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Sample records for agonist alleviates indomethacin-induced

  1. EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing

    Institute of Scientific and Technical Information of China (English)

    Guang-Liang Jiang; Wha Bin Im; Yariv Donde; Larry A Wheeler

    2009-01-01

    AIM: To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers. METHODS: In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacininduced apoptosis was assessed by flow cytometry. RESULTS: The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro , the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis. CONCLUSION: EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.

  2. The gastroprotective effect of pogostone from Pogostemonis Herba against indomethacin-induced gastric ulcer in rats.

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    Chen, Xiao-Ying; Chen, Hai-Ming; Liu, Yu-Hong; Zhang, Zhen-Biao; Zheng, Yi-Feng; Su, Zu-Qing; Zhang, Xie; Xie, Jian-Hui; Liang, Yong-Zhuo; Fu, Lu-Di; Lai, Xiao-Ping; Su, Zi-Ren; Huang, Xiao-Qi

    2016-01-01

    Pogostemonis Herba, known as "Guang-Huo-Xiang" in Chinese, has been widely used in the treatment of gastrointestinal dysfunction. Pogostone is one of the major constituents of Pogostemonis Herba. The aim was to scientifically evaluate the possible gastroprotective effect and the underlying mechanisms of pogostone against indomethacin-induced gastric ulcer in rats. Rats were orally treated with vehicle, lansoprazole (30 mg/kg) or pogostone (10, 20 and 40 mg/kg) and subsequently exposed to acute gastric lesions induced by indomethacin. Gross evaluation, histological observation, gastric mucosal superoxide dismutase activity, glutathione content, catalase activity, malonaldehyde level and prostaglandin E2 production were performed. Immunohistochemistry and reverse transcription polymerase chain reaction for cyclooxygenase-1 and cyclooxygenase-2, as well as terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, immunohistochemistry for heat-shock protein 70, B-cell lymphoma-2 and Bax were conducted. Results indicated that rats pretreated with pogostone showed remarkable protection from the gastric mucosa damage compared to vehicle-treated rats based on the ulcer index and inhibition percentage. Histologically, oral administration of pogostone resulted in observable improvement of gastric injury, characterized by reduction of necrotic lesion, flattening of gastric mucosa and alleviation of submucosal edema with hemorrhage. Pogostone pretreatment significantly raised the depressed activities of superoxide dismutase, glutathione and catalase, while reduced the elevated malonaldehyde level compared with indomethacin-induced group. Pogostone-pretreated group induced a significant increase in gastric mucosal prostaglandin E2 level and obvious up-regulation of protein levels and mRNA expressions of cyclooxygenase-1 and cyclooxygenase-2. Furthermore, antiapoptotic effect of pogostone was verified by terminal deoxynucleotidyltransferase-mediated d

  3. Curcumin prevents indomethacin-induced gastropathy in rats

    Institute of Scientific and Technical Information of China (English)

    Duangporn Thong-Ngam; Sakonwan Choochuai; Suthiluk Patumraj; Maneerat Chayanupatkul; Naruemon Klaikeaw

    2012-01-01

    AIM:To investigate the effects of curcumin on gastric microcirculation and inflammation in rats with indomethacin-induced gastric damage.METHODS:Male Sprague-Dawley rats were randomly divided into three groups.Group 1 (control group,n =5) was fed with olive oil and 5% NaHCO3-(vehicle).Group 2 [indomethacin (IMN) group,n =5] was fed with olive oil 30 min prior to indomethacin 150 mg/kg body weight (BW) dissolved in 5% NaHCO3-at time 0th and 4th h.Group 3 (IMN + Cur group,n =4) was fed with curcumin 200 mg/kg BW dissolved in olive oil 0.5 mL,30 min prior to indomethacin at 0th and 4th h.Leukocyte-endothelium interactions at postcapillary venules were recorded after acridine orange injection.Blood samples were determined for intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-α levels using enzyme linked immunosorbent assay method Finally,the stomach was removed for histopathological examination for gastric lesions and grading for neutrophil infiltration.RESULTS:In group 2,the leukocyte adherence in postcapillary venules was significantly increased compared to the control group (6.40 ± 2.30 cells/frame vs 1.20 ± 0.83 cells/frame,P =0.001).Pretreatment with curcumin caused leukocyte adherence to postcapillary venule to decline (3.00 ± 0.81 cells/frame vs 6.40 ± 2.30 cells/frame,P =0.027).The levels of ICAM-1 and TNF-α increased significantly in the indomethacintreated group compared with the control group (1106.50± 504.22 pg/mL vs 336.93 ± 224.82 pg/mL,P =0.011and 230.92 ± 114.47 pg/mL vs 47.13 ± 65.59 pg/mL,P =0.009 respectively).Pretreatment with curcumin significantly decreased the elevation of ICAM-1 and TNF-α levels compared to treatment with indomethacin alone (413.66 ± 147.74 pg/mL vs 1106.50 ± 504.22 pg/mL,P =0.019 and 58.27 ± 67.74 pg/mL vs 230.92 ± 114.47 pg/mL,P =0.013 respectively).The histological appearance of the stomach in the control group was normal.In the indomethacin-treated group,the stomachs showed a mild to

  4. Protective effect of wheat peptides against indomethacin-induced oxidative stress in IEC-6 cells.

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    Yin, Hong; Pan, Xingchang; Song, Zhixiu; Wang, Shaokang; Yang, Ligang; Sun, Guiju

    2014-01-29

    Recent studies have demonstrated that wheat peptides protected rats against non-steroidal anti-inflammatory drugs-induced small intestinal epithelial cells damage, but the mechanism of action is unclear. In the present study, an indomethacin-induced oxidative stress model was used to investigate the effect of wheat peptides on the nuclear factor-κB(NF-κB)-inducible nitric oxide synthase-nitric oxide signal pathway in intestinal epithelial cells-6 cells. IEC-6 cells were treated with wheat peptides (0, 125, 500 and 2000 mg/L) for 24 h, followed by 90 mg/L indomethacin for 12 h. Wheat peptides significantly attenuated the indomethacin-induced decrease in superoxide dismutase and glutathione peroxidase activity. Wheat peptides at 2000 mg/L markedly decreased the expression of the NF-κB in response to indomethacin-induced oxidative stress. This study demonstrated that the addition of wheat peptides to a culture medium significantly inhibited the indomethacin-induced release of malondialdehyde and nitrogen monoxide, and increased antioxidant enzyme activity in IEC-6 cells, thereby providing a possible explanation for the protective effect proposed for wheat peptides in the prevention of indomethacin-induced oxidative stress in small intestinal epithelial cells.

