ocana, Jesus A; DaSilva-Arnold, Sonia C; Bradish, Joshua R; Richey, Justin D; Warren, Simon J; Rashid, Badri; Travers, Jeffrey B; Konger, Raymond L

    2014-01-01

    Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

  10. Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice

    PubMed Central

    Allen, Amy E. Clipperton; Cragg, Cheryl L.; Wood, Alexis J.; Pfaff, Donald W.; Choleris, Elena

    2010-01-01

    Summary Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ERα) or beta (ERβ) knockout (KO) mice show that long-term inactivation of ERα decreases, while inactivation of ERβ increases, male aggression. Opposite effects were found in female αERKO and βERKO mice. The role of acute activation of ERα or ERβ in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ERβ selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15 min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: 1) effects of WAY-200070 on each sex and gonadal condition; 2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice WAY-200070 increased agonistic behaviors such as pushing down and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ERβ mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ERβ in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ERβ. Thus, acute activation of ERβ similarly mediates agonistic behavior in adult male and female CD-1 mice. PMID:20129736

  11. Dopamine D1-like receptors agonist SKF 38393 increases cFOS expression in the paraventricular nucleus of the hypothalamus--impact of acute and chronic cocaine.

    PubMed

    Chocyk, A; Czyrak, A; Wedzony, K

    2008-09-01

    The present study indicates that activation of dopamine D1-like receptors by administration of SKF 38393 leads to dose-dependent (doses: 5, 10 and 20 mg/kg) increases in the expression of cFos proteins in the rat paraventricular nucleus of the hypothalamus (PVN). This effect was abolished by administration of SCH 23390, a dopamine D1-like receptor antagonist (0.5 and 1 mg/kg, given 30 min before SKF 38393--10 mg/kg), suggesting that the apparent effect is specific for activation of dopamine D1-like receptors. Expression of cFos after SKF 38393 (10 mg/kg) was observed in some, but not all, CRF-immunoreactive neurons, as well as in small portion of oxytocin- but not vasopressin-immunoreactive neurons (double-immunofluorescence experiments). There were also certain populations of nuclei that showed expression of cFos but did not co-localize with the above markers. We also found that both acute and repeated (once daily for 5 consecutive days) exposure to cocaine (25 mg/kg) attenuated the induction of cFos expression triggered by SKF 38393 when administered 24 hours after single or the last dose of cocaine (25 mg/kg). Attenuation was observed at the same level after single and chronic exposure to cocaine, indicating a rapid functional down-regulation of dopamine D1-like receptors that are resistant to subsequent doses of cocaine. These data provide evidence for the functional role of dopamine D1-like receptors in the PVN and indicate a functional adaptation of dopamine D1-like receptors following a single dose of cocaine without further progression of adaptation or resistance of D1-like receptor-mediated genomic function in the course of repeated cocaine intake.

  12. Effect of toll-like receptor 3 agonist poly I:C on intestinal mucosa and epithelial barrier function in mouse models of acute colitis

    PubMed Central

    Zhao, Hong-Wei; Yue, Yue-Hong; Han, Hua; Chen, Xiu-Li; Lu, Yong-Gang; Zheng, Ji-Min; Hou, Hong-Tao; Lang, Xiao-Meng; He, Li-Li; Hu, Qi-Lu; Dun, Zi-Qian

    2017-01-01

    AIM To investigate potential effects of poly I:C on mucosal injury and epithelial barrier disruption in dextran sulfate sodium (DSS)-induced acute colitis. METHODS Thirty C57BL/6 mice were given either regular drinking water (control group) or 2% (w/v) DSS drinking water (model and poly I:C groups) ad libitum for 7 d. Poly I:C was administrated subcutaneously (20 μg/mouse) 2 h prior to DSS induction in mice of the poly I:C group. Severity of colitis was evaluated by disease activity index, body weight, colon length, histology and myeloperoxidase (MPO) activity, as well as the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin 17 (IL-17) and interferon-γ (IFN-γ). Intestinal permeability was analyzed by the fluorescein isothiocyanate labeled-dextran (FITC-D) method. Ultrastructural features of the colon tissue were observed under electron microscopy. Expressions of tight junction (TJ) proteins, including zo-1, occludin and claudin-1, were measured by immunohistochemistry/immunofluorescence, Western blot and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS DSS caused significant damage to the colon tissue in the model group. Administration of poly I:C dramatically protected against DSS-induced colitis, as demonstrated by less body weight loss, lower disease activity index score, longer colon length, colonic MPO activity, and improved macroscopic and histological scores. It also ameliorated DSS-induced ultrastructural changes of the colon epithelium, as observed under scanning electron microscopy, as well as FITC-D permeability. The mRNA and protein expressions of TJ protein, zo-1, occludin and claudin-1 were also found to be significantly enhanced in the poly I:C group, as determined by immunohistochemistry/immunofluorescence, Western blot and RT-qPCR. By contrast, poly I:C pretreatment markedly reversed the DSS-induced up-regulated expressions of the inflammatory cytokines TNF-α, IL-17 and IFN

  13. Suppression of acute herpetic pain-related responses by the kappa-opioid receptor agonist (-)-17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-beta-[n-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) in mice.

    PubMed

    Takasaki, Ichiro; Suzuki, Tomohiko; Sasaki, Atsushi; Nakao, Kaoru; Hirakata, Mikito; Okano, Kiyoshi; Tanaka, Toshiaki; Nagase, Hiroshi; Shiraki, Kimiyasu; Nojima, Hiroshi; Kuraishi, Yasushi

    2004-04-01

    (-)-17-Cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) is a kappa-opioid receptor agonist that has pharmacological characteristics different from typical kappa-opioid receptor agonists. This study was conducted to determine the antiallodynic and antihyperalgesic effects of TRK-820 in a mouse model of acute herpetic pain and to compare them with those of the kappa-opioid receptor agonist enadoline and the mu-opioid receptor agonist morphine. Percutaneous inoculation with herpes simplex virus type-1 induced tactile allodynia and mechanical hyperalgesia in the hind paw on the inoculated side. TRK-820 (0.01-0.1 mg/kg p.o.), enadoline (1-10 mg/kg p.o.) and morphine (5-20 mg/kg p.o.) dose dependently inhibited the allodynia and hyperalgesia, but the antiallodynic and antihyperalgesic dose of enadoline markedly decreased spontaneous locomotor activity. The antinociceptive action of TRK-820 (0.1 mg/kg) was completely antagonized by pretreatment with norbinaltorphimine, a kappa-opioid receptor antagonist, but not by naltrexone, a mu-opioid receptor antagonist. Repeated treatment with morphine (20 mg/kg, four times) resulted in the reduction of antiallodynic and antihyperalgesic effects, whereas the inhibitory potency of TRK-820 (0.1 mg/kg) was almost the same even after the fourth administration. There was no cross-tolerance in antinociceptive activities between TRK-820 and morphine. Intrathecal and intracerebroventricular, but not intraplantar, injections of TRK-820 (10-100 ng/site) suppressed the allodynia and hyperalgesia. These results suggest that TRK-820 inhibits acute herpetic pain through kappa-opioid receptors in the spinal and supraspinal levels. TRK-820 may have clinical efficacy in acute herpetic pain with enough safety margins.

  14. Impaired preprodynorphin, but not preproenkephalin, mRNA induction in the striatum of mGluR1 mutant mice in response to acute administration of the full dopamine D(1) agonist SKF-82958.

    PubMed

    Mao, Limin; Conquet, François; Wang, John Q

    2002-05-01

    Metabotropic glutamate receptor 1 (mGluR1) is highly expressed in striatonigral projection neurons of rat striatum. To define the role of mGluR1 in the regulation of striatal gene expression, the responsiveness of the three neuropeptide gene expression to a single injection of the dopamine D(1) agonist SKF-82958 was compared between mGluR1 mutant and wild-type control mice. We found that acute injection of SKF-82958 increased preprodynorphin (PPD), substance P (SP), and preproenkephalin (PPE) mRNAs in the dorsal and ventral striatum of mutant and wild-type mice in a dose-dependent manner (0.125, 0.5, and 2 mg/kg, i.p.) as revealed by quantitative in situ hybridization. However, the induction of PPD mRNA in both the dorsal and ventral striatum of mGluR1 minus sign/minus sign mice was significantly less than that of wild-type +/+ mice in response to the two higher doses of SKF-82958. In contrast to PPD, SP and PPE in the dorsal and ventral striatum of mGluR1 mutant mice were elevated to a similar level as that of wild-type mice. There were no differences in basal levels and distribution patterns of all three mRNAs between the two genotypes of mice treated with saline. These results indicate that mGluR1 selectively participates in striatonigral PPD induction in response to D(1) receptor stimulation.

  15. Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study.

    PubMed

    Altabella, Luisa; Sbriccoli, Marco; Zoratto, Francesca; Poleggi, Anna; Vinci, Ramona; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Cardone, Franco; Canese, Rossella; Adriani, Walter

    2014-01-01

    LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive and sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats' forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days), or vehicle, during adolescence (44-48 post-natal days); histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e., hippocampus, orbital prefrontal cortex), activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations.

  16. Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study

    PubMed Central

    Altabella, Luisa; Sbriccoli, Marco; Zoratto, Francesca; Poleggi, Anna; Vinci, Ramona; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Cardone, Franco; Canese, Rossella; Adriani, Walter

    2014-01-01

    LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive and sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats' forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days), or vehicle, during adolescence (44–48 post-natal days); histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e., hippocampus, orbital prefrontal cortex), activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations. PMID:25565998

  17. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    PubMed Central

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  18. Onshore rig surplus diminishes as demand rises

    SciTech Connect

    Isenberg, E.M.

    1997-09-22

    US and international onshore surplus rig supply is diminishing rapidly as rig demand in many regions continues to increase. Consequently, capital costs associated with reactivating, constructing, and refurbishing new and existing rigs are on the rise. In addition, rising operating costs are putting upward pressure on operating costs. In order to justify replacement of existing rigs, US rig day rates will need to more than double. Current rig-market indicators show that rig demand should continue to rise at current levels, or even accelerate. Day rates will have to rise to a level that justifies investments in new capacity, and with continuing rig attrition, even more rigs will have to be built to offset deletions. It is not a matter of whether this will occur, but only when. This will not necessarily threaten the operators` returns over the long-term because technological advances will continue, resulting in lower exploration and production costs. The paper discusses the drivers of increasing demand, faster recovery rates, increasing rig demand, diminishing rig supply, and escalating component costs.

  19. [Melatonin receptor agonist].

    PubMed

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.

  20. Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke

    PubMed Central

    Ichijo, Masahiko; Ishibashi, Satoru; Li, Fuying; Yui, Daishi; Miki, Kazunori; Mizusawa, Hidehiro; Yokota, Takanori

    2015-01-01

    Background and Purpose Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1) on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia. Methods In C57Bl/6 mice (n = 133) subjected to unilateral common carotid occlusion (CCAO) and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (ip) injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day); sham surgery and daily ip injection for 7 days of SEW2871 after surgery; LtCCAO and daily ip injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg); LtCCAO and daily ip injection of DMSO for 7 days after surgery; and sham surgery and daily ip injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO) 7days after the treatment termination. Neurological functions 1hour, 1, 4, and 7days and infarction volume 7days after pMCAO were evaluated. Results In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries

  1. Inflammatory nociception diminishes dopamine release and increases dopamine D2 receptor mRNA in the rat's insular cortex

    PubMed Central

    2010-01-01

    Background The insular cortex (IC) receives somatosensory afferent input and has been related to nociceptive input. It has dopaminergic terminals and D1 (D1R) -excitatory- and D2 (D2R) -inhibitory- receptors. D2R activation with a selective agonist, as well as D1R blockade with antagonists in the IC, diminish neuropathic nociception in a nerve transection model. An intraplantar injection of carrageenan and acute thermonociception (plantar test) were performed to measure the response to inflammation (paw withdrawal latency, PWL). Simultaneously, a freely moving microdyalisis technique and HPLC were used to measure the release of dopamine and its metabolites in the IC. Plantar test was applied prior, one and three hours after inflammation. Also, mRNA levels of D1 and D2R's were measured in the IC after three hours of inflammation. Results The results showed a gradual decrease in the release of dopamine, Dopac and HVA after inflammation. The decrease correlates with a decrease in PWL. D2R's increased their mRNA expression compared to the controls. In regard of D1R's, there was a decrease in their mRNA levels compared to the controls. Conclusions Our results showed that the decreased extracellular levels of dopamine induced by inflammation correlated with the level of pain-related behaviour. These results also showed the increase in dopaminergic mediated inhibition by an increase in D2R's and a decrease in D1R's mRNA. There is a possible differential mechanism regarding the regulation of excitatory and inhibitory dopaminergic receptors triggered by inflammation. PMID:21050459

  2. Activation of Cannabinoid Type Two Receptors (CB2) Diminish Inflammatory Responses in Macrophages and Brain Endothelium

    PubMed Central

    Persidsky, Yuri; Fan, Shongshan; Dykstra, Holly; Reichenbach, Nancy L.; Rom, Slava; Ramirez, Servio H.

    2016-01-01

    Chronic neuroinflammatory disorders (such as HIV associated neurodegeneration) require treatment that decreases production of inflammatory factors by activated microglia and macrophages and protection of blood brain barrier (BBB) injury secondary to activation of brain endothelium. Cannabioid type 2 receptor (CB2) is highly expressed on macrophages and brain microvasular enndothelial cells (BMVEC) and is upregulated in inflammation and HIV infection. It has been shown that CB2 activation dampened inflammatory responses in macrophages and BMVEC. In this study, we assessed by PCR array the expression of a wide range of genes increased in macrophages and BMVEC in inflammation. TNFα treatment upregulated 33 genes in primary human BMVEC, and two highly selective CB2 agonists diminished expression of 31 and 32 genes. These results were confirmed by functional assays (BBB protection after inflammatory insult and decreased migration of monocytes across BMVEC monolayers after CB2 stimulation). Similarly, CB2 stimulation in primary human macrophages led to the suppression of 35 genes out of the 50 genes upregulated by LPS. Such changes in gene expression paralleled diminished secretion of proinflammatory factors. These results indicate the potential utility of CB2 agonists for the treatment of neuroinflammation. PMID:25666933

  3. 32 CFR 776.33 - Client with diminished capacity.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 5 2012-07-01 2012-07-01 false Client with diminished capacity. 776.33 Section... Rules of Professional Conduct § 776.33 Client with diminished capacity. (a) Client with diminished capacity: (1) When a client's ability to make adequately considered decisions in connection with...

  4. 32 CFR 776.33 - Client with diminished capacity.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 5 2013-07-01 2013-07-01 false Client with diminished capacity. 776.33 Section... Rules of Professional Conduct § 776.33 Client with diminished capacity. (a) Client with diminished capacity: (1) When a client's ability to make adequately considered decisions in connection with...

  5. 32 CFR 776.33 - Client with diminished capacity.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 5 2011-07-01 2011-07-01 false Client with diminished capacity. 776.33 Section... Rules of Professional Conduct § 776.33 Client with diminished capacity. (a) Client with diminished capacity: (1) When a client's ability to make adequately considered decisions in connection with...

  6. 32 CFR 776.33 - Client with diminished capacity.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 5 2014-07-01 2014-07-01 false Client with diminished capacity. 776.33 Section... Rules of Professional Conduct § 776.33 Client with diminished capacity. (a) Client with diminished capacity: (1) When a client's ability to make adequately considered decisions in connection with...

  7. GABA receptor agonists: pharmacological spectrum and therapeutic actions.

    PubMed

    Bartholini, G

    1985-01-01

    From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by

  8. Melatonin agonists and insomnia.

    PubMed

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew

    2010-02-01

    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

  9. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised. PMID:27713285

  10. A Decade of Diminishing Sunspot Vigor

    NASA Astrophysics Data System (ADS)

    Livingston, W. C.; Penn, M.; Svalgard, L.

    2011-05-01

    1A Decade of Diminishing Sunspot Vigor William Livingston1 Matt Penn1 Leif Svalgard2 Sunspots are small dark areas on the solar disk where internal magnetism, 1500 to 3500 Gauss, has been buoyed to the surface. (Spot life times are the order of one day to a couple of weeks or more. They are thought to be dark because convection inhibits the outward transport of energy there). Their "vigor” can be described by spot area, spot brightness intensity, and magnetic field. From 2001 to 2011 we have measured field strength and brightness at the darkest position in umbrae of 1750 spots using the Zeeman splitting of the Fe 1564.8 nm line. Only one observation per spot per day is carried out during our monthly telescope time of 3-4 days average. Over this interval the temporal mean magnetic field has declined about 500 Gauss and mean spot intensity has risen about 20%. We do not understand the physical mechanism behind these changes or the effect, if any, it will have on the Earth environment. 1. wcl@noao.edu mpenn@noao.edu 2. leif@leif.org

  11. Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

    PubMed

    Papke, Roger L; Trocmé-Thibierge, Caryn; Guendisch, Daniela; Al Rubaiy, Shehd Abdullah Abbas; Bloom, Stephen A

    2011-05-01

    Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)(2)(β2)(3), (α4)(3)(β2)(2), and (α4)(2)(β2)(2)α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.

  12. Low aggregation state diminishes ferrihydrite reactivity

    NASA Astrophysics Data System (ADS)

    Braunschweig, Juliane; Heister, Katja; Meckenstock, Rainer U.

    2013-04-01

    Ferrihydrite is an abundant iron(oxy)hydroxide in soils and sediments and plays an important role in microbial iron cycling due to its high reactivity. Therefore, it is often synthesized and used in geomicrobiological and mineralogical studies. The reactivities of synthetic ferrihydrites vary between different studies and synthesis protocols. Hence, we synthesized five different ferrihydrites and characterized them with XRD, FTIR, XPS, and BET specific surface area. The reactivity of the ferrihydrite samples towards ascorbic acid was examined and compared with microbial reduction rates by Geobacter sulfurreducens. FTIR and XRD results show the presence of secondary, higher crystalline iron oxide phases like goethite and akaganeite for two samples. Consequently, those samples revealed lower biotic and abiotic reduction rates compared to pure ferrihydrite. Comparison of reduction rates with the specific surface area of all ferrihydrites showed neither correlation with abiotic reductive dissolution nor with microbial reduction. Especially one sample, characterized by a very low aggregation state and presence of secondary minerals, revealed a poor reactivity. We speculate that apart from the occurring secondary minerals also the low aggregation state played an important role. Decreasing aggregation diminishes the amount of kinks and edges on the surfaces, which are produced at contact sites in aggregates. According to dissolution theories, dissolution mainly starts at those surface defects and slows down with decreasing amount of defects. Furthermore, the non-aggregated ferrihydrite is free of micropores, a further stimulant for dissolution. Independent repetitions of experiments and syntheses according to the same protocol but without formation of secondary minerals, confirmed the low reactivity of the non-aggregated ferrihydrite. In summary, our results indicate that a decreasing aggregation state of ferrihydrite to a certain size does increase the reactivity

  13. The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin.

    PubMed

    Banki, E; Hajna, Zs; Kemeny, A; Botz, B; Nagy, P; Bolcskei, K; Toth, G; Reglodi, D; Helyes, Zs

    2014-10-01

    We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.

  14. Switching cannabinoid response from CB(2) agonists to FAAH inhibitors.

    PubMed

    Tourteau, Aurélien; Leleu-Chavain, Natascha; Body-Malapel, Mathilde; Andrzejak, Virginie; Barczyk, Amélie; Djouina, Madjid; Rigo, Benoit; Desreumaux, Pierre; Chavatte, Philippe; Millet, Régis

    2014-03-01

    A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.

  15. Biased estimates of diminishing-returns epistasis? Empirical evidence revisited.

    PubMed

    Berger, David; Postma, Erik

    2014-12-01

    Empirical evidence for diminishing fitness returns of beneficial mutations supports Fisher's geometric model. We show that a similar pattern emerges through the phenomenon of regression to the mean and that few studies correct for it. Although biases are often small, regression to the mean has overemphasized diminishing returns and will hamper cross-study comparisons unless corrected for.

  16. TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.

    PubMed

    Liu, Boyi; Fan, Lu; Balakrishna, Shrilatha; Sui, Aiwei; Morris, John B; Jordt, Sven-Eric

    2013-10-01

    Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis, and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations. L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic acid), noxious heat, and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8 completely abolished analgesia by L-menthol in all these models, although other analgesics (acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a menthol derivative that we characterized as a specific TRPM8 agonist in cultured sensory neurons and in vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L-menthol- and WS-12-induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively, with diminished side effects.

  17. Agonist-activated ion channels

    PubMed Central

    Colquhoun, David

    2006-01-01

    This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens. PMID:16402101

  18. The serotonin 5-Hydroxytryptaphan1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, stimulates sympathetic-dependent increases in venous tone during hypovolemic shock.

    PubMed

    Tiniakov, Ruslan; Scrogin, Karie E

    2006-11-01

    Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)(1A) receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of alpha(2)-adrenergic receptors, we hypothesized that the 5-HT(1A) receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of alpha(2)-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 +/- 3 mm Hg 35 min after injection, P < 0.01 versus saline) and mean circulatory filling pressure (+4.2 +/- 0.7 mm Hg, P < 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, alpha(1)-, or peripheral alpha(2)-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only alpha(1)-adrenergic receptor blockade diminished the pressor effect of the drug (P < 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of alpha(1)-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both alpha(1)- and alpha(2)-adrenergic receptors. The data suggest that 5-HT(1A) receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.

  19. Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas.

    PubMed

    Ito, Ryo; Tsujihata, Yoshiyuki; Suzuki, Masami; Miyawaki, Kazumasa; Matsuda, Kae; Takeuchi, Koji

    2016-04-01

    Sulfonylureas (SUs) are widely used insulin secretagogues, but they have adverse effects including hypoglycemia and secondary failure. Fasiglifam/TAK-875, a selective GPR40 agonist, enhances glucose-stimulated insulin secretion and improves hyperglycemia. In the present study, we compared the in vivo glucose-lowering effects of fasiglifam with SUs. The risk of secondary failure of fasiglifam and the efficacy in rats desensitized to SUs were also evaluated. Moreover, we assessed whether fasiglifam was effective when combined with SUs. In diabetic neonatally streptozotocin-induced rats 1.5 days after birth (N-STZ-1.5), oral administrations of fasiglifam (3-30 mg/kg) dose dependently improved glucose tolerance; the effect was greater than that of glibenclamide at maximal effective doses (glucose AUC: fasiglifam, -37.6%; glibenclamide, -12.3%). Although the glucose-lowering effects of glibenclamide (10 mg/kg/day) were completely diminished in N-STZ-1.5 rats after 4 weeks of treatment, effects were maintained in rats receiving fasiglifam (10 mg/kg/day), even after 15 weeks. Fasiglifam (3-10 mg/kg) was still effective in two models desensitized to SUs: 15-week glibenclamide-treated N-STZ-1.5 rats and aged Zucker diabetic fatty (ZDF) rats. Acute administration of fasiglifam (3 mg/kg) and glimepiride (10 mg/kg) in combination additively decreased glucose AUC (fasiglifam, -25.3%; glimepiride, -20.0%; combination, -43.1%). Although glimepiride (10 mg/kg) decreased plasma glucose below normal in nonfasted control rats, fasiglifam (3 mg/kg) maintained normoglycemia, and no further exaggeration of hypoglycemia was observed with combination treatment. These results indicate that GPR40 agonists could be more effective and durable than SUs. Our results also provide new insights into GPR40 pharmacology and rationale for the use of GPR40 agonists in diabetic patients with SU failure.

  20. Differential behavioral effect of the TRPM8/TRPA1 channel agonist icilin (AG-3-5).

    PubMed

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

    2007-12-01

    Molecular identification of two new transient receptor potential (TRP) channels, TRPM8 and TRPA1, has prompted an intense interest in their functional roles. We report that an acute exposure to the TRPM8/TRPA1 agonist icilin (0.01-100 microM), but not TRPV1 agonist capsaicin (10 microM), causes an atypical dose-related increase in planarian motility. This is the first demonstration of a TRPM8/TRPA1 channel subtype agonist-induced differential pharmacological effect in invertebrates and provides a novel sensitive, quantifiable end-point for studying TRP channel pharmacology.

  1. Acute and long-term effects of once-daily oral bromocriptine and a new long-acting non-ergot dopamine agonist, quinagolide, in the treatment of hyperprolactinemia: a double-blind study.

    PubMed

    Verhelst, J A; Froud, A L; Touzel, R; Wass, J A; Besser, G M; Grossman, A B

    1991-10-01

    Quinagolide (CV 205-502, Sandoz), an octahydrobenzo (g) quinoline, is a new non-ergot dopamine agonist which has specific D2 receptor activity and a long half-life, making it suitable for once-daily treatment. Recent uncontrolled reports have suggested that quinagolide may be successfully used for the clinical management of hyperprolactinemia with fewer adverse reactions than bromocriptine. This study is the first to compare quinagolide in a double-blind manner with bromocriptine, given only once-daily instead of the usual multidose regimen. In the first phase we compared, in 7 hyperprolactinemic patients, the effects over 24 h of a single oral dose of 0.05 mg quinagolide with 2.5 mg bromocriptine. Compared with placebo, both bromocriptine and quinagolide showed potent PRL-inhibiting and GH-releasing effects, with comparable effects at 24 h; no significant changes were observed in TSH, LH, FSH or cortisol. Twelve hyperprolactinemic patients were then randomized to receive either once-daily bromocriptine or quinagolide in incremental doses for a period of six months. Both drugs were found to be equally effective, and no differences were seen either in adverse reactions or PRL levels during repeated diurnal sampling. We therefore conclude that quinagolide and bromocriptine are therapeutically equivalent in long-term use, and both are equally effective when given once a day. However, some patients intolerant of bromocriptine may respond better to quinagolide, and vice versa.

  2. Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation.

    PubMed Central

    Waxman, A B; Einarsson, O; Seres, T; Knickelbein, R G; Warshaw, J B; Johnston, R; Homer, R J; Elias, J A

    1998-01-01

    Acute lung injury is a frequent and treatment-limiting consequence of therapy with hyperoxic gas mixtures. To determine if IL-11 is protective in oxygen toxicity, we compared the effects of 100% O2 on transgenic mice that overexpress IL-11 in the lung and transgene (-) controls. IL-11 markedly enhanced survival in 100% O2 with 100% of transgene (-) animals dying within 72-96 h and > 90% of transgene (+) animals surviving for more than 10 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Significant differences in copper zinc superoxide dismutase and catalase activities were not noted and the levels of total, reduced and oxidized glutathione were similar in transgene (+) and (-) animals. Glutathione reductase, glutathione peroxidase, and manganese superoxide dismutase activities were slightly higher in transgene (+) as versus (-) mice after 100% O2 exposure, and IL-11 diminished hyperoxia-induced expression of IL-1 and TNF. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-11 markedly diminished this cell death response. These studies demonstrate that IL-11 markedly diminishes hyperoxic lung injury. They also demonstrate this protection is associated with small changes in lung antioxidants, diminished hyperoxia-induced IL-1 and TNF production, and markedly suppressed hyperoxia-induced DNA fragmentation. PMID:9576762

  3. LHRH Agonists for the Treatment of Prostate Cancer: 2012

    PubMed Central

    Lepor, Herbert; Shore, Neal D

    2012-01-01

    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge (“clinical flare”) and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT. PMID:23172994

  4. LHRH Agonists for the Treatment of Prostate Cancer: 2012.

    PubMed

    Lepor, Herbert; Shore, Neal D

    2012-01-01

    The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.

  5. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  6. Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

    PubMed Central

    Perroy, Julie; Walwyn, Wendy M.; Smith, Monique L.; Vicente-Sanchez, Ana; Segura, Laura; Bana, Alia; Kieffer, Brigitte L.; Evans, Christopher J.

    2016-01-01

    Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. SIGNIFICANCE STATEMENT Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560

  7. 37 CFR 11.114 - Client with diminished capacity.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... capacity. 11.114 Section 11.114 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK... diminished capacity. (a) When a client's capacity to make adequately considered decisions in connection with... capacity, is at risk of substantial physical, financial or other harm unless action is taken and...

  8. 37 CFR 11.114 - Client with diminished capacity.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... capacity. 11.114 Section 11.114 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK... diminished capacity. (a) When a client's capacity to make adequately considered decisions in connection with... capacity, is at risk of substantial physical, financial or other harm unless action is taken and...

  9. Dopamine agonist therapy in hyperprolactinemia.

    PubMed

    Webster, J

    1999-12-01

    Introduction of the dopamine agonist bromocriptine heralded a major advance in the management of hyperprolactinemic disorders. Although its side effects of nausea, dizziness and headache and its short elimination half-life are limiting factors, its efficacy established it as a reference compound against the activity of which several dopamine agonists, like pergolide, lysuride, metergoline, terguride and dihydroergocristine, fell by the wayside. More recently, two new agents, cabergoline and quinagolide, have been introduced and appear to offer considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist, has a long plasma half-life that enables once- or twice-weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline, allowing the drug to be administered once daily. Comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. Results of a small crossover study indicate that cabergoline is better tolerated, with a trend toward activity superior to that of quinagolide. In hyperprolactinemic men and in women not seeking to become pregnant, cabergoline may be regarded as the treatment of choice.

  10. β-Adrenoreceptor agonists in the management of pain associated with renal colic: a systematic review

    PubMed Central

    Johnson, Graham David; Fakis, Apostolos; Surtees, Jane; Lennon, Robert Iain

    2016-01-01

    Objectives To determine whether β-adrenoreceptor agonists are effective analgesics for patients with renal colic through a systematic review of the literature. Setting Adult emergency departments or acute assessment units. Participants Human participants with proven or suspected renal colic. Interventions β-adrenoreceptor agonists. Outcome measures Primary: level of pain at 30 min following administration of the β-agonist. Secondary: level of pain at various time points following β-agonist administration; length of hospital stay; analgesic requirement; stone presence, size and position; degree of hydronephrosis. Results 256 records were screened and 4 identified for full-text review. No articles met the inclusion criteria. Conclusions and implications There is no evidence to support or refute the proposed use of β-agonists for analgesia in patients with renal colic. Given the biological plausibility and existing literature base, clinical trials investigating the use of β-adrenoreceptor agonists in the acute setting for treatment of the pain associated with renal colic are recommended. Trial registration number CRD42015016266. PMID:27324714

  11. Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice.

    PubMed

    Elayan, Hamzeh; Milic, Milos; Sun, Ping; Gharaibeh, Munir; Ziegler, Michael G

    2012-07-01

    Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the β(2)-agonist epinephrine more in the young. Although epinephrine and β(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the β(2)-blocking drug ICI 118551. In contrast, exercise combined with the β(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and β(2)-agonist had stopped. To test whether β(2)-agonist alone was effective, the animals that had received β(2)-blockade were then given β(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The β(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although β(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake.

  12. Melatonin receptor agonists: new options for insomnia and depression treatment.

    PubMed

    Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco

    2011-12-01

    The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.

  13. New silicon drift detector design for diminishing lateral diffusion

    NASA Astrophysics Data System (ADS)

    Hijzen, E. A.; Schooneveld, E. M.; van Eijk, C. W. E.; Hollander, R. W.

    1993-10-01

    In this paper we present a new drift detector design, which diminishes the effect of lateral diffusion. This is achieved by giving the strips a saw tooth shape. In this way a small electric field in the direction parallel to the surface and perpendicular to the drift direction is established. Therefore the electrons are confined in this direction within the length of one saw tooth. The influences of some important parameters of the saw tooth are discussed.

  14. Convenient total variation diminishing conditions for nonlinear difference schemes

    NASA Technical Reports Server (NTRS)

    Tadmor, Eitan

    1986-01-01

    Convenient conditions for nonlinear difference schemes to be total-variation diminishing (TVD) are reviewed. It is shown that such schemes share the TVD property, provided their numerical fluxes meet a certain positivity condition at extrema values but can be arbitrary otherwise. The conditions are invariant under different incremental representations of the nonlinear schemes, and thus provide a simplified generalization of the TVD conditions due to Harten and others.

  15. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia

    PubMed Central

    2014-01-01

    Background Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. Results We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Conclusions Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss. PMID:25228990

  16. Fabricating Diminishable Visual Markers for Geometric Registration in Projection Mapping.

    PubMed

    Asayama, HIrotaka; Iwai, Daisuke; Sato, Kosuke

    2017-01-24

    We propose a visual marker embedding method for the pose estimation of a projection surface to correctly map projected images onto the surface. Assuming that the surface is fabricated by a full-color or multi-material three-dimensional (3D) printer, we propose to automatically embed visual markers on the surface with mechanical accuracy. The appearance of the marker is designed such that the marker is detected by infrared cameras even when printed on a non-planar surface while its appearance can be diminished by the projection to be as imperceptible as possible to human observers. The marker placement is optimized using a genetic algorithm to maximize the number of valid viewpoints from which the pose of the object can be estimated correctly using a stereo camera system. We also propose a radiometric compensation technique to quickly diminish the marker appearance. Experimental results confirm that the pose of projection objects are correctly estimated while the appearance of the markers was diminished to an imperceptible level. At the same time, we confirmed the limitations of the current method; only one object can be handled, and pose estimation is not performed at interactive frame rates. Finally, we demonstrate the proposed technique to show that it works successfully for various surface shapes and target textures.

  17. Novel diazabicycloalkane delta opioid agonists.

    PubMed

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

    2015-09-01

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

  18. Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation

    PubMed Central

    Fraser, Graeme L; Gaudreau, Geneviève-Anne; Clarke, Paul B S; Ménard, Daniel P; Perkins, Martin N

    2000-01-01

    Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats.Subcutaneous administration of 50 μl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post-injection.Intracerebroventricular (i.c.v.) administration of the μ opioid receptor agonists, DAMGO and morphine, and the δ opioid receptor agonists, deltorphin II and SNC80, significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose-dependent manner (P<0.0001).The μ and δ agonists also significantly attenuated the antinociceptive response to acute thermal stimulation in rats (P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation.These results indicate that μ and δ opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to δ agonists in the hyperalgesia model suggests that δ opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation. PMID:10780972

  19. Reconstitution of high-affinity opioid agonist binding in brain membranes

    SciTech Connect

    Remmers, A.E.; Medzihradsky, F. )

    1991-03-15

    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  20. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.

    PubMed

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel

    2011-02-25

    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  1. Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

    PubMed Central

    Schiller, Daniela; Kanen, Jonathan W.; LeDoux, Joseph E.; Monfils, Marie-H.; Phelps, Elizabeth A.

    2013-01-01

    Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala–PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC–amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders. PMID:24277809

  2. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes.

  3. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

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

    2014-01-01

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

  4. Combination of budesonide and aminophylline diminished acute lung injury in animal model of meconium aspiration syndrome.

    PubMed

    Mokra, D; Drgova, A; Mokry, J; Bulikova, J; Pullmann, R; Durdik, P; Petraskova, M; Calkovska, A

    2008-12-01

    Combination of low-dose budesonide and low-dose aminophylline may improve lung function in reduced adverse effects compared with high-dose monotherapy. Adult rabbits intratracheally received 4 ml/kg of saline or meconium (25 mg/ml). Meconium-injured rabbits were treated at 0.5 and 2.5 h after meconium instillation by intravenous aminophylline (1.0 mg/kg), by intratracheal budesonide (0.125 mg/kg) followed by intravenous aminophylline (1.0 mg/kg), or were untreated. Although aminophylline improved some respiratory parameters, budesonide+aminophylline more effectively reduced intrapulmonary shunts and improved gas exchange, without significant cardiovascular effects. Combined treatment reduced lung edema and number of lung neutrophils to a higher extent than aminophylline alone. Both treatments reduced lung peroxidation and in vitro airway reactivity to histamine, with a better effect after aminophylline alone. Combination of budesonide and aminophylline enhanced respiratory parameters more effectively, having fewer side effects than aminophylline alone. However, no additive effect of budesonide was observed on lung peroxidation and in vitro airway reactivity.

  5. Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma

    PubMed Central

    Ramani, Vishnu C.; Zhan, Fenghuang; He, Jianbo; Barbieri, Paola; Noseda, Alessandro; Tricot, Guido; Sanderson, Ralph D.

    2016-01-01

    In most myeloma patients, even after several rounds of intensive therapy, drug resistant tumor cells survive and proliferate aggressively leading to relapse. In the present study, gene expression profiling of tumor cells isolated from myeloma patients after sequential rounds of chemotherapy, revealed for the first time that heparanase, a potent promoter of myeloma growth and progression, was elevated in myeloma cells that survived therapy. Based on this clinical data, we hypothesized that heparanase was involved in myeloma resistance to drug therapy. In several survival and viability assays, elevated heparanase expression promoted resistance of myeloma tumor cells to chemotherapy. Mechanistically, this enhanced survival was due to heparanase-mediated ERK signaling. Importantly, use of the heparanase inhibitor Roneparstat in combination with chemotherapy clearly diminished the growth of disseminated myeloma tumors in vivo. Moreover, use of Roneparstat either during or after chemotherapy diminished regrowth of myeloma tumors in vivo following therapy. These results provide compelling evidence that heparanase is a promising, novel target for overcoming myeloma resistance to therapy and that targeting heparanase has the potential to prevent relapse in myeloma and possibly other cancers. PMID:26624982

  6. Group Interaction Sustains Positive Moods and Diminishes Negative Moods.

    PubMed

    Park, Ernest S; Hinsz, Verlin B

    2015-12-01

    The social interactions of task groups were investigated for their influences on member moods. Initially, participants' received an induction of positive, negative, or neutral moods via listening to music that continued throughout the experimental session. Moods were measured after the induction. Students then made decisions on four choice dilemmas alone or as members of a four-person group. Subsequently, positive and negative moods were again measured. Positive moods of participants who worked with other group members on the task were sustained, but diminished for those working alone. Negative moods of participants working in groups diminished over time, but were sustained for those working individually. These results were interpreted in the context of motivational systems theory of group involvement (Park & Hinsz, 2006). Additionally, although there was a tendency for member moods to homogenize over assessments, this did not reach significance. Results document the affective benefits that often accompany task group interaction suggesting that group interaction has features of positive mood induction. This report highlights the need to consider social influences on affect in task settings so that group dynamics, processes, and behaviors can be better understood.

  7. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats.

    PubMed

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A

    2000-10-01

    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P < 0.001). Because the rate of alveolar fluid clearance in rats is closer to human rates, we studied beta-agonist therapy in rats, with hydrostatic pulmonary edema induced by volume overload (40% body wt infusion of Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  8. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    PubMed

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo; Taheri, Masoumeh; Komaki, Hamidreza; Etaee, Farshid

    2017-04-01

    Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB1/CB2) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB1/CB2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

  9. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    PubMed Central

    Quera Salva, M.A.; Hartley, S.

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse. PMID:23650464

  10. Reversal of endotoxic shock with the calcium channel agonist BAY k 8644

    SciTech Connect

    Ives, N.; King, J.W.; Chernow, B.; Roth, B.L.

    1986-03-05

    The hypotension and diminished myocardial function observed in sepsis and endotoxin-induced shock are difficult to overcome pharmacologically. They previously demonstrated that a down regulation of ..cap alpha../sub 1/-adrenergic receptors may contribute to the hypotension and diminished response to catecholamines seen in septic shock. They here demonstrate that the calcium channel agonist BAY k 8644 potently reverses the hypotension of experimental endotoxin (20 mg/kg Difico lipopolysaccharide) shock in rats. A dose as low as 10 ..mu..g/kg BAY k 8644 significantly elevated mean arterial pressure (MAP) in hypotensive rats. The maximum percentage increase in MAP was greater in endotoxin-treated rats compared with saline-treated controls (153% vs 120% increase respectively). BAY k 8644 also caused a dose-dependent decrease in heart rate of 37% in endotoxin-treated rats and 39% in controls. No difference in (/sup 3/H)-nitrendipine binding sites were detected comparing control and endotoxin-treated rates. These results demonstrate that calcium channel agonists might represent unique agents in pathologic states characterized by hypotension and diminished cardiac function.

  11. Dopamine receptor agonists, partial agonists and psychostimulant addiction.

    PubMed

    Pulvirenti, L; Koob, G F

    1994-10-01

    Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

  12. Inactivation of Phospholipase D Diminishes Acinetobacter baumannii Pathogenesis▿ †

    PubMed Central

    Jacobs, Anna C.; Hood, Indriati; Boyd, Kelli L.; Olson, Patrick D.; Morrison, John M.; Carson, Steven; Sayood, Khalid; Iwen, Peter C.; Skaar, Eric P.; Dunman, Paul M.

    2010-01-01

    Acinetobacter baumannii is an emerging bacterial pathogen of considerable health care concern. Nonetheless, relatively little is known about the organism's virulence factors or their regulatory networks. Septicemia and ventilator-associated pneumonia are two of the more severe forms of A. baumannii disease. To identify virulence factors that may contribute to these disease processes, genetically diverse A. baumannii clinical isolates were evaluated for the ability to proliferate in human serum. A transposon mutant library was created in a strain background that propagated well in serum and screened for members with decreased serum growth. The results revealed that disruption of A. baumannii phospholipase D (PLD) caused a reduction in the organism's ability to thrive in serum, a deficiency in epithelial cell invasion, and diminished pathogenesis in a murine model of pneumonia. Collectively, these results suggest that PLD is an A. baumannii virulence factor. PMID:20194595

  13. Social Presence Diminishes Contagious Yawning in the Laboratory

    PubMed Central

    Gallup, Andrew; Church, Allyson M.; Miller, Heather; Risko, Evan F.; Kingstone, Alan

    2016-01-01

    Contagious yawning may be a useful measure of social psychological functioning, and thus it is important to evaluate the variables influencing its expression in laboratory settings. Previous research has documented that humans yawn less frequently in crowded environments and when under direct observation, but the impact of social presence on contagious yawning remains unknown. Here we present the first study to systematically alter the degree of social presence experienced by participants in the laboratory to determine its effect on contagious yawning frequency. Our results demonstrate that both implied and actual social presence significantly diminish yawn contagion in comparison to a control condition, indicating a key social component to contagious yawning. These findings provide a framework for pursuing additional research investigating the social factors influencing contagious yawning, while also offering applications for measuring this response in laboratory settings. PMID:27112374

  14. Adaptive training diminishes distractibility in aging across species.

    PubMed

    Mishra, Jyoti; de Villers-Sidani, Etienne; Merzenich, Michael; Gazzaley, Adam

    2014-12-03

    Aging is associated with deficits in the ability to ignore distractions, which has not yet been remediated by any neurotherapeutic approach. Here, in parallel auditory experiments with older rats and humans, we evaluated a targeted cognitive training approach that adaptively manipulated distractor challenge. Training resulted in enhanced discrimination abilities in the setting of irrelevant information in both species that was driven by selectively diminished distraction-related errors. Neural responses to distractors in auditory cortex were selectively reduced in both species, mimicking the behavioral effects. Sensory receptive fields in trained rats exhibited improved spectral and spatial selectivity. Frontal theta measures of top-down engagement with distractors were selectively restrained in trained humans. Finally, training gains generalized to group and individual level benefits in aspects of working memory and sustained attention. Thus, we demonstrate converging cross-species evidence for training-induced selective plasticity of distractor processing at multiple neural scales, benefitting distractor suppression and cognitive control.

  15. [Caesarean section: History, epidemiology, and ethics to diminish its incidence].

    PubMed

    Martínez-Salazar, Gerardo Jesús; Grimaldo-Valenzuela, Pedro Mario; Vázquez-Peña, Gloria Gabriela; Reyes-Segovia, Carlos; Torres-Luna, Gabriela; Escudero-Lourdes, Gabriela Virginia

    2015-01-01

    Cesarean section has become the most performed surgery and it has been enhanced with the use of antibiotics and improvement in surgical techniques. The aim of this systematic review is to describe and clarify some historical and ethical characteristics of this surgery, pointing out some aspects about its epidemiological behavior, becoming a topic that should be treated globally, giving priority to the prevention and identification of factors that may increase the incidence rates. Today, this "epidemic" reported rates higher than fifty percent, so it is considered a worldwide public health problem. Consequently, in Mexico strategies aimed at its reduction have been implemented. However, sociocultural, economic, medicolegal and biomedical factors are aspects that may difficult this goal. As we decrease the percentage of cesarean section in nulliparous patients, we diminish the number of iterative cesarean and its associated complications. This aim must be achieved through the adherence to the guidelines which promote interest in monitoring and delivery care in health institutions of our country.

  16. Diminished P300 to physical risk in sensation seeking.

    PubMed

    Zheng, Ya; Tan, Fei; Xu, Jing; Chang, Yi; Zhang, Yuanyuan; Shen, Huijuan

    2015-04-01

    Zuckerman's theory proposes individual differences in optimal arousal and arousability level as the root of the sensation-seeking trait. The current study addressed how sensation seeking influences responses to emotional arousal at the electrophysiological level during a passive viewing task and at the psychometrical level during a self-assessment task. Electrophysiologically, high sensation seekers (HSSs) compared to low sensation seekers (LSSs) exhibited a reduced P300 for high-arousing stimuli (adventure and surreal pictures), but not for low-arousing stimuli (leisure and neutral pictures). Psychometrically, HSSs displayed a higher preference for adventure and surreal pictures whereas LSSs showed a higher preference for leisure pictures. Instead of supporting the optimal arousal hypothesis, these findings suggest that sensation seeking is associated with diminished P300 to physical risk, which may be driven by a hypoactive avoidance system in sensation seeking.