  5. Protective Effect of Wheat Peptides against Indomethacin-Induced Oxidative Stress in IEC-6 Cells

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    Hong Yin

    2014-01-01

    Full Text Available Recent studies have demonstrated that wheat peptides protected rats against non-steroidal anti-inflammatory drugs-induced small intestinal epithelial cells damage, but the mechanism of action is unclear. In the present study, an indomethacin-induced oxidative stress model was used to investigate the effect of wheat peptides on the nuclear factor-κB(NF-κB-inducible nitric oxide synthase-nitric oxide signal pathway in intestinal epithelial cells-6 cells. IEC-6 cells were treated with wheat peptides (0, 125, 500 and 2000 mg/L for 24 h, followed by 90 mg/L indomethacin for 12 h. Wheat peptides significantly attenuated the indomethacin-induced decrease in superoxide dismutase and glutathione peroxidase activity. Wheat peptides at 2000 mg/L markedly decreased the expression of the NF-κB in response to indomethacin-induced oxidative stress. This study demonstrated that the addition of wheat peptides to a culture medium significantly inhibited the indomethacin-induced release of malondialdehyde and nitrogen monoxide, and increased antioxidant enzyme activity in IEC-6 cells, thereby providing a possible explanation for the protective effect proposed for wheat peptides in the prevention of indomethacin-induced oxidative stress in small intestinal epithelial cells.

  6. Dopamine D₂-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration in mice by activating α7 nicotinic acetylcholine receptors.

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    Yasuda, Masashi; Kawahara, Ryoji; Hashimura, Hiroshi; Yamanaka, Naoki; Iimori, Maho; Amagase, Kikuko; Kato, Shinichi; Takeuchi, Koji

    2011-01-01

    We have reported that nicotine and the specific α7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating α7 nicotinic acetylcholine receptors (α7nAChR). Dopamine D₂-receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the α7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1-10 mg/kg) and metoclopramide (0.03-0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1-3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D₂-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by α7nAChR.

  7. Docosahexaenoic acid, an omega-3 polyunsaturated acid protects against indomethacin-induced gastric injury.

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    Pineda-Peña, Elizabeth Arlen; Jiménez-Andrade, Juan Miguel; Castañeda-Hernández, Gilberto; Chávez-Piña, Aracely Evangelina

    2012-12-15

    Previous studies have shown gastroprotective effect of fish oil in several experimental models. However, the mechanisms and active compounds underlying this effect are not fully understood. Fish oil has several components; among them, one of the most studied is docosahexaenoic acid (DHA), which is an omega-3 long-chain polyunsaturated fatty acid. The aim of this study was to examine the gastroprotective effect of DHA as a pure compound in a rat model of indomethacin-induced gastric injury as well as elucidate some of the mechanism(s) behind DHA's gastroprotective effect. Indomethacin was orally administered to induce an acute gastric injury (3, 10 and 30mg/kg). Omeprazol (a proton pump inhibitor, 30mg/kg, p.o.) and DHA (3, 10, 30mg/kg, p.o.) were gavaged 30 and 120min, respectively, before indomethacin insult (30mg/kg p.o.). Three hours after indomethacin administration, rats were sacrificed, gastric injury was evaluated by determining the total damaged area. A sample of gastric tissue was harvested and processed to quantify prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) levels by enzyme-linked immunosorbent assay. Indomethacin produced gastric injury in dose-dependent manner. DHA protected against indomethacin-induced gastric damage, and this effect was comparable with omeprazol's gastroprotective effect. DHA did not reverse the indomethacin-induced reduction of PGE(2) gastric levels. In contrast, DHA partially prevented the indomethacin-induced increase in LTB(4) gastric levels. This is the first report demonstrating DHA's gastroprotective effect as a pure compound. Furthermore, the results reveal that the gastroprotective effect is mediated by a decrease in gastric LTB(4) levels in indomethacin-induced gastric damage.

  8. Preventative Effects of Sodium Alginate on Indomethacin-induced Small-intestinal Injury in Mice.

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    Horibe, Sayo; Tanahashi, Toshihito; Kawauchi, Shoji; Mizuno, Shigeto; Rikitake, Yoshiyuki

    2016-01-01

    Recent advances in diagnostic technologies have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious mucosal injury in the upper and lower gastrointestinal tract (including the small intestine). A drug to treat NSAID-induced small-intestinal injury (SII) is lacking. Sodium alginate is a soluble dietary fiber extracted from brown seaweed and its solution has been used as a hemostatic agent to treat gastrointestinal bleeding due to gastric ulcers. Whether sodium alginate has therapeutic effects on NSAID-induced SII and its mechanism of action are not known. Here, we investigated if administration of two forms (high-molecular-weight (HMW) and low-molecular-weight (LMW)) of sodium alginate could ameliorate indomethacin-induced SII. Pretreatment with HMW sodium alginate or LMW sodium alginate before indomethacin administration improved ulceration and the resultant intestinal shortening was associated with reduced histological severity of mucosal injury and ameliorated mRNA expression of inflammation-related molecules in the small intestine. We found that mRNAs of secretory Muc2 and membrane-associated Muc1, Muc3 and Muc4 were expressed in the small intestine. mRNA expression of Muc1-4 was increased in indomethacin-induced SII, and these increases were prevented by sodium alginate. Thus, administration of sodium alginate could be a therapeutic approach to prevent indomethacin-induced SII.

  9. Protective effects of escin against indomethacin-induced gastric ulcer in mice.

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    Wang, Tian; Zhao, Shanshan; Wang, Yucun; Yang, Yujiao; Yao, Le; Chu, Liuxiang; Du, Hanhan; Fu, Fenghua

    2014-12-01

    Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, is reported to have a potent antiulcer activity against ethanol-induced gastric mucosal lesions. This study investigated the possible mechanisms underlying the gastroprotective effect of escin against indomethacin-induced gastric ulcer in mice. Gastric ulceration was induced by a single intragastric administration of indomethacin (18 mg/kg). The mice underwent intragastric treatment with escin at doses of 0.45, 0.9 or 1.8 mg/kg. Gastric lesion was estimated morphometrically and histopathologically 6 h after the indomethacin administration. The antioxidative parameters in gastric mucosa were measured. Moreover, the activity of myeloperoxidase and the contents of TNF-α, P-selectin and VCAM-1 in gastric tissues were determined. The results showed that escin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from a reduction in the ulcer index and an attenuation of histopathologic changes. Escin caused significant reductions of the contents of malondialdehyde, TNF-α, P-selectin, VCAM-1 and myeloperoxidase activity. The altered activities of superoxide dismutase, catalase and glutathione peroxidase in the stomach tissues were also ameliorated by escin treatment. The present study demonstrated that escin had a protective effect against indomethacin-induced gastric ulcer in mice, not only by virtue of its antioxidant potential, but also due to its anti-inflammatory effect.

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

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    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.