  17. The diminishing criterion model for metacognitive regulation of time investment.

    PubMed

    Ackerman, Rakefet

    2014-06-01

    According to the Discrepancy Reduction Model for metacognitive regulation, people invest time in cognitive tasks in a goal-driven manner until their metacognitive judgment, either judgment of learning (JOL) or confidence, meets their preset goal. This stopping rule should lead to judgments above the goal, regardless of invested time. However, in many tasks, time is negatively correlated with JOL and confidence, with low judgments after effortful processing. This pattern has often been explained as stemming from bottom-up fluency effects on the judgments. While accepting this explanation for simple tasks, like memorizing pairs of familiar words, the proposed Diminishing Criterion Model (DCM) challenges this explanation for complex tasks, like problem solving. Under the DCM, people indeed invest effort in a goal-driven manner. However, investing more time leads to increasing compromise on the goal, resulting in negative time-judgment correlations. Experiment 1 exposed that with word-pair memorization, negative correlations are found only with minimal fluency and difficulty variability, whereas in problem solving, they are found consistently. As predicted, manipulations of low incentives (Experiment 2) and time pressure (Experiment 3) in problem solving revealed greater compromise as more time was invested in a problem. Although intermediate confidence ratings rose during the solving process, the result was negative time-confidence correlations (Experiments 3, 4, and 5), and this was not eliminated by the opportunity to respond "don't know" (Experiments 4 and 5). The results suggest that negative time-judgment correlations in complex tasks stem from top-down regulatory processes with a criterion that diminishes with invested time.

  18. Adolescent intermittent ethanol exposure diminishes anhedonia during ethanol withdrawal in adulthood.

    PubMed

    Boutros, Nathalie; Semenova, Svetlana; Markou, Athina

    2014-06-01

    Adolescent alcohol use may interfere with neurodevelopment, increasing the likelihood of adult alcohol use disorders (AUDs). We investigated whether adolescent intermittent ethanol (AIE) exposure alters the adult reward response to ethanol. Adolescent rats were administered ethanol once (moderate exposure; Cohort 1) or three times per day (severe exposure; Cohort 2) in a 2 days on/2 days off pattern. In adulthood, subjects responded for electrical stimulation directed at the posterior lateral hypothalamus in a discrete-trial intracranial self-stimulation (ICSS) procedure that provides current-intensity thresholds as a measure of brain reward function. The effects of ethanol administration and withdrawal were assessed. Control rats showed dose-dependent threshold elevations after acute ethanol, indicating reward deficits. A majority of moderately AIE-exposed rats (Cohort 1) showed threshold lowering after ethanol, suggesting ethanol-induced reward enhancement in this sub-set of rats. Rats exposed to severe AIE (Cohort 2) showed no threshold elevation or lowering, suggesting a blunted affective ethanol response. Daily ethanol induced threshold elevations 24h after administration in control rats but not in either group of AIE-exposed rats, suggesting decreased sensitivity to the negative affective state of ethanol withdrawal. Withdrawal from a 4-day ethanol binge produced robust and enduring threshold elevations in all rats, although threshold elevations were diminished in rats exposed to severe AIE. These results indicate that AIE exposure diminished reward deficits associated with ethanol intoxication and withdrawal and may have increased ethanol-induced reward enhancement in a sub-set of rats. In humans, enhanced ethanol reward accompanied by reduced withdrawal severity may contribute to the development of AUDs.

  19. Acute Treatment of Migraine

    PubMed Central

    ÖZTÜRK, Vesile

    2013-01-01

    Migraine is one of the most frequent disabling neurological conditions with a major impact on the patient’s quality of life. Migraine has been described as a chronic disorder that characterized with attacks. Attacks are characterized by moderate–severe, often unilateral, pulsating headache attacks, typically lasting 4 to 72 hours. Migraine remains underdiagnosed and undertreated despite advances in the understanding of its pathophysiology. This article reviews management of migraine acute pharmacological treatment. Currently, for the acute treatment of migraine attacks, non-steroidal anti-inflammatory drugs (NSAIDs) and triptans (serotonin 5HT1B/1D receptor agonists) are recommended. Before intake of NSAID and triptans, metoclopramide or domperidone is useful. In very severe attacks, subcutaneous sumatriptan is first choice. The patient should be treated early in the attack, use an adequate dose and formulation of a medication. Ideally, acute therapy should be restricted to no more than 2 to 3 days per week to avoid medication overuse.

  20. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. Small molecule fluoride toxicity agonists.

    PubMed

    Nelson, James W; Plummer, Mark S; Blount, Kenneth F; Ames, Tyler D; Breaker, Ronald R

    2015-04-23

    Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride.

  2. Small Molecule Fluoride Toxicity Agonists

    PubMed Central

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  3. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

    PubMed Central

    Jaszberenyi, Miklos; Rick, Ferenc G.; Popovics, Petra; Block, Norman L.; Zarandi, Marta; Cai, Ren-Zhi; Vidaurre, Irving; Szalontay, Luca; Jayakumar, Arumugam R.; Schally, Andrew V.

    2014-01-01

    The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells. PMID:24379381

  4. Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.

    PubMed

    Yao, Chunxiang; Behring, Jessica B; Shao, Di; Sverdlov, Aaron L; Whelan, Stephen A; Elezaby, Aly; Yin, Xiaoyan; Siwik, Deborah A; Seta, Francesca; Costello, Catherine E; Cohen, Richard A; Matsui, Reiko; Colucci, Wilson S; McComb, Mark E; Bachschmid, Markus M

    2015-01-01

    Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.

  5. Diminished Response of Arctic Plants to Warming over Time

    PubMed Central

    Kremers, Kelseyann S.; Hollister, Robert D.; Oberbauer, Steven F.

    2015-01-01

    The goal of this study is to determine if the response of arctic plants to warming is consistent across species, locations and time. This study examined the impact of experimental warming and natural temperature variation on plants at Barrow and Atqasuk, Alaska beginning in 1994. We considered observations of plant performance collected from 1994–2000 “short-term” and those from 2007–2012 “long-term”. The plant traits reported are the number of inflorescences, inflorescence height, leaf length, and day of flower emergence. These traits can inform us about larger scale processes such as plant reproductive effort, plant growth, and plant phenology, and therefore provide valuable insight into community dynamics, carbon uptake, and trophic interactions. We categorized traits of all species monitored at each site into temperature response types. We then compared response types across traits, plant growth forms, sites, and over time to analyze the consistency of plant response to warming. Graminoids were the most responsive to warming and showed a positive response to temperature, while shrubs were generally the least responsive. Almost half (49%) of response types (across all traits, species, and sites combined) changed from short-term to long-term. The percent of plants responsive to warming decreased from 57% (short-term) to 46% (long-term). These results indicate that the response of plants to warming varies over time and has diminished overall in recent years. PMID:25767881

  6. Cognate HLA absence in trans diminishes human NK cell education

    PubMed Central

    Landtwing, Vanessa; Raykova, Ana; Pezzino, Gaetana; Béziat, Vivien; Graf, Claudine; Moretta, Alessandro; Capaul, Riccarda; Zbinden, Andrea; Malmberg, Karl-Johan; Chijioke, Obinna; Münz, Christian

    2016-01-01

    NK cells are innate lymphocytes with protective functions against viral infections and tumor formation. Human NK cells carry inhibitory killer cell Ig-like receptors (KIRs), which recognize distinct HLAs. NK cells with KIRs for self-HLA molecules acquire superior cytotoxicity against HLA– tumor cells during education for improved missing-self recognition. Here, we reconstituted mice with human hematopoietic cells from donors with homozygous KIR ligands or with a mix of hematopoietic cells from these homozygous donors, allowing assessment of the resulting KIR repertoire and NK cell education. We found that co-reconstitution with 2 KIR ligand–mismatched compartments did not alter the frequency of KIR-expressing NK cells. However, NK cell education was diminished in mice reconstituted with parallel HLA compartments due to a lack of cognate HLA molecules on leukocytes for the corresponding KIRs. This change in NK cell education in mixed human donor–reconstituted mice improved NK cell–mediated immune control of EBV infection, indicating that mixed hematopoietic cell populations could be exploited to improve NK cell reactivity against leukotropic pathogens. Taken together, these findings indicate that leukocytes lacking cognate HLA ligands can disarm KIR+ NK cells in a manner that may decrease HLA– tumor cell recognition but allows for improved NK cell–mediated immune control of a human γ-herpesvirus. PMID:27571408

  7. Overeducation and depressive symptoms: diminishing mental health returns to education.

    PubMed

    Bracke, Piet; Pattyn, Elise; von dem Knesebeck, Olaf

    2013-11-01

    In general, well-educated people enjoy better mental health than those with less education. As a result, some wonder whether there are limits to the mental health benefits of education. Inspired by the literature on the expansion of tertiary education, this article explores marginal mental health returns to education and studies the mental health status of overeducated people. To enhance the validity of the findings we use two indicators of educational attainment - years of education and ISCED97 categories - and two objective indicators of overeducation (the realised matches method and the job analyst method) in a sample of the working population of 25 European countries (unweighted sample N = 19,089). Depression is measured using an eight-item version of the CES-D scale. We find diminishing mental health returns to education. In addition, overeducated people report more depression symptoms. Both findings hold irrespective of the indicators used. The results must be interpreted in the light of the enduring expansion of education, as our findings show that the discussion of the relevance of the human capital perspective, and the diploma disease view on the relationship between education and modern society, is not obsolete.

  8. Investigation of the mechanism of agonist and inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-05-01

    This study investigated, for the D2 dopamine receptor, the relation between the ability of agonists and inverse agonists to stabilise different states of the receptor and their relative efficacies. Ki values for agonists were determined in competition versus the binding of the antagonist [3H]spiperone. Competition data were fitted best by a two-binding site model (with the exception of bromocriptine, for which a one-binding site model provided the best fit) and agonist affinities for the higher (Kh) (G protein-coupled) and lower affinity (Kl) (G protein-uncoupled) sites determined. Ki values for agonists were also determined in competition versus the binding of the agonist [3H]N-propylnorapomorphine (NPA) to provide a second estimate of Kh. Maximal agonist effects (Emax) and their potencies (EC50) were determined from concentration-response curves for agonist stimulation of guanosine-5'-O-(3-[32S]thiotriphosphate) ([35S]GTPgammaS) binding. The ability of agonists to stabilise the G protein-coupled state of the receptor (Kl/Kh determined from ligand-binding assays) did not correlate with either of two measures of relative efficacy (relative Emax, Kl/EC50) of agonists determined in [35S]GTPgammaS-binding assays, when the data for all of the compounds tested were analysed. For a subset of compounds, however, there was a relation between Kl/Kh and Emax. Competition-binding data versus [3H]spiperone and [3H]NPA for a range of inverse agonists were fitted best by a one-binding site model. Ki values for the inverse agonists tested were slightly lower in competition versus [3H]NPA compared to [3H]spiperone. These data do not provide support for the idea that inverse agonists act by binding preferentially to the ground state of the receptor.

  9. Magnesium Supplementation Diminishes Peripheral Blood Lymphocyte DNA Oxidative Damage in Athletes and Sedentary Young Man

    PubMed Central

    Petrović, Jelena; Stanić, Dušanka; Dmitrašinović, Gordana; Plećaš-Solarović, Bosiljka; Ignjatović, Svetlana; Batinić, Bojan; Popović, Dejana

    2016-01-01

    Sedentary lifestyle is highly associated with increased risk of cardiovascular disease, obesity, and type 2 diabetes. It is known that regular physical activity has positive effects on health; however several studies have shown that acute and strenuous exercise can induce oxidative stress and lead to DNA damage. As magnesium is essential in maintaining DNA integrity, the aim of this study was to determine whether four-week-long magnesium supplementation in students with sedentary lifestyle and rugby players could prevent or diminish impairment of DNA. By using the comet assay, our study demonstrated that the number of peripheral blood lymphocytes (PBL) with basal endogenous DNA damage is significantly higher in rugby players compared to students with sedentary lifestyle. On the other hand, magnesium supplementation significantly decreased the number of cells with high DNA damage, in the presence of exogenous H2O2, in PBL from both students and rugby players, and markedly reduced the number of cells with medium DNA damage in rugby players compared to corresponding control nonsupplemented group. Accordingly, the results of our study suggest that four-week-long magnesium supplementation has marked effects in protecting the DNA from oxidative damage in both rugby players and in young men with sedentary lifestyle. Clinical trial is registered at ANZCTR Trial Id: ACTRN12615001237572. PMID:27042258

  10. Desensitization of functional µ-opioid receptors increases agonist off-rate.

    PubMed

    Williams, John T

    2014-07-01

    Desensitization of µ-opioid receptors (MORs) develops over 5-15 minutes after the application of some, but not all, opioid agonists and lasts for tens of minutes after agonist removal. The decrease in function is receptor selective (homologous) and could result from 1) a reduction in receptor number or 2) a decrease in receptor coupling. The present investigation used photolysis of two caged opioid ligands to examine the kinetics of MOR-induced potassium conductance before and after MOR desensitization. Photolysis of a caged antagonist, carboxynitroveratryl-naloxone (caged naloxone), blocked the current induced by a series of agonists, and the time constant of decline was significantly decreased after desensitization. The increase in the rate of current decay was not observed after partial blockade of receptors with the irreversible antagonist, β-chlornaltrexamine (β-CNA). The time constant of current decay after desensitization was never more rapid than 1 second, suggesting an increased agonist off-rate rather than an increase in the rate of channel closure downstream of the receptor. The rate of G protein-coupled K(+) channel (GIRK) current activation was examined using photolysis of a caged agonist, carboxynitrobenzyl-tyrosine-[Leu(5)]-enkephalin. After acute desensitization or partial irreversible block of MORs with β-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity.

  11. In vitro fertilization outcome in women with diminished ovarian reserve

    PubMed Central

    Yun, Bo Hyon; Kim, Gieun; Park, Seon Hee; Noe, Eun Bee; Seo, Seok Kyo; Cho, SiHyun; Choi, Young Sik

    2017-01-01

    Objective This study aimed to identify factors that affect in vitro fertilization (IVF) outcomes in women with diminished ovarian reserve (DOR). Methods We reviewed 99 IVF cycles in 52 women with DOR between September 2010 and January 2015. DOR was defined as serum anti-Müllerian hormone level of <1.1 ng/dL or serum follicle-stimulating hormone level of ≥20 mIU/mL. Total 96 cycles in 50 patients were evaluated after excluding fertility preservation cases. Results The clinical pregnancy rate was 11.5% per cycle, and the total cancellation rate was 34.4%. Clinical pregnancy rate was significantly associated with the antral follicle count and the cause of the DOR. Age, serum anti-Müllerian hormone and follicle-stimulating hormone levels, antral follicle count, peak estradiol level, and the cause of DOR were significantly associated with cycle cancellation. However, history of previous ovarian surgery remained as a significant factor of clinical pregnancy (model 1: odds ratio [OR] 10.17, 95% confidence interval [CI] 1.46 to 70.84, P=0.019; model 2: OR 10.85, 95% CI 1.05 to 111.71, P=0.045). In cancellation models, idiopathic or previous chemotherapy group showed borderline significance (model 1: OR 3.76, 95% CI 0.83 to 17.04, P=0.086; model 2: OR 3.15, 95% CI 0.84 to 11.84, P=0.09). Conclusion DOR caused by previous ovarian surgery may show better pregnancy outcome, whereas that caused by chemotherapy could significantly increase the cycle cancellation rate. Furthermore, patients with DOR who previously received gonadotoxic agents may show reduced efficacy and increased risk of IVF cycle cancellation. PMID:28217671

  12. Rifaximin diminishes neutropenia following potentially lethal whole-body radiation.

    PubMed

    Jahraus, Christopher D; Schemera, Bettina; Rynders, Patricia; Ramos, Melissa; Powell, Charles; Faircloth, John; Brawner, William R

    2010-07-01

    Terrorist attacks involving radiological or nuclear weapons are a substantial geopolitical concern, given that large populations could be exposed to potentially lethal doses of radiation. Because of this, evaluating potential countermeasures against radiation-induced mortality is critical. Gut microflora are the most common source of systemic infection following exposure to lethal doses of whole-body radiation, suggesting that prophylactic antibiotic therapy may reduce mortality after radiation exposure. The chemical stability, easy administration and favorable tolerability profile of the non-systemic antibiotic, rifaximin, make it an ideal potential candidate for use as a countermeasure. This study evaluated the use of rifaximin as a countermeasure against low-to-intermediate-dose whole-body radiation in rodents. Female Wistar rats (8 weeks old) were irradiated with 550 cGy to the whole body and were evaluated for 30 d. Animals received methylcellulose, neomycin (179 mg/kg/d) or variably dosed rifaximin (150-2000 mg/kg/d) one hour after irradiation and daily throughout the study period. Clinical assessments (e.g. body weight) were made daily. On postirradiation day 30, blood samples were collected and a complete blood cell count was performed. Animals receiving high doses of rifaximin (i.e. 1000 or 2000 mg/kg/d) had a greater increase in weight from the day of irradiation to postirradiation day 30 compared with animals that received placebo or neomycin. For animals with an increase in average body weight from irradiation day within 80-110% of the group average, methylcellulose rendered an absolute neutrophil count (ANC) of 211, neomycin rendered an ANC of 334, rifaximin 300 mg/kg/d rendered an ANC of 582 and rifaximin 1000 mg/kg/d rendered an ANC of 854 (P = 0.05 for group comparison). Exposure to rifaximin after near-lethal whole-body radiation resulted in diminished levels of neutropenia.

  13. Diminishing sea ice in the western Arctic Ocean

    USGS Publications Warehouse

    Stone, R.S.; Belchansky, G.I.; Drobot, Sheldon; Douglas, D.C.; Levinson, D.H.; Waple, A.M.

    2004-01-01

    Since the advent of satellite passive microwave radiometry (1978), variations in sea ice extent and concentration have been carefully monitored from space. An estimated 7.4% decrease in sea ice extent has occurred in the last 25 yr (Johannessen et al. 2004), with recent record minima (e.g., Maslanik et al. 1999; Serreze et al. 2003) accounting for much of the decline. Comparisons between the time series of Arctic sea ice melt dynamics and snowmelt dates at the NOAA–CMDL Barrow Observatory (BRW) reveal intriguing correlations.Melt-onset dates over sea ice (Drobot and Anderson 2001) were cross correlated with the melt-date time series from BRW, and a prominent region of high correlation between snowmelt onset over sea ice and the BRW record of melt dates was approximately aligned with the climatological center of the Beaufort Sea Anticyclone (BSA). The BSA induces anticyclonic ice motion in the region, effectively forcing the Beaufort gyre. A weak gyre caused by a breakdown of the BSA diminishes transport of multiyear ice into this region (Drobot and Maslanik 2003). Similarly, the annual snow cycle at BRW varies with the position and intensity of the BSA (Stone et al. 2002, their Fig. 6). Thus, variations in the BSA appear to have far-reaching effects on the annual accumulation and subsequent melt of snow over a large region of the western Arctic.A dramatic increase in melt season duration (Belchansky et al. 2004) was also observed within the same region of high correlation between onset of melt over the ice pack and snowmelt at BRW (Fig. 5.7). By inference, this suggests linkages between factors that modulate the annual cycle of snow on land and processes that influence melting of snow and ice in the western Arctic Ocean.

  14. Iron diminishes the in vitro biological effect of vanadium.

    PubMed

    Ghio, Andrew J; Stonehuerner, Jacqueline; Soukup, Joleen M; Dailey, Lisa A; Kesic, Matthew J; Cohen, Mitchell D

    2015-06-01

    Mechanistic pathways underlying inflammatory injury following exposures to vanadium-containing compounds are not defined. We tested the postulate that the in vitro biological effect of vanadium results from its impact on iron homeostasis. Human bronchial epithelial (HBE) cells exposed to vanadyl sulfate (VOSO4) showed a time- and dose-dependent increase in vanadium relative to PBS. HBE cells exposed to VOSO4 and then exposed to ferric ammonium citrate (FAC) significantly increased intracellular iron import supporting an interaction between the two metals. Following exposure to VOSO4, there was an increase (336±73%) in RNA for divalent metal transporter 1 (DMT1), a major iron importer. With inclusion of VOSO4 in the incubation, vanadium could be measured in the nuclear and mitochondrial fractions and the supernatant. Non-heme iron in the nuclear and mitochondrial fractions were decreased immediately following VOSO4 exposure while there was an increased concentration of non-heme iron in the supernatant. Provision of excess iron inhibited changes in the concentration of this metal provoked by VOSO4 exposures. Using Amplex Red, VOSO4 was shown to significantly increase oxidant generation by HBE cells in a time- and dose-dependent manner. HBE cells pre-treated with FAC and then exposed to VOSO4 demonstrated a decreased generation of oxidants. Similarly, activation of the transcription factor NF-ĸB promoter and release of interleukin-6 and -8 were increased following VOSO4 exposure and these effects were diminished by pre-treatment with FAC. We conclude that an initiating event in biological effect after exposure to vanadyl sulfate is a loss of requisite cell iron.

  15. Human's choices in situations of time-based diminishing returns.

    PubMed Central

    Hackenberg, T D; Axtell, S A

    1993-01-01

    Three experiments examined adult humans' choices in situations with contrasting short-term and long-term consequences. Subjects were given repeated choices between two time-based schedules of points exchangeable for money: a fixed schedule and a progressive schedule that began at 0 s and increased by 5 s with each point delivered by that schedule. Under "reset" conditions, choosing the fixed schedule not only produced a point but it also reset the requirements of the progressive schedule to 0 s. In the first two experiments, reset conditions alternated with "no-reset" conditions, in which progressive-schedule requirements were independent of fixed-schedule choices. Experiment 1 entailed choices between a progressive-interval schedule and a fixed-interval schedule, the duration of which varied across conditions. Switching from the progressive- to the fixed-interval schedule was systematically related to fixed-interval size in 4 of 8 subjects, and in all subjects occurred consistently sooner in the progressive-schedule sequence under reset than under no-reset procedures. The latter result was replicated in a second experiment, in which choices between progressive- and fixed-interval schedules were compared with choices between progressive- and fixed-time schedules. In Experiment 3, switching patterns under reset conditions were unrelated to variations in intertrial interval. In none of the experiments did orderly choice patterns depend on verbal descriptions of the contingencies or on schedule-controlled response patterns in the presence of the chosen schedules. The overall pattern of results indicates control of choices by temporarily remote consequences, and is consistent with versions of optimality theory that address performance in situations of diminishing returns. PMID:8315364

  16. Multiple Levels of Degradation Diminish Hemostatic Potential of Thawed Plasma

    PubMed Central

    Matijevic, Nena; Kostousov, Vadim; Wang, Yao-Wei W.; Wade, Charles E.; Wang, Weiwei; Letourneau, Phillip; Hartwell, Elizabeth; Kozar, Rosemary; Ko, Tien; Holcomb, John B.

    2011-01-01

    Background Severe bleeding after injury requires transfusion of blood products, including fresh frozen plasma (FFP). Many centers are keeping thawed plasma (TP) ready for massively transfused patients. According to the American Association of Blood Banks Standards, TP is approved for transfusion up to 5 days after thawing, when stored at 1°C to 6°C. However, there are no clinical data analyzing the effects of the approved 5-day storage on plasma. We hypothesize that the hemostatic potential (HP) of freshly thawed (FFP-0) was superior to plasma stored for 5 days (FFP-5). Methods FFP from 30 single donors were thawed at 37°C and kept at 1°C to 6°C for 5 days. HP was evaluated at day 0 and 5 by measuring kinetics of thrombin generation (TG), kinetics of clot formation by thromboelastography, clotting factors and inhibitors, and cell-derived microparticles (MPs) by flow cytometry. Results When comparing FFP-5 to FFP-0, FFP-5 exhibited only 40% of the potential of FFP-0 for TG (6.2 nM/min vs. 14.3 nM/min, p < 0.0001), a slower clotting response via thromboelastography (reaction time: 4.3 minutes vs. 3.2 minutes, p < 0.0001) and a longer delay in reaching maximum thrombus generation (5.7 minutes vs. 4.6 minutes, p < 0.01). Diminished HP was accompanied by a significant decline in multiple coagulation proteins, including FV, VII, VIII, von Willebrand factor, and free Protein S, by up to 30%, and a decrease of 50% in MP counts. Conclusion The HP and clot forming ability of TP significantly declined with storage. Hence, freshly TP may have a greater ability to restore hemostasis and correct coagulopathy compared with FFP-5. The clinical consequences for transfused patients deserve further exploration. PMID:21217484

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

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

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

  18. Short-term desensitization of muscarinic cholinergic receptors in mouse neuroblastoma cells: selective loss of agonist low-affinity and pirenzepine high-affinity binding sites

    SciTech Connect

    Cioffi, C.L.; el-Fakahany, E.E.

    1986-09-01

    The effects of brief incubation with carbamylcholine on subsequent binding of (/sup 3/H)N-methylscopolamine were investigated in mouse neuroblastoma cells (clone N1E-115). This treatment demonstrated that the muscarinic receptors in this neuronal clone can be divided into two types; one which is readily susceptible to regulation by receptor agonists, whereas the other is resistant in this regard. In control cells, both pirenzepine and carbamylcholine interacted with high- and low-affinity subsets of muscarinic receptors. Computer-assisted analysis of the competition between pirenzepine and carbamylcholine with (/sup 3/H)N-methylscopolamine showed that the receptor sites remaining upon desensitization are composed mainly of pirenzepine low-affinity and agonist high-affinity binding sites. Furthermore, there was an excellent correlation between the ability of various muscarinic receptor agonists to induce a decrease in consequent (/sup 3/H)N-methylscopolamine binding and their efficacy in stimulating cyclic GMP synthesis in these cells. Thus, only the agonists that are known to recognize the receptor's low-affinity conformation in order to elicit increases in cyclic GMP levels were capable of diminishing ligand binding. Taken together, our present results suggest that the receptor population that is sensitive to regulation by agonists includes both the pirenzepine high-affinity and the agonist low-affinity receptor binding states. In addition, the sensitivity of these receptor subsets to rapid regulation by agonists further implicates their involvement in desensitization of muscarinic receptor-mediated cyclic GMP formation.

  19. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

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

  20. Long-term studies of dopamine agonists.

    PubMed

    Hubble, Jean P

    2002-02-26

    Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

  1. How to diminish calcium loss and muscle atrophy in space

    NASA Astrophysics Data System (ADS)

    Gorgolewski, S.

    perfect relaxation when asleep or awake. We have to check in space if we can thus diminish the use of medicaments or even eliminate them. Slow Yoga exercises decrease also the amount on food required because life is not so energy demanding in space as it is here under the earth's gravitation. We can stay lean and healthy with such static yet most effective physical exercises. In addition it gives us for free a vegetarian life style, just another benefit so useful in space travel.

  2. Intestinal genetic inactivation of caspase-8 diminishes migration of enterocytes

    PubMed Central

    Kaemmerer, Elke; Kuhn, Paula; Schneider, Ursula; Jeon, Min Kyung; Klaus, Christina; Schiffer, Miriam; Weisner, Danika; Liedtke, Christian; Jäkel, Jörg; Kennes, Lieven Nils; Hilgers, Ralf-Dieter; Wagner, Norbert; Gassler, Nikolaus

    2015-01-01

    AIM: To verify the hypothesis that caspase-8 (Casp8), which regulates cellular apoptosis and necroptosis, is critically involved in enterocyte migration. METHODS: Casp8-silenced Caco2 cells were used in migration assays. In addition, enterocyte-specific Casp8 heterozygous (Casp8+/∆int) or homozygous knockout mice (Casp8∆int) were generated by crossing genetically modified mice carrying loxP recombination sites in intron 2 and 4 of the murine Casp8 gene with transgenic animals expressing a cre-transgene under control of the villin promoter in a pure C57/BL6 genetic background. The nucleoside analog BrdU was injected i.p. in male Casp8+/∆int and Casp8∆int animals 4 h, 20 h, or 40 h before performing morphometric studies. Locations of anti-BrdU-immunostained cells (cellmax) in at least 50 hemi-crypts of 6 histoanatomically distinct intestinal mucosal regions were numbered and extracted for statistical procedures. For the mice cohort (n = 28), the walking distance of enterocytes was evaluated from cellmax within crypt (n = 57), plateau (n = 19), and villus (n = 172) positions, resulting in a total of 6838 observations. Data analysis was performed by fitting a three-level mixed effects model to the data. RESULTS: In cell culture experiments with Caco2 cells, Casp8 knockdown efficiency mediated by RNA interference on Casp8 transcripts was 80% controlled as determined by Western blotting. In the scratch assay, migration of Casp8-deleted Caco2 cells was significantly diminished when compared with controls (Casp8∆scramble and Caco2). In BrdU-labeled Casp8∆int mice, cellmax locations were found along the hemi-crypts in a lower position than it was for Casp8+/∆int or control (cre-negative) animals. Statistical data analysis with a three-level mixed effects model revealed that in the six different intestinal locations (distinct segments of the small and large intestine), cell movement between the three mice groups differed widely. Especially in duodenal hemi

  3. Diminished Baroreflex Control of Forearm Vascular Resistance Following Training

    NASA Technical Reports Server (NTRS)

    Mack, G. W.; Thompson, C. A.; Doerr, D. F.; Nadel, E. R.; Convertino, V. A.

    1991-01-01

    The stimulus-response characteristics of cardiopulmonary baroreflex control of forearm vascular resistance (FVR units in mm Hg x min x I00 ml/ml) were studied in 14 volunteers before and after 10 wk of endurance training. We assessed the relationship betaleen reflex stimulus (changes in central venous pressure, CVP) and response (FVR) during unloading of cardiopulmonary baroreceptors with lower body negative pressure (LBNP, 0 to - 2O mm Hg). Changes in CVP during LBNP were estimated from pressure changes in a large peripheral vein in the dependent arm of the subject in the right lateral decubitus position. Maximal oxygen uptake (VO(sub 2max)) and total blood volume increased with endurance training from 37.8 +/- 1.4 ml/min x kg and 63.6 +/- 2.1 ml/kg to 45.3 +/- 1.4 ml/ min x kg and 69.3 +/- 2.8 ml/kg respectively (P less than 0.05). Reflex forearm vasoconstriction occurred in response to a reduction in estimated CVP, and the absolute change in FVR per unit of CVP was reduced from -5.96 +/- 0.79 to -4.06 +/- 0.52 units x mm/ Hg (P less than 0.05) following exercise training but was unchanged from -6.10 to 0.57 to -6.22 +/- 0.94 units x mm/ Hg for the time control group (N = 7). Resting values for FVR were similar before and after exercise training; however, resting estimated CVP was elevated from 9.5 +/- 0.5 mm x Hg before training to 11.3 +/- 0.6 mm x Hg after training. The reduction in sensitivity of the cardiopulmonary baroreflex control of FVR was linearly related to the increase in blood volume (r = 0.65, P less than 0.05). suggesting that diminished cardiopulmonary baroreflex control of FVR in physically fit individuals is related, in part, to a training-induced blood volume expansion.

  4. Apoptosis inhibitor of macrophage (AIM) diminishes lipid droplet-coating proteins leading to lipolysis in adipocytes

    SciTech Connect

    Iwamura, Yoshihiro; Mori, Mayumi; Nakashima, Katsuhiko; Mikami, Toshiyuki; Murayama, Katsuhisa; Arai, Satoko; Miyazaki, Toru

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer AIM induces lipolysis in a distinct manner from that of hormone-dependent lipolysis. Black-Right-Pointing-Pointer AIM ablates activity of peroxisome proliferator-activated receptor in adipocytes. Black-Right-Pointing-Pointer AIM reduces mRNA levels of lipid-droplet coating proteins leading to lipolysis. -- Abstract: Under fasting conditions, triacylglycerol in adipose tissue undergoes lipolysis to supply fatty acids as energy substrates. Such lipolysis is regulated by hormones, which activate lipases via stimulation of specific signalling cascades. We previously showed that macrophage-derived soluble protein, AIM induces obesity-associated lipolysis, triggering chronic inflammation in fat tissue which causes insulin resistance. However, the mechanism of how AIM mediates lipolysis remains unknown. Here we show that AIM induces lipolysis in a manner distinct from that of hormone-dependent lipolysis, without activation or augmentation of lipases. In vivo and in vitro, AIM did not enhance phosphorylation of hormone-sensitive lipase (HSL) in adipocytes, a hallmark of hormone-dependent lipolysis activation. Similarly, adipose tissue from obese AIM-deficient and wild-type mice showed comparable HSL phosphorylation. Consistent with the suppressive effect of AIM on fatty acid synthase activity, the amount of saturated and unsaturated fatty acids was reduced in adipocytes treated with AIM. This response ablated transcriptional activity of peroxisome proliferator-activated receptor (PPAR{gamma}), leading to diminished gene expression of lipid-droplet coating proteins including fat-specific protein 27 (FSP27) and Perilipin, which are indispensable for triacylglycerol storage in adipocytes. Accordingly, the lipolytic effect of AIM was overcome by a PPAR{gamma}-agonist or forced expression of FSP27, while it was synergized by a PPAR{gamma}-antagonist. Overall, distinct modes of lipolysis appear to take place in different physiological

  5. Hematopoietic myeloid cell differentiation diminishes nucleotide excision repair.

    PubMed

    Aoki, Yuki; Sato, Ayako; Mizutani, Shuki; Takagi, Masatoshi

    2014-09-01

    Myeloid cell differentiation is the process by which stem cells develop into mature monocytes or granulocytes. This process is achieved by the sequential activation of variety of genes. Disruption of this process can result in immunodeficiency, bone marrow failure syndrome, or leukemia. Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation and can be treated by a combination of all-trans retinoic acid (ATRA) and anthracycline. This treatment can induce leukemic cell differentiation, leading to extremely high remission rates. XAB2, a molecule involved in nucleotide excision repair (NER), is downregulated during granulocyte differentiation and shows reduced expression in NB4 APL-derived cells in vitro. Differentiation of APL by ATRA treatment reduced XAB2 expression levels in vivo. These observations suggest that cellular differentiation is associated with reduced NER activity and provides new insights into combined differentiation induction. NB4 cells were more susceptible than the immature myeloid leukemic cell lines, Kasumi-3 and Kasumi-1, to the DNA interstrand crosslinking agent cisplatin.

  6. The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.

    PubMed

    Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G

    2011-01-13

    β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

  7. Diminishing Apoptosis by Deletion of Bax or Overexpression of Bcl-2 Does Not Protect against Infectious Prion Toxicity In Vivo

    PubMed Central

    Steele, Andrew D.; King, Oliver D.; Jackson, Walker S.; Hetz, Claudio A.; Borkowski, Andrew W.; Thielen, Peter; Wollmann, Robert; Lindquist, Susan

    2008-01-01

    B-cell lymphoma protein 2 (Bcl-2) and Bcl-2-associated X protein (Bax), key antiapoptotic and proapoptotic proteins, respectively, have important roles in acute and chronic models of neurologic disease. Several studies have implicated Bax and Bcl-2 in mediating neurotoxicity in prion diseases. To determine whether diminishing apoptotic cell death is protective in an infectious prion disease model we inoculated mice that either were null for proapoptotic Bax or overexpressed antiapoptotic Bcl-2. Interestingly, genetic manipulation of apoptosis did not lessen the clinical severity of disease. Moreover, some disease parameters, such as behavioral alterations and death, occurred slightly earlier in mice that are null for Bax or overexpress Bcl-2. These results suggest that Bax and Bcl-2 mediated apoptotic pathways are not the major contributing factor to the clinical or pathological features of infectious prion disease. PMID:18032675

  8. Effects of trophic poisoning with methylmercury on the appetitive elements of the agonistic sequence in fighting-fish (Betta splendens).

    PubMed

    Gouveia, Amauri; de Oliveira, Caio Maximino; Romão, Cynthia Ferreira; de Brito, Thiago Marques; Ventura, Dora Fix

    2007-11-01

    The aggressive display in Betta splendens is particularly prominent, and vital to its adaptation to the environment. Methylmercury is an organic variation of Hg that presents particularly pronounced neuro-behavioral effects. The present experiments aim to test the effect of acute and chronic poisoning with methylmercury on the display in Bettas. The animals were poisoned by trophic means in both experiments (16 ug/kg in acute poisoning; 16 ug/kg/day for chronic poisoning), and tested in agonistic pairs. The total frequency of the display was recorded, analyzing the topography of the agonistic response. The methylmercury seems to present a dose- and detoxification-dependent effect on these responses, with a more pronounced effect on motivity in acute poisoning and on emotionality in the chronic poisoning. It is possible that this effect could be mediated by alteration in the mono-amino-oxidase systems.

  9. The safety and tolerability of GLP-1 receptor agonists in the treatment of type-2 diabetes.

    PubMed

    Russell-Jones, D

    2010-09-01

    Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

  10. Peroxisome proliferator-activated receptorα agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells.

    PubMed

    González, María Del Carmen; Corton, J Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Alvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

    2012-01-01

    Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.

  11. Peroxisome Proliferator-Activated Receptorα Agonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells

    PubMed Central

    González, María del Carmen; Corton, J. Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Álvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

    2012-01-01

    Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans. PMID:22701468

  12. Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca2+ oscillations in mouse pancreatic acinar cells

    PubMed Central

    Huang, Zebing; Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Zhang, Haiying; Xia, Kunkun; Chen, Dejie; Gao, Ming; Hammer, Ronald P.; Liu, Qingrong; Xi, Zhengxiong; Fan, Xuegong; Wu, Jie

    2016-01-01

    Emerging evidence demonstrates that the blockade of intracellular Ca2+ signals may protect pancreatic acinar cells against Ca2+ overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB2Rs modulate intracellular Ca2+ signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca2+ oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB2Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca2+ oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca2+ oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB2Rs eliminates ACh-induced Ca2+ oscillations and L-arginine-induced enhancement of Ca2+ signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. PMID:27432473

  13. Muscimol as an ionotropic GABA receptor agonist.

    PubMed

    Johnston, Graham A R

    2014-10-01

    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.

  14. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute cystitis; Acute bladder infection; Acute bacterial cystitis ... cause. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  15. Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization

    PubMed Central

    Virk, Michael S.; Arttamangkul, Seksiri; Birdsong, William T.; Williams, John T.

    2009-01-01

    Buprenorphine is a weak partial agonist at mu-opioid receptors that is used for treatment of pain and addiction. Intracellular and whole cell recordings were made from locus coeruleus (LC) neurons in rat brain slices to characterize the actions of buprenorphine. Acute application of buprenorphine caused a hyperpolarization that was prevented by previous treatment of slices with the irreversible opioid antagonist, β-chlornaltrexamine (β-CNA), but was not reversed by a saturating concentration of naloxone. As expected for a partial agonist, sub-saturating concentrations of buprenorphine decreased the [Met]5 enkephalin (ME) induced hyperpolarization or outward current. When the ME induced current was decreased below a critical value, desensitization and internalization of μ-opioid receptors (MOR) was eliminated. The inhibition of desensitization by buprenorphine was not the result of prior desensitization, slow dissociation from the receptor, or elimination of receptor reserve. Treatment of slices with sub-saturating concentrations of etorphine, methadone, oxymorphone or β-CNA also reduced the current induced by ME but did not block ME-induced desensitization. Treatment of animals with buprenorphine for a week resulted in the inhibition of the current induced by ME and a block of desensitization that was not different from the acute application of buprenorphine to brain slices. These observations show the unique characteristics of buprenorphine and further demonstrate the range of agonist selective actions that are possible through G-protein coupled receptors. PMID:19494155

  16. Airway Peroxidases Catalyze Nitration of the β2-Agonist Salbutamol and Decrease Its Pharmacological Activity

    PubMed Central

    Sallans, Larry; Macha, Stephen; Brown, Kari; McGraw, Dennis W.; Kovacic, Melinda Butsch; Britigan, Bradley E.

    2011-01-01

    β2-Agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important β2-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H2O2) and nitrite (NO2−), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pKa of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for β2-agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H2O2/NO2− being the most affected. Functionally, nitrated salbutamol showed decreased affinity for β2-adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic β2-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy. PMID:20974700

  17. [Acute asthmatic crisis in children].

    PubMed

    Dubus, J C; Bodiou, A C; Buttin, C; Jouglet, T; Stremler, N; Mély, L

    2000-03-01

    Acute asthma attack in children is an attack responsible for life-threatening acute respiratory distress with partial or no response to bronchodilator drugs. The severity of the episode needs to be quickly evaluated. This presupposes a perfect knowledge of the clinical signs of severity. Treatment is urgent and first based on the administration of high doses of inhaled short-acting beta 2-agonists. In the more obstructed children, anti-cholinergic drugs can be added to nebulized beta 2-agonists. Because of their delayed effect, systemic steroids require an early prescription. Symptomatic treatments are: urgent hospitalization, oxygen if needed, proper hydratation. Continuous nebulization or intravenous perfusion of beta 2-agonists are prescribed with cardiac monitoring when no objective improvement is noted. Admission into the pediatric intensive care unit when bronchial obstruction continues will permit the association of bronchodilator drugs and the proposal of mechanical ventilation if needed. When the episode is resolved, a prophylactic treatment using inhaled corticosteroids must be prescribed. Clinical and spirometric follow-up has to be organized, and the patient and his/her family have to be educated.

  18. Corepressors of agonist-bound nuclear receptors

    SciTech Connect

    Gurevich, Igor; Aneskievich, Brian J.

    2007-09-15

    Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, 'corner') box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

  19. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

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

  20. Serotonergic agonists behave as partial agonists at the dopamine D2 receptor.

    PubMed

    Rinken, A; Ferré, S; Terasmaa, A; Owman, C; Fuxe, K

    1999-02-25

    RAT dopamine D2short receptors expressed in CHO cells were characterized by activation of [35S]GTPgammaS binding. There were no significant differences between the maximal effects seen in activation of [35S]GTPgammaS binding caused by dopaminergic agonists, but the effects of 5-HT, 8OH-DPAT and 5-methoxytryptamine amounted to 47 +/- 7%, 43 +/- 5% and 70 +/- 7% of the dopamine effect, respectively. The dopaminergic antagonist (+)butaclamol inhibited activations of both types of ligands with equal potency (pA2 = 8.9 +/- 0.1), indicating that only one type of receptor is involved. In competition with [3H]raclopride binding, dopaminergic agonists showed 53 +/- 2% of the binding sites in the GTP-dependent high-affinity state, whereas 5-HT showed only 20 +/- 3%. Taken together, the results indicate that serotonergic agonists behave as typical partial agonists for D2 receptors with potential antiparkinsonian activity.

  1. Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats.

    PubMed

    Muramatsu, Maya; Hira, Tohru; Mitsunaga, Arimi; Sato, Eri; Nakajima, Shingo; Kitahara, Yoshiro; Eto, Yuzuru; Hara, Hiroshi

    2014-06-15

    The calcium-sensing receptor (CaSR) is expressed in various tissues, including the gastrointestinal tract. To investigate the role of gut CaSR on glycemic control, we examined whether single oral administration of CaSR agonist peptides affected the glycemic response in rats. Glucose tolerance tests were performed under oral or duodenal administration of various CaSR agonist peptides (γGlu-Cys, protamine, and poly-d-lysine hydrobromide) in conscious rats. Involvement of CaSR was determined by using a CaSR antagonist. Signaling pathways underlying CaSR agonist-modified glycemia were investigated using gut hormone receptor antagonists. The gastric emptying rate after the administration of CaSR agonist peptides was measured by the phenol red recovery method. Oral and duodenal administration of CaSR agonist peptides attenuated glycemic responses under the oral glucose tolerance test, but the administration of casein did not. The promotive effect on glucose tolerance was weakened by luminal pretreatment with a CaSR antagonist. Treatment with a 5-HT3 receptor antagonist partially diminished the glucose-lowering effect of peptides. Furthermore, the gastric emptying rate was decreased by duodenal administration of CaSR agonist peptides. These results demonstrate that activation of the gut CaSR by peptide agonists promotes glucose tolerance in conscious rats. 5-HT3 receptor and the delayed gastric emptying rate appear to be involved in the glucose-lowering effect of CaSR agonist peptides. Thus, activation of gut CaSR by dietary peptides reduces glycemic responses so that gut CaSR may be a potential target for the improvement of postprandial glycemia.

  2. Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

    PubMed Central

    Arttamangkul, Seksiri; Bunzow, James R.; Williams, John T.

    2015-01-01

    Sustained activation of G protein–coupled receptors can lead to a rapid decline in signaling through acute receptor desensitization. In the case of the μ-opioid receptor (MOPr), this desensitization may play a role in the development of analgesic tolerance. It is understood that phosphorylation of MOPr promotes association with β-arrestin proteins, which then facilitates desensitization and receptor internalization. Agonists that induce acute desensitization have been shown to induce a noncanonical high-affinity agonist binding state in MOPr, conferring a persistent memory of prior receptor activation. In the current study, live-cell confocal imaging was used to investigate the role of receptor phosphorylation in agonist binding to MOPr. A phosphorylation cluster in the C-terminal tail of MOPr was identified as a mediator of agonist-induced affinity changes in MOPr. This site is unique from the primary phosphorylation cluster responsible for β-arrestin binding and internalization. Electrophysiologic measurements of receptor function suggest that both phosphorylation clusters may play a parallel role during acute receptor desensitization. Desensitization was unaffected by alanine mutation of either phosphorylation cluster, but was largely eliminated when both clusters were mutated. Overall, this work suggests that there are multiple effects of MOPr phosphorylation that appear to regulate MOPr function: one affecting β-arrestin binding and a second affecting agonist binding. PMID:25934731

  3. LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

    PubMed Central

    Ceroi, Adam; Masson, David; Roggy, Anne; Roumier, Christophe; Chagué, Cécile; Gauthier, Thierry; Philippe, Laure; Lamarthée, Baptiste; Angelot-Delettre, Fanny; Bonnefoy, Francis; Perruche, Sylvain; Biichle, Sabeha; Preudhomme, Claude; Macintyre, Elisabeth; Lagrost, Laurent; Garnache-Ottou, Francine

    2016-01-01

    Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate–binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. PMID:27702801

  4. Beef heifers with diminished numbers of antral follicles have decreased uterine protein concentrations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous research demonstrated a favorable relationship between the number of follicles detectable in the bovine ovary by ultrasonography and fertility, and bovine females with diminished numbers of antral follicles had smaller reproductive tracts. Therefore, we hypothesized that uterine function w...