  11. Ellagic acid facilitates indomethacin-induced gastric ulcer healing via COX-2 up-regulation

    Institute of Scientific and Technical Information of China (English)

    Ananya Chatterjee; Sirshendu Chatterjee; Smita Das; Arpita Saha; Subrata Chattopadhyay; Sandip K. Bandyopadhyay

    2012-01-01

    The mechanism of indomethacin-induced gastric ulcer healing by ellagic acid (EA) in experimental mice model is described in our study.Ulcer index (UI) and myeloperoxidase (MPO) activity of the stomach tissues showed maximum ulceration on the third day after indomethacin (18 mg/kg,single dose) administration.Preliminary observation of UI and MPO activity suggests that EA possesses ulcer-healing activity.Other anti-ulcer parameters such as the levels of prostaglandin E2,cyclooxygenase (COX) 1 and 2 enzymes,anti-inflammatory cytokines [interleukin (IL)-4 and -5J,pro-angiogenic factors,e.g.vascular endothelial growth factor,hepatocyte growth factor (HGF),and endothelial growth factor (EGF) were down-regulated by indomethacin.EA (7 mg/kg/day) treatment for 3 days shifted the indomethacin-induced pro-inflammatory biochemical parameters to the healing side.These activities were correlated with the ability of EA to alter the COX-2-dependent healing pathways.The ulcer-healing activity of EA was,however,compromised by pre-administration of the specific COX-2 inhibitor,celecoxib,and NS-398.Taken together,these results suggested that the EA treatment accelerates ulcer healing by inducing IL-4,EGF/HGF levds and enhances COX-2 expression.

  12. Antioxidant effects of betaine against Indomethacin-induced gastric damage in rats

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    M Alirezaei

    2016-10-01

    Full Text Available Introduction: Betaine (trimethyl glycine is known as methyl group donor and antioxidant in previous reports. The aim of this study was to assess the antioxidant effects of betaine in Indomethacin-induced gastric damages. Methods: Thirty-two adult male Sprague–Dawley rats in an experimental study were divided into four equal groups as follow: Control, Indomethacin, Betaine-indomethacin and Ascorbic acid-indomethacin. Control and indomethacin groups received normal saline and betaine and ascorbic acid-pretreated rats were administrated betaine (1.5% of the total diet and ascorbic acid (50 mg/kg body weight for 15 consecutive days, respectively. After 24 h fasting, all of the groups received indomethacin (48 mg/kg body weight and control group received distilled water. Results: Indomethacin administration increased gastric ulcer occurrence (% in comparison with control group and betaine pretreatment significantly decreased ulcer occurrence (% when compared to the other groups (P=0.0017. Gastric wall glutathione peroxidase (GPx activity was significantly lower in indomethacin group in comparison with the other groups (P=0.0012 while, betaine and ascorbic acid pretreatment increased GPx activity in comparison with indomethacin group (P=0.0012. Catalase activity was significantly higher in betaine-pretreated rats in comparison with indomethacin and ascorbic acid-indomethacin groups (P=0.0015. Lipid peroxidation significantly decreased in betaine and ascorbic acid pretreated groups (P=0.0013. Conclusion: These results showed beneficial antioxidant effects of betaine against gastric damages induced by indomethacin in rats.

  13. Immunomodulatory effect of candesartan on indomethacin-induced gastric ulcer in rats.

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    Kamel, Rehab; El Morsy, Engy M; Awad, Azza S

    2012-12-01

    Non steroidal anti-inflammatory drugs (NSAIDs) induce gastric mucosal lesions in part by induction of oxidative stress as well as the activation of inflammatory cells and the production of proinflammatory cytokines. In this study, we examined the protective effect of candesartan (2 and 5 mg/kg) on indomethacin-induced gastric mucosa damage. Pretreatment with candesartan for 10 days reduced significantly the ulcer index induced by indomethacin injection. The preventive index of 2 mg/kg (76.74%) was higher than that of 5 mg/kg (65.11%). Both doses of candesartan were able to reduce significantly the stomach malondialdehyde content compared to indomethacin-treated group. Myeloperoxidase, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant gastric levels were significantly reduced by 2 mg/kg of candesartan more than 5 mg/kg. The Th1 cytokine interferon γ was also significantly reduced by both doses of candesartan compared to indomethacin injected group. On the other hand, indomethacin significant decreased the anti-inflammatory cytokine IL-10 gastric level. Pretreatment with candesartan (2 and 5 mg/kg) reversed this effect. In conclusion, the present study indicates that pretreatment with candesartan, can protect against the stomach injury induced by indomethacin through its antioxidant and immunomodulatory effects.

  14. [Effect of dexamethasone on indomethacin-induced gastric erosion formation upon duration of the hormonal action].

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    Podvigina, T T; Morozova, O Iu; Bagaeva, T R; Filaretova, L P

    2009-07-01

    The aim of the study was to verify a dependence of dexamethasone effect on the gastric erosion formation upon duration of the hormonal action. Gastric erosions were induced by indometha cin (35 mg/kg, sc) in male rats after 24-hour fasting. The rats were given a single injection of dexamethasone at a dose of 1 mg/kg and they underwent the ulcerogenic stimulus (indomethacin) at va rious time points after the hormonal injection (1, 6, 12, 18, 24 hours as well as 3, 5, 7 days). The control rats were given dexamethasone vehicle. In 4 hours after indomethacin injection gastric erosions, corticosterone and blood glucose levels, as well as body and thymus weights were examined. The results obtained demonstrate a dependence ofdexamethasone effect on the gastric erosion formation upon duration of its action: dexamethasone attenuated or aggravated indomethacin-induced gastric erosions depending on the time of its injection. Gastroprotective action of dexamethasone was observed in the case of its injection 1, 6, and 12 hours before indomethacin. The further increase in the time interval caused transformation of gastroprotective action of dexamethasone against ulcerogenic effect. The data obtained suggest that a disturbance of carbohydrate regulation accompanied with the signs of catabolic effects of the glucocorticoid may be responsible for the ulcerogenic action of dexamethasone.

  15. The Protective Effect of Testosterone on Indomethacin Induced Gastric Ulcer in Female Sprague Dawley Rats

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    U. Akpamu

    2016-01-01

    Full Text Available Gastric ulcer has shown association with changes in sex hormones, with impact exacerbated in males. Also, males are known to be more exposed to ulcer risk factors. This study investigates the effect of testosterone on indomethacin induced gastric ulcers in adult female rats. Eighteen female rats (225 ± 25 g body weight were randomly assigned to 3 groups under standard laboratory condition. After acclimatization, animals fasted for 40 hrs but were given water ad libitum. Group A served as control while group B served as the ulcer control, in which ulcer was induced without treatment using indomethacin (40 mg/kg single orally dose. Group C was pretreated with testosterone (1 mg/kg IM eight hours before ulcer induction. Eight hours after ulcer induction, animals were sacrificed and the stomach was harvested for analysis. Results showed a significant reduction in mucus content in groups C (0.79±0.11 g and B (0.87±0.02 g compared to A (1.11±0.03 g. Gastric mucus pH was significantly acidic in group B (4.40±0.55 compared to C (5.20±0.45 and A (5.80±0.45. There was a significantly higher ulcer index in group B (4.60±0.55 mm compared to C (3.60±0.89 mm and testosterone pretreatment resulted in a 21.74% ulcer inhibition. Although weak, the findings suggest that testosterone might protect the gastric mucosa against NSAIDs in females.

  16. Protective effect of D-002, a mixture of beeswax alcohols, against indomethacin-induced gastric ulcers and mechanism of action.

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    Pérez, Yohani; Oyárzabal, Ambar; Mas, Rosa; Molina, Vivian; Jiménez, Sonia

    2013-01-01

    D-002, a mixture of higher aliphatic beeswax alcohols, produces gastroprotective and antioxidant effects. To investigate the gastroprotective effect of D-002 against indomethacin-induced ulcers, oxidative variables and myeloperoxidase (MPO) activity in the rat gastric mucosa were examined. Rats were randomized into six groups: a negative vehicle control and five indomethacin (50 mg/kg) treated groups, comprising a positive control, three groups treated orally with D-002 (5, 25 and 100 mg/kg) and one group with omeprazole 20 mg/kg intraperitoneally (ip). The contents of malondialdehyde (MDA), protein carbonyl groups (PCG), hydroxyl radical generation and catalase (CAT), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and MPO enzyme activities in the rat gastric mucosa were assessed. Indomethacin increased the content of MDA and PCG, the generation of *OH radical and MPO enzyme activity, while it decreased the CAT, GSH-PX and SOD activities as compared to the negative controls. D-002 (5-100 mg/kg) significantly and dose-dependently reduced indomethacin-induced ulceration to 75 %. Also, D-002 decreased the content of MDA and PCG, the generation of hydroxyl radicals and MPO activity as compared to the positive controls. The highest dose of D-002 (100 mg/kg) increased significantly GSH-PX and SOD activities, while all doses used increased CAT activities. Omeprazole 20 mg/kg, the reference drug, reduced significantly the ulcers (93 %), MDA and PCG, the generation of hydroxyl radicals and MPO activity, and increased the CAT, GSH-PX and SOD activities. D-002 treatment produced gastroprotective effects against indomethacin-induced gastric ulceration, which can be related to the reduction of hydroxyl radical generation, lipid peroxidation, protein oxidation and MPO activity, and to the increase of the antioxidant enzymes activities in the rat gastric mucosa.

  17. Effect of roxatidine bismuth citrate (MX1) against acetylsalicylic acid- and indomethacin-induced gastric mucosal damage in rats.

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    Marazova, K; Klouchek, E; Popov, A; Ivanov, C; Krushkov, I; Ichikawa, T; Ishihara, K; Hotta, K

    1998-10-01

    We have studied the effect of the newly synthesized agent, roxatidine bismuth citrate (N-[3-(3-(1-piperidinyl-methyl)phenoxy)propyl]-hydroxyacetamide-2- hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex), code name MX1, against acetylsalicylic acid (ASA)- and indomethacin-induced gastric mucosal damage in rats. Effects of MX1 (12.5, 50, 125, 184, 250 mg/kg) were compared to the effects of equimolar doses of roxatidine and bismuth subcitrate. Effect of MX1 (10(-6) M) on mucin biosynthesis measured by [3H] glucosamine incorporation in rat gastric corpus has been determined. MX1-pretreatment dose-dependently decreased the mean ulcer number and length in all doses used in an extent similar to that of roxatidine and more pronounced in comparison with bismuth subcitrate. The morphometrical results have been confirmed histomorphologically. The biosynthesis of mucin was found to be significantly enhanced after MX1 addition. The results of the present study suggest that MX1 has a gastroprotective effect against ASA- and indomethacin-induced ulcers which might be due both to its H2-blocking and mucus-stimulating activity.

  18. Gallic Acid Enriched Fraction of Phyllanthus emblica Potentiates Indomethacin-Induced Gastric Ulcer Healing via e-NOS-Dependent Pathway

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    Ananya Chatterjee

    2012-01-01

    Full Text Available The healing activity of gallic acid enriched ethanolic extract (GAE of Phyllanthus emblica fruits (amla against the indomethacin-induced gastric ulceration in mice was investigated. The activity was correlated with the ability of GAE to alter the cyclooxygenase- (COX- dependent healing pathways. Histology of the stomach tissues revealed maximum ulceration on the 3rd day after indomethacin (18 mg/kg, single dose administration that was associated with significant increase in inflammatory factors, namely, mucosal myeloperoxidase (MPO activity and inducible nitric oxide synthase (i-NOS expression. Proangiogenic parameters such as the levels of prostaglandin (PG E2, vascular endothelial growth factor (VEGF, hepatocyte growth factor (HGF, von Willebrand Factor VIII, and endothelial NOS (e-NOS were downregulated by indomethacin. Treatment with GAE (5 mg/kg/day and omeprazole (3 mg/kg/day for 3 days led to effective healing of the acute ulceration, while GAE could reverse the indomethacin-induced proinflammatory changes of the designated biochemical parameters. The ulcer healing activity of GAE was, however, compromised by coadministration of the nonspecific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, but not the i-NOS-specific inhibitor, L-N6-(1-iminoethyl lysine hydrochloride (L-NIL. Taken together, these results suggested that the GAE treatment accelerates ulcer healing by inducing PGE2 synthesis and augmenting e-NOS/i-NOS ratio.

  19. Gallic Acid Enriched Fraction of Phyllanthus emblica Potentiates Indomethacin-Induced Gastric Ulcer Healing via e-NOS-Dependent Pathway.

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    Chatterjee, Ananya; Chatterjee, Sirshendu; Biswas, Angshuman; Bhattacharya, Sayanti; Chattopadhyay, Subrata; Bandyopadhyay, Sandip K

    2012-01-01

    The healing activity of gallic acid enriched ethanolic extract (GAE) of Phyllanthus emblica fruits (amla) against the indomethacin-induced gastric ulceration in mice was investigated. The activity was correlated with the ability of GAE to alter the cyclooxygenase- (COX-) dependent healing pathways. Histology of the stomach tissues revealed maximum ulceration on the 3rd day after indomethacin (18 mg/kg, single dose) administration that was associated with significant increase in inflammatory factors, namely, mucosal myeloperoxidase (MPO) activity and inducible nitric oxide synthase (i-NOS) expression. Proangiogenic parameters such as the levels of prostaglandin (PG) E(2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), von Willebrand Factor VIII, and endothelial NOS (e-NOS) were downregulated by indomethacin. Treatment with GAE (5 mg/kg/day) and omeprazole (3 mg/kg/day) for 3 days led to effective healing of the acute ulceration, while GAE could reverse the indomethacin-induced proinflammatory changes of the designated biochemical parameters. The ulcer healing activity of GAE was, however, compromised by coadministration of the nonspecific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), but not the i-NOS-specific inhibitor, L-N6-(1-iminoethyl) lysine hydrochloride (L-NIL). Taken together, these results suggested that the GAE treatment accelerates ulcer healing by inducing PGE(2) synthesis and augmenting e-NOS/i-NOS ratio.