  5. Peroxidative Metabolism of β2-Agonists Salbutamol and Fenoterol and Their Analogs

    PubMed Central

    Reszka, Krzysztof J.; McGraw, Dennis W.; Britigan, Bradley E.

    2009-01-01

    Phenolic β2-adrenoreceptor agonists salbutamol, fenoterol and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm, and why the drugs appear to be less effective in patients with severe asthma exacerbations, remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these β2-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists’-derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from β2-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically-relevant concentrations of methimazole and dapsone. In alkaline buffers radicals from fenoterol and its structural analog, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic β2-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the β2-agonists. PMID:19462961

  6. Lorcaserin, a selective 5-HT(2C) receptor agonist, decreases alcohol intake in female alcohol preferring rats.

    PubMed

    Rezvani, Amir H; Cauley, Marty C; Levin, Edward D

    2014-10-01

    Serotonergic systems in the brain have been found to be important in the addiction to alcohol. The purpose of this study was to evaluate the efficacy of a novel 5-HT2c receptor agonist, lorcaserin for reducing alcohol consumption in alcohol-preferring (P) rats. Adult female rats were allowed to drink water or alcohol (12%, v/v) using a standard two-bottle choice procedure. Once stable baselines were established, the acute (0, 0.3125, 0.625 and 1.25 mg/kg, s.c.), and chronic (0, 0.625 mg/kg, sc for 10 days) effects of lorcaserin on alcohol intake and preference were assessed at different time points. In a separate experiment, the effects of lorcaserin on locomotor activity were determined. Our results show that both 0.625 and 1.25 mg/kg lorcaserin significantly reduced alcohol intake at 2, 4 and 6 h. after the drug administration. The chronic administration of 0.625 mg/kg lorcaserin significantly reduced alcohol intake up to 6h every day after the injection and there was no sign of diminished efficacy of the drug during 10-day treatment. To determine the effects of lorcaserin on sucrose intake, rats were put on a two-bottle choice of water vs a solution of 7% sucrose. The high dose of lorcaserin (1.25 mg/kg, s.c.) reduced sucrose intake only for up to 2 h. When tested for locomotor activity, lorcaserin injected 20 min before testing significantly reduced locomotor activity at all doses. However, when it was injected 5.5h before the start of the 1-h session, neither dose had a significant effect on locomotor activity. These results show the efficacy of lorcaserin in reducing alcohol intake without a significant effect on water intake and locomotion suggesting the involvement of 5-HT2c receptors in alcohol seeking behavior. Further research is warranted to determine the possible efficacy of lorcaserin or similar drugs as treatments for the treatment of alcoholism.

  7. An ethopharmacological assessment of the effects of zuclopenthixol on agonistic interactions in male mice.

    PubMed

    Manzaneque, J M; Navarro, J F

    1999-01-01

    Zuclopenthixol is a thioxanthene derivative which acts as a mixed dopamine D1/D2 receptor antagonist. Although the antiaggressive action of neuroleptic drugs is well known, the effects of zuclopenthixol on agonistic interactions have not been explored and there are no studies comparing acute and subchronic effects of this compound on aggression in rodents. In this work, we examined the action of zuclopenthixol (0.025-0.4 mg/kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after the drug administration, and encounters were videotaped and evaluated using an ethologically based analysis. After acute treatment, zuclopenthixol (0.2 and 0.4 mg/kg)-treated animals exhibited ethopharmacological profiles characterized by a decrease in offensive behaviors without impairment of motor activity (0.2 mg/kg). In contrast, the antiaggressive action of the highest dose used (0.4 mg/kg) was accompanied by a marked increase of immobility. After subchronic treatment, no tolerance to zuclopenthixol antiaggressive or motor activity was observed. Overall, this behavioral profile is similar to that observed with other typical neuroleptics.

  8. Peroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells

    PubMed Central

    Tobiasova, Zuzana; Zhang, Lufeng; Yi, Tai; Qin, Linfeng; Manes, Thomas D.; Kulkarni, Sanjay; Lorber, Marc I.; Rodriguez, Frederick C.; Choi, Je-Min; Tellides, George; Pober, Jordan S.; Kawikova, Ivana; Bothwell, Alfred L.M.

    2012-01-01

    Background Ligands activating the transcription factor peroxisome proliferator–activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown. Methods and Results We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ–dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J2, ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO+ memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects. Conclusion Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection. PMID:21690493

  9. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

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

  10. Agonists block currents through acetylcholine receptor channels.

    PubMed Central

    Sine, S M; Steinbach, J H

    1984-01-01

    We have examined the effects of high concentrations of cholinergic agonists on currents through single acetylcholine receptor (AChR) channels on clonal BC3H1 cells. We find that raised concentrations of acetylcholine (ACh; above 300 microM) or carbamylcholine (Carb; above 1,000 microM) produce a voltage- and concentration-dependent reduction in the mean single-channel current. Raised concentrations of suberyldicholine (Sub; above 3 microM) produce a voltage- and concentration-dependent increase in the number of brief duration low-conductance interruptions of open-channel currents. These observations can be quantitatively described by a model in which agonist molecules enter and transiently occlude the ion-channel of the AChR. PMID:6478036

  11. Ropinirole, a non-ergoline dopamine agonist.

    PubMed

    Jost, Wolfgang H; Angersbach, Dieter

    2005-01-01

    Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an individual patient is rendered difficult because of the large number of substances available on the market. This review article provides a closer look at the experimental and clinical studies with ropinirole published so far. Ropinirole is a non-ergoline dopamine agonist which has been proven to be effective in both, monotherapy and combination therapy of idiopathic Parkinson's disease. In addition to ameliorating bradykinesia, rigor, and tremor, ropinirole facilitates the daily life and improves depressive moods of patients with Parkinson's disease. The long-term complications of levodopa are avoided, and problems commonly associated with levodopa treatment are reduced. Ropinirole appears to have a neuroprotective effect. In addition to Parkinson's disease, ropinirole has also been used successfully in the treatment of restless legs syndrome.

  12. The identification of orally bioavailable thrombopoietin agonists.

    PubMed

    Munchhof, Michael J; Antipas, Amy S; Blumberg, Laura C; Brissette, William H; Brown, Matthew F; Casavant, Jeffrey M; Doty, Jonathan L; Driscoll, James; Harris, Thomas M; Wolf-Gouveia, Lilli A; Jones, Christopher S; Li, Qifang; Linde, Robert G; Lira, Paul D; Marfat, Anthony; McElroy, Eric; Mitton-Fry, Mark; McCurdy, Sandra P; Reiter, Lawrence A; Ripp, Sharon L; Shavnya, Andrei; Thomasco, Lisa M; Trevena, Kristen A

    2009-03-01

    Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

  13. Anti-inflammatory properties of a dual PPARgamma/alpha agonist muraglitazar in in vitro and in vivo models

    PubMed Central

    2013-01-01

    Introduction Peroxisome proliferator-activated receptor (PPAR) agonists are widely used drugs in the treatment of diabetes and dyslipidemia. In addition to their metabolic effects, PPAR isoforms PPARα and PPARγ are also involved in the regulation of immune responses and inflammation. In the present study, we investigated the effects of a dual PPARγ/α agonist muraglitazar on inflammatory gene expression in activated macrophages and on carrageenan-induced inflammation in the mouse. Methods J774 murine macrophages were activated by lipopolysaccharide (LPS) and treated with dual PPARγ/α agonist muraglitazar, PPARγ agonist GW1929 or PPARα agonist fenofibrate. The effects of PPAR agonists on cytokine production and the activation of inducible nitric oxide synthase (iNOS) pathway were investigated by ELISA, Griess method, Western blotting and quantitative RT-PCR. Nuclear translocation, DNA-binding activity and reporter gene assays were used to assess the activity of nuclear factor kappa B (NF-kB) transcription factor. Carrageenan-induced paw oedema was used as an in vivo model of acute inflammation. Results Muraglitazar as well as PPARγ agonist GW1929 and PPARα agonist fenofibrate inhibited LPS-induced iNOS expression and NO production in activated macrophages in a dose-dependent manner. Inhibition of iNOS expression by muraglitazar included both transcriptional and post-transcriptional components; the former being shared by GW1929 and the latter by fenofibrate. All tested PPAR agonists also inhibited IL-6 production, while TNFα production was reduced by muraglitazar and GW1929, but not by fenofibrate. Interestingly, the anti-inflammatory properties of muraglitazar were also translated in vivo. This was evidenced by the finding that muraglitazar inhibited carrageenan-induced paw inflammation in a dose-dependent manner in mice as did iNOS inhibitor L-NIL and anti-inflammatory steroid dexamethasone. Conclusions These results show that muraglitazar has anti

  14. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

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

    2016-02-08

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

  15. Short term health-related quality of life improvement during opioid agonist treatment

    PubMed Central

    Nosyk, B; Bray, JW; Wittenberg, E; Aden, B; Eggman, AA; Weiss, RD; Potter, J; Ang, A; Y-I, Hser; Ling, W; Schackman, BR

    2015-01-01

    Background Opioid dependence is associated with high levels of morbidity, yet sparse data exists regarding the health-related quality of life (HRQoL) of individuals with opioid dependence, particularly following treatment initiation. To inform cost-effectiveness analyses of treatment modalities, this study investigates short-term changes in HRQoL following enrollment into opioid agonist treatment (OAT), across treatment modalities and patient subgroups. Methods Data was analyzed from the Starting Treatment with Agonist Replacement Therapies (START) and Prescription Opioid Addiction Treatment Studies (POATS) randomized controlled trials. Participants included individuals dependent on prescription opioids (POs) or heroin, receiving limited-term or time-unlimited treatment. PO- or heroin-users in START received buprenorphine/naloxone (BUP/NX) or methadone (MET) over 24 weeks. PO-users in POATS received psychosocial care and short-term (4-week) taper with BUP/NX, with non-responders offered subsequent extended (12-week) stabilization and taper. HRQoL was assessed using the short-form SF-6D while in and out of OAT, with distinction between MMT and BUP/NX in START. Linear mixed effects regression models were fitted to determine the independent effects of OAT on HRQoL and characterize HRQoL trajectories. Results Treatment had a similar immediate and modest positive association with HRQoL in each patient subgroup. The association of OAT on HRQoL was statistically significant in each model, with effect sizes between 0.039 (Heroin-users receiving BUP/NX) and 0.071 (PO-users receiving MET). After initial improvement, HRQoL decreased slightly, or increased at a diminished rate. Conclusions OAT, whether delivered in time-limited or unlimited form, using BUP/NX or MET, is associated with modest immediate HRQoL improvements, with diminishing benefits thereafter. PMID:26511766

  16. Systemic administration of the neurotensin NTS₁-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats.

    PubMed

    Keiser, Ashley A; Matazel, Katelin S; Esser, Melissa K; Feifel, David; Prus, Adam J

    2014-12-01

    Agonists for the neurotensin NTS₁ receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS₁-receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS₁ agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, which suggest an ability of NTS₁-receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS₁-receptor activation on learning and memory consolidation in male Long-Evans and Brown Norway rats using a delayed nonmatch-to-position task radial arm-maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following 3-, 7-, and 24-hr delay, whereas Long-Evans rats exhibited an increase in spatial memory errors following only a 7-, and 24-hr delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hr delay. Administration of the NTS(1/2)-receptor antagonist SR142948 prior to the information trial did not affect retention-trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, the results of this study support previous findings suggesting that NTS₁-receptor agonists may improve some aspects of cognitive functioning.

  17. Acute Bronchitis

    MedlinePlus

    ... can also cause acute bronchitis. To diagnose acute bronchitis, your health care provider will ask about your symptoms and listen to your breathing. You may also have other tests. Treatments include rest, fluids, and aspirin (for adults) or ...

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

    PubMed

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

    2015-11-10

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

  19. Effects of 5-HT1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

    PubMed Central

    2013-01-01

    Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia. PMID:23496922

  20. Cell-phone use diminishes self-awareness of impaired driving.

    PubMed

    Sanbonmatsu, David M; Strayer, David L; Biondi, Francesco; Behrends, Arwen A; Moore, Shannon M

    2016-04-01

    Multitasking diminishes the self-awareness of performance that is often essential for self-regulation and self-knowledge. Participants drove in a simulator while either talking or not talking on a hands-free cell phone. Following previous research, participants who talked on a cell phone made more serious driving errors than control participants who did not use a phone while driving. Control participants' assessments of the safeness of their driving and general ability to drive safely while distracted were negatively correlated with the actual number of errors made when they were driving. By contrast, cell-phone participants' assessments of the safeness of their driving and confidence in their driving abilities were uncorrelated with their actual errors. Thus, talking on a cell phone not only diminished the safeness of participants' driving, it diminished their awareness of the safeness of their driving.

  1. Discovery of G Protein-Biased EP2 Receptor Agonists

    PubMed Central

    2016-01-01

    To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. PMID:26985320

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

    PubMed

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

    2013-10-21

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

  3. Acute opioid pretreatment potentiates naltrexone-induced drinking suppression in water-deprived rats.

    PubMed

    White, D A; Holtzman, S G

    2001-07-01

    Pretreatment with morphine-like agonists potentiates the behavioral effects of opioid antagonists, possibly reflecting a state of acute physical dependence. Several studies have used operant behavior to quantify these effects. However, little research has been done using unconditioned behavior. One objective of this study was to determine whether opioid agonist pretreatment (e.g., morphine, fentanyl, and meperidine) potentiated naltrexone-induced suppression of water consumption following deprivation. Another objective was to determine whether the agonist pretreatment interval was functionally related to efficacy for the manifestation of acute dependence. Finally, we compared temporally the effects of the three agonists. Adult male Sprague-Dawley rats were water deprived for 18, 20, or 22 h and given an injection (s.c.) of an agonist or saline. After 1.75, 3.75, or 5.75 h, animals received a single dose (s.c.) of naltrexone (0.01-30 mg/kg) or saline. Fifteen minutes later, subjects had access to water for 30 min. A time course of antinociception was constructed after agonist administration, using the tail-flick procedure. All three agonists dose dependently potentiated naltrexone-induced drinking suppression, decreasing the ED50 of naltrexone by as much as 150-fold. There was no clear relationship between agonist efficacy and pretreatment interval. Sensitization to naltrexone was seen up to 6 h after agonist administration, occurring in the apparent absence of an antinociceptive effect. These data extend the range of behavioral effects of opioid antagonists potentiated by opioid agonist pretreatment to suppression of drinking and show that such potentiation can occur in the absence of a prototypical agonist effect.

  4. Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity.

    PubMed

    Gurevich, V V; Pals-Rylaarsdam, R; Benovic, J L; Hosey, M M; Onorato, J J

    1997-11-14

    The rapid decrease of a response to a persistent stimulus, often termed desensitization, is a widespread biological phenomenon. Signal transduction by numerous G protein-coupled receptors appears to be terminated by a strikingly uniform two-step mechanism, most extensively characterized for the beta2-adrenergic receptor (beta2AR), m2 muscarinic cholinergic receptor (m2 mAChR), and rhodopsin. The model predicts that activated receptor is initially phosphorylated and then tightly binds an arrestin protein that effectively blocks further G protein interaction. Here we report that complexes of beta2AR-arrestin and m2 mAChR-arrestin have a higher affinity for agonists (but not antagonists) than do receptors not complexed with arrestin. The percentage of phosphorylated beta2AR in this high affinity state in the presence of full agonists varied with different arrestins and was enhanced by selective mutations in arrestins. The percentage of high affinity sites also was proportional to the intrinsic activity of an agonist, and the coefficient of proportionality varies for different arrestin proteins. Certain mutant arrestins can form these high affinity complexes with unphosphorylated receptors. Mutations that enhance formation of the agonist-receptor-arrestin complexes should provide useful tools for manipulating both the efficiency of signaling and rate and specificity of receptor internalization.

  5. Agonistic behavior in food animals: review of research and techniques.

    PubMed

    McGlone, J J

    1986-04-01

    One type of social behavior--agonistic behavior--is commonly observed among food animals. Agonistic behaviors are those behaviors which cause, threaten to cause or seek to reduce physical damage. Agonistic behavior is comprised of threats, aggression and submission. While any one of these divisions of agonistic behavior may be observed alone, they usually are found, in sequence, from the start to the end of an interaction. Food animals may show interspecific or intraspecific agonistic behaviors. Interspecific agonistic behavior has not been extensively studied but it is agriculturally important because farm workers may become injured or killed by aggressive food animals. Types of intraspecific agonistic behavior are: when animals are brought together, intermale fighting, resource defense, inter-gender fighting and aberrant aggression. Common pitfalls in research on agonistic behavior among food animals include too few replicates to detect a biological difference, the assumptions of the analysis are not met, only aggression and not submission or other agonistic behavior components are measured, incomplete description of the behaviors are reported and a complete, quantitive ethogram did not form the basis for selecting behavioral measures.

  6. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal.

  7. Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history.

    PubMed

    Gould, Robert W; Garg, Pradeep K; Garg, Sudha; Nader, Michael A

    2013-01-01

    Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ~6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [¹¹C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4β2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for

  8. δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice

    PubMed Central

    Pradhan, Amynah A; Smith, Monique L; Zyuzin, Jekaterina; Charles, Andrew

    2014-01-01

    Background and Purpose Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. Experimental Approach Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. Key Results NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that δ-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. Conclusions and Implications These data show that δ-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ-opioid receptors are a promising therapeutic target for this disorder. PMID:24467301

  9. D-Cycloserine: Agonist turned antagonist.

    PubMed

    Lanthorn, T H

    1994-10-01

    D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.

  10. Inverse agonist properties of atypical antipsychotic drugs.

    PubMed

    Akam, Elizabeth; Strange, Philip G

    2004-06-01

    Mechanisms of action of several atypical antipsychotic drugs have been examined at the D(2) dopamine receptor expressed in CHO cells. The drugs tested were found to exhibit inverse agonist activity at the D(2) dopamine receptor based on their effects to potentiate forskolin-stimulated cyclic AMP (cAMP) accumulation. Each of the antipsychotic drugs tested (clozapine, olanzapine, quetiapine and risperidone) increased cAMP accumulation to the same extent. The increase in cAMP was also similar to that seen with typical antipsychotic drugs. Inverse agonism at the D(2) dopamine receptor seems, therefore, to be a property common to all classes of antipsychotic drugs. The effect of sodium ions on the binding of the drugs to the receptor was also assessed. Each of the atypical antipsychotic drugs tested here bound with higher affinity in the absence of sodium ions. Previous studies have shown that some antipsychotic drugs are insensitive to sodium ions and some bind with higher affinity in the presence of sodium ions. Given that all of these antipsychotic drugs are inverse agonists, it may be concluded that this sodium ion sensitivity is unrelated to mechanisms of inverse agonism.

  11. Spearman's Law of Diminishing Returns in Hierarchical Models of Intelligence for Children and Adolescents

    ERIC Educational Resources Information Center

    Reynolds, Matthew R.; Keith, Timothy Z.

    2007-01-01

    Spearman's "law of diminishing returns" or SLODR refers to a decrease in "g" saturation as ability level increases. SLODR has been demonstrated in a number of intellectual batteries but several important aspects of the phenomenon are not yet well understood. We investigated the presence of SLODR in the Kaufman Assessment…

  12. Perceptions of Absenteeism and Diminished Engagement among Instructors and Nonlicensed Students in Medical Assistant Programs

    ERIC Educational Resources Information Center

    Miller, Russell

    2012-01-01

    Adult nonlicensed students can experience diminished engagement and increased absenteeism while attempting to complete medical assistant programs. The purpose of this qualitative, multisite narrative case study was to explore the perceptions, meanings, and interpretations of instructors and students. The theoretical foundation focused on the…

  13. DIMINISHED INJURY IN HYPOTRANSFERENEMIC MICE AFTER EXPOSURE TO A METAL-RICH PARTICLE

    EPA Science Inventory

    Using the hypotransferrinemic (Hp) mouse model, we studied the effect of altered iron homeostasis on the lung?s defense against catalytically active metal. The homozygotic (hpx/hpx) Hp mice had greatly diminished concentrations of both serum and lavage transferrin relative to ...

  14. Epstein-Barr Virus Reactivation Associated with Diminished Cell-Mediated Immunity in Antarctic Expeditioners

    NASA Technical Reports Server (NTRS)

    Pierson, Duane L.; Mehta, Satish K.; Cooley, Helen; Dubow, Robin; Lugg, Desmond

    1999-01-01

    Reactivation of Epstein-Barr virus (EBV) and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at two Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity skin testing was used as an indicator of the CMI response, which was evaluated two times before winter isolation and three times during isolation. At all five evaluation times, 8 or more of the 16 subjects had a diminished. CMI response. Diminished CMI was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal CMI responses for all five tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, after, and during the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least one occasion. The probability of EBV shedding increased (p=0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (p<0.0005) when CMI responsiveness was diminished than when CMI status was normal. The findings indicate that the psychosocial, physical, and other stresses associated with working and living in physical isolation during the Antarctic winter results in diminished CMI and an accompanying increased reactivation and shedding of latent viruses.

  15. Direct Instruction and Music Literacy: One Approach to Augmenting the Diminishing?

    ERIC Educational Resources Information Center

    Lowe, Geoffrey; Belcher, Steven

    2012-01-01

    One of the many challenges facing music educators is diminishing class time in lower secondary school in the face of the increasingly crowded curriculum and the advent of arts "taster" courses. However, music educators are still expected to be able to produce musically literate students capable of completing high level music courses in…

  16. Epstein-Barr virus reactivation associated with diminished cell-mediated immunity in antarctic expeditioners

    NASA Technical Reports Server (NTRS)

    Mehta, S. K.; Pierson, D. L.; Cooley, H.; Dubow, R.; Lugg, D.

    2000-01-01

    Epstein-Barr virus (EBV) reactivation and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at 2 Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity (DTH) skin testing was used as an indicator of the CMI response, that was evaluated 2 times before winter isolation and 3 times during isolation. At all 5 evaluation times, 8 or more of the 16 subjects had a diminished CMI response. Diminished DTH was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal DTH responses for all 5 tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, during, and after the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least 1 occasion. The probability of EBV shedding increased (P = 0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (P < 0.0005) when DTH response was diminished than when DTH was normal. The findings indicate that the psychosocial, physical, and other stresses associated with working and living in physical isolation during the Antarctic winter result in diminished CMI and an accompanying increased reactivation and shedding of latent viruses.

  17. Challenging the Presumption of Diminished Capacity to Parent: Does Divorce Really Change Parenting Practices?

    ERIC Educational Resources Information Center

    Strohschein, Lisa

    2007-01-01

    The purpose of this paper is to determine whether divorced parents exhibit a diminished capacity to parent in the period following divorce. Using 2 waves of data from a national survey of Canadian children, the current study prospectively follows 5,004 children living in 2-biological parent households at initial interview and compares changes in…

  18. Less Guilty by Reason of Adolescence: Developmental Immaturity, Diminished Responsibility, and the Juvenile Death Penalty

    ERIC Educational Resources Information Center

    Steinberg, Laurence; Scott, Elizabeth S.

    2003-01-01

    The authors use a developmental perspective to examine questions about the criminal culpability of juveniles and the juvenile death penalty. Under principles of criminal law, culpability is mitigated when the actor's decision-making capacity is diminished, when the criminal act was coerced, or when the act was out of character. The authors argue…

  19. Nonsuicidal self-injury and diminished pain perception: the role of emotion dysregulation.

    PubMed

    Franklin, Joseph C; Aaron, Rachel V; Arthur, Michael S; Shorkey, S Paul; Prinstein, Mitchell J

    2012-08-01

    Nonsuicidal self-injury (NSSI) is the deliberate destruction of one's own body tissue in the absence of suicidal intent (e.g., cutting or burning the skin). Previous studies have found that people with a history of NSSI display diminished pain perception. However, it remains unclear why this effect occurs. In the present study, we used a sample of participants with (n = 25) and without (n = 47) a history of NSSI to test the hypothesis that emotion dysregulation partially explains why NSSI is associated with diminished pain perception. Pain perception was quantified as pain threshold, pain tolerance, and pain intensity ratings assessed during the cold pressor task. Nonsuicidal self-injury was associated with increased emotion dysregulation and diminished pain perception. Results showed that emotion dysregulation was correlated with diminished pain perception within both groups, demonstrating that this association exists regardless of NSSI history. Results also specified that emotion dysregulation partially accounted for the association between NSSI and pain tolerance but not other pain variables. Overall, results were consistent with the hypothesis that emotion dysregulation may increase NSSI risk in part by increasing the willingness to experience the pain involved in self-injury. Studies are needed to more directly investigate this hypothesis.

  20. Diminishing Marginal Returns and the Production of Education: An International Analysis

    ERIC Educational Resources Information Center

    Harris, Douglas N.

    2007-01-01

    Diminishing marginal returns (DMR) to school inputs could explain a wide variety of findings in the research literature. One important example is the influential finding by Heyneman and Loxley that school inputs are the 'predominant influence' on achievement in developing nations, where input levels are low, even though the same school inputs have…

  1. Rehearsal Strategies Can Enlarge or Diminish the Spacing Effect: Pure versus Mixed Lists and Encoding Strategy

    ERIC Educational Resources Information Center

    Delaney, Peter F.; Verkoeijen, Peter P. J. L.

    2009-01-01

    Using 5 experiments, the authors explored the dependency of spacing effects on rehearsal patterns. Encouraging rehearsal borrowing produced opposing effects on mixed lists (containing both spaced and massed repetitions) and pure lists (containing only one or the other), magnifying spacing effects on mixed lists but diminishing spacing effects on…

  2. Dietary long-chain omega-3 fatty acids do not diminish eosinophilic pulmonary inflammation in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of fish oil supplements on diminishing airway inflammation in asthma have been studied in mouse models and human intervention trials with varying results. However, the independent effects of the main omega-3 PUFAs found in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (D...

  3. Diminished neurosteroid sensitivity of synaptic inhibition and altered location of the alpha4 subunit of GABA(A) receptors in an animal model of epilepsy.

    PubMed

    Sun, Chengsan; Mtchedlishvili, Zakaria; Erisir, Alev; Kapur, Jaideep

    2007-11-14

    In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA(A) receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA(A) receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5alpha][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the alpha4 subunit. Expression of the alpha4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the alpha4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The alpha4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and alpha4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.

  4. Fates of endocytosed somatostatin sst2 receptors and associated agonists.

    PubMed Central

    Koenig, J A; Kaur, R; Dodgeon, I; Edwardson, J M; Humphrey, P P

    1998-01-01

    Somatostatin agonists are rapidly and efficiently internalized with the somatostatin sst2 receptor. The fate of internalized agonists and receptors is of critical importance because the rate of ligand recycling back to the cell surface can limit the amount of radioligand accumulated inside the cells, whereas receptor recycling might be of vital importance in providing the cell surface with dephosphorylated, resensitized receptors. Furthermore the accumulation of radioisotope-conjugated somatostatin agonists inside cancer cells resulting from receptor-mediated internalization has been used as a treatment for cancers that overexpress somatostatin receptors. In the present study, radio-iodinated agonists at the sst2 somatostatin receptor were employed to allow quantitative analysis of the fate of endocytosed agonist. After endocytosis, recycling back to the cell surface was the main pathway for both 125I-labelled somatostatin-14 (SRIF-14) and the more stable agonist 125I-labelled cyclo(N-Me-Ala-Tyr-d-Trp-Lys-Abu-Phe) (BIM-23027; Abu stands for aminobutyric acid), accounting for 75-85% of internalized ligand when re-endocytosis of radioligand was prevented. We have shown that there is a dynamic cycling of both somatostatin agonist ligands and receptors between the cell surface and internal compartments both during agonist treatment and after surface-bound agonist has been removed, unless steps are taken to prevent the re-activation of receptors by recycled agonist. Internalization leads to increased degradation of 125I-labelled SRIF-14 but not 125I-labelled BIM-23027. The concentration of recycled agonist accumulating in the extracellular medium was sufficient to re-activate the receptor, as measured both by the inhibition of forskolin-stimulated adenylate cyclase and the recovery of surface receptor number after internalization. PMID:9820803

  5. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration

    PubMed Central

    Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.

    2014-01-01

    Recent results from laboratory investigations and clinical trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are associated with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clinical benefits of ER agonists for augmenting cognitive function may triumph over the associated side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory molecules with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concentrated on finding the most plausible molecular pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS. PMID:25245209

  6. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

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

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

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

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

  8. Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia

    PubMed Central

    Zhang, Yonghua; Kimelberg, Harold K.

    2005-01-01

    Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury. PMID:18369397

  9. Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins.

    PubMed

    Melkes, Barbora; Hejnova, Lucie; Novotny, Jiri

    2016-12-01

    There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala(2),N-MePhe(4),Gly(5)-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2. Interestingly, cholesterol depletion strongly enhanced the ability of morphine to elevate receptor mobility but significantly reduced or even eliminated the effect of DAMGO and endomorphin-2, respectively. Moreover, the ability of DAMGO and endomorphin-2 to influence MOR-YFP movement was diminished by pertussis toxin treatment. The results obtained by agonist-stimulated [(35)S]GTPγS binding assays indicated that DAMGO exhibited higher efficacy than morphine and endomorphin-2 did and that the efficacy of DAMGO, contrary to the latter agonists, was enhanced by cholesterol depletion. Overall, our study provides clear evidence that biased MOR agonists diversely affect receptor mobility in plasma membranes as well as MOR/G protein coupling and that the regulatory effect of different ligands depends on the membrane cholesterol content. These findings help to delineate the fundamental properties of MOR regarding their interaction with biased MOR ligands and cognate G proteins.

  10. Diminished social motivation negatively impacts reputation management: autism spectrum disorders as a case in point.

    PubMed

    Chevallier, Coralie; Molesworth, Catherine; Happé, Francesca

    2012-01-01

    Human beings are endowed with a unique motivation to be included in social interactions. This natural social motivation, in turn, is thought to encourage behaviours such as flattery or self-deprecation aimed to ease interaction and to enhance the reputation of the individual who produces them. If this is the case, diminished social interest should affect reputation management. Here, we use Autism Spectrum Disorders (ASDs)--primarily characterised by pervasive social disinterest--as a model to investigate the effect of social motivation on reputation management. Children first rated a set of pictures and were then given the opportunity to inflate their initial ratings in front of an experimenter who declared that she had drawn the picture. Contrary to the controls, children with ASD did not enhance their ratings in the drawer's presence. Moreover, participants' flattery behaviour correlated with self-reports of social enjoyment. Our findings point to a link between diminished social interest and reputation management.

  11. Learning to diminish the effects of proactive interference: Reducing false memory for young and older adults

    PubMed Central

    Jacoby, Larry L.; Wahlheim, Christopher N.; Rhodes, Matthew G.; Daniels, Karen A.; Rogers, Chad S.

    2011-01-01

    Results from two experiments revealed that prior experience with proactive interference (PI) diminished PI’s effects for both young and older adults. Participants were given two rounds of experience, with different materials, in a situation that produced PI. Comparisons with a control condition showed that the effects of PI on accuracy and on high-confidence intrusion errors (false memory) were reduced on the second round, as compared with those on the first. Also, the ability of confidence to diagnose accuracy of responding improved across rounds. Effects of prior experience with PI depended on feedback given at the time of test (Experiment 1). At least in part, the diminishment of PI resulted from participants’ allocating more attention to interference items during study in the second round than in the first (Experiment 2). Implications of the results for interpreting age differences in PI and false memory are discussed. PMID:20852244

  12. Less guilty by reason of adolescence: developmental immaturity, diminished responsibility, and the juvenile death penalty.

    PubMed

    Steinberg, Laurence; Scott, Elizabeth S

    2003-12-01

    The authors use a developmental perspective to examine questions about the criminal culpability of juveniles and the juvenile death penalty. Under principles of criminal law, culpability is mitigated when the actor's decision-making capacity is diminished, when the criminal act was coerced, or when the act was out of character. The authors argue that juveniles should not be held to the same standards of criminal responsibility as adults, because adolescents' decision-making capacity is diminished, they are less able to resist coercive influence, and their character is still undergoing change. The uniqueness of immaturity as a mitigating condition argues for a commitment to a legal environment under which most youths are dealt with in a separate justice system and none are eligible for capital punishment.

  13. Diminished Social Motivation Negatively Impacts Reputation Management: Autism Spectrum Disorders as a Case in Point

    PubMed Central

    Chevallier, Coralie; Molesworth, Catherine; Happé, Francesca

    2012-01-01

    Human beings are endowed with a unique motivation to be included in social interactions. This natural social motivation, in turn, is thought to encourage behaviours such as flattery or self-deprecation aimed to ease interaction and to enhance the reputation of the individual who produces them. If this is the case, diminished social interest should affect reputation management. Here, we use Autism Spectrum Disorders (ASDs) –primarily characterised by pervasive social disinterest– as a model to investigate the effect of social motivation on reputation management. Children first rated a set of pictures and were then given the opportunity to inflate their initial ratings in front of an experimenter who declared that she had drawn the picture. Contrary to the controls, children with ASD did not enhance their ratings in the drawer's presence. Moreover, participants' flattery behaviour correlated with self-reports of social enjoyment. Our findings point to a link between diminished social interest and reputation management. PMID:22303483

  14. Ventral striatal hypoactivation is associated with apathy but not diminished expression in patients with schizophrenia

    PubMed Central

    Kirschner, Matthias; Hager, Oliver M.; Bischof, Martin; Hartmann, Matthias N.; Kluge, Agne; Seifritz, Erich; Tobler, Philippe N.; Kaiser, Stefan

    2016-01-01

    Background Negative symptoms of schizophrenia can be grouped in 2 dimensions: apathy and diminished expression. Increasing evidence suggests that negative symptoms are associated with altered neural activity of subcortical and cortical regions in the brain reward system. However, the neurobiological basis of the distinct symptom dimensions within negative symptoms is still poorly understood. The primary aim of our study was to examine the neural correlates of the negative symptom dimensions apathy and diminished expression during a reward processing task. Methods Patients with schizophrenia and healthy controls underwent event-related fMRI while performing a variant of the Monetary Incentive Delay Task. We assessed negative symptom dimensions using the Brief Negative Symptom Scale. Results We included 27 patients and 25 controls in our study. Both groups showed neural activation indicated by blood oxygen–level dependent signal in the ventral striatum during reward anticipation. Ventral striatal activation during reward anticipation showed a strong negative correlation with apathy. Importantly, this effect was not driven by cognitive ability, medication, depressive or positive symptoms. In contrast, no significant correlation with the diminished expression dimension was observed. Limitations Although the results remain significant when controlling for chlorpromazine equivalents, we cannot fully exclude potential confounding effects of medication with atypical antipsychotics. Conclusion The specific correlation of ventral striatal hypoactivation during reward anticipation with apathy demonstrates a differentiation of apathy and diminished expression on a neurobiological level and provides strong evidence for different pathophysiological mechanisms underlying these 2 negative symptom dimensions. Our findings contribute to a multilevel framework in which apathy and motivational impairment in patients with schizophrenia can be described on psychopathological

  15. Diminished growth hormone secretion in blind males after L-dopa stimulation.

    PubMed

    Fatranská, M; Jurcovicová, J; Németh, S; Vigas, M

    1988-12-01

    Growth hormone secretion after L-dopa administration (1000 mg p.o.) was investigated in young adult normal and blind volunteers. The average increment of plasma growth hormone after L-dopa stimulation in the blind was below the criterion for a positive response (less than 5 ng ml-1). The control volunteers showed normal response. After L-dopa stimulation there was a significantly diminished growth hormone response in the young adult blind compared to control volunteers.

  16. Quantifying agonist activity at G protein-coupled receptors.

    PubMed

    Ehlert, Frederick J; Suga, Hinako; Griffin, Michael T

    2011-12-26

    When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors. Receptors behave as quantal switches that alternate between active and inactive states (Figure 1). The active state interacts with specific G proteins or other signaling partners. In the absence of ligands, the inactive state predominates. The binding of agonist increases the probability that the receptor will switch into the active state because its affinity constant for the active state (K(b)) is much greater than that for the inactive state (K(a)). The summation of the random outputs of all of the receptors in the population yields a constant level of receptor activation in time. The reciprocal of the concentration of agonist eliciting half-maximal receptor activation is equivalent to the observed affinity constant (K(obs)), and the fraction of agonist-receptor complexes in the active state is defined as efficacy (ε) (Figure 2). Methods for analyzing the downstream responses of GPCRs have been developed that enable the estimation of the K(obs) and relative efficacy of an agonist. In this report, we show how to modify this analysis to estimate the agonist K(b) value relative to that of another agonist. For assays that exhibit constitutive activity, we show how to estimate K(b) in absolute units of M(-1). Our method of analyzing agonist concentration-response curves consists of global nonlinear regression using the operational model. We describe a procedure using the software application, Prism (GraphPad Software, Inc., San Diego, CA). The analysis yields an estimate of the product of K(obs) and a parameter proportional to efficacy (

  17. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  18. Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

    SciTech Connect

    Sun Yang; Kojima, Chikara; Chignell, Colin; Mason, Ronald; Waalkes, Michael P.

    2011-09-15

    Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm{sup 2}) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: > Arsenic transformation adapted to UV-induced apoptosis. > Arsenic transformation diminished oxidant response. > Arsenic transformation enhanced UV-induced DNA damage.

  19. 5-HT1A Agonist Properties Contribute to a Robust Response to Vilazodone in the Novelty Suppressed Feeding Paradigm

    PubMed Central

    Garcia-Garcia, Alvaro L.; Navarro-Sobrino, Míriam; Pilosof, Gila; Banerjee, Pradeep; Dranovsky, Alex

    2016-01-01

    Background: Differences in 5-HT1A receptor function have been implicated in vulnerability to depression and in response to treatment. Adding 5-HT1A partial agonists to selective serotonin reuptake inhibitors has been touted as a strategy to increase their efficacy. Here we use the novelty suppressed feeding paradigm to compare the effects of vilazodone, a high-potency selective serotonin reuptake inhibitor, with high affinity for 5-HT1A receptors to the reference selective serotonin reuptake inhibitor fluoxetine across several mouse strains that differ in their response to selective serotonin reuptake inhibitors. Methods: To confirm 5-HT1A agonist activity, body temperature was measured after acute administration of vilazodone or fluoxetine, as administration of 5-HT1A agonists induces hypothermia. We next used 3 strains of mice to examine the effects of the drugs on latency in the novelty suppressed feeding, a paradigm generally sensitive to chronic but not acute effects of antidepressants. Results: Vilazodone induces robust hypothermia and blocks stress-induced hyperthermia in a 5-HT1A-dependent manner, consistent with agonist effects at 5-HT1A autoreceptors. In 129SvEv mice, vilazodone (10mg/kg/d) reduces the latency to eat in the novelty suppressed feeding test within 8 days, while no effect of fluoxetine (20mg/kg/d) was detected at that time. In contrast, both vilazodone and fluoxetine are effective at decreasing latency to eat in the novelty suppressed feeding paradigm in a strain with low autoreceptor levels. In mice with higher autoreceptor levels, no significant difference was detected between fluoxetine and vehicle (P=.8) or vilazodone and vehicle (P=.06). Conclusion: In mice, vilazodone may offer advantages in time of onset and efficacy over a reference selective serotonin reuptake inhibitor in the novelty suppressed feeding test. PMID:27352617

  20. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation.

  1. Resolution of acute inflammation in the lung.

    PubMed

    Levy, Bruce D; Serhan, Charles N

    2014-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung.

  2. Resolution of Acute Inflammation In The Lung

    PubMed Central

    Levy, Bruce D.; Serhan, Charles N.

    2015-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized pro-resolving mediators, specifically lipoxins, resolvins, protectins and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung. PMID:24313723

  3. Effects of Long-Term Treatment with Estradiol and Estrogen Receptor Subtype Agonists on Serotonergic Function in Ovariectomized Rats.

    PubMed

    Benmansour, Saloua; Adeniji, Opeyemi S; Privratsky, Anthony A; Frazer, Alan

    2016-01-01

    Acute estradiol treatment was reported to slow the clearance of serotonin via activation of estrogen receptors (ER)β and/or GPR30 and to block the ability of a selective serotonin reuptake inhibitor (SSRI) to slow serotonin clearance via activation of ERα. In this study, the behavioral consequences of longer-term treatments with estradiol or ER subtype-selective agonists and/or an SSRI were examined in the forced swim test (FST). Ovariectomized rats were administered the following for 2 weeks: estradiol, ERβ agonist (diarylpropionitrile, DPN), GPR30 agonist (G1), ERα agonist (PPT), and/or the SSRI sertraline. Similar to sertraline, longer-term treatment with estradiol, DPN or G1 induced an antidepressant-like effect. By contrast, PPT did not, even though it blocked the antidepressant-like effect of sertraline. Uterus weights, used as a peripheral measure of estrogenic activity, were increased by estradiol and PPT but not DPN or G1 treatment. A second part of this study investigated, using Western blot analyses in homogenates from hippocampus, whether these behavioral effects are accompanied by changes in the activation of specific signaling pathways and/or TrkB. Estradiol and G1 increased phosphorylation of Akt, ERK and TrkB. These effects were similar to those obtained after treatment with sertraline. Treatment with DPN increased phosphorylation of ERK and TrkB, but it did not alter that of Akt. Treatment with PPT increased phosphorylation of Akt and ERK without altering that of TrkB. In conclusion, activation of at least TrkB and possibly ERK may be involved in the antidepressant-like effect of estradiol, ERβ and GPR30 agonists whereas Akt activation may not be necessary.

  4. EFFECTS OF LONG-TERM TREATMENT WITH ESTRADIOL AND ESTROGEN RECEPTOR SUBTYPE AGONISTS ON SEROTONERGIC FUNCTION IN OVARIECTOMIZED RATS

    PubMed Central

    Benmansour, Saloua; Adeniji, Opeyemi S.; Privratsky, Anthony A.; Frazer, Alan

    2015-01-01

    Acute estradiol treatment was reported to slow the clearance of serotonin via activation of estrogen receptors (ER)β and/or GPR30 and to block the ability of a selective serotonin reuptake inhibitor (SSRI) to slow serotonin clearance via activation of ERα. In this study, the behavioral consequences of longer-term treatments with estradiol or ER subtype-selective agonists and/or an SSRI were examined in the forced swim test (FST). Ovariectomized rats were administered for two weeks: estradiol, ERβ agonist (DPN), GPR30 agonist (G1), ERα agonist (PPT), and/or the SSRI sertraline. Similar to sertraline, longer-term treatment with estradiol, DPN or G1 induced an antidepressant- like effect. By contrast, PPT did not, even though it blocked the antidepressant-like effect of sertraline. Uterus weights, used as a peripheral measure of estrogenic activity, were increased by estradiol and PPT but not DPN or G1 treatment. A second part of this study investigated, using Western blot analyses in homogenates from hippocampus, whether these behavioral effects are accompanied by changes in the activation of specific signaling pathways and/or TrkB. Estradiol and G1 increased phosphorylation of Akt, ERK and TrkB. These effects were similar to those obtained after treatment with sertraline. Treatment with DPN increased phosphorylation of ERK and TrkB but it did not alter that of Akt. Treatment with PPT increased phosphorylation of Akt and ERK without altering that of TrkB. In conclusion, activation of at least TrkB and possibly ERK may be involved in the antidepressant-like effect of estradiol, ERβ and GPR30 agonists whereas Akt activation may not be necessary. PMID:26159182

  5. [Histrelin acetate--the first once yearly LHRH agonist].

    PubMed

    Altarac, Silvio

    2011-01-01

    Long-acting synthetic luteinising hormone-releasing hormone agonists have become the mainstay for androgen-deprivation therapy, because they avoid the physical and psychological discomfort associated with orchidectomy and lack the potential cardiotoxicity associated with estrogens such as diethylstilbestrol. Currently available luteinising hormone-releasing hormone agonist analogues include leuprolide, goserelin, triptorelin, degarelix and buserelin were administered as either intramuscular or subcutaneous depot injections on a 1, 2, 3 or 6 months basis. Histrelin acetate is the first long-acting luteinising hormone-releasing hormone agonist available as a once-yearly subcutaneous implant.

  6. Toll-like receptor agonists in cancer therapy

    PubMed Central

    Adams, Sylvia

    2010-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

  7. [Acute pancreatitis].