  20. Gastroprotective potentials of the ethanolic extract of Mukia maderaspatana against indomethacin-induced gastric ulcer in rats.

    Science.gov (United States)

    Gomathy, G; Venkatesan, D; Palani, S

    2015-01-01

    This study investigated the protective effects of the ethanolic extract of Mukia maderaspatana against indomethacin-induced gastric ulcer in rats. Gastric ulceration was induced by single intraperitoneal injection of indomethacin (30 mg/kg b.wt.). M. maderaspatana extract produced significant reduction in gastric mucosal lesions, malondialdehyde and serum tumour necrosis factor-α associated with a significant increase in gastric juice mucin content and gastric mucosal catalase, nitric oxide and prostaglandin E2 levels. The volume and acidity of the gastric juice decreased in pretreated rats. The plant extract was evaluated in the gastric juice of rats, untreated has showed near normal levels in pretreated rats. The M. maderaspatana was able to decrease acidity and increase the mucosal defence in the gastric area, therefore justifying its use as an antiulcerogenic agent. Ranitidine significantly increased pH value and decreased pepsin activity and gastric juice free and total acidity. The anti-ulcer effect was further confirmed histologically.

  1. Gastroprotective effect of epoxy clerodane diterpene isolated from Tinospora cordifolia Miers (Guduchi) on indomethacin-induced gastric ulcer in rats.

    Science.gov (United States)

    Antonisamy, Paulrayer; Dhanasekaran, Muniyappan; Ignacimuthu, Savarimuthu; Duraipandiyan, Veeramuthu; Balthazar, Joseph Devadass; Agastian, Paul; Kim, Jong-Hoon

    2014-06-15

    The present study evaluated the gastroprotective effect of epoxy clerodane diterpene (ECD), isolated from Tinospora cordifolia on indomethacin-induced gastric ulcer in rats. Administration of indomethacin exhibits extreme levels of ulcer index (UI) and myeloperoxidase (MPO) activity. Indomethacin down regulated PGE2, anti-inflammatory cytokines (IL-4, IL-10) and pro-angiogenic factors (VEGF and EGF). The ECD pretreatment considerably increased the levels of PGE2, anti-inflammatory cytokines and pro-angiogenic factors. The ulcer-healing activity of ECD was inhibited by pre-administration of the specific COX-1 inhibitor (SC560) and nonspecific NOS inhibitor (L-NAME), which indicates the involvement of PGE2 and NOS in ECD induced ulcer healing activity. These findings suggest that ECD exerts its antiulcer activity by reinforcement of defensive elements and diminishing the offensive elements.

  2. Healing property of the Piper betel phenol, allylpyrocatechol against indomethacin-induced stomach ulceration and mechanism of action

    Institute of Scientific and Technical Information of China (English)

    S Bhattacharya; D Banerjee; AK Bauri; S Chattopadhyau; SK Bandyopadhyay

    2007-01-01

    AIM: To evaluate the protective activity of allylpyrocatechol (APC), the major antioxidant constituent of Piper betel,against the indomethacin-induced stomach ulceration in the rat model and correlates with its antioxidative and mucin protecting properties.METHODS: Male Sprague-Dawley rats were divided into five groups. Normal control rats (group Ⅰ ) were given the vehicle oral dose of gum acacia in distilled water (1 mL per rat); ulcerated control and treated rats (groups Ⅱ-Ⅴ) were given a single dose of indomethacin (30 mg/kg body wt.); group Ⅱ rats were sacrificed 4 h after indomethacin administration; groups Ⅲ-Ⅴ rats were given the vehicle (1 mL per rat) or APC (2 mg/kg body wt.) or misoprostol (1.43 μg/kg body wt.) once daily by oral intubation for 7 d starting from 4 h after the indomethacin administration. After 7 d, the stomach tissues were excised for histological examination and biochemical analysis.RESULTS: Treatment with APC (2 mg/kg body wt per day) and misoprostol (1.43 μg/kg body wt per day) for 7 d could effectively heal the stomach ulceration as revealed from the ulcer index and histopathological studies. Compared to the zero day ulcerated group,treatment with APC and misoprostol reduced the ulcer index by 93.4% and 85.4% respectively (P<0.05). Both APC and misoprostol accelerated ulcer healing observed in natural recovery (P<0.05), their respective healing capacities not being significantly different. The healing capacities of APC and misoprostol could be attributed to their antioxidant activity as well as the ability to enhance the mucin content of the gastric tissues. Compared to the ulcerated untreated rats, those treated with APC and misoprostol showed near normal MDA levels, while the protein levels were 86% and 78% of the normal value respectively (P<0.05). Likewise, both APC and misoprostol increased the SOD, catalase, and mucin levels significantly (P<0.05), the effect of APC being better.CONCLUSION: APC can protect

  3. Gastroprotective and Antioxidant Effects of Lobaria pulmonaria and Its Metabolite Rhizonyl Alcohol on Indomethacin-Induced Gastric Ulcer.

    Science.gov (United States)

    Atalay, Fadime; Odabasoglu, Fehmi; Halici, Mesut; Cakir, Ahmet; Cadirci, Elif; Aslan, Ali; Aydin Berktas, Ozlem; Kazaz, Cavit

    2015-11-01

    Two lichen metabolites, rhizonaldehyde (1) and rhizonyl alcohol (2), were isolated from the acetone extract of Lobaria pulmonaria by chromatographic methods, and their chemical structures were determined by UV/VIS, IR, and 1D- and 2D-NMR spectroscopic methods. The gastroprotective and in vivo antioxidant activities of extracts of L. pulmonaria and its metabolites, 1 and 2, were investigated in indomethacin-induced ulcer models in rats. The gastric lesions were significantly reduced by acetone, hexane, and CHCl3 extracts, with 75.3-41.5% inhibition. Rhizonyl alcohol (2) significantly reduced the gastric lesions with an inhibition rate of 84.6-42.8%, whereas rhizonaldehyde (1) significantly increased the gastric lesions. Antioxidant parameters and myeloperoxidase activities were also evaluated in the gastric tissues of the rats. Indomethacin caused oxidative stress, which resulted in lipid peroxidation in gastric tissues by decreasing the levels of the antioxidants as compared to healthy rat tissues. In contrast to indomethacin, all extracts and rhizonyl alcohol (2) caused a significant decrease in lipid peroxidation levels and an increase in antioxidant parameters, superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase, and reduced glutathione in gastric tissues. The administration of rhizonyl alcohol (2) also resulted in a decrease in gastric myeloperoxidase activity increased by indomethacin. The gastroprotective effect of rhizonyl alcohol (2) can be attributed to its antioxidant properties and its suppressing effect on neutrophil infiltration into gastric tissues.

  4. Prevention by lansoprazole, a proton pump inhibitor, of indomethacin -induced small intestinal ulceration in rats through induction of heme oxygenase-1.

    Science.gov (United States)

    Yoda, Y; Amagase, K; Kato, S; Tokioka, S; Murano, M; Kakimoto, K; Nishio, H; Umegaki, E; Takeuchi, K; Higuchi, K

    2010-06-01

    The effect of lansoprazole, a proton pump inhibitor (PPI), on indomethacin-induced small intestinal ulceration was examined in rats, particularly in relation to heme oxygenase (HO)-1. The animals were administered indomethacin (10 mg/kg, p.o.) and killed 24 h later. Lansoprazole (30-100 mg/kg, p.o.) and omeprazole (30-100 mg/kg, p.o.) were given 30 min before the administration of indomethacin, while tin-protoporphyrin IX (SnPP: 30 mg/kg, i.v.), an inhibitor of HO-1, was injected 10 min before indomethacin or lansoprazole. Indomethacin produced hemorrhagic lesions in the small intestine, accompanied with an increase of mucosal invasion of enterobacteria, inducible nitric oxide synthase (iNOS) expression, and myeloperoxidase (MPO) activity in the mucosa. Pretreatment with lansoprazole dose- dependently reduced the severity of the indomethacin-induced intestinal lesions, with suppression of the increased MPO activity, while omeprazole had no effect. Pretreatment with SnPP significantly exacerbated these intestinal lesions and almost totally abolished the protective effect of lansoprazole. The up-regulation of iNOS mRNA expression following indomethacin was suppressed by lansoprazole in a SnPP-inhibitable manner, although the enhanced enterobacterial invasion remained unaffected. The amount of HO-1 protein in the intestinal mucosa was significantly increased by lansoprazole but not by omeprazole. Prior administration of carbon monoxide (CO)-releasing molecule-2 (CORM-2; 10 mg/kg, i.p.) significantly reduced the severity of these lesions and the enhancement of mucosal iNOS mRNA expression induced in the small intestine by indomethacin. These results suggest that lansoprazole prevents indomethacin-induced small intestinal ulceration, and this effect is associated with inhibition of iNOS expression, through up-regulation of HO-1/CO production in the mucosa.

  5. Motor, Visual and Emotional Deficits in Mice after Closed-Head Mild Traumatic Brain Injury Are Alleviated by the Novel CB2 Inverse Agonist SMM-189

    Directory of Open Access Journals (Sweden)

    Anton Reiner

    2014-12-01

    Full Text Available We have developed a focal blast model of closed-head mild traumatic brain injury (TBI in mice. As true for individuals that have experienced mild TBI, mice subjected to 50–60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2, we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50–60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.

  6. Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189.

    Science.gov (United States)

    Reiner, Anton; Heldt, Scott A; Presley, Chaela S; Guley, Natalie H; Elberger, Andrea J; Deng, Yunping; D'Surney, Lauren; Rogers, Joshua T; Ferrell, Jessica; Bu, Wei; Del Mar, Nobel; Honig, Marcia G; Gurley, Steven N; Moore, Bob M

    2014-12-31

    We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50-60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.

  7. Effect of hesperidin and neohesperidin from bittersweet orange (Citrus aurantium var. bigaradia) peel on indomethacin-induced peptic ulcers in rats.

    Science.gov (United States)

    Hamdan, Dalia I; Mahmoud, Mona F; Wink, Michael; El-Shazly, Assem M

    2014-05-01

    Hesperidin and neohesperidin are the major flavanones isolated from bittersweet orange. It was recently reported that they have potent anti-inflammatory effects in various inflammatory models. In the present study, the effects of hesperidin and neohesperidin on indomethacin-induced ulcers in rats and the underlying mechanisms were investigated. Gastric ulcers were induced in rats with a single dose of indomethacin. The effects of pretreatment with hesperidin and neohesperidin were assessed in comparison with omeprazole as reference standard. Ulcer index, gene expression of gastric cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), lipid peroxidation product, malondialdhyde (MDA), and reduced glutathione (GSH) content in stomach were measured. Furthermore, gross and histopathological examination was performed. Our results indicated that both hesperidin and neohesperidin significantly aggravated gastric damage caused by indomethacin administration as evidenced by increased ulcer index and histopathological changes of stomach.

  8. Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury.

    Science.gov (United States)

    Chiou, Shiun-Kwei; Hodges, Amy; Hoa, Neil

    2010-09-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin are a major cause of gastric erosions and ulcers. Induction of apoptosis by NSAIDs is an important mechanism involved. Understanding how NSAIDs affect genes that regulate apoptosis is useful for designing therapeutic or preventive strategies and for evaluating the efficacy of safer drugs being developed. We investigated whether growth arrest and DNA damage-inducible 45alpha (GADD45alpha), a stress signal response gene involved in regulation of DNA repair and induction of apoptosis, plays a part in NSAID-induced gastric mucosal injury and apoptosis in vivo in mice and in vitro in cultured human AGS and rat RGM-1 gastric epithelial cells. Intraperitoneal administration of sulindac and indomethacin both resulted in up-regulation of GADD45alpha expression and induction of significant injury and apoptosis in gastric mucosa of wild-type mice. GADD45alpha(-/-) mice were markedly more resistant to both sulindac- and indomethacin-induced gastric mucosal injury and apoptosis than wild-type mice. Sulindac sulfide and indomethacin treatments also concentration-dependently increased GADD45alpha expression and apoptosis in AGS and RGM-1 cells. Antisense suppression of GADD45alpha expression significantly reduced sulindac and indomethacin-induced activation of caspase-9 and apoptosis in AGS cells. Pretreatments with exogenous prostaglandins and small interfering RNA suppression of cyclooxygenase (COX)-1 and -2 did not affect up-regulation of GADD45alpha by sulindac sulfide and indomethacin in AGS cells. These findings indicate that GADD45alpha up-regulation is a COX-independent mechanism that is required for induction of severe gastric mucosal apoptosis and injury by NSAIDs, probably via a capase-9-dependent pathway of programmed cell death.