    PubMed

    Hecker, M; Mayer, K; Askevold, I; Collet, P; Weigand, M A; Krombach, G A; Padberg, W; Hecker, A

    2014-03-01

    Acute pancreatitis is a potentially fatal disease with individually differing expression of systemic involvement. For this reason early diagnosis with subsequent risk stratification is essential in the clinical management of this frequent gastroenterological disorder. Severe forms of acute pancreatitis occur in approximately 20 % of cases often requiring intensive care monitoring and interdisciplinary therapeutic approaches. In the acute phase adequate fluid replacement and sufficient analgesic therapy is of major therapeutic importance. Concerning the administration of antibiotics and the nutritional support of patients with acute pancreatitis a change in paradigms could be observed in recent years. Furthermore, endoscopic, radiological or surgical interventions can be necessary depending on the severity of the disease and potential complications.

  8. Bronchitis - acute

    MedlinePlus

    ... to breathe. Other symptoms of bronchitis are a cough and coughing up mucus. Acute means the symptoms ... diagnosed with chronic bronchitis, you must have a cough with mucus on most days for at least ...

  9. Acute Bronchitis

    MedlinePlus

    ... bronchitis? Acute bronchitis is inflammation of your bronchial tree. The bronchial tree consists of tubes that carry air into your ... weeks or months. This happens because the bronchial tree takes a while to heal. A lasting cough ...

  10. Chronic treatment in vivo with β-adrenoceptor agonists induces dysfunction of airway β2-adrenoceptors and exacerbates lung inflammation in mice

    PubMed Central

    Lin, Rui; Degan, Simone; Theriot, Barbara S; Fischer, Bernard M; Strachan, Ryan T; Liang, Jiurong; Pierce, Richard A; Sunday, Mary E; Noble, Paul W; Kraft, Monica; Brody, Arnold R; Walker, Julia KL

    2012-01-01

    BACKGROUND AND PURPOSE Inhalation of a β-adrenoceptor agonist (β-agonist) is first-line asthma therapy, used for both prophylaxis against, and acute relief of, bronchoconstriction. However, repeated clinical use of β-agonists leads to impaired bronchoprotection and, in some cases, adverse patient outcomes. Mechanisms underlying this β2-adrenoceptor dysfunction are not well understood, due largely to the lack of a comprehensive animal model and the uncertainty as to whether or not bronchorelaxation in mice is mediated by β2-adrenoceptors. Thus, we aimed to develop a mouse model that demonstrated functional β-agonist-induced β2-adrenoceptor desensitization in the context of allergic inflammatory airway disease. EXPERIMENTAL APPROACH We combined chronic allergen exposure with repeated β-agonist inhalation in allergen-treated BALB/C mice and examined the contribution of β2-adrenoceptors to albuterol-induced bronchoprotection using FVB/NJ mice with genetic deletion of β2-adrenoceptors (KO). Associated inflammatory changes – cytokines (ELISA), cells in bronchoalevolar lavage and airway remodelling (histology) and β2-adrenoceptor density (radioligand binding) – were also measured. KEY RESULTS β2-Adrenoceptors mediated albuterol-induced bronchoprotection in mice. Chronic treatment with albuterol induced loss of bronchoprotection, associated with exacerbation of the inflammatory components of the asthma phenotype. CONCLUSIONS AND IMPLICATIONS This animal model reproduced salient features of human asthma and linked loss of bronchoprotection with airway pathobiology. Accordingly, the model offers an advanced tool for understanding the mechanisms of the effects of chronic β- agonist treatment on β-adrenoceptor function in asthma. Such information may guide the clinical use of β-agonists and provide insight into development of novel β-adrenoceptor ligands for the treatment of asthma. PMID:22013997

  11. Intracellular observations on the effects of muscarinic agonists on rat sympathetic neurones.

    PubMed Central

    Brown, D. A.; Constanti, A.

    1980-01-01

    1 Responses of single neurones in isolated superior cervical ganglia of the rat to muscarinic agonists were recorded with intracellular microelectrodes. 2 (+/-)-Muscarine (1 to 10 microM) and methylfurmethide (1 to 3 microM) produced reversible membrane depolarizations (less than or equal to 15 mV) accompanied by a fall in input conductance and an increased tendency toward repetitive spike discharges. The spike configuration was unchanged. 3 Analysis of steady-state current/voltage curves revealed the most consistent muscarinic effect to be a large reduction (approximately 50% at 10 microM muscarine) in input slope conductance around rest potential. This conductance decrease diminished as the membrane was hyperpolarized, and the normal increase in slope conductance with membrane depolarization was depressed. The current/voltage curves in the between -65 and -88 mV (i.e. 9 to 28 mV hyperpolarized to rest potential). 4 Divalent cations (10 mM [Ca2+] or [Mg2+]) showed a small muscarine-like effect on the current/voltage and slope conductance/voltage curves, but did not affect the action of muscarine itself. 5 Tetraethylammonium (TEA, 5 mM) also had a small muscarine-like effect, and depressed or reversed the action of muscarine. However, TEA differed from muscarine in blocking orthodromic transmission and prolonging direct spike repolarization. 6 It is concluded that the primary effect of muscarinic agonists is to alter the rectifying properties of the cell within the potential range -80 to -40 mV. PMID:7470731

  12. Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.

    PubMed

    Mathews, Jennifer L; Peng, Xuemei; Xiong, Wennan; Zhang, Ao; Negus, S Stevens; Neumeyer, John L; Bidlack, Jean M

    2005-11-01

    Previous research has shown that compounds with mixed kappa and mu activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a kappa opioid receptor agonist and a mu opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K(i) values of 0.078 and 0.20 nM for the kappa and mu opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[(35) S]thiotriphosphate) binding assay, MCL-145 produced an E(max) value of 80% for the kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.

  13. In vitro fertilization outcomes in women with surgery induced diminished ovarian reserve after endometrioma operation: Comparison with diminished ovarian reserve without ovarian surgery

    PubMed Central

    Hong, Su Been; Lee, Na Ra; Kim, Hoon; Jee, Byung Chul; Suh, Chang Suk; Kim, Seok Hyun; Choi, Young Min

    2017-01-01

    Objective To compare the in vitro fertilization (IVF) outcomes between women with diminished ovarian reserve (DOR) after endometrioma operation and women with DOR without ovarian surgery. Methods This retrospective case-control study included 124 women aged under 40 and had DOR (serum anti-Müllerian hormone level <1.1 ng/mL or antral follicle count ≤6). They participated in fresh first and/or second IVF cycles between March in 2010 and December in 2015. Basal characteristics and IVF outcomes were compared between 47 cycles (32 women) with surgery-induced DOR and 119 cycles (92 women) with DOR without ovarian surgery. Results Basal characteristics were similar in both groups except that the median ages were lower in the surgery-induced DOR group compared to the DOR group without ovarian surgery. The data regarding the controlled ovarian stimulation and IVF cycle outcomes showed similar result in both groups. Also, clinical pregnancy and live birth rate were not different significantly between two groups. Conclusion In the same condition of DOR, clinical pregnancy and live birth rate were not different significantly between two groups regarding etiology of DOR. PMID:28217673

  14. PPAR-γ agonist pioglitazone affects rat gouty arthritis by regulating cytokines.

    PubMed

    Wang, R-C; Jiang, D-M

    2014-08-28

    The objective was to study peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone regulation effect and its mechanism of expression of cytokines on acute gouty arthritis synovial in rats. Rats with unilateral ankle were injected with artificial monosodium urate (MSU) crystals to make the acute gouty arthritis model. Taking the synovium 48 h after the injection of MSU and using RT-PCR, we assessed the effect of pioglitazone (20 mg·kg(-1)·day(-1), oral administration) on synovial expression, by detecting tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ). The pioglitazone treatment group showed synovial expression of TNF-α, and IFN-γ was significantly lower than in the control group; the inhibition rates were 78.5 and 60.4%. The IL-1 expression difference was not statistically significant between the two groups. Pioglitazone has anti-inflammatory effects on acute gouty arthritis by inhibiting the expression of TNF-α and IFN-γ.

  15. Aryl hydrocarbon receptor agonists trigger avoidance of novel food in rats.

    PubMed

    Mahiout, Selma; Pohjanvirta, Raimo

    2016-12-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of dioxins, but also plays important physiological roles, which are only beginning to unfold. Previous studies have surprisingly unveiled that low doses of the potent AHR agonist TCDD induce a strong and persistent avoidance of novel food items in rats. Here, we further examined the involvement of the AHR in the avoidance response in Sprague-Dawley rats with three established AHR agonists: 6-formylindolo(3,2-b)carbazole (FICZ), β-naphthoflavone (BNF) and benzo[a]pyrene (BaP); with a novel selective AHR modulator (C2); and with an activator of another nuclear receptor, CAR: 2,4,6-tryphenyldioxane-1,3 (TPD). As sensitive indices of AHR or CAR activity, we used Cyp1a1 and Cyp2b1 gene expression, as they are, respectively, the drug-metabolizing enzymes specifically regulated by them. We further attempted to address the roles played by enhanced neophobia and conditioned taste aversion (CTA) in the avoidance behaviour. All AHR agonists triggered practically total avoidance of novel chocolate, but the durations varied. Likewise, acutely subtoxic doses of C2, differing by 25-fold, all elicited a similar outcome. In contrast, TPD did not influence chocolate consumption at all. If rats were initially accustomed to chocolate for 6h after single FICZ or BNF exposure, avoidance was still clearly present two weeks later when chocolate was offered again. Hence, the avoidance response appears to specifically involve the AHR instead of being triggered by induction of intestinal or hepatic nuclear receptor signalling in general. It is also shared by both endogenous and exogenous AHR activators. Moreover, this behavioural change in rats seems to contain elements of both CTA and enhanced neophobia, but further clarification of this is still required.

  16. Noribogaine is a G-protein biased κ-opioid receptor agonist.

    PubMed

    Maillet, Emeline L; Milon, Nicolas; Heghinian, Mari D; Fishback, James; Schürer, Stephan C; Garamszegi, Nandor; Mash, Deborah C

    2015-12-01

    Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50=9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6'-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations>1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

  17. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist.

    PubMed

    Gassaway, M M; Rives, M-L; Kruegel, A C; Javitch, J A; Sames, D

    2014-07-15

    Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. However, in spite of three decades of basic and clinical investigations, the molecular target of tianeptine, as well as its mechanism of action, remains elusive. Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (K(i Human) of 383±183 nM and EC(50 Human) of 194±70 nM  and EC(50 Mouse) of 641±120 nM for G-protein activation). Tianeptine was also a full δ-opioid receptor (DOR) agonist, although with much lower potency (EC(50 Human) of 37.4±11.2 μM and EC(50 Mouse) of 14.5±6.6  μM for G-protein activation). In contrast, tianeptine was inactive at the κ-opioid receptor (KOR, both human and rat). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions.

  18. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist

    PubMed Central

    Gassaway, M M; Rives, M-L; Kruegel, A C; Javitch, J A; Sames, D

    2014-01-01

    Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. However, in spite of three decades of basic and clinical investigations, the molecular target of tianeptine, as well as its mechanism of action, remains elusive. Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (Ki Human of 383±183 nM and EC50 Human of 194±70 nM  and EC50 Mouse of 641±120 nM for G-protein activation). Tianeptine was also a full δ-opioid receptor (DOR) agonist, although with much lower potency (EC50 Human of 37.4±11.2 μM and EC50 Mouse of 14.5±6.6  μM for G-protein activation). In contrast, tianeptine was inactive at the κ-opioid receptor (KOR, both human and rat). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions. PMID:25026323

  19. CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception.

    PubMed

    Hasanein, Parisa; Parviz, Mohsen; Keshavarz, Mansoor; Javanmardi, Kazem

    2007-01-01

    1. Recent studies have suggested that the basolateral nucleus of the amygdala (BLA) participates in the processing of pain information, especially noxious somatic information. Cannabinoid receptors or CB1 mRNA are expressed more in the BLA than in other nuclei of the amygdala. Thus, the aim of the present study was to examine whether CB1 receptors in the BLA may be involved in modulating acute and/or tonic nociceptive processing. 2. Adult rats were exposed to intra-BLA microinjection of the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo [1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN 55,212-2 (1, 2.5, 5 or 10 microg/side)] and subjected to the tail flick and formalin tests. 3. The rats demonstrated a dose-dependent increase in latency to withdraw from a thermal noxious stimulus in the tail flick test and a decrease in formalin-induced pain behaviours. The antinociceptive effects of the CB1 receptor agonist WIN 55,212-2 (10 microg/side) in both tests were attenuated in the presence of the selective CB1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide (AM251; 0.55 ng/side). Administration of the CB1 receptor antagonist AM251 (0.55, 5.5, or 55.5 ng/side) alone did not alter the nociceptive thresholds in either test. Bilateral microinjection of the selective CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 1 microg/side) had no effect on the antinociception produced by WIN 55,212-2, suggesting that the antinociceptive actions of WIN 55,212-2 are mediated by CB1 receptors. 4. The findings suggest the existence of a CB1-mediated inhibitory system in the BLA that, when activated, can diminish responsivity to acute and tonic noxious stimuli, but that normally has no tonic effect on the response threshold of these stimuli.

  20. Octopaminergic agonists for the cockroach neuronal octopamine receptor.

    PubMed

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  1. (R)-(-)-10-methyl-11-hydroxyaporphine: a highly selective serotonergic agonist.

    PubMed

    Cannon, J G; Mohan, P; Bojarski, J; Long, J P; Bhatnagar, R K; Leonard, P A; Flynn, J R; Chatterjee, T K

    1988-02-01

    Prior work in these laboratories identified (+/-)-5-hydroxy-6-methyl-2- (di-n-propylamino)tetralin as a dopaminergic agonist prodrug. The ortho methyl hydroxy aromatic substitution pattern in this molecule has now been incorporated into the aporphine ring system to give a congener of the dopaminergic agonist apomorphine in which the position 10 OH group has been replaced by methyl. Preparation of the target compound involved acid-catalyzed rearrangement of the 3-(1-phenyltetrazolyl) ether of morphine and subsequent molecular modification of the product, the 10-(1-phenyltetrazolyl) ether of (R)-(-)-apomorphine. Surprisingly, the target compound elicited no responses in any assays for effects at dopamine receptors, but rather it displayed pharmacological properties consistent with its being a serotonergic agonist with a high degree of selectivity for 5-HT1A receptors similar to the serotonergic agonist 8-hydroxy-2-(di-n-propylamino)tetralin.

  2. Agonist Replacement for Stimulant Dependence: A Review of Clinical Research

    PubMed Central

    Stoops, William W.; Rush, Craig R.

    2013-01-01

    Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that agonist replacement therapy may be effective for managing stimulant use disorders, however, the clinical selection of an agonist replacement medication likely needs to be based on the pharmacological mechanism of the medication and the stimulant abused by patients. Specifically, dopamine releasers appear most effective for reducing cocaine use whereas dopamine reuptake inhibitors appear most effective for reducing amphetamine use. PMID:23574440

  3. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype.

  4. Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology

    PubMed Central

    Borovac, Josip Anđelo

    2016-01-01

    Dopamine agonists (DA) are therapeutic agents that are commonly used in the treatment of Parkinson’s disease (PD). They can reduce undesired motor fluctuations and delay the administration of levodopa therapy. However, this drug family is associated with specific side effects that can significantly diminish the quality of life among PD patients. Some of them impose significant risks for individuals who have a history of cardiovascular diseases, psychosis, and depression, or those older patients who suffer from renal or hepatic insufficiency. Various pharmacokinetic and pharmacodynamic considerations need to be taken into account when administering DA therapy. The goal of this review is to provide a comprehensive, up-to-date overview of DA therapeutic modalities for PD. PMID:27505015

  5. Acute asthma: under attack.

    PubMed

    Kissoon, Niranjan

    2002-06-01

    The burden of asthma (death, disability, and an increasing prevalence) makes it a major public health problem worldwide. In an effort to decrease this burden, investigators are studying many aspects of this disease. The role of race, ethnicity, infections, and pollutants as triggers, as well as the risk factors are now being defined. Research into methods to decrease acute exacerbations and improve emergency and in-hospital management, using standardized protocols and incentives for follow-up care, has yielded valuable information but has met with limited success. Adherence to the national guidelines has been poor and to some extent can be attributed to the lack of a practical method of measuring the degree of lung inflammation and cumbersome treatment protocols. Exhaled nitric oxide is a noninvasive marker of inflammation and may provide a rational method to titrate corticosteroid and leukotriene receptor antagonist therapy. The best route and dosing regimen for corticosteroid administration (oral vs intramuscular vs nebulized) are the subject of several studies, with no clear-cut winner. The burden of asthma in developing countries with limited financial resources has also triggered a search for simpler, cheaper, and practical methods for beta-agonist delivery using indigenous spacers. Recent research in asthma has unveiled our incomplete knowledge of the disease but has also provided a sense of where efforts should be expended. Research into the genetics and pharmacogenetics of asthma and into the societal factors limiting the delivery of optimal care is likely to yield useful and practical information.

  6. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  7. Selection of Parasites with Diminished Drug Sensitivity by Amodiaquine-Containing Antimalarial Regimens in Uganda

    PubMed Central

    Nawaz, Fatima; Nsobya, Samuel L.; Kiggundu, Moses; Joloba, Moses; Rosenthal, Philip J.

    2009-01-01

    Background Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy. Methods We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized to treatment with AQ/SP, AS/AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro sensitivity to monodesethylamodiaquine (MDAQ) was measured with a histidine rich protein-2-based ELISA, and potential resistance-mediating polymorphisms pfmdr-1were evaluated. Results Parasites from subjects previously treated with AQ/SP or AS/AQ within 12 weeks were less sensitive to MDAQ (n=18; mean IC50 62.9 nM; range 12.7–158.3 nM) than parasites from those not treated within 12 weeks (n=43; mean IC50 37.5 nM; range 6.3–184.7 nM; p=0.0085) or only those in the treatment arm that did not contain AQ (n=20; mean IC50 28.8 nM; range 6.3–121.8 nM; p=0.0042). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr-1 86Y and 1246Y) increased after prior AQ therapy, although differences were not significant. Conclusions Prior therapy selected for diminished response to MDAQ, suggesting that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr-1. PMID:19905933

  8. Factors diminishing the effectiveness of phosphorus loading from municipal effluent: critical information for TMDL analyses.

    PubMed

    Effler, Steven W; Auer, Martin T; Peng, Feng; Perkins, MaryGail; O'Donnell, Susan M; Prestigiacomo, Anthony R; Matthews, David A; DePetro, Phillip A; Lambert, Renn S; Minott, Natalie M

    2012-03-01

    Factors that diminish the effectiveness of phosphorus inputs from a municipal wastewater treatment facility (Metro) in contributing to phosphorus levels and its availability to support algae growth in a culturally eutrophic urban lake (Onondaga Lake, NY) were characterized and quantified. These factors included the bioavailability and settling characteristics of particulate phosphorus from this effluent, the dominant form (70%) of phosphorus in this input, and the plunging of the discharge to stratified layers in the lake. Supporting studies included: (1) chemical and morphometric characterization of the phosphorus-enriched particles of this effluent, compared to particle populations of the tributaries and lake, with an individual particle analysis technique; (2) conduct of algal bioavailability assays of the particulate phosphorus of the effluent; (3) conduct of multiple size class settling velocity measurements on effluent particles; and (4) determinations of the propensity of the discharge to plunge, and documentation of plunging through three-dimensional monitoring of a tracer adjoining the outfall. All of these diminishing effects were found to be operative for the Metro effluent in Onondaga Lake and will be integrated into a forthcoming phosphorus "total maximum daily load" analysis for the lake, through appropriate representation in a supporting mechanistic water quality model. The particulate phosphorus in the effluent was associated entirely with Fe-rich particles formed in the phosphorus treatment process. These particles did not contribute to concentrations in pelagic portions of the lake, due to local deposition associated with their large size. Moreover, this particulate phosphorus was found to be nearly entirely unavailable to support algae growth. While substantial differences are to be expected for various inputs, the effective loading concept and the approaches adopted here to assess the diminishing factors are broadly applicable.

  9. The TP73 Gene Polymorphism (rs4648551, A>G) Is Associated with Diminished Ovarian Reserve

    PubMed Central

    Vagnini, Laura Diniz; Renzi, Adriana; Oliveira-Pelegrin, Gabriela Ravanelli; Canas, Maria do Carmo Tomitão; Petersen, Claudia Guilhermino; Mauri, Ana Lucia; Oliveira, João Batista Alcantara; Baruffi, Ricardo Luiz Razera; Cavagna, Mario; Franco Junior, José Gonçalves

    2015-01-01

    It’s known that the members of the TP53 family are involved in the regulation of female reproduction. Studies in mice showed that the TP73 gene (member of this family) plays a role in the size of follicular pool, ovulation rate and maintenance of genomic stability. In the present study we analyzed data from 605 patients with ≤ 37 years attending their first intracytoplasmic sperm injection (ICSI). The association between the TP73 polymorphism (rs4648551, A>G) and the following parameters related to ovarian reserve, like age, antral follicular count (AFC), anti-Mullerian hormone levels (AMH) and ovarian response prediction index (ORPI) was evaluated. Our results showed an association of the AA genotype with diminished ovarian reserve (AMH <1, AFC ≤9). Women presenting the AA genotype had a 2.0-fold increased risk for having AMH <1 and AFC ≤9 (OR 2.0, 95% CI 1.23-3.31, P = 0.005). Patients presenting AA genotype had the lowest levels of AMH (P = 0.02), the lowest number of antral follicles (P = 0.01) and the lowest ORPI (P = 0.007). Analyzing the alleles, we can see an enrichment of the A allele in the group of diminished ovarian reserve (OR 1.4, 95%CI 1.02-1.83, P = 0.04). To the best of our knowledge, the present study is the first to analyze this polymorphism in humans for assessing the numbers of ovarian follicles and AMH levels and, therefore, the ovarian reserve. Our findings can contribute to the use of this polymorphism as a potential marker of diminished ovarian reserve. PMID:25794170

  10. Self-focused cognitive emotion regulation style as associated with widespread diminished EEG fractal dimension.

    PubMed

    Bornas, Xavier; Tortella-Feliu, Miquel; Balle, Maria; Llabrés, Jordi

    2013-01-01

    The cognitive regulation of emotions is important for human adaptation. Self-focused emotion regulation (ER) strategies have been linked to the development and persistence of anxiety and depression. A vast array of research has provided valuable knowledge about the neural correlates of the use of specific self-focused ER strategies; however, the resting neural correlates of cognitive ER styles, which reflect an individual's disposition to engage in different forms of ER in order to manage distress, are largely unknown. In this study, associations between theoretically negative ER style (self-focused or not) and the complexity (fractal dimension, FD) of the resting EEG at frontal, central, parietal, and occipital regions were investigated in 58 healthy volunteers. The Cognitive Emotion Regulation Questionnaire was used as the self-report measure of ER style. Results showed that a diminished FD over the scalp significantly correlated with self-focused ER style scores, even after controlling for negative affect, which has been also considered to influence the use of ER strategies. The lower the EEG FD, the higher were the self-focused ER style scores. Correlational analyses of specific self-focused ER strategies showed that self-blaming and rumination were negatively associated with diminished FD of the EEG, but catastrophizing and blaming others were not. No significant correlations were found for ER strategies more focused on situation or others. Results are discussed within the self-organized criticality theory of brain dynamics: The diminished FD of the EEG may reflect a disposition to engage in self-focused ER strategies as people prone to ruminate and self-blame show a less complex resting EEG activity, which may make it more difficult for them to exit their negative emotional state.

  11. Beta2-agonists and exercise-induced asthma.

    PubMed

    Anderson, Sandra D; Caillaud, Corinne; Brannan, John D

    2006-01-01

    Beta2-agonists taken immediately before exercise provide significant protection against exercise- induced asthma (EIA) in most patients. However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First, there is a significant minority (15-20%) of asthmatics whose EIA is not prevented by beta2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use, there is a decline in duration of the protective effect of long-acting beta2-agonists. Third, if breakthrough EIA occurs, recovery of lung function is slower in response to a beta2-agonist, and additional doses are often required to achieve pre-exercise values. If a person who takes a beta2-agonist daily experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of EIA. These problems likely result from desensitization of the beta2-receptor on the mast cell, which enhances mediator release, and on the bronchial smooth muscle, which enhances the bronchoconstrictor response and delays recovery from EIA. These effects are reversed within 72 h after cessation of a beta2-agonists. The important clinical question is: Are we actually compromising the beneficial effects of beta2-agonists on the prevention and recovery from EIA by prescribing them daily? Patients with EIA need to ensure that their doses of inhaled corticosteroid or other anti-inflammatory therapy are optimized so that, if necessary, a beta2-agonist can be used intermittently as prophylactic medication with greater confidence in the outcome.

  12. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  13. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  14. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  15. Opioid receptor agonists reduce brain edema in stroke.

    PubMed

    Yang, Li; Wang, Hezhen; Shah, Kaushik; Karamyan, Vardan T; Abbruscato, Thomas J

    2011-04-06

    Cerebral edema is a leading cause of mortality in stroke patients. The purpose of this study was to assess a non-selective opioid receptor agonist, biphalin, in decreasing reducing brain edema formation using both in vitro and in vivo models of stroke. For the in situ model of ischemia, hippocampal slices were exposed to oxygen glucose deprivation (OGD) conditions and we observed that hippocampal water content was increased, compared to normoxia. Treatment with the mu agonist, Tyr-D-Ala', N-CH, -Phe4, Glyol-Enkephalin (DAMGO), delta opioid agonists, D-pen(2), D-phe(5) enkephalin (DPDPE), and kappa agonist, U50 488, all significantly decreased brain slice water gain. Interestingly, the non-selective agonist, biphalin, exhibited a statistically significant (P<0.01) greater effect in decreasing water content in OGD-exposed hippocampal slices, compared with mu, delta, and kappa selective opioid agonists. Moreover, biphalin exhibited anti-edematous effects in a dose responsive manner. The non-selective opioid antagonist, naloxone, returned the water content nearly back to original OGD values for all opioid agonist treatments, supporting that these effects were mediated by an opioid receptor pathway. Furthermore, biphalin significantly decreased edema (53%) and infarct (48%) ratios, and neuronal recovery from stroke, compared with the vehicle-treated groups in a 12h permanent middle cerebral artery occlusion (MCAO) model of focal ischemia. Biphalin also significantly decreased the cell volume increase in primary neuronal cells exposed to OGD condition. These data suggest that opioid receptor activation may provide neuroprotection during stroke and further investigations are needed in the development of novel opioid agonist as efficacious treatments for brain ischemia.

  16. Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

    PubMed Central

    Vang, Derek; Paul, Jinny A.; Nguyen, Julia; Tran, Huy; Vincent, Lucile; Yasuda, Dennis; Zaveri, Nurulain T.; Gupta, Kalpna

    2015-01-01

    Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia. PMID:26294734

  17. β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

    PubMed Central

    Chiarella, Sergio E.; Soberanes, Saul; Urich, Daniela; Morales-Nebreda, Luisa; Nigdelioglu, Recep; Green, David; Young, James B.; Gonzalez, Angel; Rosario, Carmen; Misharin, Alexander V.; Ghio, Andrew J.; Wunderink, Richard G.; Donnelly, Helen K.; Radigan, Kathryn A.; Perlman, Harris; Chandel, Navdeep S.; Budinger, G.R. Scott; Mutlu, Gökhan M.

    2014-01-01

    Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β2-adrenergic receptor (β2AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β2AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β2AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the β2AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β2AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by β2AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events. PMID:24865431

  18. Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice.

    PubMed

    Vang, Derek; Paul, Jinny A; Nguyen, Julia; Tran, Huy; Vincent, Lucile; Yasuda, Dennis; Zaveri, Nurulain T; Gupta, Kalpna

    2015-12-01

    Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia.

  19. [N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties.

    PubMed

    Marczak, Ewa D; Jinsmaa, Yunden; Li, Tingyou; Bryant, Sharon D; Tsuda, Yuko; Okada, Yoshio; Lazarus, Lawrence H

    2007-10-01

    [N-allyl-Dmt1]-endomorphin-1 and -2 ([N-allyl-Dmt1]-EM-1 and -2) are new selective micro-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2',6'-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5'-O-(3-[35S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-allyl-Dmt1]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine- and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone- and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.

  20. Costs of water treatment due to diminished water quality: A case study in Texas

    NASA Astrophysics Data System (ADS)

    Dearmont, David; McCarl, Bruce A.; Tolman, Deborah A.

    1998-04-01

    The cost of municipal water treatment due to diminished water quality represents an important component of the societal costs of water pollution. Here the chemical costs of municipal water treatment are expressed as a function of raw surface water quality. Data are used for a 3-year period for 12 water treatment plants in Texas. Results show that when regional raw water contamination is present, the chemical cost of water treatment is increased by 95 per million gallons (per 3785 m3) from a base of 75. A 1% increase in turbidity is shown to increase chemical costs by 0.25%.

  1. Diminished KCC2 confounds synapse-specificity of LTP during senescence

    PubMed Central

    Ferando, Isabella; Faas, Guido; Mody, Istvan

    2016-01-01

    Synapse-specificity of LTP ensures that no interference arises from inputs irrelevant to the memory to be encoded. In hippocampi of aged (21-28 months-old) mice LTP was relayed to unstimulated synapses blemishing its synapse-specificity. Diminished levels of the K+/Cl– cotransporter KCC2 and a depolarizing GABAA receptor-mediated synaptic component following LTP were the most likely causes for spreading the potentiation, unveiling novel mechanisms hindering information storage in the aged brain, and identifying KCC2 as a potential target for intervention. PMID:27500406

  2. Infrared light irradiation diminishes effective charge transfer in slow sodium channel gating system

    NASA Astrophysics Data System (ADS)

    Plakhova, Vera B.; Bagraev, Nikolai T.; Klyachkin, Leonid E.; Malyarenko, Anna M.; Romanov, Vladimir V.; Krylov, Boris V.

    2001-02-01

    Effects of infrared light irradiation (IR) on cultured dorsal root ganglia cells were studied by the whole-cell patch-clamp technique. The IR field is demonstrated to diminish the effective charge transfer in the activation system from 6.2 +-0.6 to 4.5 +-0.4 in units of electron charge per e-fold change in membrane potential. The effects was blocked with ouabain. Our data is the first indication that sodium pump might be the molecular sensor of infrared irradiation in animal kingdom.

  3. Infrared light irradiation diminishes effective charge transfer in slow sodium channel gating system

    NASA Astrophysics Data System (ADS)

    Plakhova, Vera B.; Bagraev, Nikolai T.; Klyachkin, Leonid E.; Malyarenko, Anna M.; Romanov, Vladimir V.; Krylov, Boris V.

    2000-02-01

    Effects of infrared light irradiation (IR) on cultured dorsal root ganglia cells were studied by the whole-cell patch-clamp technique. The IR field is demonstrated to diminish the effective charge transfer in the activation system from 6.2 +-0.6 to 4.5 +-0.4 in units of electron charge per e-fold change in membrane potential. The effects was blocked with ouabain. Our data is the first indication that sodium pump might be the molecular sensor of infrared irradiation in animal kingdom.

  4. A new class of high accuracy TVD schemes for hyperbolic conservation laws. [Total Variation Diminishing

    NASA Technical Reports Server (NTRS)

    Chakravarthy, S. R.; Osher, S.

    1985-01-01

    A new family of high accuracy Total Variation Diminishing (TVD) schemes has been developed. Members of the family include the conventional second-order TVD upwind scheme, various other second-order accurate TVD schemes with lower truncation error, and even a third-order accurate TVD approximation. All the schemes are defined with a five-point grid bandwidth. In this paper, the new algorithms are described for scalar equations, systems, and arbitrary coordinates. Selected numerical results are provided to illustrate the new algorithms and their properties.

  5. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions.

    PubMed

    Stoessl, A J; Szczutkowski, E; Glenn, B; Watson, I

    1991-11-29

    The effects of selective NK-1, NK-2 and NK-3 tachykinin agonists in midbrain dopamine cell containing regions were investigated in the rat. The NK-3 agonist senktide induced locomotion, rearing and sniffing following infusion into the substantia nigra pars compacta, and to a lesser extent in the ventral tegmental area. These behavioural responses were not seen following infusion of the selective NK-1 agonist [Sar9,Met (O2)11]SP or the NK-2 agonist [N1e10]NKA4-10. In contrast, grooming was induced only by the NK-1 agonist administered into the substantia nigra. Yawning, chewing mouth movements and wet dog shakes were all seen following infusion of senktide into the ventral tegmental area. These findings suggest that (i) dopamine-mediated behavioural responses seen following tachykinin administration into the midbrain are dependent upon stimulation of NK-3 tachykinin receptors, (ii) tachykinin-induced grooming is mediated by stimulation of NK-1 receptors and (iii) some of the previously described 5-HT mediated behaviours seen following administration of NK-3 tachykinin agonists are probably generated by stimulation of 5-HT cell bodies in the ventral tegmental area.

  6. Histamine H3-receptor inverse agonists as novel antipsychotics.

    PubMed

    Ito, Chihiro

    2009-06-01

    Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

  7. Contribution of Endogenous Spinal Endomorphin 2 to Intrathecal Opioid Antinociception in Rats Is Agonist-Dependent and Sexually Dimorphic

    PubMed Central

    Kumar, Arjun; Liu, Nai-Jiang; Madia, Priyanka A.; Gintzler, Alan R.

    2016-01-01

    Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females resulted from neither insufficient levels of testosterone nor mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil’s analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management, but also helps explain variable sex-dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet. Perspective The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes. PMID:26342648

  8. Rat alpha6beta2delta GABAA receptors exhibit two distinct and separable agonist affinities.

    PubMed

    Hadley, Stephen H; Amin, Jahanshah

    2007-06-15

    The onset of motor learning in rats coincides with exclusive expression of GABAA receptors containing alpha6 and delta subunits in the granule neurons of the cerebellum. This development temporally correlates with the presence of a spontaneously active chloride current through alpha6-containing GABAA receptors, known as tonic inhibition. Here we report that the coexpression of alpha6, beta2, and delta subunits produced receptor-channels which possessed two distinct and separable states of agonist affinity, one exhibiting micromolar and the other nanomolar affinities for GABA. The high-affinity state was associated with a significant level of spontaneous channel activity. Increasing the level of expression or the ratio of beta2 to alpha6 and delta subunits increased the prevalence of the high-affinity state. Comparative studies of alpha6beta2delta, alpha1beta2delta, alpha6beta2gamma2, alpha1beta2gamma2 and alpha4beta2delta receptors under equivalent levels of expression demonstrated that the significant level of spontaneous channel activity is uniquely attributable to alpha6beta2delta receptors. The pharmacology of spontaneous channel activity arising from alpha6beta2delta receptor expression corresponded to that of tonic inhibition. For example, GABAA receptor antagonists, including furosemide, blocked the spontaneous current. Further, the neuroactive steroid 5alpha-THDOC and classical glycine receptor agonists beta-alanine and taurine directly activated alpha6beta2delta receptors with high potency. Specific mutation within the GABA-dependent activation domain (betaY157F) impaired both low- and high-affinity components of GABA agonist activity in alpha6betaY157Fdelta receptors, but did not attenuate the spontaneous current. In comparison, a mutation located between the second and third transmembrane segments of the delta subunit (deltaR287M) significantly diminished the nanomolar component and the spontaneous activity. The possibility that the high affinity state

  9. Histologic effect of a postnatal slow-release GnRH agonist on feline gonads.

    PubMed

    Carranza, A; Faya, M; Fernandez, P; Barbeito, C; Gobello, C

    2015-05-01

    In postnatal domestic cats, GnRH agonists suppressed fecal concentrations of sexual steroids and delayed puberty. The aim of this study was to describe the gross and microscopic morphometric effects of a single administration of the GnRH agonist, deslorelin acetate, on the gonads of postnatally treated cats. Twenty-seven postnatal male (n = 14) and female (n = 13) kittens were randomly assigned to one of the following treatment groups within the first 24 hours of birth: deslorelin acetate (1.6 mg, subcutaneous; DA, n = 16) or control that remained untreated (CO, n = 11) and spayed or castrated immediately after the onset of puberty. After surgical removal, the gonads were gross and histologically assessed. Sertoli cells also were examined immunohistochemically. Comparisons between the treatments were carried out by the Student t test. Gross gonadal wet weight and volume as well as gonadosomatic index were significantly lower in the DA than those in the CO males; these same parameters were not different in females. Primordial (461.4 + 3.0 vs. 1074.3 + 117.5; P < 0.01), primary (59.1 + 13.5 vs. 165.4 + 24.6; P < 0.01), and secondary (17.5 + 2.6 vs. 31.17 + 8.1; P < 0.05) follicles per mm(2) were decreased in DA than in CO gonads. Epididymal sperm motility and morphology were normal in all but two DA cats that had too few sperm to be evaluated. Germinal epithelial height (μm; 39.68 + 0.92 vs. 72.7 + 1.2; P < 0.01) and most of their cellular components as well as the Sertoli (cm(3); 0.1 + 0.02 vs. 0.24 + 0.05; P < 0.01) cells were diminished in the DA cats. Gonadotropin-releasing hormone agonist endocrine disruption during the neonatal critical reproductive time window may have a potential as a contraceptive agent in domestic felids.

  10. A comparative study of the effects of some 5-HT1A receptor agonists on the blood pressure of pithed rats.

    PubMed

    Castillo, C; Bobadilla, R A; Ibarra, M; Castillo, E F; Hong, E

    1995-01-01

    The intention of this study was to supply additional information about direct effects of the 5-HT1A receptor agonist indorenate on the arterial blood pressure. The effects of indorenate were compared with those of buspirone and ipsapirone (all selective 5-HT1A agonists) on the blood pressure of pithed rats. These compounds increased the blood pressure in a dose-dependent fashion. The effects of either ipsapirone or buspirone were clearly inhibited with 100 micrograms/kg of prazosin (selective alpha 1-adrenoceptor antagonist), whereas 1 mg/kg of this blocker elicited only a mild inhibition of the pressor effect of indorenate. Pindolol (100 micrograms/kg; a beta-adrenoceptor and 5-HT1 receptor blocker) was unable to modify the effects of all the 5-HT1A agonists tested. In addition, the 5-HT2 receptor and weak alpha 1-adrenoceptor blocker ketanserin (10-100 micrograms/kg) antagonized the pressor effect of indorenate. Nevertheless, only a mild inhibition was observed in the case of both ipsapirone and buspirone. On the other hand, the latter drugs diminished the blood pressure of pithed rats intravenously infused with norepinephrine, but indorenate was inactive. However, in rats infused with quipazine, all the 5-HT1A agonists failed to reduce blood pressure. These results indicate that buspirone and ipsapirone behaved as partial alpha 1-adrenoceptor agonists. Furthermore, the results show that indorenate-elicited pressor effects are probably due to stimulation of 5-HT2 receptors. Thus, unlike ipsapirone and buspirone, indorenate did not show conclusively activity related with alpha 1-adrenoceptors.

  11. In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist.

    PubMed

    Panayi, Fany; Sors, Aurore; Bert, Lionel; Martin, Brigitte; Rollin-Jego, Gaelle; Billiras, Rodolphe; Carrié, Isabelle; Albinet, Karine; Danober, Laurence; Rogez, Nathalie; Thomas, Jean-Yves; Pira, Luigi; Bertaina-Anglade, Valérie; Lestage, Pierre

    2017-03-14

    S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.

  12. The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicks.

    PubMed

    Grabarevic, Z; Tisljar, M; Artukovic, B; Bratulic, M; Dzaja, P; Seiwerth, S; Sikiric, P; Peric, J; Geres, D; Kos, J

    1997-01-01

    We describe the effects of nitric oxide (NO) agonists and antagonists and the influence of a novel organoprotective pentadecapeptide BPC 157, on the development of pulmonary hypertension syndrome and tissue lesions in chicks. Acute toxicity, which includes single dose application of saline (1 mL intraperitoneally (i.p.)), BPC 157 (10 micrograms/kg bw), L-NAME (NO antagonist, doses 50, 100, 150 mg/kg bw) and L-arginine (NO agonist/100 mg/kg bw with their combination L-NAME + BPC 157; L-NAME + L-arginine) was investigated. In this experiment pathohistological examination of the spleen, heart, liver and lungs and hematological analysis was conducted. In the chronic toxicity experiment, the animals were treated daily for 5 weeks with L-NAME (10 mg/kg bw), L-arginine (100 mg/kg bw), BPC 157 (10 micrograms/kg bw) and their combinations (L-NAME + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine) i.p. Seven animals from each group, including controls (saline 1 mL i.p.) were killed every week. Application of L-NAME caused pulmonary hypertension syndrome (PHS) in the treated chicks, which was prevented by the simultaneous application of L-arginine and BPC 157. Pathohistological examination of both acute and chronic toxicity revealed that L-NAME caused severe tissue damage (myocardial and hepatic cell necrosis, necrosis of the lymphoid cells in the spleen) while L-arginine provoked predominantly congestion, edema and hemorrhages in all organs. The effect of L-NAME was successfully inhibited by the application of L-arginine and BPC 157 but the latter substance did not cause any tissue or organ damage. Hematological analysis shows significant hemoglobin and leukocyte number decrease in the L-NAME-treated groups of chicks.

  13. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  14. Prevention Effects Ameliorate the Prospective Association Between Nonsupportive Parenting and Diminished Telomere Length

    PubMed Central

    Yu, Tianyi; Beach, Steven R. H.; Philibert, Robert A.

    2014-01-01

    Telomere length (TL) is an indicator of general systemic aging, with diminished TL associated with several chronic diseases of aging and with heightened mortality risk. Research has begun to focus on the ways in which stress contributes to telomere attrition. The purposes of this study were (a) to establish whether exposure to nonsupportive parenting, defined as high levels of conflict and rancor with low levels of warmth and emotional support, at age 17 would forecast TL 5 years later; and (b) to determine whether participation in an efficacious family-centered prevention program could ameliorate any associations that emerged. Rural African American adolescents participated in the Adults in the Making (AIM) program or a control condition. Primary caregivers provided data on nonsupportive parenting during a pretest when adolescents were age 17. Adolescents provided data on anger at the pretest and at a posttest administered 7 months later. When the youths were age 22, TL was assayed from a blood draw. The results indicated that heightened nonsupportive parenting forecast diminished TL among young adults in the control condition but not among those who participated in AIM; socioeconomic status risk, life stress, and the use of alcohol and cigarettes at age 17, and blood pressure and body mass index at age 22, were controlled. Subsequent exploratory analyses suggested that AIM-induced reductions in adolescents’ anger served as a mediator connecting group assignment to TL. The results suggest that the cellular-level sequelae of nonsupportive parenting and stress are not immutable. PMID:24599483

  15. When is diminishment a form of enhancement? Rethinking the enhancement debate in biomedical ethics

    PubMed Central

    Earp, Brian D.; Sandberg, Anders; Kahane, Guy; Savulescu, Julian

    2014-01-01

    The enhancement debate in neuroscience and biomedical ethics tends to focus on the augmentation of certain capacities or functions: memory, learning, attention, and the like. Typically, the point of contention is whether these augmentative enhancements should be considered permissible for individuals with no particular “medical” disadvantage along any of the dimensions of interest. Less frequently addressed in the literature, however, is the fact that sometimes the diminishment of a capacity or function, under the right set of circumstances, could plausibly contribute to an individual's overall well-being: more is not always better, and sometimes less is more. Such cases may be especially likely, we suggest, when trade-offs in our modern environment have shifted since the environment of evolutionary adaptation. In this article, we introduce the notion of “diminishment as enhancement” and go on to defend a welfarist conception of enhancement. We show how this conception resolves a number of definitional ambiguities in the enhancement literature, and we suggest that it can provide a useful framework for thinking about the use of emerging neurotechnologies to promote human flourishing. PMID:24550792

  16. Diminished expression of an antiviral ribonuclease in response to pneumovirus infection in vivo.

    PubMed

    Moreau, Joanne M; Dyer, Kimberly D; Bonville, Cynthia A; Nitto, Takeaki; Vasquez, Nora L; Easton, Andrew J; Domachowske, Joseph B; Rosenberg, Helene F

    2003-08-01

    The mouse eosinophil-associated ribonucleases (mEars) are species specific, divergent orthologs of the human antiviral RNase A ribonucleases, eosinophil-derived neurotoxin (RNase 2) and eosinophil cationic protein (RNase 3). We show here that mEar 2 is also an antiviral ribonuclease, as micromolar concentrations promote a approximately sixfold reduction in the infectivity of pneumonia virus of mice (PVM) for target respiratory epithelial cells in vitro. Although initially identified as a component of eosinophilic leukocytes, mEar 2 mRNA and protein were also detected in lung tissue accompanied by enzymatically active mEar 2 in bronchoalveolar lavage fluid (BALF). At t=3 days post-inoculation with PVM (strain J3666), we observed the characteristic inflammatory response accompanied by diminished expression of total mEar mRNA and protein in lung tissue and a corresponding fivefold drop in ribonuclease activity in BALF. No change in mEar expression was observed in response to infection with PVM strain 15, a replication-competent strain of PVM that does not elicit a cellular inflammatory response. However, mEar expression is not directly dependent on inflammation per se, as diminished expression of mEar mRNA and BAL ribonuclease activity were also observed in PVM-infected, inflammation-deficient, MIP-1alpha -/- mice. We propose that this mechanism may represent a novel virus-mediated evasion strategy, with a mechanism that is linked in some fashion to virus-specific pathogenicity.