  9. Anti-ulcerogenic activity of aqueous extract of Carica papaya seed on indomethacin-induced peptic ulcer in male albino rats

    Institute of Scientific and Technical Information of China (English)

    Hussein O B Oloyede; Matthew C Adaja; Taofeek O Ajiboye; Musa O Salawu

    2015-01-01

    OBJECTIVE:Carica papaya is an important fruit with its seeds used in the treatment of ulcer in Nigeria. This study investigated the anti-ulcerogenic and antioxidant activities of aqueous extract of Carica papaya seed against indomethacin-induced peptic ulcer in male rats. METHODS:Thirty male rats were separated into 6 groups (A–F) of ifve rats each. For 14 d before ulcer induction with indomethacin, groups received once daily oral doses of vehicle (distil ed water), cimetidine 200 mg/kg body weight (BW), or aqueous extract of C. papaya seed at doses of 100, 150 or 200 mg/kg BW (groups A, B, C, D, E and F, respectively). Twenty-four hours after the last treatment, groups B, C, D, E and F were treated with 100 mg/kg BW of indomethacin to induce ulcer formation. RESULTS:Carica papaya seed extract signiifcantly (P<0.05) increased gastric pH and percentage of ulcer inhibition relative to indomethacin-induced ulcer rats. The extract signiifcantly (P<0.05) decreased gastric acidity, gastric acid output, gastric pepsin secretion, ulcer index and gastric secretion volume relative to group B. These results were similar to that achieved by pretreatment with cimetidine. Speciifc activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase in the extract-treated groups (D, E and F) were increased signiifcantly over the group B (P<0.05). Pretreatment with the seed extract protected rats from the indomethacin-mediated decrease in enzyme function experienced by the group B. Similarly, indomethacin-mediated decrease in reduced glutathione level and indomethacin-mediated increase in malondialdehyde were reversed by Carica papaya extract. CONCLUSION:In this study, pretreatment with aqueous extract of Carica papaya seed exhibited anti-ulcerogenic and antioxidant effects, which may be due to the enhanced antioxidant enzymes.

  10. Upregulation and activation of caspase-3 or caspase-8 and elevation of intracellular free calcium mediated apoptosis of indomethacin-induced K562 cells

    Institute of Scientific and Technical Information of China (English)

    张广森; 周光飚; 戴崇文

    2004-01-01

    Background A nonsteroidal anti-inflammatory drug, indomethacin, has been shown to have anti-leukemic activity and induce leukemic cell opoptosis. This study was to elucidate the mechanism of indomethacin-induced K562 cell apoptosis.Methods K562 cells were grown in RPMI 1640 medium and treated with different doses of indomethacin (0 μmol/L, 100 μmol/L, 200 μmol/L, 400 μmol/L, 800 μmol/L) for 72 hours. The cells were harvested, and cell viability or apoptosis was analyzed using MTT assay and AO/EB stain, combining laser scanning confocal microscopy (LSCM) technique separately. For the localization and distribution of intracellular caspase-3 or caspase-8 protein, immunofluorescence assay was carried out. To reveal the activation of caspase-3 or caspase-8 in indomethacin-treated cells, Western blot detection was used. The change in intracellular free calcium was determined by Fluo-3/ Am probe labeling combined with LSCM. Results Indomethacin could lead to K562 cell apoptosis and inhibit cell viability in a concentration-dependent manner. An increased expression of intracellular caspase-3 or caspase-8 was observed at higher doses of indomethacin (400-800 μmol/L). Western blot results showed upregrulation and activation in both caspase-3 and caspase-8 protein. Under indomethacin intervention, the levels of intracellular free calcium showed a significant increase. Blocking the activity of cyclooxygenase did not abolish the effects of indomethacin on K562 cell apoptosis.Conclusions Activation and upregulation of caspase-3 or caspase-8 protein were responsible for Indomethacin-induced K562 cell apoptosis. Variation of intracellular free calcium might switch on the apoptotic pathway and the proapoptotic effect of indomethacin might be cyclooxygenase-independent.

  11. The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat

    DEFF Research Database (Denmark)

    Munro, G; Hansen, Rikke Rie; Erichsen, Hk

    2012-01-01

    ACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA). KEY RESULTS: When administered...... before carrageenan, both diclofenac (30 mg·kg(-1) ) and PNU-120596 (30 mg·kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU......-120596 attenuated the carrageenan-induced increase in levels of TNF-α and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac...

  12. Novel mixed NOP/MOP agonist BU08070 alleviates pain and inhibits gastrointestinal motility in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms.

    Science.gov (United States)

    Sobczak, Marta; Cami-Kobeci, Gerta; Sałaga, Maciej; Husbands, Stephen M; Fichna, Jakub

    2014-08-05

    The opioid and nociceptin systems play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of BU08070, a novel mixed MOP/NOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo in physiological conditions and in animal models mimicking symptoms of irritable bowel syndrome (IBS), including diarrhea and abdominal pain. The effect of BU08070 on muscle contractility in vitro was characterized in the ileum and colon. To assess the effect of BU08070 in vivo, the following parameters were assessed: whole GI transit, gastric emptying, geometric center, colonic bead expulsion, fecal pellet output and time to castor oil-induced diarrhea. The antinociceptive activity of BU08070 was characterized in the mustard oil (MO)-induced abdominal pain model and the writhing test, alone and in the presence of MOP and NOP antagonists. in vitro, BU08070 (10(-10)-10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent manner. in vivo, BU08070 prolonged the whole GI transit and inhibited colonic bead expulsion. The antitransit and antidiarrheal effects of BU08070 were observed already at the dose of 0.1 mg/kg (i.p.). BU08070 reversed hypermotility and reduced pain in mouse models mimicking IBS-D symptoms. Our results suggest that BU08070 has a potential of becoming an efficient drug in IBS-D therapy. Here we also validate mixed NOP/MOP receptor targeting as possible future treatment of functional GI diseases.

  13. Comparison of the protective effects of various antiulcer agents alone or in combination on indomethacin-induced gastric ulcers in rats.

    Science.gov (United States)

    Izzettin, Fikret Vehbi; Sancar, Mesut; Okuyan, Betul; Apikoglu-Rabus, Sule; Cevikbas, Ugur

    2012-05-01

    The aim of this study which was structured with the objective of determination of the optimum protective therapy against the long term NSAID therapy-induced ulcers was to compare the gastro-protective effects of various antiulcer drugs (ranitidine, omeprazole, bismuth and misoprostol) alone or in combination with each other in different doses on indomethacin-induced gastric ulcers in rats. In this experimental study the protective effect of misoprostol (100 μg/kg/day and 10 μg/kg/day i.g.), omeprazole (5 mg/kg/day and 1.5 mg/kg/day i.p.), ranitidine (40 mg/kg/day and 10 mg/kg/day i.p.), bismuth (70 mg/kg/day and 15 mg/kg/day i.g.), combinations of misoprostol (10 μg/kg/day i.g.) plus omeprazole (1.5mg/kg/day i.p.) and misoprostol (10 μg/kg/day i.g.) plus ranitidine (10 mg/kg/day i.p.) are investigated on indomethacin (50 mg/kg/day s.c.) induced gastric ulcers. Half an hour before indomethacin administration, each group received the above treatment regimens for 5 days. After 5-day treatment, the rats were sacrificed and histopathological and hematological examinations were performed. The following regimens were found to be effective in the prevention of indomethacin-induced gastric lesions: 100 μg/kg misoprostol, 10 μg/kg misoprostol, 5mg/kg omeprazole, combination of 10 μg/kg misoprostol plus 1.5 mg/kg omeprazole and 10 μg/kg misoprostol plus 10 mg/kg ranitidine. The prevention rates achieved by these treatments were 71.4%, 50%, 47.6%, 52.4% and 50%, respectively. As a result of this study, misoprostol and omeprazol were found to be effective in protection against NSAID-induced gastric problems; while, ranitidine and bismuth were not. Also, the combinations of these agents were not found to have additive or synergistic effects.