  17. Diminished foraging performance of a mutant zebrafish with reduced population of ultraviolet cones

    PubMed Central

    Novales Flamarique, Iñigo

    2016-01-01

    Ultraviolet (UV) cones are photoreceptors that sense light in the range 300–450 nm and are found in the retinas of non-mammalian vertebrates and small mammals. Despite their widespread presence across taxa, the functions that these cones exert in the lives of animals remain largely unknown. In this study, I used the zebrafish lor (lots of rods) mutant, characterized by a diminished UV cone population compared to that of wild-type zebrafish, to test whether its foraging performance differed from that of the wild-type (control). The mean location distance and angle (variables that are reliable indicators of foraging performance) at which control fish detected zooplankton prey were, on average, 24 and 90% greater than corresponding measures for lor fish. Such inferior foraging performance of the mutant could be explained by reduced contrast perception of the prey, resulting from the diminished population of UV cones and associated sensitivity. Thus, UV cones enhance the foraging performance of zebrafish, a crucial ecological function that may explain why small zooplanktivorous fishes retain UV cones throughout their lives. PMID:26936243

  18. Boundary Variation Diminishing (BVD) reconstruction: A new approach to improve Godunov schemes

    NASA Astrophysics Data System (ADS)

    Sun, Ziyao; Inaba, Satoshi; Xiao, Feng

    2016-10-01

    This paper presents a new approach, so-called boundary variation diminishing (BVD), for reconstructions that minimize the discontinuities (jumps) at cell interfaces in Godunov type schemes. It is motivated by the observation that diminishing the jump at the cell boundary can effectively reduce the dissipation in numerical flux. Differently from the existing practices which seek high-order polynomials within mesh cells while assuming discontinuities being always at the cell interfaces, the BVD strategy presented in this paper switches between a high-order polynomial and a jump-like reconstruction that allows a discontinuity being partly represented within the mesh cell rather than at the interface. Excellent numerical results have been obtained for both scalar and Euler conservation laws with substantially improved solution quality in comparison with the existing methods. It is shown that new schemes of high fidelity for both continuous and discontinuous solutions can be devised by the BVD guideline with properly-chosen candidate reconstruction schemes. This work provides a simple and accurate alternative of great practical significance to the current high-order Godunov paradigm which overly pursues the smoothness within mesh cells under the questionable premiss that discontinuities only appear at cell interfaces.

  19. Diminished Auditory Responses during NREM Sleep Correlate with the Hierarchy of Language Processing

    PubMed Central

    Furman-Haran, Edna; Arzi, Anat; Levkovitz, Yechiel; Malach, Rafael

    2016-01-01

    Natural sleep provides a powerful model system for studying the neuronal correlates of awareness and state changes in the human brain. To quantitatively map the nature of sleep-induced modulations in sensory responses we presented participants with auditory stimuli possessing different levels of linguistic complexity. Ten participants were scanned using functional magnetic resonance imaging (fMRI) during the waking state and after falling asleep. Sleep staging was based on heart rate measures validated independently on 20 participants using concurrent EEG and heart rate measurements and the results were confirmed using permutation analysis. Participants were exposed to three types of auditory stimuli: scrambled sounds, meaningless word sentences and comprehensible sentences. During non-rapid eye movement (NREM) sleep, we found diminishing brain activation along the hierarchy of language processing, more pronounced in higher processing regions. Specifically, the auditory thalamus showed similar activation levels during sleep and waking states, primary auditory cortex remained activated but showed a significant reduction in auditory responses during sleep, and the high order language-related representation in inferior frontal gyrus (IFG) cortex showed a complete abolishment of responses during NREM sleep. In addition to an overall activation decrease in language processing regions in superior temporal gyrus and IFG, those areas manifested a loss of semantic selectivity during NREM sleep. Our results suggest that the decreased awareness to linguistic auditory stimuli during NREM sleep is linked to diminished activity in high order processing stations. PMID:27310812

  20. Topoisomerase II{alpha} expression correlates with diminished disease-free survival in invasive breast cancer

    SciTech Connect

    O'Connor, John K. . E-mail: joconno@yahoo.com; Hazard, Lisa J.; Lee, R. Jeffrey; Fischbach, Jennifer; Gaffney, David K.

    2006-08-01

    Purpose: Topoisomerase II{alpha} (Topo II{alpha}) plays a role in DNA replication and is the molecular target for anthracyline-based chemotherapy. The purpose of this study was to evaluate the relationship between Topo II{alpha} expression and survival in patients with invasive breast cancer. Methods and Materials: Formalin-fixed, paraffin-embedded tumor specimens from 24 women with invasive breast cancer were stained for Topo II{alpha} expression. All women underwent mastectomy. Radiotherapy was given at University of Utah Department of Radiation Oncology. Of the patients, 23 (96%) received chemotherapy. The level of Topo II{alpha} expression within tumor cells was compared with clinical factors and overall survival. Results: The median percentage of tumor cells expressing Topo II{alpha} was 70%. Increased Topo II{alpha} tumor expression significantly correlated with diminished disease-free survival. Five-year disease-free survival was 100% for patients with <70% of breast cancer cells expressing Topo II{alpha} compared with 42% for patients with {>=}70% Topo II{alpha} expression (p 0.008). The level of Topo II{alpha} expression within tumor cells correlated with T stage (p = 0.008) but not with other pathologic factors. Conclusions: Increased Topo II{alpha} expression significantly correlated with diminished disease-free survival in patients with invasive breast cancer. These findings may indicate a role for Topo II{alpha} expression as a prognostic factor in breast cancer.

  1. Diminished Antimicrobial Peptide and Antifungal Antibiotic Activities against Candida albicans in Denture Adhesive

    PubMed Central

    Bates, Amber M.; Garaicoa, Jorge L.; Fischer, Carol L.; Brogden, Kim A.

    2017-01-01

    The underlying causes of denture stomatitis may be related to the long-term use of adhesives, which may predispose individuals to oral candidiasis. In this study, we hypothesize that antimicrobial peptides and antifungal antibiotics have diminished anti-Candida activities in denture adhesive. To show this, nine antimicrobial peptides and five antifungal antibiotics with and without 1.0% denture adhesive were incubated with Candida albicans strains ATCC 64124 and HMV4C in radial diffusion assays. In gels with 1.0% adhesive, HNP-1, HBD2, HBD3, IP-10, LL37 (only one strain), histatin 5 (only one strain), lactoferricin B, and SMAP28 showed diminished activity against C. albicans. In gels with 1.0% adhesive, amphotericin B and chlorhexidine dihydrochloride were active against both strains of C. albicans. These results suggest that denture adhesive may inactivate innate immune mediators in the oral cavity increasing the risk of C. albicans infections, but inclusion of antifungal antibiotics to denture adhesive may aid in prevention or treatment of Candida infections and denture stomatitis. PMID:28178179

  2. When is diminishment a form of enhancement? Rethinking the enhancement debate in biomedical ethics.

    PubMed

    Earp, Brian D; Sandberg, Anders; Kahane, Guy; Savulescu, Julian

    2014-01-01

    The enhancement debate in neuroscience and biomedical ethics tends to focus on the augmentation of certain capacities or functions: memory, learning, attention, and the like. Typically, the point of contention is whether these augmentative enhancements should be considered permissible for individuals with no particular "medical" disadvantage along any of the dimensions of interest. Less frequently addressed in the literature, however, is the fact that sometimes the diminishment of a capacity or function, under the right set of circumstances, could plausibly contribute to an individual's overall well-being: more is not always better, and sometimes less is more. Such cases may be especially likely, we suggest, when trade-offs in our modern environment have shifted since the environment of evolutionary adaptation. In this article, we introduce the notion of "diminishment as enhancement" and go on to defend a welfarist conception of enhancement. We show how this conception resolves a number of definitional ambiguities in the enhancement literature, and we suggest that it can provide a useful framework for thinking about the use of emerging neurotechnologies to promote human flourishing.

  3. Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: possible role in osmoregulation.

    PubMed

    Hussy, N; Deleuze, C; Pantaloni, A; Desarménien, M G; Moos, F

    1997-08-01

    1. To evaluate the implication of taurine in the physiology of supraoptic neurones, we (i) investigated the agonist properties of taurine on glycine and GABAA receptors of supraoptic magnocellular neurones acutely dissociated from adult rats, using whole-cell voltage clamp, (ii) studied the effects of taurine and strychnine in vivo by extracellular recordings of supraoptic vasopressin neurones in anaesthetized rats, and (iii) measured the osmolarity-dependent release of endogenous taurine from isolated supraoptic nuclei by HPLC. 2. GABA, glycine and taurine evoked rapidly activating currents that all reversed close to the equilibrium potential for Cl-, indicating activation of Cl(-)-selective channels. Glycine-activated currents were reversibly blocked by strychnine (IC50 of 35 nM with 100 microM glycine), but were unaffected by the GABAA antagonist gabazine (1-3 microM). GABA-activated currents were reversibly antagonized by 3 microM gabazine, but not by strychnine (up to 1 microM). 3. Responses to 1 mM taurine were blocked by strychnine but not by gabazine and showed no additivity with glycine-induced currents, indicating selective activation of glycine receptors. Responses to 10 mM taurine were partially antagonized by gabazine, the residual current being blocked by strychnine. Thus, taurine is also a weak agonist of GABAA receptors. 4. In the presence of gabazine, taurine activated glycine receptors with an EC50 of 406 microM. Taurine activated at most 70% of maximal glycine currents, suggesting that it is a partial agonist of glycine receptors. 5. In vivo, locally applied strychnine (300 nM) increased and taurine (1 mM) decreased the basal electrical activity of vasopressin neurones in normally hydrated rats. The effect of strychnine was markedly more pronounced in water-loaded rats. 6. Taurine, which is concentrated in supraoptic glial cells, could be released from isolated supraoptic nuclei upon hyposmotic stimulation. Decreases in osmolarity of 15 and 30

  4. 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists.

    PubMed

    Harmon, Jennifer L; Wills, Lauren P; McOmish, Caitlin E; Demireva, Elena Y; Gingrich, Jay A; Beeson, Craig C; Schnellmann, Rick G

    2016-04-01

    In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) β subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP

  5. Acute exertional anterior compartment syndrome in an adolescent female.

    PubMed

    Fehlandt, A; Micheli, L

    1995-01-01

    Acute compartment syndromes usually occur as a complication of major trauma. While the chronic exertional anterior tibial compartment syndrome is well described in the sports medicine literature, reports of acute tibial compartment syndromes due to physical exertion, or repetitive microtrauma, are rare. The case of an adolescent female who developed an acute anterior compartment syndrome from running in a soccer game is described in this report. Failure to recognize the onset of an acute exertional compartment syndrome may lead to treatment delay and serious complications. Whereas the chronic exertional anterior compartment syndrome is characterized by pain that diminishes with the cessation of exercise, the onset of the acute exertional anterior compartment syndrome is heralded by pain that continues, or increases, after exercise has stopped. Compartment pressure measurement confirms the clinical diagnosis and helps guide treatment. True compartment syndromes require urgent fasciotomy.

  6. Delayed administration of the GLP-1 receptor agonist liraglutide improves metabolic and functional recovery after cerebral ischemia in rats.

    PubMed

    Dong, Wenbin; Miao, Yunping; Chen, Aiying; Cheng, Min; Ye, Xiaodi; Song, Fahuan; Zheng, Gaoli

    2017-02-22

    Glucagon-like peptide 1 receptor (GLP-1R) agonists administered before or immediately after induction of experimental stroke have been shown to provide acute neuroprotection. Here, we determined whether delayed treatment with a GLP-1R agonist could improve metabolic and functional recovery after stroke. Rats were subjected to middle cerebral artery occlusion (MCAO) and given the well-established GLP-1R agonist liraglutide (50, 100, or 200μg/kg) or normal saline (NS) daily for 4 weeks, starting 1 day after MCAO. Cerebral glucose metabolism and neurological deficits were evaluated using (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging and modified neurological severity score (mNSS) test. Levels of neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), von Willebrand factor (vWF), and GLP-1R were assessed by immunohistochemical staining and Western blot analysis. PET imaging showed that animals treated with liraglutide had significantly higher (18)F-FDG accumulation in the cerebral infarction compared with animals treated with NS. Liraglutide significantly reduced the mNSS score. It also greatly increased the expression of NeuN, GFAP, vWF, and GLP-1R in the cerebral ischemic area at postoperative week 4. These results demonstrated metabolic and functional recovery after delayed treatment with liraglutide in a rat model of cerebral ischemia.

  7. Novel Small Molecule Agonist of TGR5 Possesses Anti-Diabetic Effects but Causes Gallbladder Filling in Mice.

    PubMed

    Briere, Daniel A; Ruan, Xiaoping; Cheng, Christine C; Siesky, Angela M; Fitch, Thomas E; Dominguez, Carmen; Sanfeliciano, Sonia Gutierrez; Montero, Carlos; Suen, Chen S; Xu, Yanping; Coskun, Tamer; Michael, M Dodson

    2015-01-01

    Activation of TGR5 via bile acids or bile acid analogs leads to the release of glucagon-like peptide-1 (GLP-1) from intestine, increases energy expenditure in brown adipose tissue, and increases gallbladder filling with bile. Here, we present compound 18, a non-bile acid agonist of TGR5 that demonstrates robust GLP-1 secretion in a mouse enteroendocrine cell line yet weak GLP-1 secretion in a human enteroendocrine cell line. Acute administration of compound 18 to mice increased GLP-1 and peptide YY (PYY) secretion, leading to a lowering of the glucose excursion in an oral glucose tolerance test (OGTT), while chronic administration led to weight loss. In addition, compound 18 showed a dose-dependent increase in gallbladder filling. Lastly, compound 18 failed to show similar pharmacological effects on GLP-1, PYY, and gallbladder filling in Tgr5 knockout mice. Together, these results demonstrate that compound 18 is a mouse-selective TGR5 agonist that induces GLP-1 and PYY secretion, and lowers the glucose excursion in an OGTT, but only at doses that simultaneously induce gallbladder filling. Overall, these data highlight the benefits and potential risks of using TGR5 agonists to treat diabetes and metabolic diseases.

  8. Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator.

    PubMed

    Montesinos, M Carmen; Desai-Merchant, Avani; Cronstein, Bruce N

    2015-12-01

    Impaired wound healing, as it occurs in diabetes mellitus or long-term corticoid treatment, is commonly associated with disability, diminished quality of life, and high economic costs. Selective agonists of the A2A receptor subtype of adenosine, an endogenous regulator of inflammation, promote tissue repair in animal models, both healthy and with impaired healing. Plasmin-mediated proteolysis of fibrin and other matrix proteins is essential for cell migration at sites of injury. Since adenosine A2A receptor activation increases plasminogen activator release from macrophages and mast cells, we studied the effect of a selective agonist, CGS-21680, on full-thickness excisional wound closure in wild-type, urokinase plasminogen activator (uPA)-deficient, and tissue plasminogen activator (tPA)-deficient mice. Wound closure was impaired in tPA- and uPA-deficient mice as compared with wild-type mice, and topical application of CGS-21680 significantly increased the rate at which wounds closed in wild-type mice and uPA-deficient mice, but not in tPA-deficient mice. Immunostaining of tissue sections showed that tPA was present in endothelial cells and histiocytes by day 3 post-wound and also by day 6. In contrast, uPA was more prominent in these cell types only by day 6 post-wound. Our results confirm that plasminogen activation contributes to wound repair and are consistent with the hypothesis that adenosine A2A receptor activation promotes wound closure by a mechanism that depends upon tPA, but not uPA. Moreover, our results suggest that topical adenosine A2A receptor agonists may be useful in promotion of wound closure in patients with impaired wound healing.

  9. Cooperation of structurally different aryl hydrocarbon receptor agonists and β-catenin in the regulation of CYP1A expression.

    PubMed

    Vaas, Sebastian; Kreft, Luisa; Schwarz, Michael; Braeuning, Albert

    2014-11-05

    The ligand-activated nuclear receptor AhR (aryl hydrocarbon receptor) mediates the response of hepatocytes to various exogenous compounds. AhR is classically activated by planar, aromatic hydrocarbons, but also by other, structurally rather unrelated compounds. Recent data show that the canonical Wnt/β-catenin signaling pathway is also involved in the regulation of hepatic zonal gene expression and drug metabolism in mammalian liver. Previous studies indicate that the loss of β-catenin in hepatocytes diminishes the response to the AhR agonists 3-methylcholanthrene (3MC) in vivo and to 2,3,7,8-tetrachlorodibenzo-[p]-dioxin in vitro. The knockout of β-catenin also impairs the zonal pattern of AhR target gene induction by 3MC. However, it is presently unknown whether the chemical nature of the AhR agonist influences the AhR/β-catenin interaction. Moreover, no information is available about the dose-response curves of AhR activation in the absence or presence of Wnt/β-catenin signaling. In the present study, we have analyzed AhR-dependent responses to different concentrations of structurally unrelated AhR agonists in vivo and in vitro. The results demonstrate that β-catenin is essential to obtain the maximum AhR response. Moreover, using transgenic mouse models which allow for the ablation of β-catenin at different age of mice, we demonstrate that the presence of β-catenin, not postnatal developmental effects in β-catenin-deficient livers, is responsible for the observed interplay of β-catenin and the AhR.

  10. A screen for Fli-1 transcriptional modulators identifies PKC agonists that induce erythroid to megakaryocytic differentiation and suppress leukemogenesis.

    PubMed

    Liu, Tangjingjun; Yao, Yao; Zhang, Gang; Wang, Ye; Deng, Bin; Song, Jialei; Li, Xiaogang; Han, Fei; Xiao, Xiao; Yang, Jue; Xia, Lei; Li, You-Jun; Plachynta, Maksym; Zhang, Mu; Yan, Chen; Mu, Shuzhen; Luo, Heng; Zacksenhaus, Eldad; Hao, Xiaojiang; Ben-David, Yaacov

    2016-12-30

    The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. Fli-1 was initially isolated following retrovirus insertional mutagenesis screens for leukemic initiator genes, and accordingly, inhibition of this transcription factor can suppress leukemia through induction of erythroid differentiation. To search for modulators of Fli-1, we hereby performed repurposing drug screens with compounds isolated from Chinese medicinal plants. We identified agents that can transcriptionally activate or inhibit a Fli-1 reporter. Remarkably, agents that increased Fli-1 transcriptional activity conferred a strong anti-cancer activity upon Fli-1-expressing leukemic cells in culture. As opposed to drugs that suppress Fli1 activity and lead to erythroid differentiation, growth suppression by these new Fli-1 transactivating compounds involved erythroid to megakaryocytic conversion (EMC). The identified compounds are structurally related to diterpene family of small molecules, which are known agonists of protein kinase C (PKC). In accordance, these PKC agonists (PKCAs) induced PKC phosphorylation leading to activation of the mitogen-activated protein kinase (MAPK) pathway, increased cell attachment and EMC, whereas pharmacological inhibition of PKC or MAPK diminished the effect of our PKCAs. Moreover, in a mouse model of leukemia initiated by Fli-1 activation, the PKCA compounds exhibited strong anti-cancer activity, which was accompanied by increased presence of CD41/CD61 positive megakaryocytic cells in leukemic spleens. Thus, PKC agonists offer a novel approach to combat Fli-1-induced leukemia, and possibly other cancers,by inducing EMC in part through over-activation of the PKC-MAPK-Fli-1 pathway.

  11. Agonist-induced changes in the phosphorylation of the myosin- binding subunit of myosin light chain phosphatase and CPI17, two regulatory factors of myosin light chain phosphatase, in smooth muscle.

    PubMed Central

    Niiro, Naohisa; Koga, Yasuhiko; Ikebe, Mitsuo

    2003-01-01

    The inhibition of myosin light chain phosphatase (MLCP) enhances smooth muscle contraction at a constant [Ca2+]. There are two components, myosin-binding subunit of MLCP (MBS) and CPI17, thought to be responsible for the inhibition of MLCP by external stimuli. The phosphorylation of MBS at Thr-641 and of CPI17 at Thr-38 inhibits the MLCP activity in vitro. Here we determined the changes in the phosphorylation of MBS and CPI17 after agonist stimulation in intact as well as permeabilized smooth muscle strips using phosphorylation-site-specific antibodies as probes. The CPI17 phosphorylation transiently increased after agonist stimulation in both alpha-toxin skinned and intact fibres. The time course of the increase in CPI17 phosphorylation after stimulation correlated with the increase in myosin regulatory light chain (MLC) phosphorylation. The increase in CPI17 phosphorylation was significantly diminished by Y27632, a Rho kinase inhibitor, and GF109203x, a protein kinase C inhibitor, suggesting that both the protein kinase C and Rho kinase pathways influence the change in CPI17 phosphorylation. On the other hand, a significant level of MBS phosphorylation at Thr-641, an inhibitory site, was observed in the resting state for both skinned and intact fibres and the agonist stimulation did not significantly alter the MBS phosphorylation level at Thr-641. While the removal of the agonist markedly decreased MLC phosphorylation and induced relaxation, the phosphorylation of MBS was unchanged, while CPI17 phosphorylation markedly diminished. These results strongly suggest that the phosphorylation of CPI17 plays a more significant role in the agonist-induced increase in myosin phosphorylation and contraction of smooth muscle than MBS phosphorylation in the Ca2+-independent activation mechanism of smooth muscle contraction. PMID:12296769

  12. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  13. Postnatal treatment of rats with adrenergic receptor agonists or antagonists influences differentiation of sexual behavior.

    PubMed

    Jarzab, B; Sickmöller, P M; Geerlings, H; Döhler, K D

    1987-12-01

    The aim of the study was to investigate the possible role of the adrenergic system in development and differentiation of neural centers controlling sexual behavior in adulthood. For this purpose normal and androgenized female rats were treated with the alpha 1-receptor antagonist prazosin, the alpha 2-receptor agonist clonidine, or the alpha 2-receptor antagonist yohimbine-HCl throughout the first week of life. In adulthood all animals were ovariectomized and, after appropriate hormone-priming, they were tested for the capacity to display female and male sexual behavior patterns. Alteration of adrenergic transmission during the critical postnatal period for sexual differentiation of neural centers resulted in significant changes in the capacity to express female lordosis behavior in adulthood. In nonandrogenized animals clonidine significantly reduced the capacity for lordosis behavior. In androgenized animals clonidine had the opposite effect; it attenuated the inhibitory effect of testosterone propionate (TP) on differentiation of lordosis behavior. Prazosin, which was without effect in nonandrogenized animals, also attenuated the inhibitory effect of TP on differentiation of lordosis behavior. Yohimbine was without effect in androgenized and nonandrogenized animals. There was no influence of any of the adrenergic drugs on differentiation of male sexual behavior. In conclusion, differentiation of lordosis behavior seems to be mediated or modulated via adrenergic transmission. The defeminizing effect of testosterone postnatally on the differentiation of lordosis behavior seems to be expressed via alpha 1-adrenergic transmission, and diminished adrenergic activity during the postnatal period seems to protect the developing brain against this effect of testosterone.

  14. Investigational peptide and peptidomimetic μ and δ opioid receptor agonists in the relief of pain

    PubMed Central

    Giri, Aswini Kumar; Hruby, Victor J

    2014-01-01

    Introduction Current methods for treating prolonged and neuropathic pain are inadequate and lead to toxicities that greatly diminish quality of life. Therefore, new approaches to the treatment of pain states are needed to address these problems. Areas covered The review primarily reviews approaches that have been taken in the peer-reviewed literature of multivalent ligands that interact with both μ and δ opioid receptors as agonists, and in some cases, also with pharmacophores for antagonist ligands that interact with other receptors as antagonists to block pain. Expert opinion Although there are a number of drugs currently on the market for the treatment of pain; none of them are 100% successful. In the authors’ opinion, it is clear that new directions and modalities are needed to better address the treatment of prolonged and neuropathic pain; one drug or class clearly is not the answer for all pain therapy. Undoubtedly, there are many different phenotypes of prolonged and neuropathic pain and this should be one avenue to further develop appropriate therapies. PMID:24329035

  15. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  16. Hydrogen sulfide diminishes the levels of thymic stromal lymphopoietin in activated mast cells.

    PubMed

    Han, Na-Ra; Moon, Phil-Dong; Jeong, Hyun-Ja; Kim, Hyung-Min

    2016-03-01

    Bamboo salt (BS) is a Korean traditional type of salt and has been reported to have therapeutic effects on allergic inflammation. Thymic stromal lymphopoietin (TSLP) aggravates inflammation in the pathogenesis of allergic reactions, such as allergic rhinitis (AR). To confirm an active compound of BS, we investigated the effect of sulfur, a compound of BS, on the levels of TSLP in a human mast cell line, HMC-1 cells and a mouse model of AR using hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaSH). We treated NaSH or BS in HMC-1 cells and activated the HMC-1 cells with phorbol myristate acetate and calcium ionophore A23187 (PMACI). ELISA for the production measurement of TSLP, PCR for the mRNA expression measurement of TSLP, and western blot analysis for the expression measurement of upstream mediators were performed. Mice were treated with NaSH and sensitized with ovalbumin (OVA). The levels of TSLP were measured in serum and nasal mucosa tissue in an OVA-induced AR mouse model. NaSH or BS diminished the production and mRNA expression of TSLP as well as interleukin (IL)-6 and tumor necrosis factor (TNF)-α in the PMACI-activated HMC-1 cells. NaSH or BS diminished the level of intracellular calcium in the PMACI-activated HMC-1 cells. NaSH or BS reduced the expression and activity of caspase-1 in the PMACI-activated HMC-1 cells. And NaSH or BS inhibited the expression of receptor interacting protein-2 and the phosphorylation of extracellular signal-regulated kinase in the PMACI-activated HMC-1 cells. The translocation of NF-κB into the nucleus as well as the phosphorylation and degradation of IκBα in the cytoplasm were diminished by NaSH or BS in the PMACI-activated HMC-1 cells. Furthermore, NaSH inhibited the production of TSLP, IL-6, and IL-8 in TNF-α-activated HMC-1 cells. Finally, the administration of NaSH showed a decrease in number of rubs on mice with OVA-induced AR. And the levels of immunoglobulin E and TSLP in the serum and the level of TSLP in the

  17. Acute Pancreatitis

    PubMed Central

    Geokas, Michael C.

    1972-01-01

    For many decades two types of acute pancreatitis have been recognized: the edematous or interstitial and the hemorrhagic or necrotic. In most cases acute pancreatitis is associated with alcoholism or biliary tract disease. Elevated serum or urinary α-amylase is the most important finding in diagnosis. The presence of methemalbumin in serum and in peritoneal or pleural fluid supports the diagnosis of the hemorrhagic form of the disease in patients with a history and enzyme studies suggestive of pancreatitis. There is no characteristic clinical picture in acute pancreatitis, and its complications are legion. Pancreatic pseudocyst is probably the most common and pancreatic abscess is the most serious complication. The pathogenetic principle is autodigestion, but the precise sequence of biochemical events is unclear, especially the mode of trypsinogen activation and the role of lysosomal hydrolases. A host of metabolic derangements have been identified in acute pancreatitis, involving lipid, glucose, calcium and magnesium metabolism and changes of the blood clotting mechanism, to name but a few. Medical treatment includes intestinal decompression, analgesics, correction of hypovolemia and other supportive and protective measures. Surgical exploration is advisable in selected cases, when the diagnosis is in doubt, and is considered imperative in the presence of certain complications, especially pancreatic abscess. PMID:4559467

  18. Implicit Total Variation Diminishing (TVD) schemes for steady-state calculations

    NASA Technical Reports Server (NTRS)

    Yee, H. C.; Warming, R. F.; Harten, A.

    1983-01-01

    The application of a new implicit unconditionally stable high resolution total variation diminishing (TVD) scheme to steady state calculations. It is a member of a one parameter family of explicit and implicit second order accurate schemes developed by Harten for the computation of weak solutions of hyperbolic conservation laws. This scheme is guaranteed not to generate spurious oscillations for a nonlinear scalar equation and a constant coefficient system. Numerical experiments show that this scheme not only has a rapid convergence rate, but also generates a highly resolved approximation to the steady state solution. A detailed implementation of the implicit scheme for the one and two dimensional compressible inviscid equations of gas dynamics is presented. Some numerical computations of one and two dimensional fluid flows containing shocks demonstrate the efficiency and accuracy of this new scheme.

  19. Glutathione diminishes tributyltin- and dibutyltin-induced loss of lytic function in human natural killer cells.

    PubMed

    Powell, Jeralyn J; Davis, McLisa V; Whalen, Margaret M

    2009-01-01

    This study investigated whether reduced glutathione (GSH) was able to alter the negative effects of tributyltin (TBT) or dibutyltin (DBT) on the lytic function of human natural killer (NK) cells. NK cells are an initial immune defense against the development of tumors or viral infections. TBT and DBT are widespread environmental contaminants, due to their various industrial applications. Both TBT and DBT have been shown to decrease the ability of NK cells to lyse tumor cells (lytic function). The results indicated that the presence of GSH during the exposure of NK cells to TBT or DBT diminished the negative effect of the butyltin on the lytic function of NK cells. This suggests that the interaction of TBT and DBT with functionally relevant sulfhydryl groups in NK cells may be part of the mechanism by which they decrease NK lytic function.

  20. Marching into battle: synchronized walking diminishes the conceptualized formidability of an antagonist in men

    PubMed Central

    Fessler, Daniel M. T.; Holbrook, Colin

    2014-01-01

    Paralleling behaviours in other species, synchronized movement is central to institutionalized collective human activities thought to enhance cooperation, and experiments demonstrate that synchrony has this effect. The influence of synchrony on cooperation may derive from an evolutionary history wherein such actions served to signal coalitional strength to both participants and observers—including adversaries. If so, then synchronous movement should diminish individuals' estimations of a foe's formidability. Envisioned physical size and strength constitute the dimensions of a representation that summarizes relative fighting capacity. Experiencing synchrony should therefore lead individuals to conceptualize an antagonist as smaller and weaker. We found that men who walked synchronously with a male confederate indeed envisioned a purported criminal as less physically formidable than did men who engaged in this task without synchronizing. PMID:25165456

  1. "Queasy does it": false alcohol beliefs and memories may lead to diminished alcohol preferences.

    PubMed

    Clifasefi, Seema L; Bernstein, Daniel M; Mantonakis, Antonia; Loftus, Elizabeth F

    2013-05-01

    Studies have shown that false memories can be implanted via innocuous suggestions, and that these memories can play a role in shaping people's subsequent attitudes and preferences. The current study explored whether participants (N=147) who received a false suggestion that they had become ill drinking a particular type of alcohol would increase their confidence that the event had occurred, and whether their new-found belief would subsequently affect their alcohol preferences. Results indicated that participants who received a suggestion that they had gotten sick drinking rum or vodka before the age of 16 reported increased confidence that the suggested experience had occurred. Moreover, participants who received a false alcohol suggestion also showed a strong trend to report diminished preference for the specified type of alcohol after the false suggestion. Implantation of a false memory related to one's past drinking experiences may influence current drink preferences and could be an important avenue for further exploration in the development of alcohol interventions.

  2. Metacognitive monitoring and control processes in children with autism spectrum disorder: Diminished judgement of confidence accuracy.

    PubMed

    Grainger, Catherine; Williams, David M; Lind, Sophie E

    2016-05-01

    Metacognition consists of monitoring processes (the ability to accurately represent one's own mental states) and control processes (the ability to control one's cognitive processes effectively). Both processes play vital roles in self-regulated learning. However, currently it is unclear whether these processes are impaired in individuals with autism spectrum disorders (ASDs). This study aimed to assess metacognition in thirty-two children with ASD, and 30 IQ-/age-matched neurotypical children, using a judgment of confidence task. It was found that children with ASD showed diminished accuracy in their judgments of confidence, indicating metacognitive monitoring impairments in ASD. Children with ASD also used monitoring to influence control processes significantly less than neurotypical children, despite little evidence of impairments in overall control ability.

  3. Comparisons of TVD schemes applied to the Navier-Stokes equations. [total variation diminishing

    NASA Technical Reports Server (NTRS)

    Buelow, Philip E.

    1989-01-01

    In this study, the following total variation diminishing (TVD) schemes for solving the Navier-Stokes equations have been tested: the Chakravarthy and Szema (1985) upwind biased TVD scheme, the Harten's upwind TVD scheme described by Yee et al. (1983), and the Yee's (1985) symmetric TVD scheme. The schemes have been compared using three test cases. The first case was the one-dimensional shock tube problem which tested the shock-capturing abilities of the schemes. Chakravarthy's and Harten's schemes gave similar results which were found to be more accurate than the results from Yee's scheme. The second case was a compressible boundary layer which tested the schemes's abilities to solve fiscous flows. In this case, the three schemes yielded almost identical results. Finally, the shock/boundary-layer interaction case studied experimentally by Hakkinen et al. (1959) was computed. Here, Chakravarthy's and Yee's schemes compared most favorably with the published data, with Yee's scheme giving slightly better results.

  4. Diminishing Risk for Age-Related Macular Degeneration with Nutrition: A Current View

    PubMed Central

    Schleicher, Molly; Weikel, Karen; Garber, Caren; Taylor, Allen

    2013-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Clinical hallmarks of AMD are observed in one third of the elderly in industrialized countries. Preventative interventions through dietary modification are attractive strategies, because they are more affordable than clinical therapies, do not require specialists for administration and many studies suggest a benefit of micro- and macro-nutrients with respect to AMD with few, if any, adverse effects. The goal of this review is to provide information from recent literature on the value of various nutrients, particularly omega-3 fatty acids, lower glycemic index diets and, perhaps, some carotenoids, with regard to diminishing risk for onset or progression of AMD. Results from the upcoming Age-Related Eye Disease Study (AREDS) II intervention trial should be particularly informative. PMID:23820727

  5. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone

    PubMed Central

    Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H.A.; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K.; Connor, James; Giasson, Benoit; Harris, Z. Leah; Dunaief, Joshua L.

    2016-01-01

    Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. PMID:26303407

  6. Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration

    PubMed Central

    Painter, Michio W.; Brosius Lutz, Amanda; Cheng, Yung-Chih; Latremoliere, Alban; Duong, Kelly; Miller, Christine M.; Posada, Sean; Cobos, Enrique J.; Zhang, Alice X.; Wagers, Amy J.; Havton, Leif A.; Barres, Ben; Omura, Takao

    2014-01-01

    SUMMARY The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro nor in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired de-differentiation, myelin clearance and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance. PMID:25033179

  7. Market value of asteroidal precious metals in an age of diminishing terrestrial resources

    USGS Publications Warehouse

    Kargel, Jeffrey S.; ,

    1996-01-01

    In the next century Mankind may have to choose from two options for our supply and usage of some nonrenewable natural resources, such as gold, platinum metals, and fossil fuels: learn to live with diminishing supplies of these materials obtained at ever increasing economic and environmental cost, or reach into difficult places and develop new technologies to give us what we need to sustain economic growth. Either prospect faces formidable technological and economic challenges. Exploitation of asteroids for precious and strategic metals is a possible environmentally friendly remedy for impending shortages of some resources. Certain types of asteroids could completely replace terrestrial sources of platinum metals. Asteroid metal mining may become a 21st-century space industry worth ten to fifty billion dollars annually (1995 dollars). Asteroids could make the United States and other countries self sufficient in many strategic metals, and it could usher new technologies and increase our applications of existing technologies that depend on these metals.

  8. Rehearsal strategies can enlarge or diminish the spacing effect: pure versus mixed lists and encoding strategy.

    PubMed

    Delaney, Peter F; Verkoeijen, Peter P J L

    2009-09-01

    Using 5 experiments, the authors explored the dependency of spacing effects on rehearsal patterns. Encouraging rehearsal borrowing produced opposing effects on mixed lists (containing both spaced and massed repetitions) and pure lists (containing only one or the other), magnifying spacing effects on mixed lists but diminishing spacing effects on pure lists. Rehearsing with borrowing produced large spacing effects on mixed lists but not on pure lists for both free recall (Experiment 1) and recognition (Experiment 2). In contrast, rehearsing only the currently visible item produced spacing effects on both mixed lists and pure lists in free recall (Experiment 3) and recognition (Experiment 4). Experiment 5 demonstrated these effects using a fully within-subjects design. Rehearse-aloud protocols showed that rehearsal borrowing redistributed study from massed to spaced items on mixed lists, especially during massed presentations.

  9. [Acute myocardial infarction during tocolytic treatment with ritodrine].

    PubMed

    Fornet, I; Calvo, M; Gimeno, M; Canser, E; Alonso, E; Gilsanz, F

    2006-05-01

    Ritodrine, a beta2-adrenergic agonist with a selective effect on the uterine muscle, is prescribed to prevent premature labor and to treat a hypertonic uterus. At therapeutic doses ritodrine has chronotropic and peripheral vasodilator effects. At high doses it has been related to sporadic cases of subendocardial necrosis, pulmonary edema, and death in pregnancy. We report the case of a pregnant woman who had a non-Q wave acute myocardial infarction after administration of ritodrine.

  10. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,4)-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter (3H)SR 95531 (2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter (3H)Ro15-4513 or (3H)flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.

  11. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    PubMed

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K

    1991-07-01

    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  12. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  13. Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

    PubMed Central

    Voulalas, Pamela J.; Ji, Yadong; Jiang, Li; Asgar, Jamila; Ro, Jin Y.; Masri, Radi

    2016-01-01

    Neuropathic pain resulting from spinal cord injury is often accompanied by maladaptive plasticity of the central nervous system, including the opioid receptor-rich periaqueductal gray (PAG). Evidence suggests that sensory signaling via the PAG is robustly modulated by dopamine D1- and D2-like receptors, but the effect of damage to the spinal cord on D1 and D2 receptor protein expression and function in the PAG has not been examined. Here we show that 21 days after a T10 or C6 spinothalamic tract lesion, both mice and rats display a remarkable decline in the expression of D1 receptors in the PAG, revealed by western blot analysis. These changes were associated with a significant reduction in hindpaw withdrawal thresholds in lesioned animals compared to sham-operated controls. We investigated the consequences of diminished D1 receptor levels by quantifying D1-like receptor-mediated phosphorylation of ERK1,2 and CREB, events that have been observed in numerous brain structures. In naïve animals, western blot analysis revealed that ERK1,2, but not CREB phosphorylation was significantly increased in the PAG by the D1-like agonist SKF 81297. Using immunohistochemistry, we found that SKF 81297 increased ERK1,2 phosphorylation in the PAG of sham animals. However, in lesioned animals, basal pERK1,2 levels were elevated and did not significantly increase after exposure to SKF 81297. Our findings provide support for the hypothesis that molecular adaptions resulting in a decrease in D1 receptor expression and signaling in the PAG are a consequence of SCL. PMID:27932310

  14. Vision-guided ocular growth in a mutant chicken model with diminished visual acuity

    PubMed Central

    Ritchey, Eric R.; Zelinka, Christopher; Tang, Junhua; Liu, Jun; Code, Kimberly A.; Petersen-Jones, Simon; Fischer, Andy J.

    2012-01-01

    Visual experience is known to guide ocular growth. We tested the hypothesis that vision-guided ocular growth is disrupted in a model system with diminished visual acuity. We examine whether ocular elongation is influenced by form-deprivation (FD) and lens-imposed defocus in the Retinopathy, Globe Enlarged (RGE) chicken. Young RGE chicks have poor visual acuity, without significant retinal pathology, resulting from a mutation in guanine nucleotide-binding protein β3 (GNB3), also known as transducin β3 or Gβ3. The mutation in GNB3 destabilizes the protein and causes a loss of Gβ3 from photoreceptors and ON-bipolar cells. (Ritchey et al. 2010)FD increased ocular elongation in RGE eyes in a manner similar to that seen in wild-type (WT) eyes. By comparison, the excessive ocular elongation that results from hyperopic defocus was increased, whereas myopic defocus failed to significantly decrease ocular elongation in RGE eyes. Brief daily periods of unrestricted vision interrupting FD prevented ocular elongation in RGE chicks in a manner similar to that seen in WT chicks. Glucagonergic amacrine cells differentially expressed the immediate early gene Egr1 in response to growth-guiding stimuli in RGE retinas, but the defocus-dependent up-regulation of Egr1 was lesser in RGE retinas compared to that of WT retinas. We conclude that high visual acuity, and the retinal signaling mediated by Gβ3, is not required for emmetropization and the excessive ocular elongation caused by FD and hyperopic defocus. However, the loss of acuity and Gβ3 from RGE retinas causes enhanced responses to hyperopic defocus and diminished responses to myopic defocus. PMID:22824538

  15. Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1

    PubMed Central

    Xu, Wenjie; Aleynikov, Tatyana; Cullen, Paul J.; Lanni, Frederick; Andes, David R.

    2016-01-01

    Biofilm formation on implanted medical devices is a major source of lethal invasive infection by Candida albicans. Filamentous growth of this fungus is tied to biofilm formation because many filamentation-associated genes are required for surface adherence. Cell cycle or cell growth defects can induce filamentation, but we have limited information about the coupling between filamentation and filamentation-associated gene expression after cell cycle/cell growth inhibition. Here we identified the CDK activating protein kinase Cak1 as a determinant of filamentation and filamentation-associated gene expression through a screen of mutations that diminish expression of protein kinase-related genes implicated in cell cycle/cell growth control. A cak1 diminished expression (DX) strain displays filamentous growth and expresses filamentation-associated genes in the absence of typical inducing signals. In a wild-type background, expression of filamentation-associated genes depends upon the transcription factors Bcr1, Brg1, Efg1, Tec1, and Ume6. In the cak1 DX background, the dependence of filamentation-associated gene expression on each transcription factor is substantially relieved. The unexpected bypass of filamentation-associated gene expression activators has the functional consequence of enabling biofilm formation in the absence of Bcr1, Brg1, Tec1, Ume6, or in the absence of both Brg1 and Ume6. It also enables filamentous cell morphogenesis, though not biofilm formation, in the absence of Efg1. Because these transcription factors are known to have shared target genes, we suggest that cell cycle/cell growth limitation leads to activation of several transcription factors, thus relieving dependence on any one. PMID:27935965

  16. Chronic Alternate Day Fasting Results in Reduced Diastolic Compliance and Diminished Systolic Reserve in Rats

    PubMed Central

    Ahmet, Ismayil; Wan, Ruiqian; Mattson, Mark P; Lakatta, Edward G.; Talan, Mark I.

    2010-01-01

    Background Based on animal experiments and limited data from few human trials, alternate day fasting (ADF) resulted in weight loss; prolonged life; reduced metabolic risk factors for diabetes and cardiovascular diseases; and reduced prevalence of age-related diseases. The present study is the first comprehensive examination of the long-term effects of ADF on general cardiovascular fitness in rats. Methods and Results Four months old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months with serial echocardiography. A comprehensive hemodynamic evaluation including a combined dobutamine - volume stress test was performed at the end of the study, and hearts were harvested for histological assessment. The six-month long ADF diet resulted in a 9% reduction (p<0.01) of cardiomyocyte diameter and 3 fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the E/A in Doppler-measured mitral flow was reduced (p<0.01). Pressure-volume loop analyses revealed a “stiff” heart during diastole in ADF rats, while combined dobutamine and volume loading showed a significant reduction in LV diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve. Conclusion Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted. PMID:20932467

  17. Diminished pulmonary function in pectus excavatum: from denying the problem to finding the mechanism

    PubMed Central

    Obermeyer, Robert J.; Nuss, Donald

    2016-01-01

    Background Recently, technical improvement in the ability to measure lung function and the severity of chest deformity have enabled progress in understanding the mechanism of limitations of lung function in pectus excavatum. Methods After establishing that most patients with pectus excavatum do have symptoms of exercise intolerance, easy fatigability, and shortness of breath with exertion, lung function has been evaluated by a variety of methods in different centers. Spirometry, plethysmography, exercise testing, oculo electronic plethysmography, and imaging methods have been used to assess lung function in pectus excavatum and its response to surgery. Results Not all patients with pectus excavatum have subnormal static pulmonary function testing; some have above-average values. However, in more than 1500 adult and pediatric surgical patients with anatomically severe pectus excavatum at a single center, the bell curve of FVC, FEV1, and FEF 25-75 is shifted to significantly lower values in pectus excavatum. The curve is shifted to higher values after operation by approximately one standard deviation. Previous work has demonstrated that patients with more anatomically severe pectus excavatum are more likely to have diminished PFT’s. A mechanism for this effect is seen by oculo electronic plethysmography, which demonstrates that the depressed portion of the chest does not move on respiration. After Nuss procedure, the chest wall motion used to create suction to draw air into the lungs is indistinguishable from that of persons with a normal chest, and the intrathoracic volume is markedly increased. Conclusions Pectus excavatum is accompanied in most patients by diminished static pulmonary function. Correction by Nuss procedure results in improvement in chest wall motion; this improvement in the thoracic bellows action is accompanied by improvement in pulmonary function testing. PMID:27747180

  18. Behavioural Adaptation to diminished Gravity in Fish - a Parabolic Aircraft Flight Study

    NASA Astrophysics Data System (ADS)

    Forster, A.; Anken, R.; Hilbig, R.

    During the micro gravity phases in the course of parabolic aircraft flights PFs some fish of a given batch were frequently shown to exhibit sensorimotor disorders in terms of revealing so-called looping responses LR or spinning movements SM both forms of motion sickness a kinetosis In order to gain some insights into the time-course of the behavioural adaptation towards diminished gravity in total 272 larval cichlid fish Oreochromis mossambicus were subjected to PFs and their respective behaviour was monitored With the onset of the first parabola P1 15 9 of the animals revealed a kinetotic behaviour whereas kinetoses were shown in 6 5 1 5 and 1 of the animals in P5 P10 and P15 With P20 the animals had adapted completely 0 swimming kinetotically Since the relative decrease of kinetotic animals was especially prominent from P5 to P10 a detailed analysis of the behaviour was undertaken Regarding SM a ratio of 2 9 in P5 decreased to 0 5 in P10 Virtually all individuals showing a SM in P5 had regained a normal behaviour with P10 The SM animals in P10 had all exhibited a normal swimming behaviour in P5 The ratio of LR-fish also decreased from P5 3 6 to P10 1 0 In contrast to the findings regarding SM numerous LM specimens did not regain a normal postural control and only very few animals behaving normally in P5 began to sport a LM behaviour by P10 Summarizing most kinetotic animals rapidly adapted to diminished gravity but few individual fish who swam normally at the beginning of the flights may loose sensorimotor control

  19. Mechanisms of diminished natural killer cell activity in pregnant women and neonates

    SciTech Connect

    Baley, J.E.; Schacter, B.Z.

    1985-05-01

    Because alterations in natural killer (NK) activity in the perinatal period may be important in the maintenance of a healthy pregnancy, the mechanisms by which these alterations are mediated in neonates and in pregnant and postpartum women was examined. NK activity, as measured in a 4-hr /sup 51/Cr-release assay and compared with adult controls, is significantly diminished in all three trimesters of pregnancy and in immediately postpartum women. In postpartum women, NK activity appears to be higher than in pregnant women, although this does not reach statistical significance. Pregnant and postpartum women have normal numbers of large granular lymphocytes and normal target cell binding in an agarose single cell assay but decreased lysis of the bound target cells. NK activity of mononuclear cells from postpartum women, in addition, demonstrate a shift in distribution to higher levels of resistance to gamma-irradiation. Further, sera from postpartum women cause a similar shift to increased radioresistance in mononuclear cells from adult controls. Because radioresistance is a property of interleukin 2-stimulated NK, the shift to radioresistance may represent lymphokine-mediated stimulation occurring during parturition. In contrast, cord blood cells have a more profound decrease in NK activity as determined by /sup 51/Cr-release assay and decreases in both binding and lysis of bound target cells in the single cell assay. The resistance of NK activity in cord cells to gamma-irradiation is also increased, as seen in postpartum women. Cord blood serum, however, did not alter radioresistance or inhibit NK activity. The results suggest that the observed diminished NK activity in pregnant women and neonates arise by different mechanisms: an absence of mature NK cells in the neonate and an alteration of the NK cell in pregnancy leading to decreased killing.

  20. Vision-guided ocular growth in a mutant chicken model with diminished visual acuity.

    PubMed

    Ritchey, Eric R; Zelinka, Christopher; Tang, Junhua; Liu, Jun; Code, Kimberly A; Petersen-Jones, Simon; Fischer, Andy J

    2012-09-01

    Visual experience is known to guide ocular growth. We tested the hypothesis that vision-guided ocular growth is disrupted in a model system with diminished visual acuity. We examine whether ocular elongation is influenced by form-deprivation (FD) and lens-imposed defocus in the Retinopathy, Globe Enlarged (RGE) chicken. Young RGE chicks have poor visual acuity, without significant retinal pathology, resulting from a mutation in guanine nucleotide-binding protein β3 (GNB3), also known as transducin β3 or Gβ3. The mutation in GNB3 destabilizes the protein and causes a loss of Gβ3 from photoreceptors and ON-bipolar cells (Ritchey et al., 2010). FD increased ocular elongation in RGE eyes in a manner similar to that seen in wild-type (WT) eyes. By comparison, the excessive ocular elongation that results from hyperopic defocus was increased, whereas myopic defocus failed to significantly decrease ocular elongation in RGE eyes. Brief daily periods of unrestricted vision interrupting FD prevented ocular elongation in RGE chicks in a manner similar to that seen in WT chicks. Glucagonergic amacrine cells differentially expressed the immediate early gene Egr1 in response to growth-guiding stimuli in RGE retinas, but the defocus-dependent up-regulation of Egr1 was lesser in RGE retinas compared to that of WT retinas. We conclude that high visual acuity, and the retinal signaling mediated by Gβ3, is not required for emmetropization and the excessive ocular elongation caused by FD and hyperopic defocus. However, the loss of acuity and Gβ3 from RGE retinas causes enhanced responses to hyperopic defocus and diminished responses to myopic defocus.

  1. Weathering by tree-root-associating fungi diminishes under simulated Cenozoic atmospheric CO2 decline

    NASA Astrophysics Data System (ADS)

    Quirk, J.; Leake, J. R.; Banwart, S. A.; Taylor, L. L.; Beerling, D. J.

    2014-01-01

    Trees dominate terrestrial biotic weathering of silicate minerals by converting solar energy into chemical energy that fuels roots and their ubiquitous nutrient-mobilising fungal symbionts. These biological activities regulate atmospheric CO2 concentrations ([CO2]a) over geologic timescales by driving calcium and magnesium fluvial ion export and marine carbonate formation. However, the important stabilising feedbacks between [CO2]a and biotic weathering anticipated by geochemical carbon cycle models remain untested. We report experimental evidence for a negative feedback across a declining Cenozoic [CO2]a range from 1500 to 200 ppm, whereby low [CO2]a curtails mineral surface alteration via trenching and etch pitting by arbuscular mycorrhizal (AM) and ectomycorrhizal (EM) fungal partners of tree roots. Optical profile imaging using vertical scanning interferometry reveals changes in nanoscale surface topography consistent with a dual mode of attack involving delamination and trenching by AM and EM fungal hyphae on phyllosilicate mineral flakes. This is consistent with field observations of micropores in feldspar, hornblende and basalt, purportedly caused by EM fungi, but with little confirmatory evidence. Integrating these findings into a process-based biotic weathering model revealed that low [CO2]a effectively acts as a "carbon starvation" brake, causing a three-fold drop in tree-driven fungal weathering fluxes of calcium and magnesium from silicate rock grains as [CO2]a falls from 1500 to 200 ppm. The feedback is regulated through the action of low [CO2]a on host tree productivity and provides empirical evidence for the role of [CO2]a starvation in diminishing the contribution of trees and mycorrhizal fungi to rates of biological weathering. More broadly, diminished tree-driven weathering under declining [CO2]a may provide an important contributory mechanism stabilising Earth's [CO2]a minimum over the past 24 million years.

  2. Weathering by tree root-associating fungi diminishes under simulated Cenozoic atmospheric CO2 decline

    NASA Astrophysics Data System (ADS)

    Quirk, J.; Leake, J. R.; Banwart, S. A.; Taylor, L. L.; Beerling, D. J.

    2013-10-01

    Trees dominate terrestrial biotic weathering of silicate minerals by converting solar energy into chemical energy that fuels roots and their ubiquitous nutrient-mobilising fungal symbionts. These biological activities regulate atmospheric CO2 ([CO2]a) over geologic timescales by driving calcium and magnesium fluvial ion export and marine carbonate formation, but the important stabilising feedbacks between [CO2]a and biotic weathering anticipated by geochemical carbon cycle models remain untested. We report experimental evidence for a negative feedback across a declining Cenozoic [CO2]a range from 1500 ppm to 200 ppm, whereby low [CO2]a curtails mineral surface alteration via trenching and etch pitting by arbuscular mycorrhizal (AM) and ectomycorrhizal (EM) fungal partners of tree roots. Optical profile imaging using vertical scanning interferometry reveals changes in nanoscale surface topography consistent with a dual mode of attack involving delamination and trenching by AM and EM fungal hyphae on phyllosilicate mineral flakes. This is consistent with field observations of micropores in feldspar, hornblende and basalt, purportedly caused by EM fungi, but with little confirmatory evidence. Integrating these findings into a process-based biotic weathering model revealed that low [CO2]a effectively acts as a "carbon starvation" brake, causing a three-fold drop in tree-driven fungal weathering fluxes of calcium and magnesium from silicate rock grains as [CO2]a falls from 1500 ppm to 200 ppm. The feedback is regulated through the action of low [CO2]a on host tree productivity and provides empirical evidence for the role of [CO2]a starvation in diminishing the contribution of trees and mycorrhizal fungi to rates of biological weathering. More broadly, diminished tree-driven weathering under declining [CO2]a may provide an important contributory mechanism stabilising Earth's [CO2]a minimum over the past 24 million years.

  3. Opposite effects of mu and delta opioid receptor agonists on excitatory propagation induced in rat somatosensory and insular cortices by dental pulp stimulation.

    PubMed

    Yokota, Eiko; Koyanagi, Yuko; Nakamura, Hiroko; Horinuki, Eri; Oi, Yoshiyuki; Kobayashi, Masayuki

    2016-08-15

    The insular cortex (IC) contributes to nociceptive information processing. IC neurons express opioid receptors, including the mu (MOR), kappa (KOR), and delta (DOR) subtypes. Opioidergic agonists suppress excitatory synaptic transmission in the cerebral cortex. In addition, morphine injection into the IC reduces responses to noxious thermal stimuli. However, the mechanisms of the opioid-dependent modulation of cortical excitation at the macroscopic level, which bridge the cellular and behavioral findings, have remained unknown. The present in vivo optical imaging study aimed to examine the effects of the agonists of each subtype on cortical excitatory propagation in the IC and the neighboring cortices, the primary (S1) and secondary somatosensory (S2) areas. To assess the opioidergic effects on the cortical circuits, we applied electrical stimulation to the maxillary 1st molar pulp, which induced excitation in the ventral part of S1 and the S2/insular oral region (IOR). The initial excitatory response was observed 10-14ms after stimulation, and then excitation propagated concentrically. DAMGO (10-100μM), an MOR agonist, suppressed the amplitude of cortical excitation and shrank the maximum excitation areas in S1 and S2/IOR. In contrast, 10-100μM DPDPE, a DOR agonist, increased the amplitude of excitation and expanded the area of maximum excitation. U50488 (10-100μM), a KOR agonist, had little effect on cortical excitation. These results suggest that MOR-induced suppression of excitatory propagation in the IC is an underlying mechanism of the powerful analgesic effects of MOR agonists. In contrast, DOR may play a minor role in suppressing acute pain.

  4. Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

    PubMed

    Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

    1998-03-01

    The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are.

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

    PubMed Central

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

    2015-01-01

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

  6. The dopamine D1 receptor agonist SKF 38393 improves temporal order memory performance in maternally deprived rats.

    PubMed

    Lejeune, Stéphanie; Dourmap, Nathalie; Martres, Marie-Pascale; Giros, Bruno; Daugé, Valérie; Naudon, Laurent

    2013-11-01

    Previously, we showed that maternal deprivation (MD) (3h/day, postnatal-day 1-14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor. Besides we examined whether an agonist of the DA receptor D1, the SKF38393, could have a beneficial effect on the performance of deprived (D) rats in the TMT. We observed that MD induced a significant reduction of the extracellular level of DOPAC in the mPFC and in the density of the D1 receptor in the anterior cingulate cortex, a sub-region of mPFC. On the other hand, we observed that an acute systemic injection of a D1 receptor agonist, SKF38393, was effective to correct the memory deficiency of D rats in the TMT, when administered before the retrieval phase. We showed that a stress suffered by rats during the perinatal period led to dysfunction of the adult DA system, possibly triggering greater vulnerability to cognitive and mood disorders. Interestingly, an acute administration of a D1 receptor agonist in adulthood was sufficient to improve the deficit in the temporal memory. A better understanding of this phenomenon would permit the development of treatments adapted to patients with a history of early traumatic experiences.

  7. Sleep-promoting action of IIK7, a selective MT2 melatonin receptor agonist in the rat

    PubMed Central

    Fisher, Simon P.; Sugden, David

    2009-01-01

    Several novel melatonin receptor agonists, in addition to various formulations of melatonin itself, are either available or in development for the treatment of insomnia. Melatonin is thought to exert its effects principally through two high affinity, G-protein coupled receptors, MT1 and MT2, though it is not known which subtype is responsible for the sleep-promoting action. The present study used radiotelemetry to record EEG and EMG in un-restrained freely moving rats to monitor the sleep-wake behaviour and examined the acute sleep-promoting activity of an MT2 receptor subtype selective melatonin analog, IIK7. IIK7 is a full agonist at the MT2 receptor subtype but a partial agonist at the MT1 receptor and has ∼90-fold higher affinity for MT2 than MT1. Like melatonin, IIK7 (10 mg/kg i.p.) significantly reduced NREM sleep onset latency and transiently increased the time spent in NREM sleep, but did not alter REM sleep latency or the amount of REM sleep. An analysis of the EEG power spectrum showed no change in delta (1–4 Hz) or theta activity (5–8 Hz) following IIK7 administration. Core body temperature was slightly decreased (∼0.3 °C) by IIK7 compared to vehicle-treated rats. The acute and transient changes in the sleep-wake cycle mimic the changes seen with melatonin and suggest that its sleep-promoting activity is mediated by activation of the MT2 receptor subtype. PMID:19429170

  8. Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton.

    PubMed

    Shen, Wei; Xue, Jingwei; Zhao, Zekai; Zhang, Can

    2013-11-01

    In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is separated from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl-pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compounds showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compound 2g (EC₅₀: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC₅₀: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC₅₀ of 2.06 μM and 0.307 μM (tacalcitol: 2.07 μM and 0.057 μM) and showed no significant effect on serum calcium.

  9. Compulsive eating and weight gain related to dopamine agonist use.

    PubMed

    Nirenberg, Melissa J; Waters, Cheryl

    2006-04-01

    Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors ("punding"). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side-effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.

  10. Effects of acute and chronic psychological stress on platelet aggregation in mice.

    PubMed

    Matsuhisa, Fumikazu; Kitamura, Nobuo; Satoh, Eiki

    2014-03-01

    Although psychological stress has long been known to alter cardiovascular function, there have been few studies on the effect of psychological stress on platelets, which play a pivotal role in cardiovascular disease. In the present study, we investigated the effects of acute and chronic psychological stress on the aggregation of platelets and platelet cytosolic free calcium concentration ([Ca(2+)]i). Mice were subjected to both transportation stress (exposure to novel environment, psychological stress) and restraint stress (psychological stress) for 2 h (acute stress) or 3 weeks (2 h/day) (chronic stress). In addition, adrenalectomized mice were subjected to similar chronic stress (both transportation and restraint stress for 3 weeks). The aggregation of platelets from mice and [Ca(2+)]i was determined by light transmission assay and fura-2 fluorescence assay, respectively. Although acute stress had no effect on agonist-induced platelet aggregation, chronic stress enhanced the ability of the platelet agonists thrombin and ADP to stimulate platelet aggregation. However, chronic stress failed to enhance agonist-induced increase in [Ca(2+)]i. Adrenalectomy blocked chronic stress-induced enhancement of platelet aggregation. These results suggest that chronic, but not acute, psychological stress enhances agonist-stimulated platelet aggregation independently of [Ca(2+)]i increase, and the enhancement may be mediated by stress hormones secreted from the adrenal glands.

  11. Captive female gorilla agonistic relationships with clumped defendable food resources.

    PubMed

    Scott, Jennifer; Lockard, Joan S

    2006-07-01

    Minimal feeding competition among female mountain gorillas (Gorilla gorilla beringei) has resulted in egalitarian social relationships with poorly defined agonistic dominance hierarchies. Thus, gorillas are generally viewed as non-competitive egalitarian folivores that have had little need to develop effective competitive strategies to access food resources. However, this generalization is inconsistent with more recent research indicating that most gorillas are frugivorous, feeding on patchily distributed food resources. The current study at Howletts Wild Animal Park, Kent, England, explores the effects of clumped and defendable foods on female gorilla agonistic relationships among three groups of western lowland gorillas (G. g. gorilla), conditions that are predicted to lead to well-differentiated agonistic dominance hierarchies among female primates. The Howletts gorillas foraged all day on low-energy/-nutrient, high-fiber foods widely distributed around their enclosure by the keepers. However, they also had periodic access to high-energy foods (e.g., nuts, raisins, strawberries, etc.) that the keepers would spread in a clumped and defendable patch. Frequencies of agonistic and submissive behaviors between females and proximity data were gathered. High-status females were found to monopolize the food patch and kept the low-status females at bay with cough-grunt threat vocalizations or by chasing them away. Agonistic interactions were initiated mostly by females of high status; these were directed towards females of low status and were generally not reciprocal. In addition, females of low status engaged in submissive behaviors the most often, which they directed primarily at females of high status, especially in response to aggression by the latter. Agonistic interactions between high- and low-status females had decided outcomes more often than not, with low-status females the losers. Competition over highly desirable foods distributed in defendable clumps at

  12. Treatment for acute asthma in the Emergency Department: practical aspects.

    PubMed

    Urso, D L

    2010-03-01

    This article describes the management of acute asthma exacerbation in the Emergency Department (ED). An asthma exacerbation can be defined as clinical worsening of disease or an asymptomatic decrease in peak flows. Acute exacerbations of asthma may represent reactions to airway irritants or failures of chronic treatment. Hospitalizations and ED visits account for a large proportion of the health-care cost burden of asthma. The assessment of an asthma exacerbation constitutes a process with two different dimensions: to determine the severity of attack, and to evaluate the response to treatment. The principal goals of managing an asthma acute exacerbation may be summarized as maintenance of adequate arterial oxygen saturation with supplemental oxygen, relief of airflow obstruction with repetitive administration of short acting beta-2 agonists (SABA), and treatment of airway inflammation with systemic corticosteroids (CS) to prevent future relapses. SABA, oxygen, and CS form the basis of management of acute asthma exacerbation but a role is emerging for anthicolinergics.

  13. Acute Vestibulopathy

    PubMed Central

    Cha, Yoon-Hee

    2011-01-01

    The presentation of acute vertigo may represent both a common benign disorder or a life threatening but rare one. Familiarity with the common peripheral vestibular disorders will allow the clinician to rapidly “rule-in” a benign disorder and recognize when further testing is required. Key features of vertigo required to make an accurate diagnosis are duration, chronicity, associated symptoms, and triggers. Bedside tests that are critical to the diagnosis of acute vertigo include the Dix-Hallpike maneuver and canalith repositioning manuever, occlusive ophthalmoscopy, and the head impulse test. The goal of this review is to provide the clinician with the clinical and pathophysiologic background of the most common disorders that present with vertigo to develop a logical differential diagnosis and management plan. PMID:23983835

  14. Partial agonistic action of endomorphins in the mouse spinal cord.

    PubMed

    Mizoguchi, H; Wu, H E; Narita, M

    2001-09-07

    The partial agonistic properties of endogenous mu-opioid peptides endomorphin-1 and endomorphin-2 for G-protein activation were determined in the mouse spinal cord, monitoring the increases in guanosine-5'-o-(3-[35S]thio)triphosphate binding. The G-protein activation induced by endogenous opioid peptide beta-endorphin in the spinal cord was significantly, but partially, attenuated by co-incubation with endomorphin-1 or endomorphin-2. The data indicates that endomorphin-1 and endomorphin-2 are endogenous partial agonists for mu-opioid receptor in the mouse spinal cord.

  15. Synthesis and activity of small molecule GPR40 agonists.

    PubMed

    Garrido, Dulce M; Corbett, David F; Dwornik, Kate A; Goetz, Aaron S; Littleton, Thomas R; McKeown, Steve C; Mills, Wendy Y; Smalley, Terrence L; Briscoe, Celia P; Peat, Andrew J

    2006-04-01

    The first report on the identification and structure-activity relationships of a novel series of GPR40 agonists based on a 3-(4-{[N-alkyl]amino}phenyl)propanoic acid template is described. Structural modifications to the original screening hit yielded compounds with a 100-fold increase in potency at the human GPR40 receptor and pEC(50)s in the low nanomolar range. The carboxylic acid moiety is not critical for activity but typically elicits an agonistic response higher than those observed with carboxamide replacements. These compounds may prove useful in unraveling the therapeutic potential of this receptor for the treatment of Type 2 diabetes.

  16. Acute Blindness.

    PubMed

    Meekins, Jessica M

    2015-09-01

    Sudden loss of vision is an ophthalmic emergency with numerous possible causes. Abnormalities may occur at any point within the complex vision pathway, from retina to optic nerve to the visual center in the occipital lobe. This article reviews specific prechiasm (retina and optic nerve) and cerebral cortical diseases that lead to acute blindness. Information regarding specific etiologies, pathophysiology, diagnosis, treatment, and prognosis for vision is discussed.

  17. Anaphylaxis: acute treatment and management.

    PubMed

    Ring, Johannes; Grosber, Martine; Möhrenschlager, Matthias; Brockow, Knut

    2010-01-01

    Anaphylaxis is the maximal variant of an acute life-threatening immediate-type allergy. Due to its often dramatic onset and clinical course, practical knowledge in the management of these reactions is mandatory both for physicians and patients. It has to be distinguished between acute treatment modalities and general recommendations for management of patients who have suffered from an anaphylactic reaction. Acute treatment comprises general procedures like positioning, applying an intravenous catheter, call for help, comfort of the patient as well as the application of medication. The acute treatment modalities are selected depending upon the intensity of the clinical symptomatology as they are categorized in 'severity grades'. First of all it is important to diagnose anaphylaxis early and consider several differential diagnoses. This diagnosis is purely clinical and laboratory tests are of no help in the acute situation. Epinephrine is the essential antianaphylactic drug in the pharmacologic treatment. It should be first applied intramuscularly, only in very severe cases or under conditions of surgical interventions intravenous application can be tried. Furthermore, glucocorticosteroids are given in order to prevent protracted or biphasic courses of anaphylaxis; they are of little help in the acute treatment. Epinephrine autoinjectors can be used by the patient him/herself. Histamine H(1)-antagonists are valuable in mild anaphylactic reactions; they should be given intravenously if possible. The replacement of volume is crucial in antianaphylactic treatment. Crystalloids can be used in the beginning, in severe shock colloid volume substitutes have to be applied. Patients suffering from an anaphylactic episode should be observed over a period of 4-10 h according to the severity of the symptomatology. It is crucial to be aware or recognize risk patients as for example patients with severe uncontrolled asthma, or under beta-adrenergic blockade. When bronchial

  18. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

  19. Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response.

    PubMed

    Battinelli, Elisabeth M; Markens, Beth A; Kulenthirarajan, Rajesh A; Machlus, Kellie R; Flaumenhaft, Robert; Italiano, Joseph E

    2014-01-02

    Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 5'-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential.

  20. Inhibition of K+ permeability diminishes alpha 2-adrenoceptor mediated effects on norepinephrine release

    SciTech Connect

    Zimanyi, I.; Folly, G.; Vizi, E.S.

    1988-05-01

    The effect of two different potassium channel blockers, 4-aminopyridine (4-AP) and quinine, on the alpha 2-adrenoceptor mediated modulation of norepinephrine (NE) release was investigated. Pairs of mouse vasa deferentia were loaded with /sup 3/H-norepinephrine (/sup 3/H-NE), superfused continuously, and stimulated electrically. 4-AP (5.3 x 10(-4) M), and quinine (10(-5) M) enhanced the stimulation-evoked release of tritium significantly. The electrically induced release of radioactivity was reduced by alpha 2-adrenoceptor agonists (1-NE and xylazine) and enhanced by the alpha 2-adrenoceptor antagonist yohimbine. Both effects were affected markedly by 4-AP or quinine: the depressant action of 1-NA and xylazine was partially antagonized and the facilitatory effect of yohimbine was completely abolished during the blockade of the potassium channels. It is suggested that the blockade of the potassium permeability counteracts negative feedback modulation; therefore, it seems likely that the stimulation of alpha 2-adrenoceptors leads to an enhanced potassium permeability and hyperpolarization of varicose axon terminals.

  1. Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder.

    PubMed

    Hart, Amy B; Gamazon, Eric R; Engelhardt, Barbara E; Sklar, Pamela; Kähler, Anna K; Hultman, Christina M; Sullivan, Patrick F; Neale, Benjamin M; Faraone, Stephen V; de Wit, Harriet; Cox, Nancy J; Palmer, Abraham A

    2014-04-22

    Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.

  2. Exposure to the Selective κ-Opioid Receptor Agonist Salvinorin A Modulates the Behavioral and Molecular Effects of Cocaine in Rats

    PubMed Central

    Chartoff, Elena H; Potter, David; Damez-Werno, Diane; Cohen, Bruce M; Carlezon, William A

    2008-01-01

    Stress and chronic exposure to drugs of abuse can trigger addictive and depressive disorders. Both stimuli increase activity of dynorphin, a neuropeptide that acts at κ-opioid receptors (KORs). In humans, KOR agonists cause dysphoria, raising the possibility that dynorphin modulates the depressive-like effects of stress and chronic drug use. We examined if KOR activation alters sensitivity to stimulant drugs by assessing the effects of the selective KOR agonist, salvinorin A (SalvA), on cocaine-induced locomotor activity and c-Fos expression. Acute administration of SalvA blocked the locomotor-stimulant effects of cocaine, whereas repeated SalvA together with concomitant exposure to activity testing chambers potentiated the locomotor response to a cocaine challenge. In contrast, repeated SalvA administered in home cages rather than the activity chambers failed to potentiate the locomotor response to a cocaine challenge. One potential explanation for these findings is that activation of KORs disrupts context conditioning: acute locomotor responses to SalvA alone did not fully habituate with repeated testing in the activity chambers. The effects of SalvA on locomotor activity paralleled its effects on cocaine-induced c-Fos expression in the dorsal striatum: acute SalvA attenuated cocaine-induced c-Fos, whereas repeated SalvA potentiated it when administered in the activity chambers but not the home cage. Acute SalvA also blocked the locomotor stimulant effects of the DI receptor agonist SKF 82958, whereas repeated SalvA potentiated these effects when administered in the activity chambers. These findings suggest that SalvA regulates the stimulant effects of cocaine through interactions with DI receptor-mediated signaling in the dorsal striatum. PMID:18185499

  3. Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury.

    PubMed

    Wagenaar, Gerry T M; Laghmani, El Houari; Fidder, Melissa; Sengers, Rozemarijn M A; de Visser, Yvonne P; de Vries, Louwe; Rink, Rick; Roks, Anton J M; Folkerts, Gert; Walther, Frans J

    2013-09-01

    Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 μg·kg(-1)·day(-1)] and AT2 [dKcAng-(1-7); 5-20 μg·kg(-1)·day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester (25 mg·kg(-1)·day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.

  4. Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

    PubMed Central

    Chun, Lani S.; Moritz, Amy E.; Miller, Brittney N.; Doyle, Trevor B.; Conroy, Jennie L.; Padron, Adrian; Meade, Julie A.; Xiao, Jingbo; Hu, Xin; Dulcey, Andrés E.; Han, Yang; Duan, Lihua; Titus, Steve; Bryant-Genevier, Melanie; Barnaeva, Elena; Ferrer, Marc; Javitch, Jonathan A.; Beuming, Thijs; Shi, Lei; Southall, Noel T.; Marugan, Juan J.; Sibley, David R.

    2014-01-01

    A high-throughput screening campaign was conducted to interrogate a 380,000+ small-molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and β-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate β-arrestin recruitment. One such compound (MLS1547; 5-chloro-7-[(4-pyridin-2-ylpiperazin-1-yl)methyl]quinolin-8-ol) is a highly efficacious agonist at D2 receptor–mediated G protein–linked signaling, but does not recruit β-arrestin as demonstrated using two different assays. This compound does, however, antagonize dopamine-stimulated β-arrestin recruitment to the D2 receptor. In an effort to investigate the chemical scaffold of MLS1547 further, we characterized a set of 24 analogs of MLS1547 with respect to their ability to inhibit cAMP accumulation or stimulate β-arrestin recruitment. A number of the analogs were similar to MLS1547 in that they displayed agonist activity for inhibiting cAMP accumulation, but did not stimulate β-arrestin recruitment (i.e., they were highly biased). In contrast, other analogs displayed various degrees of G protein signaling bias. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure-activity relationship of the functionally selective properties of this series of compounds. In summary, we have identified and characterized a novel G protein–biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties. PMID:24755247

  5. Disrupting the prefrontal cortex diminishes the human ability to build a good reputation.

    PubMed

    Knoch, Daria; Schneider, Frédéric; Schunk, Daniel; Hohmann, Martin; Fehr, Ernst

    2009-12-08

    Reputation formation pervades human social life. In fact, many people go to great lengths to acquire a good reputation, even though building a good reputation is costly in many cases. Little is known about the neural underpinnings of this important social mechanism, however. In the present study, we show that disruption of the right, but not the left, lateral prefrontal cortex (PFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) diminishes subjects' ability to build a favorable reputation. This effect occurs even though subjects' ability to behave altruistically in the absence of reputation incentives remains intact, and even though they are still able to recognize both the fairness standards necessary for acquiring and the future benefits of a good reputation. Thus, subjects with a disrupted right lateral PFC no longer seem to be able to resist the temptation to defect, even though they know that this has detrimental effects on their future reputation. This suggests an important dissociation between the knowledge about one's own best interests and the ability to act accordingly in social contexts. These results link findings on the neural underpinnings of self-control and temptation with the study of human social behavior, and they may help explain why reputation formation remains less prominent in most other species with less developed prefrontal cortices.

  6. Mass Conservative and Total Variation Diminishing Implementation of Various Hydrological Flow Routing Methods

    NASA Astrophysics Data System (ADS)

    Schwanenberg, Dirk; Alvarado Montero, Rodolfo

    2016-04-01

    Hydrological flow routing methods are widely used as components of distributed hydrological models and in operational flow forecasting systems, often in combination with data assimilation and predictive control techniques. The most popular ones such as the Muskingum-Cunge approach implement variable parameters to relate the storage to the topology of the river reach and numerical parameters of the schematization. Although this often increases the accuracy of the approach, it may also lead to mass errors and other numerical issues. Whereas fixes for the mass error has been previously discussed by several authors, the numerical robustness is still not properly addressed. We present a novel approach to reformulate hydrological routing schemes as a cascade of implicit pool routing models. Its numerical implementation is mass conservative and total variation diminishing, i.e. the solution does not oscillate or overshoot, for arbitrary time steps. It is shown that these numerical properties are achieved regardless of the accuracy of the scheme and its physical routing characteristics. Numerical experiments compare the computational performance and accuracy of the novel, reformulated approach with existing schemes including linear reservoir routing, nonlinear reservoir routing, and the original Muskingum-Cunge method. We show that the approach can reproduce the original schemes, if these are already mass conservative, otherwise fixes the mass conservation in the reformulated version and improves the solution at sharp gradients by suppressing numerical oscillations, overshooting or negative flows.

  7. Increased outdoor recreation, diminished ozone layer pose ultraviolet radiation threat to eye

    SciTech Connect

    Not Available

    1989-02-24

    The long-term effects of ultraviolet (UV) light on the eye are of increasing concern as many people live longer and spend more of that time in outdoor recreation and as the diminishing ozone layer filters less UV light. Ultraviolet radiation is strongest at high altitude, low latitude, and open for reflective environments (sand, snow, or water). For people who lack an eye lens (aphakics), UV light is transmitted directly onto the retina. Cumulative exposure to the 300- to 400-nm range of UV light is one factor causing cataracts. Ophthalmologists say cataracts cause visual deficits for more than 3.5 million people in the United States. Cumulative UV exposure may lead to age-related macular degeneration. At a Research to Prevent Blindness conference in Arlington, VA, John S. Werner, PhD, professor of psychology and neurosciences at the University of Colorado, Boulder, described how his group demonstrated the effects of UV light on retinal cones. Different types of intraocular lenses were placed in each eye of eight patients who had undergone bilateral cataract surgery. After five years, retinal cones chronically exposured to UV radiation had less sensitivity for short wavelengths (440 nm) by a factor of 1.7.

  8. Amygdalin blocks bladder cancer cell growth in vitro by diminishing cyclin A and cdk2.

    PubMed

    Makarević, Jasmina; Rutz, Jochen; Juengel, Eva; Kaulfuss, Silke; Reiter, Michael; Tsaur, Igor; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A

    2014-01-01

    Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25-10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.

  9. Diminished n1 auditory evoked potentials to oddball stimuli in misophonia patients.

    PubMed

    Schröder, Arjan; van Diepen, Rosanne; Mazaheri, Ali; Petropoulos-Petalas, Diamantis; Soto de Amesti, Vicente; Vulink, Nienke; Denys, Damiaan

    2014-01-01

    Misophonia (hatred of sound) is a newly defined psychiatric condition in which ordinary human sounds, such as breathing and eating, trigger impulsive aggression. In the current study, we investigated if a dysfunction in the brain's early auditory processing system could be present in misophonia. We screened 20 patients with misophonia with the diagnostic criteria for misophonia, and 14 matched healthy controls without misophonia, and investigated any potential deficits in auditory processing of misophonia patients using auditory event-related potentials (ERPs) during an oddball task. Subjects watched a neutral silent movie while being presented a regular frequency of beep sounds in which oddball tones of 250 and 4000 Hz were randomly embedded in a stream of repeated 1000 Hz standard tones. We examined the P1, N1, and P2 components locked to the onset of the tones. For misophonia patients, the N1 peak evoked by the oddball tones had smaller mean peak amplitude than the control group. However, no significant differences were found in P1 and P2 components evoked by the oddball tones. There were no significant differences between the misophonia patients and their controls in any of the ERP components to the standard tones. The diminished N1 component to oddball tones in misophonia patients suggests an underlying neurobiological deficit in misophonia patients. This reduction might reflect a basic impairment in auditory processing in misophonia patients.

  10. Diminished amygdala activation and behavioral threat response following traumatic brain injury

    PubMed Central

    Palmer, Christopher P.; Metheny, Hannah E.; Elkind, Jaclynn A.; Cohen, Akiva S.

    2016-01-01

    Each year, approximately 3.8 million people suffer mild to moderate traumatic brain injuries (mTBI) that result in an array of neuropsychological symptoms and disorders. Despite these alarming statistics, the neurological bases of these persistent, debilitating neuropsychological symptoms are currently poorly understood. In this study we examined the effects of mTBI on the amygdala, a brain structure known to be critically involved in the processing of emotional stimuli. Seven days after lateral fluid percussion injury (LFPI), mice underwent a series of physiological and behavioral experiments to assess amygdala function. Brain injured mice exhibited a decreased threat response in a cued fear conditioning paradigm, congruent with a decrease in amygdala excitability determined with basolateral amygdala (BLA) field excitatory post synaptic potentials together with voltage sensitive dye imaging (VSD). Furthermore, beyond exposing a general decrease in the excitability the primary input of the amygdala, the lateral amygdala (LA), VSD also revealed a decrease in the relative strength or activation of internuclear amygdala circuit projections after LFPI. Thus, not only does activation of the LA require increased stimulation, but the proportion of this activation that is propagated to the primary output of the amygdala, the central amygdala, is also diminished following LFPI. Intracellular recordings revealed no changes in the intrinsic properties of BLA pyramidal neurons after LFPI. This data suggests that mild to moderate TBI has prominent effects on amygdala function and provides a potential neurological substrate for many of the neuropsychological symptoms suffered by TBI patients. PMID:26791254

  11. Increased conformity offers diminishing returns for reducing total knee replacement wear.

    PubMed

    Fregly, Benjamin J; Marquez-Barrientos, Carlos; Banks, Scott A; DesJardins, John D

    2010-02-01

    Wear remains a significant problem limiting the lifespan of total knee replacements (TKRs). Though increased conformity between TKR components has the potential to decrease wear, the optimal amount and planes of conformity have not been investigated. Furthermore, differing conformities in the medial and lateral compartments may provide designers the opportunity to address both wear and kinematic design goals simultaneously. This study used a computational model of a Stanmore knee simulator machine and a previously validated wear model to investigate this issue for simulated gait. TKR geometries with different amounts and planes of conformity on the medial and lateral sides were created and tested in two phases. The first phase utilized a wide range of sagittal and coronal conformity combinations to blanket a physically realistic design space. The second phase performed a focused investigation of the conformity conditions from the first phase to which predicted wear volume was sensitive. For the first phase, sagittal but not coronal conformity was found to have a significant effect on predicted wear volume. For the second phase, increased sagittal conformity was found to decrease predicted wear volume in a nonlinear fashion, with reductions gradually diminishing as conformity increased. These results suggest that TKR geometric design efforts aimed at minimizing wear should focus on sagittal rather than coronal conformity and that at least moderate sagittal conformity is desirable in both compartments.

  12. Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers.

    PubMed

    Wu, Yanjue; Cao, Zhiming; Klein, William L; Luo, Yuan

    2010-06-01

    Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to beta-amyloid peptide (Abeta) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Abeta(1-42) in transgenic Caenorhabditis elegans was alleviated by Abeta oligomer inhibitors Ginkgo biloba extract and its constituents [Wu, Y., Wu, Z., Butko, P., Christen, Y., Lambert, M.P., Klein, W.L., Link, C.D., Luo, Y., 2006. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J. Neurosci. 26(50): 13102-13113]. In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: (1) a delay in paralysis, (2) increased expression of small heat shock protein HSP16.2, and (3) significant reduction of Abeta oligomers in a heat shock time-dependent manner. These results suggest that transient heat shock lessens Abeta toxicity by diminishing Abeta oligomerization, which provides a link between up regulation of endogenous chaperone proteins and protection against Abeta proteotoxicity in vivo.

  13. Marriage of scintillator and semiconductor for synchronous radiotherapy and deep photodynamic therapy with diminished oxygen dependence.

    PubMed

    Zhang, Chen; Zhao, Kuaile; Bu, Wenbo; Ni, Dalong; Liu, Yanyan; Feng, Jingwei; Shi, Jianlin

    2015-02-02

    Strong oxygen dependence and limited penetration depth are the two major challenges facing the clinical application of photodynamic therapy (PDT). In contrast, ionizing radiation is too penetrative and often leads to inefficient radiotherapy (RT) in the clinic because of the lack of effective energy accumulation in the tumor region. Inspired by the complementary advantages of PDT and RT, we present herein the integration of a scintillator and a semiconductor as an ionizing-radiation-induced PDT agent, achieving synchronous radiotherapy and depth-insensitive PDT with diminished oxygen dependence. In the core-shell Ce(III)-doped LiYF4@SiO2@ZnO structure, the downconverted ultraviolet fluorescence from the Ce(III)-doped LiYF4 nanoscintillator under ionizing irradiation enables the generation of electron-hole (e(-)-h(+)) pairs in ZnO nanoparticles, giving rise to the formation of biotoxic hydroxyl radicals. This process is analogous to a type I PDT process for enhanced antitumor therapeutic efficacy.

  14. Topiramate diminishes fear memory consolidation and extinguishes conditioned fear in rats

    PubMed Central

    do Prado-Lima, Pedro Antônio Schmidt; Perrenoud, Myriam Fortes; Kristensen, Christian Haag; Cammarota, Martin; Izquierdo, Ivan

    2011-01-01

    Background Topiramate has been recognized as a drug that can induce memory and cognitive impairment. Using the one-trial inhibitory avoidance task, we sought to verify the effect of topiramate on consolidation and extinction of aversive memory. Our hypothesis was that topiramate inhibits the consolidation and enhances the extinction of this fear memory. Methods In experiment 1, which occured immediately or 3 hours after training, topiramate was administered to rats, and consolidation of memory was verified 18 days after the conditioning session. In experiment 2, which occured 18–22 days after the training session, rats were submitted to the extinction protocol. Rats received topiramate 14 days before or during the extinction protocol. Results Topiramate blocked fear memory retention (p < 0.01) and enhanced fear memory extinction (p < 0.001) only when administered during the extinction protocol. Limitations This experimental design did not allow us to determine whether topiramate also blocked the reconsolidation of fear memory. Conclusion Topiramate diminishes fear memory consolidation and promotes extinction of inhibitory avoidance memory. PMID:21392483

  15. Amygdalin Blocks Bladder Cancer Cell Growth In Vitro by Diminishing Cyclin A and cdk2

    PubMed Central

    Makarević, Jasmina; Rutz, Jochen; Juengel, Eva; Kaulfuss, Silke; Reiter, Michael; Tsaur, Igor; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A.

    2014-01-01

    Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25–10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug. PMID:25136960

  16. Diminished serum repetin levels in patients with schizophrenia and bipolar disorder.

    PubMed

    Wang, Shuai; Ren, Huixun; Xu, Jie; Yu, Yanjun; Han, Shuiping; Qiao, Hui; Cheng, Shaoli; Xu, Chang; An, Shucheng; Ju, Bomiao; Yu, Chengyuan; Wang, Chanyuan; Wang, Tao; Yang, Zhenjun; Taylor, Ethan Will; Zhao, Lijun

    2015-01-23

    Repetin (RPTN) protein is a member of S100 family and is known to be expressed in the normal epidermis. Here we show that RPTN is ubiquitously expressed in both mouse and human brain, with relatively high levels in choroid plexus, hippocampus and prefrontal cortex. To investigate the expression of RPTN in neuropsychiatric disorders, we determined serum levels of RPTN in patients with schizophrenia (n = 88) or bipolar disorder (n = 34) and in chronic psychostimulant users (n = 91). We also studied its expression in a mouse model of chronic unpredictable mild stress (CUMS). The results showed that serum RPTN levels were significantly diminished in patients with schizophrenia and bipolar disorder or in psychostimulant users, compared with healthy subjects (n = 115) or age-matched controls (n = 92) (p < 0.0001). In CUMS mice, RPTN expression in hippocampus and prefrontal cortex was reduced with progression of the CUMS procedure; the serum RPTN level remained unchanged. Since CUMS is a model for depression and methamphetamine (METH) abuse induced psychosis recapitulates many of the psychotic symptoms of schizophrenia, the results from this study may imply that RPTN plays a potential role in emotional and cognitive processing; its decrease in serum may indicate its involvement in the pathogenesis of schizophrenia and bipolar disorder.

  17. The central role of diminishing sea ice in recent Arctic temperature amplification.

    PubMed

    Screen, James A; Simmonds, Ian

    2010-04-29

    The rise in Arctic near-surface air temperatures has been almost twice as large as the global average in recent decades-a feature known as 'Arctic amplification'. Increased concentrations of atmospheric greenhouse gases have driven Arctic and global average warming; however, the underlying causes of Arctic amplification remain uncertain. The roles of reductions in snow and sea ice cover and changes in atmospheric and oceanic circulation, cloud cover and water vapour are still matters of debate. A better understanding of the processes responsible for the recent amplified warming is essential for assessing the likelihood, and impacts, of future rapid Arctic warming and sea ice loss. Here we show that the Arctic warming is strongest at the surface during most of the year and is primarily consistent with reductions in sea ice cover. Changes in cloud cover, in contrast, have not contributed strongly to recent warming. Increases in atmospheric water vapour content, partly in response to reduced sea ice cover, may have enhanced warming in the lower part of the atmosphere during summer and early autumn. We conclude that diminishing sea ice has had a leading role in recent Arctic temperature amplification. The findings reinforce suggestions that strong positive ice-temperature feedbacks have emerged in the Arctic, increasing the chances of further rapid warming and sea ice loss, and will probably affect polar ecosystems, ice-sheet mass balance and human activities in the Arctic.

  18. Dietary berries and ellagic acid diminish estrogen-mediated mammary tumorigenesis in ACI rats.

    PubMed

    Aiyer, Harini S; Srinivasan, Cidambi; Gupta, Ramesh C

    2008-01-01

    Estrogen acts as a complete mammary carcinogen in ACI rats. Prevention studies in this model allowed us to identify agents that are effective against estrogen-induced mammary carcinogenesis. In this study, we investigated efficacy of dietary berries and ellagic acid to reduce estrogen-mediated mammary tumorigenesis. Female ACI rats (8-9 wk) were fed either AIN-93M diet (n = 25) or diet supplemented with either powdered blueberry (n = 19) and black raspberry (n = 19) at 2.5% wt/wt each or ellagic acid (n = 22) at 400 ppm. Animals received implants of 17beta-estradiol 2 wk later, were palpated periodically for mammary tumors, and were euthanized after 24 wk. No differences were found in tumor incidence at 24 wk; however, tumor volume and multiplicity were reduced significantly after intervention. Compared with the control group (average tumor volume = 685 +/- 240 mm3 and tumor multiplicity = 8.0 +/- 1.3), ellagic acid reduced the tumor volume by 75% (P < 0.005) and tumor multiplicity by 44% (P < 0.05). Black raspberry followed closely, with tumor volume diminished by > 69% (P < 0.005) and tumor multiplicity by 37% (P = 0.07). Blueberry showed a reduction (40%) only in tumor volume. This is the first report showing the significant efficacy of both ellagic acid and berries in the prevention of solely estrogen-induced mammary tumors.

  19. Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization.

    PubMed

    Fonken, Laura K; Kitt, Meagan M; Gaudet, Andrew D; Barrientos, Ruth M; Watkins, Linda R; Maier, Steven F

    2016-11-01

    Aged animals exhibit diminished circadian rhythms, and both aging and circadian disruption sensitize neuroinflammatory responses. Microglia-the innate immune cell of the central nervous system-possess endogenous timekeeping mechanisms that regulate immune responses. Here, we explored whether aging is associated with disrupted diurnal rhythms in microglia and neuroinflammatory processes. First, hippocampal microglia isolated from young rats (4 months F344XBN) rhythmically expressed circadian clock genes, whereas microglia isolated from the hippocampus of aged rats (25 months) had aberrant Per1 and Per2 rhythms. Unstimulated microglia from young rats exhibited robust rhythms of TNFα and IL-1β mRNA expression, whereas those from aged rats had flattened and tonically elevated cytokine expression. Similarly, microglial activation markers were diurnally regulated in the hippocampus of young but not aged rats and diurnal differences in responsiveness to both ex vivo and in vivo inflammatory challenges were abolished in aged rats. Corticosterone is an entraining signal for extra-suprachiasmatic nucleus circadian rhythms. Here, corticosterone stimulation elicited similar Per1 induction in aged and young microglia. Overall, these results indicate that aging dysregulates circadian regulation of neuroinflammatory functions.

  20. Polymeric nanoparticle-aptamer bioconjugates can diminish the toxicity of mercury in vivo.

    PubMed

    Hu, Xiangang; Tulsieram, Kurt Lomas; Zhou, Qixing; Mu, Li; Wen, Jianping

    2012-01-05

    Targeted delivery drugs by nanoparticles and aptamers is a hot issue; however, the application to ameliorate toxicity of toxicants is unknown, and the information about nanoparticle-aptamer toxicology and pharmacology is limited. In this work, nanoparticle-aptamer was synthesized and then its toxicological and pharmacological information was studied. Mercury was selected as a model toxicant and the antidote was entrapped by nanoparticle-aptamer. The nanoparticle-aptamer with a suitable size of 120 nm avoided aptamer biodegradation and achieved an effective release of antidote. Rats were orally administered mercury-contaminated rice and then nanoparticle-aptamer was intravenously injected. The nanoparticle-aptamer markedly reduced the quantity of mercury in both the brain and kidney, and enhanced the excretion of urinary mercury. Water Maze and Open Field tests showed that nanoparticle-aptamer ameliorated the neurotoxicity and improved the learning and memory of rats. The pharmacology of nanoparticle-aptamer involved slow antidote release, antidote-toxicant antagonism, enhancement of crucial enzymes activity and decreased lipid peroxidation. Toxicology of nanoparticle-aptamer was also studied by hematologic tests (creatinine, urea, red and white blood cell), and exhibited little toxicity. Nanoparticle-aptamer can diminish the toxicity of mercury in vivo with few adverse effects, and is a potential tool in reducing the hazards of toxicants to human health.

  1. The addition of body armor diminishes dynamic postural stability in military soldiers.

    PubMed

    Sell, Timothy C; Pederson, Jonathan J; Abt, John P; Nagai, Takashi; Deluzio, Jennifer; Wirt, Michael D; McCord, Larry J; Lephart, Scott M

    2013-01-01

    Poor postural stability has been identified as a risk factor for lower extremity musculoskeletal injury. The additional weight of body armor carried by Soldiers alters static postural stability and may predispose Soldiers to lower extremity musculoskeletal injuries. However, static postural stability tasks poorly replicate the dynamic military environment, which places considerable stress on the postural control system during tactical training and combat. Therefore, the purpose of this study was to examine the effects of body armor on dynamic postural stability during single-leg jump landings. Thirty-six 101st Airborne Division (Air Assault) Soldiers performed single-leg jump landings in the anterior direction with and without wearing body armor. The dynamic postural stability index and the individual stability indices (medial-lateral stability index, anterior-posterior stability index, and vertical stability index) were calculated for each condition. Paired sample t-tests were performed to determine differences between conditions. Significant differences existed for the medial-lateral stability index, anterior-posterior stability index, vertical stability index, and dynamic postural stability index (p < 0.05). The addition of body armor resulted in diminished dynamic postural stability, which may result in increased lower extremity injuries. Training programs should address the altered dynamic postural stability while wearing body armor in attempts to promote adaptations that will result in safer performance during dynamic tasks.

  2. Inhibition of the Pim1 Oncogene Results in Diminished Visual Function

    PubMed Central

    Yin, Jun; Shine, Lisa; Raycroft, Francis; Deeti, Sudhakar; Reynolds, Alison; Ackerman, Kristin M.; Glaviano, Antonino; O'Farrell, Sean; O'Leary, Olivia; Kilty, Claire; Kennedy, Ciaran; McLoughlin, Sarah; Rice, Megan; Russell, Eileen; Higgins, Desmond G.; Hyde, David R.; Kennedy, Breandan N.

    2012-01-01

    Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3–5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors result in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function. PMID:23300608

  3. Diminished contractile responses of isolated conduit arteries in two rat models of hypertension.

    PubMed

    Zemancíková, Anna; Török, Jozef

    2013-08-31

    Hypertension is accompanied by thickening of arteries, resulting in marked changes in their passive and active mechanical properties. The aim of this study was to demonstrate that the large conduit arteries from hypertensive individuals may not exhibit enhanced contractions in vitro, as is often claimed. Mechanical responses to vasoconstrictor stimuli were measured under isometric conditions using ring arterial segments isolated from spontaneously hypertensive rats, N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated Wistar rats, and untreated Wistar rats serving as normotensive control. We found that thoracic aortas from both types of hypertensive rats had a greater sensitivity but diminished maximal developed tension in response to noradrenaline, when compared with that from normotensive rats. In superior mesenteric arteries, the sensitivity to noradrenaline was similar in all examined rat groups but in L-NAME-treated rats, these arteries exhibited decreased active force when stimulated with high noradrenaline concentrations, or with 100 mM KCl. These results indicate that hypertension leads to specific biomechanical alterations in diverse arterial types which are reflected in different modifications in their contractile properties.

  4. Increases in Physical Activity Result in Diminishing Increments in Daily Energy Expenditure in Mice.

    PubMed

    O'Neal, Timothy J; Friend, Danielle M; Guo, Juen; Hall, Kevin D; Kravitz, Alexxai V

    2017-02-06

    Exercise is a common component of weight loss strategies, yet exercise programs are associated with surprisingly small changes in body weight [1-4]. This may be due in part to compensatory adaptations, in which calories expended during exercise are counteracted by decreases in other aspects of energy expenditure [1, 5-10]. Here we examined the relationship between a rodent model of voluntary exercise- wheel running- and total daily energy expenditure. Use of a running wheel for 3 to 7 days increased daily energy expenditure, resulting in a caloric deficit of ∼1 kcal/day; however, total daily energy expenditure remained stable after the first week of wheel access, despite further increases in wheel use. We hypothesized that compensatory mechanisms accounted for the lack of increase in daily energy expenditure after the first week. Supporting this idea, we observed a decrease in off-wheel ambulation when mice were using the wheels, indicating behavioral compensation. Finally, we asked whether individual variation in wheel use within a group of mice would be associated with different levels of daily energy expenditure. Despite a large variation in wheel running, we did not observe a significant relationship between the amount of daily wheel running and total daily energy expenditure or energy intake across mice. Together, our experiments support a model in which the transition from sedentary to light activity is associated with an increase in daily energy expenditure, but further increases in physical activity produce diminishingly small increments in daily energy expenditure.

  5. Combined Vorticity Confinement and Total Variation Diminishing Technique for Modeling of Blade Tip Vortex

    NASA Astrophysics Data System (ADS)

    Povitsky, Alex; Pierson, Kristopher

    2013-11-01

    The Vorticity Confinement (VC) approach is combined with Total Variation Diminishing (TVD) technique to avoid over-confinement and divergence of upwind second-order of approximation schemes. The TVD schemes were combined with the first (constant confinement parameter ɛ) and second (constant unit-less confinement parameter c) VC formulations and with adoptive VC formulation by Hahn and Iaccarino. Combined VC/TVD techniques were first applied to convected Taylor vortex, which represent a model of wing tip vortex. For the former two VC methods combination of the second-order upwind discretization scheme with VC shows significant over-confinement of vortex whereas the first-order discretization scheme leads to strong dissipation of vortex. While the latter VC technique shows acceptable results for first-order upwind scheme, it either diverges or strongly over-confines when the second-order upwind discretization scheme is used. The VC/TVD techniques were tested with non-differentiable minmod and Van Leer flux limiters and with differentiable Van Albada limiter. The combination of VC and TVD with differential limiter computes most accurate vortex. The proposed technique is applied to tip vortex generated by rotating blade. Implementation of combined VC with TVD equipped with differential flux limiter to CFD code FLUENT shows much more close comparison to experimental results in terms of vortex velocity profile and size of vortex core compared to the same CFD code without VC approach. Grant support from ARO, AFRL, DAGSI.

  6. Application of the Diminishing Returns Concept in the Hydroecologic Restoration of Riverscapes

    SciTech Connect

    Diefenderfer, Heida L.; Johnson, Gary E.; Skalski, John R.; Breithaupt, Stephen A.; Coleman, Andre M.

    2012-03-17

    Principles for optimizing the number and placement of ecological restoration actions on rivers and coasts would be useful in project engineering design and program planning. This study demonstrated that the yield of inundated floodplain habitat area from dike breaching conforms to a diminishing returns model. The aggregate effects of establishing hydrologic connections between a tidally influenced main stem river and the floodplain were experimentally examined using a hydrodynamic model. Restoration clusters of size 1, 4, 8, and more, replicated and randomized within the landscape, yielded average wetted floodplain area conforming with an exponential rise to maximum curve2(0.99)r=. Analysis of the average incremental change in floodplain inundation produced per breach showed that opening 25 % of the channels crossing the dike provided the maximum return on investment as measured by wetted area. Midstream breaches yielded 60 % and upstream breaches 2 % of the wetted area produced by downstream breaches. Dike-breach restoration programs therefore can be optimized by strategic determination of the spatial configuration and number of demolitions, though biological factors such as the accessibility of floodplain habitat and total length of channels connected also need to be considered. These findings have implications for cost-benefit analyses in restoration program planning.

  7. GILT expression in B cells diminishes cathepsin S steady-state protein expression and activity

    PubMed Central

    Phipps-Yonas, Hannah; Semik, Vikki; Hastings, Karen Taraszka

    2013-01-01

    MHC class II-restricted Ag processing requires protein degradation in the endocytic pathway for the activation of CD4+ T cells. Gamma-interferon-inducible lysosomal thiol reductase (GILT) facilitates Ag processing by reducing protein disulfide bonds in this compartment. Lysosomal cysteine protease cathepsin S (CatS) contains disulfide bonds and mediates essential steps in MHC class II-restricted processing, including proteolysis of large polypeptides and cleavage of the invariant chain. We sought to determine whether GILT’s reductase activity regulates CatS expression and function. Confocal microscopy confirmed that GILT and CatS colocalized within lysosomes of B cells. GILT expression posttranscriptionally decreased the steady-state protein expression of CatS in primary B cells and B-cell lines. GILT did not substantially alter the expression of other lysosomal proteins, including H2-M, H2-O, or CatL. GILT’s reductase active site was necessary for diminished CatS protein levels, and GILT expression decreased the half-life of CatS, suggesting that GILT-mediated reduction of protein disulfide bonds enhances CatS degradation. GILT expression decreased the proteolysis of a CatS selective substrate. This study illustrates a physiologic mechanism that regulates CatS and has implications for fine tuning MHC class II-restricted Ag processing and for the development of CatS inhibitors, which are under investigation for the treatment of autoimmune disease. PMID:23012103

  8. Pulsed Ultrasound Fails To Diminish Delayed-Onset Muscle Soreness Symptoms

    PubMed Central

    Stay, Jeffrey C.; Richard, Mark D.; Draper, David O.; Schulthies, Shane S.; Durrant, Earlene

    1998-01-01

    Objective: We investigated the effects of pulsed ultrasound on swelling, muscle soreness perception, relaxed-elbow extension angle, and muscular strength. Design and Setting: Eight sets of concentric and eccentric actions induced delayed-onset muscle soreness of the elbow flexors. Group 1 received 20% pulsed ultrasound treatments (1-MHz, 7 minutes, 1.5 W/ cm2 temporal peak intensity) twice a day immediately after postexercise assessments and at 3, 24, 27, 48, 51, 72, and 75 hours postexercise. Group 2 received sham treatments immediately after postexercise assessments and at 3,27, 51, and 75 hours postexercise and true treatments of pulsed ultrasound at 24, 48, and 72 hours postexercise. Group 3 received sham treatments of no ultrasonic output immediately after postexercise assessments and at 3, 24, 27, 48, 51, 72, and 75 hours postexercise. Subjects: Thirty-six college-age females. Measurements: We recorded upper-arm circumference, perceived soreness, relaxed-elbow extension angle, and elbow-flexion strength before (pretest), immediately postexercise, and at 24, 48, 72, and 96 hours postexercise. Results: We noted differences over time but no treatment effect between groups or interactions between time and group for upper-arm circumference, perceived soreness, relaxed-elbow extension angle, or elbow-flexion strength. Conclusions: Pulsed ultrasound as used in this study did not significantly diminish the effects of delayed-onset muscle soreness on soreness perception, swelling, relaxed-elbow extension angle, and strength. PMID:16558532

  9. Diminished testing benefits in young adults with attention-deficit hyperactivity disorder.

    PubMed

    Dudukovic, Nicole M; Gottshall, Jackie L; Cavanaugh, Patricia A; Moody, Christine T

    2015-01-01

    Memory retrieval has been shown to enhance the long-term retention of tested material; however, recent research suggests that limiting attention during retrieval can decrease the benefits of testing memory. The present study examined whether testing benefits are reduced in young adults with attention-deficit hyperactivity disorder (ADHD). College students with and without ADHD read three short prose passages, each followed by a free recall test, a restudy period or a distractor task. Two days later participants recalled the passages. Although participants without ADHD did not show a significant benefit of testing over restudying, testing did produce recall benefits relative to not taking a test. These testing benefits were diminished in participants with ADHD, who did not show any advantage of testing over either restudying or no test. The absence of testing benefits in the ADHD group is likely due in part to decreased recall on the initial test. These findings have implications for improving educational practices among individuals with ADHD and also speak to the need to examine individual differences in the effectiveness of testing as a learning strategy.

  10. Diminished neural responses predict enhanced intrinsic motivation and sensitivity to external incentive.

    PubMed

    Marsden, Karen E; Ma, Wei Ji; Deci, Edward L; Ryan, Richard M; Chiu, Pearl H

    2015-06-01

    The duration and quality of human performance depend on both intrinsic motivation and external incentives. However, little is known about the neuroscientific basis of this interplay between internal and external motivators. Here, we used functional magnetic resonance imaging to examine the neural substrates of intrinsic motivation, operationalized as the free-choice time spent on a task when this was not required, and tested the neural and behavioral effects of external reward on intrinsic motivation. We found that increased duration of free-choice time was predicted by generally diminished neural responses in regions associated with cognitive and affective regulation. By comparison, the possibility of additional reward improved task accuracy, and specifically increased neural and behavioral responses following errors. Those individuals with the smallest neural responses associated with intrinsic motivation exhibited the greatest error-related neural enhancement under the external contingency of possible reward. Together, these data suggest that human performance is guided by a "tonic" and "phasic" relationship between the neural substrates of intrinsic motivation (tonic) and the impact of external incentives (phasic).

  11. Failure to Demonstrate That Playing Violent Video Games Diminishes Prosocial Behavior

    PubMed Central

    Tear, Morgan J.; Nielsen, Mark

    2013-01-01

    Background Past research has found that playing a classic prosocial video game resulted in heightened prosocial behavior when compared to a control group, whereas playing a classic violent video game had no effect. Given purported links between violent video games and poor social behavior, this result is surprising. Here our aim was to assess whether this finding may be due to the specific games used. That is, modern games are experienced differently from classic games (more immersion in virtual environments, more connection with characters, etc.) and it may be that playing violent video games impacts prosocial behavior only when contemporary versions are used. Methods and Findings Experiments 1 and 2 explored the effects of playing contemporary violent, non-violent, and prosocial video games on prosocial behavior, as measured by the pen-drop task. We found that slight contextual changes in the delivery of the pen-drop task led to different rates of helping but that the type of game played had little effect. Experiment 3 explored this further by using classic games. Again, we found no effect. Conclusions We failed to find evidence that playing video games affects prosocial behavior. Research on the effects of video game play is of significant public interest. It is therefore important that speculation be rigorously tested and findings replicated. Here we fail to substantiate conjecture that playing contemporary violent video games will lead to diminished prosocial behavior. PMID:23844191

  12. Diminished pore pressure in low-porosity crystalline rock under tensional failure: Apparent strengthening by dilatancy

    NASA Astrophysics Data System (ADS)

    Schmitt, Douglas R.; Zoback, Mark D.

    1992-01-01

    Rupture tests on internally pressurized, thin-walled hollow cylinders of Westerly granite with impermeable inner membranes suggest that the conventional, or Terzaghi, effective stress law does not describe tensile failure at high internal pressurization rates near 6 MPa/s. Unjacketed and saturated samples, with an initial pore pressure and for which the inner cavity pressure was increased rapidly with respect to the diffusivity, display substantially increased apparent tensile strengths and deformational moduli much higher than similarly configured but more slowly pressurized tests. Alternatively, the properties of completely dry test pieces with no pore pressure show little, if any, dependence on pressurization rate. Further, the behavior of the rapid unjacketed tests was similar to that for completely dry samples. These observations cannot be explained by the predicted undrained response, but they provide indirect evidence for diminished pore pressure effects reminiscent of dilatant hardening observed in compressive failure experiments. Calculated pore pressure diffusion rates support this suggestion as pore pressure perturbations cannot be damped out on the time scale of the rapidly pressurized tests. It is not clear if these effects are produced by elastic microcrack dilatancy, of which the nonlinear stress-strain curve of granites is symptomatic, or the irreversible production of new porosity as in compressive shear failure tests.

  13. A change will do us good: threats diminish typical preferences for male leaders.

    PubMed

    Brown, Elizabeth R; Diekman, Amanda B; Schneider, Monica C

    2011-07-01

    The current research explores role congruity processes from a new vantage point by investigating how the need for change might shift gender-based leadership preferences. According to role congruity theory, favorability toward leaders results from alignment between what is desired in a leadership role and the characteristics stereotypically ascribed to the leader. Generally speaking, these processes lead to baseline preferences for male over female leaders. In this research, the authors propose that a shift in gender-based leadership preferences will emerge under conditions of threat. Because the psychological experience of threat signals a need for change, individuals will favor candidates who represent new directions in leadership rather than consistency with past directions in leadership. Specifically, they find that threat evokes an implicit preference for change over stability (Experiment 1) and gender stereotypes align women with change but men with stability (Experiments 2a and 2b). Consequently, the typical preference for male leaders is diminished, or even reversed, under threat (Experiments 3 and 4). Moreover, the shift away from typical gender-based leadership preferences occurs especially among individuals who highly legitimize the sociopolitical system (Experiment 4), suggesting that these preference shifts might serve to protect the underlying system.

  14. Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

    PubMed Central

    Harouaka, Djamila; Engle, Ronald E.; Wollenberg, Kurt; Diaz, Giacomo; Tice, Ashley B.; Zamboni, Fausto; Govindarajan, Sugantha; Alter, Harvey; Kleiner, David E.; Farci, Patrizia

    2016-01-01

    Analysis of hepatitis C virus (HCV) replication and quasispecies distribution within the tumor of patients with HCV-associated hepatocellular carcinoma (HCC) can provide insight into the role of HCV in hepatocarcinogenesis and, conversely, the effect of HCC on the HCV lifecycle. In a comprehensive study of serum and multiple liver specimens from patients with HCC who underwent liver transplantation, we found a sharp and significant decrease in HCV RNA in the tumor compared with surrounding nontumorous tissues, but found no differences in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression. HCV genetic diversity was significantly higher in livers containing HCC compared with control non-HCC cirrhotic livers. Tracking of individual variants demonstrated changes in the viral population between tumorous and nontumorous areas, the extent of which correlated with the decline in HCV RNA, suggesting HCV compartmentalization within the tumor. In contrast, compartmentalization was not observed between nontumorous areas and serum, or in controls between different areas of the cirrhotic liver or between liver and serum. Our findings indicate that HCV replication within the tumor is restricted and compartmentalized, suggesting segregation of specific viral variants in malignant hepatocytes. PMID:26787866

  15. “Queasy does it”: False alcohol beliefs and memories may lead to diminished alcohol preferences

    PubMed Central

    Clifasefi, Seema L.; Bernstein, Daniel M.; Mantonakis, Antonia; Loftus, Elizabeth F.

    2013-01-01

    Studies have shown that false memories can be implanted via innocuous suggestions, and that these memories can play a role in shaping people’s subsequent attitudes and preferences. The current study explored whether participants (N=147) who received a false suggestion that they had become ill drinking a particular type of alcohol would increase their confidence that the event had occurred, and whether their new-found belief would subsequently affect their alcohol preferences. Results indicated that participants who received a suggestion that they had gotten sick drinking rum or vodka before the age of 16 reported increased confidence that the suggested experience had occurred. Moreover, participants who received a false alcohol suggestion also showed a strong trend to report diminished preference for the specified type of alcohol after the false suggestion. Implantation of a false memory related to one’s past drinking experiences may influence current drink preferences and could be an important avenue for further exploration in the development of alcohol interventions. PMID:23500110

  16. Air pollution particles diminish bacterial clearance in the primed lungs of mice

    SciTech Connect

    Sigaud, Samuel; Goldsmith, Carroll-Ann W.; Zhou Hongwei; Yang Zhiping; Fedulov, Alexey; Imrich, Amy; Kobzik, Lester

    2007-08-15

    Epidemiological studies reveal increased incidence of lung infection when air pollution particle levels are increased. We postulate that one risk factor for bacterial pneumonia, prior viral infection, can prime the lung for greater deleterious effects of particles via the interferon-gamma (IFN-{gamma}) characteristic of successful host anti-viral responses. To test this postulate, we developed a mouse model in which mice were treated with {gamma}-interferon aerosol, followed by exposure to concentrated ambient particles (CAPs) collected from urban air. The mice were then infected with Streptococcus pneumoniae and the effect of these treatments on the lung's innate immune response was evaluated. The combination of IFN-{gamma} priming and CAPs exposure enhanced lung inflammation, manifest as increased polymorphonuclear granulocyte (PMN) recruitment to the lung, and elevated expression of pro-inflammatory cytokine mRNAs. Combined priming and CAPs exposure resulted in impaired pulmonary bacterial clearance, as well as increased oxidant production and diminished bacterial uptake by alveolar macrophages (AMs) and PMNs. The data suggest that priming and CAPs exposure lead to an inflamed alveolar milieu where oxidant stress causes loss of antibacterial functions in AMs and recruited PMNs. The model reported here will allow further analysis of priming and CAPs exposure on lung sensitivity to infection.

  17. Diminished amygdala activation and behavioral threat response following traumatic brain injury.

    PubMed

    Palmer, Christopher P; Metheny, Hannah E; Elkind, Jaclynn A; Cohen, Akiva S

    2016-03-01

    Each year, approximately 3.8 million people suffer mild to moderate traumatic brain injuries (mTBI) that result in an array of neuropsychological symptoms and disorders. Despite these alarming statistics, the neurological bases of these persistent, debilitating neuropsychological symptoms are currently poorly understood. In this study we examined the effects of mTBI on the amygdala, a brain structure known to be critically involved in the processing of emotional stimuli. Seven days after lateral fluid percussion injury (LFPI), mice underwent a series of physiological and behavioral experiments to assess amygdala function. Brain-injured mice exhibited a decreased threat response in a cued fear conditioning paradigm, congruent with a decrease in amygdala excitability determined with basolateral amygdala (BLA) field excitatory post-synaptic potentials together with voltage-sensitive dye imaging (VSD). Furthermore, beyond exposing a general decrease in the excitability of the primary input of the amygdala, the lateral amygdala (LA), VSD also revealed a decrease in the relative strength or activation of internuclear amygdala circuit projections after LFPI. Thus, not only does activation of the LA require increased stimulation, but the proportion of this activation that is propagated to the primary output of the amygdala, the central amygdala, is also diminished following LFPI. Intracellular recordings revealed no changes in the intrinsic properties of BLA pyramidal neurons after LFPI. This data suggests that mild to moderate TBI has prominent effects on amygdala function and provides a potential neurological substrate for many of the neuropsychological symptoms suffered by TBI patients.

  18. The Agonistic Approach: Reframing Resistance in Qualitative Research

    ERIC Educational Resources Information Center

    Vitus, Kathrine

    2008-01-01

    The agonistic approach--aimed at embracing opposing perspectives as part of a qualitative research process and acknowledging that process as fundamentally political--sheds light on both the construction of and the resistance to research identities. This approach involves reflexively embedding interview situations into the ethnographic context as a…

  19. Once-weekly glucagon-like peptide 1 receptor agonists.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep

    2015-07-01

    The once-weekly glucagon-like peptide 1 receptor agonists (QW GLP1RA) represent a major advancement in diabetes pharmaco-therapeutics. This review describes the basic, clinical, and comparative pharmacology of this novel class of drugs. It highlights the clinical placement and posology of these drugs.

  20. Use of ß-adrenergic agonists in hybrid catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  1. Dopamine agonists in prevention of ovarian hyperstimulation syndrome.

    PubMed

    Kasum, Miro; Vrčić, Hrvoje; Stanić, Patrik; Ježek, Davor; Orešković, Slavko; Beketić-Orešković, Lidija; Pekez, Marijeta

    2014-01-01

    The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4-21 days), the dose of cabergoline (0.5 mg or 0.25 mg orally) and in the regimens used. At present, the best known effective regimen is 0.5 mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5 mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome.

  2. [Alpha 2-adrenoceptor agonists for the treatment of chronic pain].

    PubMed

    Kulka, P J

    1996-04-25

    The antinociceptive effect of alpha(2)-adrenoceptor agonists is mediated by activation of descending inhibiting noradrenergic systems, which modulates 'wide-dynamic-range' neurones. Furthermore, they inhibit the liberation of substance P and endorphines and activate serotoninergic neurones. Despite this variety of antinociceptive actions, there is still little experience with alpha(2)-adrenoceptor agonists as therapeutic agents for use in chronic pain syndromes. Studies in animals and patients have shown that the transdermal, epidural and intravenous administration of the alpha(2)-adrenoceptor agonist clonidine reduces pain intensity in neuropathic pain syndromes for periods varying from some hours up to 1 month. Patients suffering from lancinating or sharp pain respond best to this therapy. Topically applied clonidine (200-300 microg) relieves hyperalgesia in sympathetically maintained pain. Epidural administration of 300 microg clonidine dissolved in 5 ml NaCl 0.9 % has also been shown to be effective. In patients suffering from cancer pain tolerant to opioids, pain control has proved possible again with combinations of opioids and clonidine. In isolated cases clonidine has been administered epidurally at a dose of 1500 microg/day for almost 5 months without evidence for any histotoxic property of clonidine. Side effects often observed during administration of alpha(2)-adrenoceptor agonists are dry mouth, sedation, hypotension and bradycardia. Therapeutic interventions are usually not required.

  3. Role of nicotine receptor partial agonists in tobacco cessation

    PubMed Central

    Maity, Nivedita; Chand, Prabhat; Murthy, Pratima

    2014-01-01

    One in three adults in India uses tobacco, a highly addictive substance in one or other form. In addition to prevention of tobacco use, offering evidence-based cessation services to dependent tobacco users constitutes an important approach in addressing this serious public health problem. A combination of behavioral methods and pharmacotherapy has shown the most optimal results in tobacco dependence treatment. Among currently available pharmacological agents, drugs that preferentially act on the α4 β2-nicotinic acetyl choline receptor like varenicline and cytisine appear to have relatively better cessation outcomes. These drugs are in general well tolerated and have minimal drug interactions. The odds of quitting tobacco use are at the very least doubled with the use of partial agonists compared with placebo and the outcomes are also superior when compared to nicotine replacement therapy and bupropion. The poor availability of partial agonists and specifically the cost of varenicline, as well as the lack of safety data for cytisine has limited their use world over, particularly in developing countries. Evidence for the benefit of partial agonists is more robust for smoking rather than smokeless forms of tobacco. Although more studies are needed to demonstrate their effectiveness in different populations of tobacco users, present literature supports the use of partial agonists in addition to behavioral methods for optimal outcome in tobacco dependence. PMID:24574554

  4. Dopamine receptor agonists for protection and repair in Parkinson's disease.

    PubMed

    Ferrari-Toninelli, Giulia; Bonini, Sara A; Cenini, Giovanna; Maccarinelli, Giuseppina; Grilli, Mariagrazia; Uberti, Daniela; Memo, Maurizio

    2008-01-01

    Dopamine agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease. It is generally believed that treatment with these drugs is symptomatic rather than curative and it does not stop or delay the progression of neuronal degeneration. However, several dopamine agonists of the D2-receptor family have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson's disease models. Here we summarize some recent molecular evidences underlining the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson's disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These neuroprotective activities are molecule-specific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role.

  5. Amylin and Amylin Agonists for Treating Psychiatric Diseases and Disorders

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methods and compositions for treating psychiatric diseases and disorders are disclosed. The methods provided generally involve the administration of an amylin or an amylin agonist to a subject in order to treat psychiatric diseases and disorders, and conditions associated with psychiatric diseases a...

  6. Vasodilators in Acute Heart Failure: Review of the Latest Studies

    PubMed Central

    Levy, Phillip D.; Laribi, Said; Mebazaa, Alexandre

    2014-01-01

    Vasodilators play an important role in the management of acute heart failure, particularly when increased afterload is the precipitating cause of decompensation. The time-honored approach to afterload reduction has been largely focused on use of intravenous nitrovasodilators and, when properly dosed, this class of agents does provide substantial symptom relief for patients with acute hypertensive heart failure. Despite this, nitrovasodilators have never been shown to diminish mortality or provide any post-discharge outcome benefit leading to an on-going search for viable and more effective alternatives. While no new vasodilators have been approved for use in acute heart failure since nesiritide more than a decade ago, a number of novel agents have been developed, with some showing significant promise in recent clinical trials. In this review, we summarize the latest study data as it relates to vasodilator therapy and provide a glimpse into the not too distant future state of acute heart failure care. PMID:24855585

  7. Macrophages and Myeloid Dendritic Cells Lose T Cell-Stimulating Function in Simian Immunodeficiency Virus Infection Associated with Diminished IL-12 and IFN-α Production.

    PubMed

    Wonderlich, Elizabeth R; Wu, Wen-Chi; Normolle, Daniel P; Barratt-Boyes, Simon M

    2015-10-01

    Impaired T cell responses are a defining characteristic of HIV infection, but the extent to which altered mononuclear phagocyte function contributes to this defect is unclear. We show that mononuclear phagocytes enriched from rhesus macaque lymph nodes have suppressed ability to stimulate CD4 T cell proliferation and IFN-γ release after acute SIV infection. When individual populations were isolated, myeloid dendritic cells (mDC) and macrophages but not plasmacytoid DC (pDC) had suppressed capacity to stimulate CD4 T cell proliferation, with macrophage function declining as infection progressed. Macrophages, but not pDC or mDC, had suppressed capacity to induce IFN-γ release from CD4 T cells in acute infection, even after stimulation with virus-encoded TLR7/8 ligand. Changes in expression of costimulatory molecules did not explain loss of function postinfection. Conversely, pDC and mDC had marked loss of IFN-α and IL-12 production, respectively, and macrophages lost production of both cytokines. In T cell cocultures without TLR7/8 ligand, macrophages were the primary source of IL-12, which was profoundly suppressed postinfection and correlated with loss of IFN-γ release by T cells. TLR7/8-stimulated pDC, mDC and macrophages all produced IL-12 in T cell cocultures, which was suppressed in chronic infection. Supplementing IL-12 enhanced mDC-driven IFN-γ release from T cells, and IL-12 and IFN-α together restored function in TLR7/8-activated macrophages. These findings reveal loss of macrophage and mDC T cell-stimulating function in lymph nodes of SIV-infected rhesus macaques associated with diminished IL-12 and IFN-α production that may be a factor in AIDS immunopathogenesis.

  8. A PPAR-gamma agonist protects from radiation-induced intestinal toxicity

    PubMed Central

    Sottili, Mariangela; Gerini, Chiara; Desideri, Isacco; Bastida, Cinzia; Pallotta, Stefania; Castiglione, Francesca; Bonomo, Pierluigi; Meattini, Icro; Greto, Daniela; Cappelli, Sabrina; Di Brina, Lucia; Loi, Mauro; Biti, Giampaolo; Livi, Lorenzo

    2016-01-01

    Objective Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating for use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells. Methods Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 µM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days. Results Rosiglitazone markedly reduced histological signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression of Collagen1, Mmp13, Tnfα and Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth. Conclusion Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation. PMID:28344789

  9. Antidepressant-like action of intracerebral 6-fluoronorepinephrine, a selective full α-adrenoceptor agonist.

    PubMed

    Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

    2011-04-01

    The present study examined the ability of 6-fluoronorepinephrine (6FNE), a full selective α-adrenoceptor agonist, to produce antidepressant-like effects in mice. The drug, administered in the 4th ventricle, produced marked anti-immobility effects at mid-dose range in the acute forced swim, tail suspension and repeated open-space forced swim tests with minimal effect on open-field motor activity and also reversed anhedonia following lipopolysaccharide administration. Its antidepressant effects were equal to or greater than that of an established systemic antidepressant, desmethylimipramine, given subacutely. Experiments with α-adrenoceptor antagonists indicated that the drug acts primarily via the α2-receptor in contrast to endogenous catecholamines which appear to control depressive behaviour primarily via the α1-receptor. Antidepressant activity declined at higher doses signifying a possible pro-depressant effect of one of the α-adrenoceptor subtypes. Compared to the selective α2-agonist, dexmedetomidine, 6FNE showed equivalent antidepressant action in the tail suspension test but appeared to have a greater efficacy or speed of action in the repeated open-space forced swim test which produces a more sustained depression. Studies of regional brain Fos expression induced during the antidepressant tests showed that 6FNE tended to inhibit neural activity in two stress-responsive regions (locus coeruleus and paraventricular hypothalamus) but to enhance activity in two areas involved in motivated behaviour (nucleus accumbens shell and lateral septal nucleus) producing a neural pattern consistent with antidepressant action. It is concluded that 6FNE elicits a rapid and effective antidepressant and anti-stress response that may compare favourably with available antidepressants.

  10. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors.

    PubMed

    Corton, J Christopher; Apte, Udayan; Anderson, Steven P; Limaye, Pallavi; Yoon, Lawrence; Latendresse, John; Dunn, Corrie; Everitt, Jeffrey I; Voss, Kenneth A; Swanson, Cynthia; Kimbrough, Carie; Wong, Jean S; Gill, Sarjeet S; Chandraratna, Roshantha A S; Kwak, Mi-Kyoung; Kensler, Thomas W; Stulnig, Thomas M; Steffensen, Knut R; Gustafsson, Jan-Ake; Mehendale, Harihara M

    2004-10-29

    The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1alpha (PGC-1alpha). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor alpha (PPARalpha), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPARalpha. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPARalpha, including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPARalpha-null mice due to inadequate tissue repair. These results demonstrate that PPARalpha mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.

  11. Efficacy and kinetics of opioid action on acutely dissociated neurons.

    PubMed

    Ingram, S; Wilding, T J; McCleskey, E W; Williams, J T

    1997-07-01

    Opioids have been shown to cause a potent inhibition of neurons in the locus ceruleus (LC) in vivo in brain slices and isolated neurons; however, the kinetics of opioid action have not been described. In this study, we used acutely isolated LC neurons to examine opioid and alpha2-adrenoceptor action on potassium and calcium currents. [Met]Enkephalin (ME), [D-Ser2,Leu5,Thr6]-enkephalin, etorphine, and [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin increased potassium conductance, whereas morphine and naloxone were antagonists. The time constant of potassium channel activation was approximately 0.7 sec and was the same for each agonist. The amplitude of the current and the time constant of decay were dependent on the agonist, suggesting that agonist efficacy and affinity, respectively, determined these parameters. The amplitude of potassium current induced by the alpha2-adrenoceptor agonist UK14304 was not significantly different from that induced by ME, but the time constant of current activation was half that of ME, and the decline was more rapid. When potassium conductances were blocked with the combination of internal cesium and external barium, opioid and alpha2 agonists had no effect at potentials more negative than -50 mV and decreased barium currents at potentials between -40 and +20 mV. Both morphine and clonidine caused a small inhibition of barium current. In dorsal root ganglion cells, morphine alone had small and inconsistent effects on the calcium current, but it always competitively antagonized the inhibition caused by [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin. The results in isolated LC neurons suggest 1) the amplitude and time course of the opioid-induced potassium current depend on agonist efficacy and affinity and 2) the coupling of both mu-opioid and alpha2-adrenoceptors to calcium channels seems to be more efficient than that to potassium channels.

  12. Identification of raloxifene as a novel CB2 inverse agonist.

    PubMed

    Kumar, Pritesh; Song, Zhao-Hui

    2013-05-24

    The purpose of the current study was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. Our results demonstrated that by acting on CB2, raloxifene enhances forskolin-stimulated cAMP accumulation in a concentration-dependant manner. Furthermore, our data showed that raloxifene competes concentration-dependently for specific [(3)H]CP-55,940 binding to CB2. In addition, raloxifene pretreatment caused a rightward shift of the concentration-response curves of the cannabinoid agonists CP-55,940, HU-210, and WIN55,212-2. Raloxifene antagonism is most likely competitive in nature, as these rightward shifts were parallel and were not associated with any changes in the efficacy of cannabinoid agonists on CB2. Our discovery that raloxfiene is an inverse agonist for CB2 suggests that it might be possible to repurpose this FDA-approved drug for novel therapeutic indications for which CB2 is a target. Furthermore, identifying raloxifene as a CB2 inverse agonist also provides important novel mechanisms of actions to explain the known therapeutic effects of raloxifene.

  13. Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells

    SciTech Connect

    Payton-Stewart, Florastina; Tilghman, Syreeta L.; Williams, LaKeisha G.; Winfield, Leyte L.

    2014-08-08

    Highlights: • The methyl-substituted benzimidazole was more effective at inhibiting growth in MDA-MB 231 cells. • The naphthyl-substituted benzimidazole was more effective at inhibiting growth in MCF-7 cells than ICI. • The benzimidazole molecules demonstrated a dose-dependent reduction in ERE transcriptional activity. • The benzimidazole molecules had binding mode in ERα and ERβ comparable to that of the co-crystallized ligand. - Abstract: Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulfonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel, while the naphthyl analog did not significantly alter gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules

  14. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  15. Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization

    PubMed Central

    Naito, Yusuke; Tanabe, Yuko; Lee, Alfred Kihoon; Hamel, Edith; Takahashi, Hideto

    2017-01-01

    Alzheimer’s disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, AβOs diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging revealed that AβO treatment reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology in AD. PMID:28211900

  16. Diminished Metal Accumulation in Riverine Fishes Exposed to Acid Mine Drainage over Five Decades

    PubMed Central

    Jeffree, Ross A.; Markich, Scott J.; Twining, John R.

    2014-01-01

    Bony bream (Nematalosa erebi) and black catfish (Neosilurus ater) were sampled from the fresh surface waters of the Finniss River in tropical northern Australia, along a metal pollution gradient draining the Rum Jungle copper/uranium mine, a contaminant source for over five decades. Paradoxically, populations of both fish species exposed to the highest concentrations of mine-related metals (cobalt, copper, lead, manganese, nickel, uranium and zinc) in surface water and sediment had the lowest tissue (bone, liver and muscle) concentrations of these metals. The degree of reduction in tissue concentrations of exposed populations was also specific to each metal and inversely related to its degree of environmental increase above background. Several explanations for diminished metal bioaccumulation in fishes from the contaminated region were evaluated. Geochemical speciation modeling of metal bioavailability in surface water showed no differences between the contaminated region and the control sites. Also, the macro-nutrient (calcium, magnesium and sodium) water concentrations, that may competitively inhibit metal uptake, were not elevated with trace metal contamination. Reduced exposure to contaminants due to avoidance behavior was unlikely due to the absence of refugial water bodies with the requisite metal concentrations lower than the control sites and very reduced connectivity at time of sampling. The most plausible interpretation of these results is that populations of both fish species have modified kinetics within their metal bioaccumulation physiology, via adaptation or tolerance responses, to reduce their body burdens of metals. This hypothesis is consistent with (i) reduced tissue concentrations of calcium, magnesium and sodium (macro-nutrients), in exposed populations of both species, (ii) experimental findings for other fish species from the Finniss River and other contaminated regions, and (iii) the number of generations exposed to likely selection pressure

  17. Diminished glucose transport and phosphorylation in Alzheimer`s disease determined by dynamic FDG-PET

    SciTech Connect

    Piert, M.; Koeppe, R.A.; Giordani, B.; Berent, S.; Kuhl, D.E.

    1996-02-01

    Using dynamic [{sup 18}F] fluorodeoxyglucose (FDG) and PET, kinetic rate constants that describe influx (K{sub 1}) and efflux (k{sub 2}) of FDG as well s phosphorylation (k{sub 3}) and dephosphorylation (k{sub 4}) were determined in patients with probable Alzheimer`s disease and similarly aged normal controls. The regional cerebral metabolic rate for glucose (CMR{sub glu}) was calculated from individually fitted rate constants in frontal, temporal, parietal and occipital cerebral cortex, caudate nucleus, putamen, thalamus and cerebellar cortex. Dynamic PET scans were obtained in normal controls (n = 10, mean age = 67) and Alzheimer`s disease patients (n = 8, mean age = 67) for 60 min following injection of 10 mCi of FDG. The Alzheimer`s disease group was characterized by decreases of the CMR{sub glu} ranging from 13.3% in the frontal to 40.9% in the parietal cortex, which achieved significance in all regions except the thalamus. K{sub 1} was significantly reduced in the parietal (p < 0.01) and temporal cortices (p < 0.005), temporal and occipital cortex, and in the putamen and cerebellum (p < 0.05). The rate constants k{sub 2} and k{sub 4} were unchanged in the Alzheimer`s disease group. These data suggest that hypometabolism in Alzheimer`s disease is related to reduced glucose phosphorylation activity as well as diminished glucose transport, particularly in the most metabolically affected areas of the brain, the parietal and temporal cortex. 60 refs., 2 figs., 2 tabs.

  18. Diminishing returns from increased percent Bt cotton: the case of pink bollworm.

    PubMed

    Huang, Yunxin; Wan, Peng; Zhang, Huannan; Huang, Minsong; Li, Zhaohua; Gould, Fred

    2013-01-01

    Regional suppression of pests by transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) has been reported in several cropping systems, but little is known about the functional relationship between the ultimate pest population density and the pervasiveness of Bt crops. Here we address this issue by analyzing 16 years of field data on pink bollworm (Pectinophora gossypiella) population density and percentage of Bt cotton in the Yangtze River Valley of China. In this region, the percentage of cotton hectares planted with Bt cotton increased from 9% in 2000 to 94% in 2009 and 2010. We find that as the percent Bt cotton increased over the years, the cross-year growth rate of pink bollworm from the last generation of one year to the first generation of the next year decreased. However, as the percent Bt cotton increased, the within-year growth rate of pink bollworm from the first to last generation of the same year increased, with a slope approximately opposite to that of the cross-year rates. As a result, we did not find a statistically significant decline in the annual growth rate of pink bollworm as the percent Bt cotton increased over time. Consistent with the data, our modeling analyses predict that the regional average density of pink bollworm declines as the percent Bt cotton increases, but the higher the percent Bt cotton, the slower the decline in pest density. Specifically, we find that 95% Bt cotton is predicted to cause only 3% more reduction in larval density than 80% Bt cotton. The results here suggest that density dependence can act against the decline in pest density and diminish the net effects of Bt cotton on suppression of pink bollworm in the study region. The findings call for more studies of the interactions between pest density-dependence and Bt crops.

  19. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.

    PubMed

    Veit, Guido; Avramescu, Radu G; Perdomo, Doranda; Phuan, Puay-Wah; Bagdany, Miklos; Apaja, Pirjo M; Borot, Florence; Szollosi, Daniel; Wu, Yu-Sheng; Finkbeiner, Walter E; Hegedus, Tamas; Verkman, Alan S; Lukacs, Gergely L

    2014-07-23

    Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.

  20. Mycobacterium tuberculosis has diminished capacity to counteract redox stress induced by elevated levels of endogenous superoxide

    PubMed Central

    Tyagi, Priyanka; Dharmaraja, Allimuthu T.; Bhaskar, Ashima; Chakrapani, Harinath; Singh, Amit

    2015-01-01

    Mycobacterium tuberculosis (Mtb) has evolved protective and detoxification mechanisms to maintain cytoplasmic redox balance in response to exogenous oxidative stress encountered inside host phagocytes. In contrast, little is known about the dynamic response of this pathogen to endogenous oxidative stress generated within Mtb. Using a noninvasive and specific biosensor of cytoplasmic redox state of Mtb, we for first time discovered a surprisingly high sensitivity of this pathogen to perturbation in redox homeostasis induced by elevated endogenous reactive oxygen species (ROS). We synthesized a series of hydroquinone-based small molecule ROS generators and found that ATD-3169 permeated mycobacteria to reliably enhance endogenous ROS including superoxide radicals. When Mtb strains including multidrug-resistant (MDR) and extensively drug-resistant (XDR) patient isolates were exposed to this compound, a dose-dependent, long-lasting, and irreversible oxidative shift in intramycobacterial redox potential was detected. Dynamic redox potential measurements revealed that Mtb had diminished capacity to restore cytoplasmic redox balance in comparison with Mycobacterium smegmatis (Msm), a fast growing nonpathogenic mycobacterial species. Accordingly, Mtb strains were extremely susceptible to inhibition by ATD-3169 but not Msm, suggesting a functional linkage between dynamic redox changes and survival. Microarray analysis showed major realignment of pathways involved in redox homeostasis, central metabolism, DNA repair, and cell wall lipid biosynthesis in response to ATD-3169, all consistent with enhanced endogenous ROS contributing to lethality induced by this compound. This work provides empirical evidence that the cytoplasmic redox poise of Mtb is uniquely sensitive to manipulation in steady-state endogenous ROS levels, thus revealing the importance of targeting intramycobacterial redox metabolism for controlling TB infection. PMID:25819161

  1. The cardioprotective effect of mildronate is diminished after co-treatment with L-carnitine.

    PubMed

    Kuka, Janis; Vilskersts, Reinis; Cirule, Helena; Makrecka, Marina; Pugovics, Osvalds; Kalvinsh, Ivars; Dambrova, Maija; Liepinsh, Edgars

    2012-06-01

    Mildronate, an inhibitor of L-carnitine biosynthesis and uptake, is a cardioprotective drug whose mechanism of action is thought to rely on the changes in concentration of L-carnitine in heart tissue. In the present study, we compared the cardioprotective effect of mildronate (100 mg/kg) and a combination of mildronate and L-carnitine (100 + 100 mg/kg) administered for 14 days with respect to the observed changes in l-carnitine level and carnitine palmitoyltransferase I (CPT-I)-dependent fatty acid metabolism in the heart tissues. Concentrations of L-carnitine and its precursor γ-butyrobetaine (GBB) were measured by ultraperformance liquid chromatography with tandem mass spectrometry. In addition, mitochondrial respiration, activity of CPT-I, and expression of CPT-IA/B messenger RNA (mRNA) were measured. Isolated rat hearts were subjected to ischemia-reperfusion injury. Administration of mildronate induced a 69% decrease in L-carnitine concentration and a 6-fold increase in GBB concentration in the heart tissue as well as a 27% decrease in CPT-I-dependent mitochondrial respiration on palmitoyl-coenzyme A. In addition, mildronate treatment induced a significant reduction in infarct size and also diminished the ischemia-induced respiration stimulation by exogenous cytochrome c. Treatment with a combination had no significant impact on L-carnitine concentration, CPT-I-dependent mitochondrial respiration, and infarct size. Our results demonstrated that the mildronate-induced decrease in L-carnitine concentration, concomitant decrease in fatty acid transport, and maintenance of the intactness of outer mitochondrial membrane in heart mitochondria are the key mechanisms of action for the anti-infarction activity of mildronate.

  2. Persistent ERK/MAPK Activation Promotes Lactotrope Differentiation and Diminishes Tumorigenic Phenotype

    PubMed Central

    Booth, Allyson; Trudeau, Tammy; Gomez, Crystal; Lucia, M. Scott

    2014-01-01

    The signaling pathways that govern the lactotrope-specific differentiated phenotype, and those that control lactotrope proliferation in both physiological and pathological lactotrope expansion, are poorly understood. Moreover, the specific role of MAPK signaling in lactotrope proliferation vs differentiation, whether activated phosphorylated MAPK is sufficient for prolactinoma tumor formation remain unknown. Given that oncogenic Ras mutations and persistently activated phosphorylated MAPK are found in human tumors, including prolactinomas and other pituitary tumors, a better understanding of the role of MAPK in lactotrope biology is required. Here we directly examined the role of persistent Ras/MAPK signaling in differentiation, proliferation, and tumorigenesis of rat pituitary somatolactotrope GH4 cells. We stimulated Ras/MAPK signaling in a persistent, long-term manner (over 6 d) in GH4 cells using two distinct approaches: 1) a doxycycline-inducible, oncogenic V12Ras expression system; and 2) continuous addition of exogenous epidermal growth factor. We find that long-term activation of the Ras/MAPK pathway over 6 days promotes differentiation of the bihormonal somatolactotrope GH4 precursor cell into a prolactin-secreting, lactotrope cell phenotype in vitro and in vivo with GH4 cell xenograft tumors. Furthermore, we show that persistent activation of the Ras/MAPK pathway not only fails to promote cell proliferation, but also diminishes tumorigenic characteristics in GH4 cells in vitro and in vivo. These data demonstrate that activated MAPK promotes differentiation and is not sufficient to drive tumorigenesis, suggesting that pituitary lactotrope tumor cells have the ability to evade the tumorigenic fate that is often associated with Ras/MAPK activation. PMID:25361391

  3. Diminished metal accumulation in riverine fishes exposed to acid mine drainage over five decades.

    PubMed

    Jeffree, Ross A; Markich, Scott J; Twining, John R

    2014-01-01

    Bony bream (Nematalosa erebi) and black catfish (Neosilurus ater) were sampled from the fresh surface waters of the Finniss River in tropical northern Australia, along a metal pollution gradient draining the Rum Jungle copper/uranium mine, a contaminant source for over five decades. Paradoxically, populations of both fish species exposed to the highest concentrations of mine-related metals (cobalt, copper, lead, manganese, nickel, uranium and zinc) in surface water and sediment had the lowest tissue (bone, liver and muscle) concentrations of these metals. The degree of reduction in tissue concentrations of exposed populations was also specific to each metal and inversely related to its degree of environmental increase above background. Several explanations for diminished metal bioaccumulation in fishes from the contaminated region were evaluated. Geochemical speciation modeling of metal bioavailability in surface water showed no differences between the contaminated region and the control sites. Also, the macro-nutrient (calcium, magnesium and sodium) water concentrations, that may competitively inhibit metal uptake, were not elevated with trace metal contamination. Reduced exposure to contaminants due to avoidance behavior was unlikely due to the absence of refugial water bodies with the requisite metal concentrations lower than the control sites and very reduced connectivity at time of sampling. The most plausible interpretation of these results is that populations of both fish species have modified kinetics within their metal bioaccumulation physiology, via adaptation or tolerance responses, to reduce their body burdens of metals. This hypothesis is consistent with (i) reduced tissue concentrations of calcium, magnesium and sodium (macro-nutrients), in exposed populations of both species, (ii) experimental findings for other fish species from the Finniss River and other contaminated regions, and (iii) the number of generations exposed to likely selection pressure

  4. A diminished aortic-cardiac reflex during hypotension in aerobically fit young men

    NASA Technical Reports Server (NTRS)

    Shi, X.; Crandall, C. G.; Potts, J. T.; Williamson, J. W.; Foresman, B. H.; Raven, P. B.

    1993-01-01

    We compared the aortic-cardiac baroreflex sensitivity in eight average fit (AF: VO2max = 44.7 +/- 1.3 ml.kg-1 x min-1) and seven high fit (HF: VO2max = 64.1 +/- 1.7 ml.min-1 x kg-1) healthy young men during hypotension elicited by steady state sodium nitroprusside (SN) infusion. During SN mean arterial pressure (MAP) was similarly decreased in AF (-12.6 +/- 1.0 mm Hg) and HF (-12.1 +/- 1.1 mm Hg). However, the increases in heart rate (HR) were less (P < 0.023) in HF (15 +/- 3 bpm) than AF (25 +/- 1 bpm). When sustained neck suction (NS, -22 +/- 1 torr in AF and -20 +/- 1 torr in HF, P > 0.05) was applied to counteract the decreased carotid sinus transmural pressure during SN, thereby isolating the aortic baroreceptors, the increased HR remained less (P < 0.021) in HF (8 +/- 2 bpm) than AF (16 +/- 2 bpm). During both SN infusion and SN+NS, the calculated gains (i.e., delta HR/delta MAP) were significantly greater in AF (2.1 +/- 0.3 and 1.3 +/- 0.2 bpm.mm Hg-1) than HF (1.2 +/- 0.2 and 0.6 +/- 0.2 bpm.mm Hg-1). However, the estimated carotid-cardiac baroreflex sensitivity (i.e., the gain difference between the stage SN and SN + NS) was not different between AF (0.7 +/- 0.2 bpm.mm Hg-1) and HF (0.6 +/- 0.1 bpm.mm Hg-1). These data indicated that the aortic-cardiac baroreflex sensitivity during hypotension was significantly diminished with endurance exercise training.

  5. Diminished Wastewater Treatment: Evaluation of Septic System Performance Under a Climate Change Scenario

    NASA Astrophysics Data System (ADS)

    Cooper, J.; Loomis, G.; Kalen, D.; Boving, T. B.; Morales, I.; Amador, J.

    2015-12-01

    The effects of climate change are expected to reduce the ability of soil-based onsite wastewater treatment systems (OWTS), to treat domestic wastewater. In the northeastern U.S., the projected increase in atmospheric temperature, elevation of water tables from rising sea levels, and heightened precipitation will reduce the volume of unsaturated soil and oxygen available for treatment. Incomplete removal of contaminants may lead to transport of pathogens, nutrients, and biochemical oxygen demand (BOD) to groundwater, increasing the risk to public health and likelihood of eutrophying aquatic ecosystems. Advanced OWTS, which include pre-treatment steps and provide unsaturated drainfields of greater volume relative to conventional OWTS, are expected to be more resilient to climate change. We used intact soil mesocosms to quantify water quality functions for two advanced shallow narrow drainfield types and a conventional drainfield under a current climate scenario and a moderate climate change scenario of 30 cm rise in water table and 5°C increase in soil temperature. While no fecal coliform bacteria (FCB) was released under the current climate scenario, up to 109 CFU FCB/mL (conventional) and up to 20 CFU FCB/mL (shallow narrow) were released under the climate change scenario. Total P removal rates dropped from 100% to 54% (conventional) and 71% (shallow narrow) under the climate change scenario. Total N removal averaged 17% under both climate scenarios in the conventional, but dropped from 5.4% to 0% in the shallow narrow under the climate change scenario, with additional leaching of N in excess of inputs indicating release of previously held N. No significant difference was observed between scenarios for BOD removal. The initial data indicate that while advanced OWTS retain more function under the climate change scenario, all three drainfield types experience some diminished treatment capacity.

  6. Oral glucocorticoids diminish the efficacy of allergen-specific immunotherapy in experimental feline asthma.

    PubMed

    Chang, Chee-hoon; Cohn, Leah A; Declue, Amy E; Liu, Hong; Reinero, Carol R

    2013-08-01

    Allergen-specific rush immunotherapy (RIT) shows promise in treating asthma; however, pet cats will likely require at least initial concurrent glucocorticoids (GCs) to control serious clinical signs. How the immunosuppressive effects of GCs would impact RIT in cats is unknown. The hypothesis of this study was that oral, but not inhaled GCs will diminish the efficacy of RIT in experimental feline asthma. Cats (n=6/group) were sensitized using Bermuda grass allergen (BGA) and randomized to receive BGA-specific RIT for 9 months with an oral GC (prednisolone 10mg daily), inhaled GC (fluticasone 220 μg twice daily), or placebo administered for the first 6 months. Bronchoalveolar lavage fluid (BALF) percent eosinophils and other immunological assays were performed. Eosinophilic airway inflammation was suppressed in all groups at month 6 of RIT (group mean ± SD, 5 ± 2%, 13 ± 4%, and 7 ± 2% for oral GC, inhaled GC, and placebo, respectively; P=0.291). BALF percent eosinophils significantly increased over time only in oral GC/RIT cats between months 6 and 9 (P=0.031). Placebo/RIT cats had significant decreases over time in BGA-specific serum IgE (P=0.031). Concentration of interleukin (IL)-5 in BALF significantly increased over time in inhaled GC/RIT cats (P=0.031). No significant differences were found between groups at month 6 or over time in each group for BGA-specific lymphocyte blastogenesis, percent blood T regulatory cells, or number of IL-10-producing cells. Given the significant increase of airway eosinophilia over time in RIT cats initially treated with an oral GC, inhaled GCs might be better for dampening eosinophilic inflammation until RIT normalizes the dysregulated immune system.

  7. Effects of dehydroepiandrosterone (DHEA) on follicular dynamics in a diminished ovarian reserve in vivo model.

    PubMed

    Hassa, Hikmet; Aydin, Yunus; Ozatik, Orhan; Erol, Kevser; Ozatik, Yasemin

    2015-06-01

    The objective of this study was to determine whether there are changes in primary, primordial, and growing follicles after dehydroepiandrosterone (DHEA) administration in rats that have diminished ovarian reserve (DOR) due to 4-vinylcyclohexene diepoxide (VCD) application, and to examine the mechanism of the probable effect of DHEA on folliculogenesis. Two groups of Wistar rats were used. In Group A unilateral oophorectomy (eight rats) was carried out on day-0. The remaining study ovary was removed by relaparotomy after VCD (160 mg/kg, intraperitoneally) was administered for 15 days. In Group B unilateral oophorectomy (eight rats) was carried out on day-0. The remaining study ovary was removed by relaparotomy after VCD (160 mg/kg, intraperitoneally) administration for 15 days followed by DHEA (60 mg/kg body weight) daily for 45 days. Primordial, primary, and growing (secondary+antral) follicles were counted in 1,664 sections from 32 ovaries. In all three types of follicles (primordial, primary, and growing), the number of follicles significantly decreased in the study ovaries compared to the control ovaries in both Group A and Group B. In Group B, atresia rates were significantly lower in the study ovary compared to the control ovary in all of the follicular groups: primordial (p=0.02), primary (p=0.01), and growing (p=.027). To demonstrate the probable effects of DHEA on follicular dynamics, we also compared the study ovaries in both groups; the primordial (p=0.027), primary (p=0.031), and growing (p=0.04) number of follicles were significantly higher in Group B compared to Group A. In conclusion, our findings suggest that DHEA administration in DOR rats due to VCD results in a larger follicular pool. Decreased atresia may be one of the possible effects of DHEA in DOR cases. Whatever the mechanism, DHEA treatment potentially may be useful clinically as a means to increase the number of gonadotropin-responsive follicles for ovarian stimulation.

  8. Glucolipotoxicity diminishes cardiomyocyte TFEB and inhibits lysosomal autophagy during obesity and diabetes.

    PubMed

    Trivedi, Purvi C; Bartlett, Jordan J; Perez, Lester J; Brunt, Keith R; Legare, Jean Francois; Hassan, Ansar; Kienesberger, Petra C; Pulinilkunnil, Thomas

    2016-12-01

    Impaired cardiac metabolism in the obese and diabetic heart leads to glucolipotoxicity and ensuing cardiomyopathy. Glucolipotoxicity causes cardiomyocyte injury by increasing energy insufficiency, impairing proteasomal-mediated protein degradation and inducing apoptosis. Proteasome-evading proteins are degraded by autophagy in the lysosome, whose metabolism and function are regulated by master regulator transcription factor EB (TFEB). Limited studies have examined the impact of glucolipotoxicity on intra-lysosomal signaling proteins and their regulators. By utilizing a mouse model of diet-induced obesity, type-1 diabetes (Akita) and ex-vivo model of glucolipotoxicity (H9C2 cells and NRCM, neonatal rat cardiomyocyte), we examined whether glucolipotoxicity negatively targets TFEB and lysosomal proteins to dysregulate autophagy and cause cardiac injury. Despite differential effects of obesity and diabetes on LC3B-II, expression of proteins facilitating autophagosomal clearance such as TFEB, LAMP-2A, Hsc70 and Hsp90 were decreased in the obese and diabetic heart. In-vivo data was recapitulated in H9C2 and NRCM cells, which exhibited impaired autophagic flux and reduced TFEB content when exposed to a glucolipotoxic milieu. Notably, overloading myocytes with a saturated fatty acid (palmitate) but not an unsaturated fatty acid (oleate) depleted cellular TFEB and suppressed autophagy, suggesting a fatty acid specific regulation of TFEB and autophagy in the cardiomyocyte. The effect of glucolipotoxicity to reduce TFEB content was also confirmed in heart tissue from patients with Class-I obesity. Therefore, during glucolipotoxicity, suppression of lysosomal autophagy was associated with reduced lysosomal content, decreased cathepsin-B activity and diminished cellular TFEB content likely rendering myocytes susceptible to cardiac injury.

  9. 12 Years of NPK Addition Diminishes Carbon Sink Potential of a Nutrient Limited Peatland

    NASA Astrophysics Data System (ADS)

    Larmola, T.; Bubier, J. L.; Juutinen, S.; Moore, T. R.

    2011-12-01

    Peatlands store about a third of global soil carbon. Our aim was to study whether the vegetation feedbacks of nitrogen (N) deposition lead to stronger carbon sink or source in a nutrient limited peatland ecosystem. We investigated vegetation structure and ecosystem CO2 exchange at Mer Bleue Bog, Canada, that has been fertilized for 7-12 years. We have applied 5 and 20 times ambient annual wet N deposition (0.8 g N m-2) with or without phosphorus (P) and potassium (K). Gross photosynthesis, ecosystem respiration and net CO2 exchange (NEE) were measured weekly during the growing season using chamber technique. Under the highest N(PK) treatments, the light saturated photosynthesis (PSmax) was reduced by 20-30% compared to the control treatment, whereas under moderate N and PK additions PSmax slightly increased or was similar to the control. The ecosystem respiration showed similar trends among the treatments, but changes in the rates were less pronounced. High nutrient additions led to up to 65% lower net CO2 uptake than that in the control: In the NPK plots with cumulative N additions of 70, 19, and 0 g N m-2, the daytime NEE in May-July 2011 averaged 0.8 (se. 0.3), 2.0 (se. 0.4), and 2.4 (se. 0.3) μmol m-2 s-1, respectively. In the N only plots with cumulative N additions of 45, 19, and 0 g N m-2, the daytime NEE in May-July 2011 averaged 0.8 (se. 0.2), 2.6 (se. 0.4), and 1.8 (se. 0.3) μmol m-2 s-1, respectively. The reduced plant photosynthetic capacity and diminished carbon sink potential in the highest nutrient treatments correlated with the loss of peat mosses and were not compensated for by the increased vascular plant biomass that has mainly been allocated to woody shrub stems.

  10. Diminishing Returns from Increased Percent Bt Cotton: The Case of Pink Bollworm

    PubMed Central

    Zhang, Huannan; Huang, Minsong; Li, Zhaohua; Gould, Fred

    2013-01-01

    Regional suppression of pests by transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) has been reported in several cropping systems, but little is known about the functional relationship between the ultimate pest population density and the pervasiveness of Bt crops. Here we address this issue by analyzing 16 years of field data on pink bollworm (Pectinophora gossypiella) population density and percentage of Bt cotton in the Yangtze River Valley of China. In this region, the percentage of cotton hectares planted with Bt cotton increased from 9% in 2000 to 94% in 2009 and 2010. We find that as the percent Bt cotton increased over the years, the cross-year growth rate of pink bollworm from the last generation of one year to the first generation of the next year decreased. However, as the percent Bt cotton increased, the within-year growth rate of pink bollworm from the first to last generation of the same year increased, with a slope approximately opposite to that of the cross-year rates. As a result, we did not find a statistically significant decline in the annual growth rate of pink bollworm as the percent Bt cotton increased over time. Consistent with the data, our modeling analyses predict that the regional average density of pink bollworm declines as the percent Bt cotton increases, but the higher the percent Bt cotton, the slower the decline in pest density. Specifically, we find that 95% Bt cotton is predicted to cause only 3% more reduction in larval density than 80% Bt cotton. The results here suggest that density dependence can act against the decline in pest density and diminish the net effects of Bt cotton on suppression of pink bollworm in the study region. The findings call for more studies of the interactions between pest density-dependence and Bt crops. PMID:23874678

  11. Effects of an intrathecally administered benzodiazepine receptor agonist, antagonist and inverse agonist on morphine-induced inhibition of a spinal nociceptive reflex.

    PubMed Central

    Moreau, J. L.; Pieri, L.

    1988-01-01

    1. The effects of an intrathecally administered benzodiazepine receptor (BZR) agonist (midazolam, up to 50 micrograms), antagonist (flumazenil, Ro 15-1788, 5 micrograms) and inverse agonist (Ro 19-4603, 15 micrograms) on nociception and on morphine-induced antinociception were studied in rats. 2. By themselves, none of these compounds significantly altered pain threshold. 3. The BZR agonist midazolam enhanced the morphine-induced antinociceptive effect whereas the antagonist flumazenil did not alter it. In contrast, the BZR inverse agonist Ro 19-4603 decreased the morphine-induced antinociceptive effect. 4. Naloxone (1 mg kg-1 i.p.) completely reversed all these effects. 5. These results demonstrate that BZR agonists and inverse agonists are able to affect, by allosteric up- or down-modulation of gamma-aminobutyric acidA (GABAA)-receptors, the transmission of nociceptive information at the spinal cord level, when this transmission is depressed by mu-opioid receptor activation. PMID:2898960

  12. Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

    PubMed Central

    Kwilasz, Andrew J.

    2012-01-01

    Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist Δ9-tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1–10 mg/kg) and CP55940 (0.0032–0.32 mg/kg) dose-dependently blocked acid- stimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiation-related depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans. PMID:22892341

  13. An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons

    PubMed Central

    Hayashi, Yoshinori; Morinaga, Saori; Liu, Xia; Zhang, Jing; Wu, Zhou; Yokoyama, Takeshi; Nakanishi, Hiroshi

    2016-01-01

    Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca2+-activated K+ (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (INMDA-OUT), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activated INMDA-OUT, whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects on INMDA-OUT. A direct perfusion of 3,5′-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitated INMDA-OUT, which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation of INMDA-OUT caused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons. PMID:27298516

  14. Interpreting the "g" Loadings of Intelligence Test Composite Scores in Light of Spearman's Law of Diminishing Returns

    ERIC Educational Resources Information Center

    Reynolds, Matthew R.

    2013-01-01

    The linear loadings of intelligence test composite scores on a general factor ("g") have been investigated recently in factor analytic studies. Spearman's law of diminishing returns (SLODR), however, implies that the "g" loadings of test scores likely decrease in magnitude as g increases, or they are nonlinear. The purpose of…

  15. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and ...

  16. Effects of intracellular alkalinization on resting and agonist-induced vascular tone.

    PubMed

    Danthuluri, N R; Deth, R C

    1989-03-01

    To evaluate the influence of intracellular alkalinization on basal and agonist-induced vascular tone, we studied the effect of NH4Cl on rat aorta. NH4Cl induced a gradually developing contraction in a dose-dependent manner. Although the contractile response to 20 mM NH4Cl was associated with a latent period (LP) of 23.4 +/- 2.8 min, intracellular pH (pHi) measurements in cultured rat aortic smooth muscle cells showed that NH4Cl-induced intracellular alkalinization was immediate and transient, returning to basal pHi levels in about 30-35 min. Agents that elevate Ca2+, such as A23187 and high KCl, significantly reduced the LP associated with 20 mM NH4Cl-induced contraction. NH4Cl-induced contractions were sensitive to extracellular Ca2+ removal and to the addition of forskolin (1 microM); however, NH4Cl by itself did not cause Ca2+-influx as shown by 45Ca-uptake studies. Addition of 20 mM NH4Cl to precontracted tissues resulted in a transient relaxation, which was complete in approximately 10 min, followed by a contraction above the original level of tone. NH4Cl pretreatment caused time-dependent alterations in both the rapid and slow phases of phenylephrine and angiotensin II contractions. Rapid-phase of phenylephrine and angiotensin II contractions. Rapid-phase responses were diminished at shorter NH4Cl incubation times (10 min), whereas slow-phase response was augmented after a longer incubation (20 min). Overall, the vasorelaxant and vasoconstrictor effects induced by NH4Cl suggest a complex relationship between intracellular alkalinization and arterial contractility.

  17. Investigating the Efficacy of Novel TrkB Agonists to Augment Stroke Recovery

    NASA Astrophysics Data System (ADS)

    Warraich, Zuha

    Stroke remains the leading cause of adult disability in developed countries. Most survivors live with residual motor impairments that severely diminish independence and quality of life. After stroke, the only accepted treatment for these patients is motor rehabilitation. However, the amount and kind of rehabilitation required to induce clinically significant improvements in motor function is rarely given due to the constraints of our current health care system. Research reported in this dissertation contributes towards developing adjuvant therapies that may augment the impact of motor rehabilitation and improve functional outcome. These studies have demonstrated reorganization of maps within motor cortex as a function of experience in both healthy and brain-injured animals by using intracortical microstimulation technique. Furthermore, synaptic plasticity has been identified as a key neural mechanism in directing motor map plasticity, evidenced by restoration of movement representations within the spared cortical tissue accompanied by increase in synapse number translating into motor improvement after stroke. There is increasing evidence that brain-derived neurotrophic factor (BDNF) modulates synaptic and morphological plasticity in the developing and mature nervous system. Unfortunately, BDNF itself is a poor candidate because of its short half-life, low penetration through the blood brain barrier, and activating multiple receptor units, p75 and TrkB on the neuronal membrane. In order to circumvent this problem efficacy of two recently developed novel TrkB agonists, LM22A-4 and 7,8-dihydroxyflavone, that actively penetrate the blood brain barrier and enhance functional recovery. Findings from these dissertation studies indicate that administration of these pharmacological compounds, accompanied by motor rehabilitation provide a powerful therapeutic tool for stroke recovery.

  18. Acute laminitis.

    PubMed

    Baxter, G M

    1994-12-01

    Laminitis is an inflammation of the sensitive laminae along the dorsal aspect of the digit and is considered to be a secondary complication of several predisposing or primary factors. Affected horses are usually very lame, have increased digital pulses, are painful to hoof testers along the toe of the foot, and have evidence of downward rotation or distal displacement of the distal phalanx present on radiographs. Treatments for acute laminitis include anti-inflammatory drugs, anti-endotoxin therapy, vasodilators, antithrombotic therapy, corrective trimming and shoeing, and surgical procedures. Treatment regimens are very controversial and the true efficacy of these treatments is unknown. The quality of laminae damage that occurs with laminitis, however, probably has greater influence on the success of treatment and outcome of the horse than the treatment regimen itself.

  19. Lymphocyte surface markers in acute rheumatic fever and post-streptococcal acute glomerulonephritis.

    PubMed Central

    Williams, R C; Zabriskie, J B; Mahros, F; Hassaballa, F; Abdin, Z H

    1977-01-01

    Lymphocyte cell-surface markers were examined in forty children with acute rheumatic fever (ARF) and twelve with acute post-streptococal glomerulonephritis (AGN) and compared to thirty-six normal controls of similar age. Cell-surface-marker studies included surface Ig using fluorescein-labelled F(ab)2 anti-F(AB')2, IgG aggregate binding cells, and EAC rosettes. T cells were identified both as 'active' rosettes and total E-binding cells. Proportions and absolute numbers of cells bearing surface Ig and Fc receptors were elevated in subjects with AGN (Pless than0-01-0-5), whereas proportions of cells producing EAC rosettes were diminished. Patients with acute rheumatic carditis or chorea showed a substantial elevation in proportions and numbers of active T-cell rosettes (Pless than0-01). Streptococcal antigen binding cells capable of forming rosettes with autologous cells coated with group A streptococcal membranes were elevated in the acute phase of both rheumatic fever and acute glomerulonephritis(Pless than0-01). The majority of such cells were removed by passage over insolubilized Ig-anti-IgG columns and appeared to be B cells. PMID:300301

  20. Stimulation by alpha-adrenergic agonists of Ca2+ fluxes, mitochondrial oxidation and gluconeogenesis in perfused rat liver.

    PubMed Central

    Taylor, W M; Reinhart, P H; Bygrave, F L

    1983-01-01

    Glucose output from perfused livers of 48 h-starved rats was stimulated by phenylephrine (2 microM) when lactate, pyruvate, alanine, glycerol, sorbitol, dihydroxyacetone or fructose were used as gluconeogenic precursors. Phenylephrine-induced increases in glucose output were immediately preceded by a transient efflux of Ca2+ and a sustained increase in oxygen uptake. Phenylephrine decreased the perfusate [lactate]/[pyruvate] ratio when sorbitol or glycerol was present, but increased the ratio when alanine, dihydroxyacetone or fructose was present. Phenylephrine induced a rapid increase in the perfusate [beta-hydroxybutyrate]/[acetoacetate] ratio and increased total ketone-body output by 40-50% with all substrates. The oxidation of [1-14C]octanoate or 2-oxo[1-14C]glutarate to 14CO2 was increased by up to 200% by phenylephrine. All responses to phenylephrine infusion were diminished after depletion of the hepatic alpha-agonist-sensitive pool of Ca2+ and returned toward maximal responses after Ca2+ re-addition. Phenylephrine-induced increases in glucose output from lactate, sorbitol and glycerol were inhibited by the transaminase inhibitor amino-oxyacetate by 95%, 75% and 66% respectively. Data presented suggest that the mobilization of an intracellular pool of Ca2+ is involved in the activation of gluconeogenesis by alpha-adrenergic agonists in perfused rat liver. alpha-Adrenergic activation of gluconeogenesis is apparently accompanied by increases in fatty acid oxidation and tricarboxylic acid-cycle flux. An enhanced transfer of reducing equivalents from the cytoplasmic to the mitochondrial compartment may also be involved in the stimulation of glucose output from the relatively reduced substrates glycerol and sorbitol and may arise principally from an increased flux through the malate-aspartate shuttle. PMID:6882384

  1. N-acetylcysteine effectively diminished meconium-induced oxidative stress in adult rabbits.

    PubMed

    Mokra, D; Drgova, A; Mokry, J; Antosova, M; Durdik, P; Calkovska, A

    2015-02-01

    decreased TBARS (P<0.001) and ECP, and increased TAS (both P<0.05) compared to Mec group. Concluding, N-acetylcysteine diminished meconium-induced inflammation and oxidative lung injury.

  2. Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function.

    PubMed

    Hurwitz, Barry E; Coryell, Virginia T; Parker, Meela; Martin, Pedro; Laperriere, Arthur; Klimas, Nancy G; Sfakianakis, George N; Bilsker, Martin S

    2009-10-19

    The study examined whether deficits in cardiac output and blood volume in a CFS (chronic fatigue syndrome) cohort were present and linked to illness severity and sedentary lifestyle. Follow-up analyses assessed whether differences in cardiac output levels between CFS and control groups were corrected by controlling for cardiac contractility and TBV (total blood volume). The 146 participants were subdivided into two CFS groups based on symptom severity data, severe (n=30) and non-severe (n=26), and two healthy non-CFS control groups based on physical activity, sedentary (n=58) and non-sedentary (n=32). Controls were matched to CFS participants using age, gender, ethnicity and body mass. Echocardiographic measures indicated that the severe CFS participants had 10.2% lower cardiac volume (i.e. stroke index and end-diastolic volume) and 25.1% lower contractility (velocity of circumferential shortening corrected by heart rate) than the control groups. Dual tag blood volume assessments indicated that the CFS groups had lower TBV, PV (plasma volume) and RBCV (red blood cell volume) than control groups. Of the CFS subjects with a TBV deficit (i.e. > or = 8% below ideal levels), the mean+/-S.D. percentage deficit in TBV, PV and RBCV were -15.4+/-4.0, -13.2+/-5.0 and -19.1+/-6.3% respectively. Lower cardiac volume levels in CFS were substantially corrected by controlling for prevailing TBV deficits, but were not affected by controlling for cardiac contractility levels. Analyses indicated that the TBV deficit explained 91-94% of the group differences in cardiac volume indices. Group differences in cardiac structure were offsetting and, hence, no differences emerged for left ventricular mass index. Therefore the findings indicate that lower cardiac volume levels, displayed primarily by subjects with severe CFS, were not linked to diminished cardiac contractility levels, but were probably a consequence of a co-morbid hypovolaemic condition. Further study is needed to address

  3. Diminished forearm vasomotor response to central hypervolemic loading in aerobically fit individuals

    NASA Technical Reports Server (NTRS)

    Shi, X.; Gallagher, K. M.; SMith, S. A.; Bryant, K. H.; Raven, P. B.; Blomqvist, C. G. (Principal Investigator)

    1996-01-01

    The aim of this study was to test the hypothesis that cardiopulmonary baroreflex control of forearm vascular resistance (FVR) during central hypervolemic loading was less sensitive in exercise trained high fit individuals (HF) compared to untrained average fit individuals (AF). Eight AF (age: 24 +/- 1 yr and weight: 78.9 +/- 1.7 kg) and eight HF (22 +/- 1 yr 79.5 +/- 2.4 kg) voluntarily participated in the investigation. Maximal aerobic power (determined on a treadmill), plasma volume and blood volume (Evans blue dilution method) were significantly greater in the HF than AF (60.8 +/- 0.7 vs. 41.2 +/- 1.9 ml.kg-1.min-1, 3.96 +/- 0.17 vs 3.36 +/- 0.08 1, and 6.33 +/- 0.23 vs 5.28 +/- 0.13 1). Baseline heart rate (HR), central venous pressure (CVP), mean arterial pressure (MAP, measured by an intraradial catheter or a Finapres finger cuff), forearm blood flow (FBF, plethysmography), and FVR, calculated from the ratio (MAP-CVP)/FBF, were not different between the HF and the AF. Lower body negative pressure (LBNP, -5, -10, -15, and -20 torr) and passive leg elevation (LE, 50 cm) combined with lower body positive pressure (LBPP, +5, +10, and +20 torr) were utilized to elicit central hypovolemia and hypervolemia, respectively. Range of CVP (from LBNP to LE+LBPP) was similar in the AF (from -3.9 to +1.9 mm Hg) and HF (from -4.0 to +2.2 mm Hg). However, FVR/CVP was significantly less in the HF (-1.8 +/- 0.1 unit.mm Hg-1) than AF (-34 +/- 0.1 unit.mm Hg-1). The FVR decrease in response to increase in CVP was significantly diminished in the HF (-1.46 +/- 0.45 unit.mm Hg-1) compared to the AF (-4.40 +/- 0.97 unit.mm Hg-1), and during LBNP induced unloading the FVR/CVP of the HF (-2.01 +/- 0.49 unit.mm Hg-1) was less (P < 0.08) than the AF (-3.28 +/- 0.69 unit.mm Hg-1). We concluded that the cardiopulmonary baroreceptor mediated FVR reflex response was significantly less sensitive to changes in CVP in individuals who practice exercise training.

  4. Kangaroo mother care diminishes pain from heel lance in very preterm neonates: A crossover trial

    PubMed Central

    Johnston, C Celeste; Filion, Francoise; Campbell-Yeo, Marsha; Goulet, Celine; Bell, Linda; McNaughton, Kathryn; Byron, Jasmine; Aita, Marilyn; Finley, G Allen; Walker, Claire-Dominique

    2008-01-01

    Background Skin-to-skin contact, or kangaroo mother care (KMC) has been shown to be efficacious in diminishing pain response to heel lance in full term and moderately preterm neonates. The purpose of this study was to determine if KMC would also be efficacious in very preterm neonates. Methods Preterm neonates (n = 61) between 28 0/7 and 31 6/7 weeks gestational age in three Level III NICU's in Canada comprised the sample. A single-blind randomized crossover design was employed. In the experimental condition, the infant was held in KMC for 15 minutes prior to and throughout heel lance procedure. In the control condition, the infant was in prone position swaddled in a blanket in the incubator. The primary outcome was the Premature Infant Pain Profile (PIPP), which is comprised of three facial actions, maximum heart rate, minimum oxygen saturation levels from baseline in 30-second blocks from heel lance. The secondary outcome was time to recover, defined as heart rate return to baseline. Continuous video, heart rate and oxygen saturation monitoring were recorded with event markers during the procedure and were subsequently analyzed. Repeated measures analysis-of-variance was employed to generate results. Results PIPP scores at 90 seconds post lance were significantly lower in the KMC condition (8.871 (95%CI 7.852–9.889) versus 10.677 (95%CI 9.563–11.792) p < .001) and non-significant mean differences ranging from 1.2 to1.8. favoring KMC condition at 30, 60 and 120 seconds. Time to recovery was significantly shorter, by a minute(123 seconds (95%CI 103–142) versus 193 seconds (95%CI 158–227). Facial actions were highly significantly lower across all points in time reaching a two-fold difference by 120 seconds post-lance and heart rate was significantly lower across the first 90 seconds in the KMC condition. Conclusion Very preterm neonates appear to have endogenous mechanisms elicited through skin-to-skin maternal contact that decrease pain response, but not as

  5. Food image-induced brain activation is not diminished by insulin infusion

    PubMed Central

    Belfort-DeAguiar, Renata; Seo, Dongju; Naik, Sarita; Hwang, Janice; Lacadie, Cheryl; Schmidt, Christian; Constable, R. Todd; Sinha, Rajita; Sherwin, Robert

    2016-01-01

    Background/Objective The obesity epidemic appears to be driven in large part by our modern environment inundated by food cues, which may influence our desire to eat. While insulin decreases food intake in both animals and humans, the effect of insulin on motivation for food in the presence of food cues is not known. Therefore, the aim of this study was to evaluate the effect of an intravenous insulin infusion on the brain response to visual food cues, hunger and food craving in non-obese human subjects. Subjects/Methods Thirty-four right-handed healthy non-obese subjects (19F/15M, age: 29±8 yrs.; BMI: 23.1±2.1 kg/m2) were divided in two groups matched by age, and BMI: the Insulin Group (18 subjects) underwent a hyperinsulinemic-euglycemic-clamp, and the control group (16 subjects) received an intravenous saline infusion, while viewing high and low-calorie food and non-food pictures during a functional MRI scan. Motivation for food was determined via analogue scales for hunger, wanting and liking ratings. Results Food images induced brain responses in the hypothalamus, striatum, amygdala, insula, ventromedial prefrontal cortex (PFC), dorsolateral PFC, and occipital lobe (whole brain correction, P<0.05). Wanting (P<0.001) and liking (P<0.001) ratings were significantly higher for the food than the non-food images, but not different between insulin and saline infusion groups. Hunger ratings increased throughout the MRI scan and correlated with preference for high-calorie food pictures (r=0.70; P<0.001). However neither brain activity nor food craving were affected by hyperinsulinemia or hormonal status (leptin and ghrelin levels) (P=NS). Conclusion Our data demonstrate that visual food cues induce a strong response in motivation/reward and cognitive-executive control brain regions in non-obese subjects, but that these responses are not diminished by hyperinsulinemia per se. These findings suggest that our modern food cue saturated environment may be sufficient to

  6. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.

  7. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

  8. β2-Adrenoceptor agonists in the regulation of mitochondrial biogenesis.

    PubMed

    Peterson, Yuri K; Cameron, Robert B; Wills, Lauren P; Trager, Richard E; Lindsey, Chris C; Beeson, Craig C; Schnellmann, Rick G

    2013-10-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB.

  9. Integrating costimulatory agonists to optimize immune-based cancer therapies.

    PubMed

    Pardee, Angela D; Wesa, Amy K; Storkus, Walter J

    2009-03-01

    While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients.

  10. Integrating costimulatory agonists to optimize immune-based cancer therapies

    PubMed Central

    Pardee, Angela D; Wesa, Amy K

    2009-01-01

    While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients. PMID:20046961

  11. Dopamine agonists and the suppression of impulsive motor actions in Parkinson disease.

    PubMed

    Wylie, Scott A; Claassen, Daniel O; Huizenga, Hilde M; Schewel, Kerilyn D; Ridderinkhof, K Richard; Bashore, Theodore R; van den Wildenberg, Wery P M

    2012-08-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in 38 PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared with an off-agonist state, patients on their agonists were no more susceptible to reacting impulsively but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off-agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less-proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication.

  12. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  13. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed.

  14. Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

    PubMed Central

    Bohonowych, Jessica E. S.; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T.; Denison, Michael S.

    2010-01-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [3H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  15. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-09-15

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven.

  16. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed Central

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-01-01

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven. PMID:27738363

  17. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    PubMed

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  18. Glucagon-like peptide-1 receptors agonists (GLP1 RA).

    PubMed

    Kalra, Sanjay

    2013-10-01

    The glucagon-like peptide-1 receptors agonists (GLP1RA) are a relatively new class of drugs, used for management of type 2 diabetes. This review studies the characteristics of these drugs, focusing upon their mechanism of action, intra-class differences, and utility in clinical practice. It compares them with other incretin based therapies, the dipeptidyl peptidase-IV inhibitors, and predicts future developments in the use of these molecules, while highlighting the robust indications for the use of these drugs.

  19. Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

    DTIC Science & Technology

    2010-07-01

    or 9), although these compounds still showed anti-DHT effects (lanes 2 vs. 6, 8, or 10). Figure 4 . The effects of DHEA derivatives on PSA...2009 - 30 JUN 2010 4 . TITLE AND SUBTITLE Dehydroepiandrosterone Derivatives as Potent Antiandrogens 5a. CONTRACT NUMBER with Marginal Agonist...words) We hypothesized that dehydroepiandrosterone ( DHEA ) metabolites or their synthetic derivatives are able to bind to the androgen receptor with

  20. Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.

    PubMed

    Duarte, E P; Oliveira, C R; Carvalho, A P

    1988-03-01

    The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of

  1. The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists.

    PubMed

    Seely, Kathryn A; Levi, Mark S; Prather, Paul L

    2009-07-01

    The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examined whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act as ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal G-protein activity in membranes prepared from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body weight in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, trans-resveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/inverse agonists at CB1 receptors at dietary relevant concentrations. Therefore, these polyphenols and their

  2. Neuroprotective effects mediated by dopamine receptor agonists against malonate-induced lesion in the rat striatum.

    PubMed

    Fancellu, R; Armentero, M-T; Nappi, G; Blandini, F

    2003-10-01

    In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study we used the malonate model to explore the neuroprotective potential of dopamine agonists. Rats were injected intraperitoneally with increasing concentrations of D1, D2, or mixed D1/D2 dopamine agonists prior to intrastriatal injection of malonate. Administration of increasing doses of the D2-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D1-specific agonist SKF-38393, as well as the mixed D1/D2 agonist apomorphine, conferred higher neuroprotection at lower than at higher drug concentrations. Our data suggest that malonate- induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D1 and D2 agonists showing different profiles of efficacy.

  3. State of the art: therapeutic controversies in severe acute asthma.

    PubMed

    Gibbs, M A; Camargo, C A; Rowe, B H; Silverman, R A

    2000-07-01

    This is a transcript of the 1999 SAEM State-of-the-Art session on "Therapeutic Controversies in Severe Acute Asthma," presented at the 1999 SAEM annual meeting in Boston. The aim of this session was to address some of the current controversies in the management of acute asthma exacerbations, a major issue in emergency medicine. Despite many recent advances in asthma management, morbidity and mortality remain high. While many of us have strong feelings on how asthma patients should be treated, many of our assertions are not based on good science, and there are numerous areas of controversy. This discussion focuses on the controversy over beta agonist treatment for acute asthma, the physiology of corticosteroids in asthma, and the emergency use of leukotriene-modifying agents.

  4. Agonistic sounds signal male quality in the Lusitanian toadfish.

    PubMed

    Amorim, M Clara P; Conti, Carlotta; Modesto, Teresa; Gonçalves, Amparo; Fonseca, Paulo J

    2015-10-01

    Acoustic communication during agonistic behaviour is widespread in fishes. Yet, compared to other taxa, little is known on the information content of fish agonistic calls and their effect on territorial defence. Lusitanian toadfish males (Halobatrachus didactylus) are highly territorial during the breeding season and use sounds (boatwhistles, BW) to defend nests from intruders. BW present most energy in either the fundamental frequency, set by the contraction rate of the sonic muscles attached to the swimbladder, or in the harmonics, which are multiples of the fundamental frequency. Here we investigated if temporal and spectral features of BW produced during territorial defence reflect aspects of male quality that may be important in resolving disputes. We found that higher mean pulse period (i.e. lower fundamental frequency) reflected higher levels of 11-ketotestosterone (11KT), the main teleost androgen which, in turn, was significantly related with male condition (relative body mass and glycogen content). BW dominant harmonic mean and variability decreased with sonic muscle lipid content. We found no association between BW duration and male quality. Taken together, these results suggest that the spectral content of fish agonistic sounds may signal male features that are key in fight outcome.

  5. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.

  6. Contact- and agonist-regulated microvesiculation of human platelets.

    PubMed

    Zhang, Yanjun; Liu, Xiao; Liu, Li; Zaske, Ana-Maria; Zhou, Zhou; Fu, Yuanyuan; Yang, Xi; Conyers, Jodie L; Li, Min; Dong, Jing-fei; Zhang, Jianning

    2013-08-01

    After exposure to an agonist, platelets are activated and become aggregated. They also shed membrane microparticles that participate in the pathogenesis of thrombosis, hyper-coagulation and inflammation. However, microvesiculation can potentially disrupt the integrity of platelet aggregation by shedding the membrane receptors and phosphatidylserine critical for forming and stabilising a platelet clot. We tested the hypothesis that adhesion and microvesiculation are functions of different subsets of platelets at the time of haemostasis by real-time monitoring of agonist-induced morphological changes and microvesiculation of human platelets.We identified two types of platelets that are adherent to fibrinogen: a high density bubble shape (HDBS) and low-density spread shape (LDSS). Adenosine diphosphate (ADP) predominantly induced HDBS platelets to vesiculate, whereas LDSS platelets were highly resistant to such vesiculation. Thrombin-receptor activating peptide (TRAP) stabilised platelets against microvesiculation by promoting a rapid HDBS-to-LDSS morphological transition. These activities of ADP and TRAP were reversed for platelets in suspension, independent of an engagement integrin αIIbβ3. As the result of membrane contact, LDSS platelets inhibited the microvesiculation of HDBS platelets in response to ADP. Aspirin and clopidogrel inhibited ADP-induced microvesiculation through different mechanisms. These results suggest that platelet aggregation and microvesiculation occur in different subsets of platelets and are differently regulated by agonists, platelet-platelets and platelet-fi