  14. A Direct Comparison of Anti-ulcer Effects of Coenzyme Q10 and Vitamin C on Indomethacin-induced Gastric Ulcer in Rat: A Controlled Experimental Study

    Directory of Open Access Journals (Sweden)

    2013-08-01

    Full Text Available Introduction: Indomethacin increases generation of mitochondrial reactive oxygen species (ROS which have a crucial role in the indomethacin-induced gastric ulcer. Coenzyme Q10 has an antioxidant activity on mitochondria and cell membranes and protects lipids from oxidation and is essential for stabilizing biological membranes. Superoxide dismutase (SOD acts as one of the defense mechanisms against free radicals. When the generation of ROS overwhelms, the antioxidant defense, lipid peroxiation of cell membrane occurs and cause cell damage. Materials and Methods: Male adult Wistar rats were divided into A and B groups. The rats in group A were then further divided into three subgroups of 6 animals each and received one of the following treatments: Animals in the first subgroup received saline. Animals in the second subgroup received saline and indomethacin. Animals in the third subgroup received vitamin C and indomethacin. The rats in group B were also further divided into 3 subgroups of 6 rats each and treated with one of the following treatments: Animals in first subgroup received 1% Tween 80 as vehicle. Animals In second subgroup received 1% Tween 80 and indomethacin. Animals in third subgroup received CoQ10 and indomethacin. Four hours after the last treatment, animals were killed and the stomachs removed were cut and gastric mucosal lesions were examined. Ulcer indexes were determined and SOD activity measured in plasma                                                             Results: Pretreatment with both vitamin C and coenzyme Q10 was associated with attenuation of ulcer index and increased SOD activity compared with animals treated with indomethacin alone (P

  15. Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-κB and Nrf2.

    Science.gov (United States)

    Carrasco-Pozo, Catalina; Castillo, Rodrigo L; Beltrán, Caroll; Miranda, Alfonso; Fuentes, Jocelyn; Gotteland, Martin

    2016-01-01

    The aim of this study was to determine the gastrointestinal protection by quercetin against indomethacin-induced oxidative stress and inflammation, with specific interest in studying the underlying molecular mechanisms. We hypothesized that the quercetin-protective effect relies on its antioxidant and antiinflammatory properties. Rats were pretreated with quercetin (50- or 100-mg/kg, ig single dose), 30 min before INDO administration (40-mg/kg ig single dose). Caco-2 cells were treated with INDO (250 and 500 μM) in the absence or presence of quercetin (10 μg/ml). Quercetin prevented the decrease in nuclear translocation of Nrf2, a key regulator of the antioxidant response, and the increase in reactive oxygen species levels induced by INDO by inhibiting the enhancement of NADPH oxidase and xanthine oxidase activities as well as the reduction in superoxide dismutase and glutathione peroxidase activities in gastric and ileal tissues. Quercetin also prevented INDO-induced ICAM-1 and P-selectin expressions and the increase of myeloperoxidase activity in gastric and ileal tissues and NF-κB activation and IL-8 production in Caco-2 cells. Quercetin did not affect the inhibition of TNFα-mediated production of prostaglandin E2 induced by INDO in Caco-2 cells. The protective effects of quercetin observed in the gastric and ileal mucosa of rats as well as in Caco-2 cells relied on the ability of this flavonol to prevent NF-κB activation and increase Nrf2 translocation. This study supports the concept that quercetin may be useful in the prevention and/or treatment of nonsteroidal antiinflammatory drug-associated side effects, without interfering with their therapeutic efficacy.

  16. Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine.

    Science.gov (United States)

    Choi, Y H; Lee, U; Suh, J H; Kim, Y G; Lee, M; Oh, E; Lee, M G

    2011-05-01

    After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ϵ-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.

  17. Effects of oral adenosine 5'-triphosphate and adenosine in enteric-coated capsules on indomethacin-induced permeability changes in the human small intestine: a randomized cross-over study

    Directory of Open Access Journals (Sweden)

    Bours Martijn JL

    2007-06-01

    Full Text Available Abstract Background It is well-known that nonsteroidal anti-inflammatory drugs (NSAIDs can cause damage to the small bowel associated with disruption of mucosal barrier function. In healthy human volunteers, we showed previously that topical administration of adenosine 5'-triphosphate (ATP by naso-intestinal tube attenuated a rise in small intestinal permeability induced by short-term challenge with the NSAID indomethacin. This finding suggested that ATP may be involved in the preservation of intestinal barrier function. Our current objective was to corroborate the favourable effect of ATP on indomethacin-induced permeability changes in healthy human volunteers when ATP is administered via enteric-coated capsules, which is a more practically feasible mode of administration. Since ATP effects may have been partly mediated through its breakdown to adenosine, effects of encapsulated adenosine were tested also. Methods By ingesting a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by five-hour collection of total urine, small intestinal permeability was assessed in 33 healthy human volunteers by measuring the urinary lactulose/rhamnose excretion ratio. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC. Basal permeability of the small intestine was assessed as a control condition (no indomethacin, no ATP/adenosine. As a model of increased small intestinal permeability, two dosages of indomethacin were ingested at 10 h (75 mg and 1 h (50 mg before ingesting the lactulose/rhamnose test drink. At 1.5 h before indomethacin ingestion, two dosages of placebo, ATP (2 g per dosage or adenosine (1 g per dosage were administered via enteric-coated hydroxypropyl methylcellulose (HPMC capsules with Eudragit© L30D-55. Results Median urinary lactulose/rhamnose excretion ratio (g/g in the control condition was 0.032 (interquartile range: 0.022–0.044. Compared to the

  18. Potentiation of indomethacin-induced anti-inflammatory response by pioglitazone in carrageenan-induced acute inflammation in rats: Role of PPARγ receptors.

    Science.gov (United States)

    Houshmand, Gholamreza; Mansouri, Mohammad Taghi; Naghizadeh, Bahareh; Hemmati, Ali Asghar; Hashemitabar, Mahmoud

    2016-09-01

    This study aimed to assess the interaction between anti-inflammatory effects of pioglitazone (peroxysome proliferator activated receptor-gamma (PPARγ) agonist, PGL), and indomethacin (cyclooxygenase (COX) inhibitor, IND) and to evaluate the possible underlying mechanisms. Paw edema induced by carrageenan was used to induce inflammation. Different doses of IND (0.3-10mg/kg) and PGL (1-20mg/kg) alone or in combination were administered intraperitoneally to rats. Paw tissue levels of PPARγ, COX-2, and prostaglandin E2 and serum levels of TNF-α and IL-10 were also estimated. Doses of IND and PGL showed a statistically significant anti-inflammatory effect. Combination of a non-effective dose of IND (0.3mg/kg) with increasing doses of PGL (1-10mg/kg) resulted in potentiated anti-inflammation and vise versa. IND, PGL and the combination were able to reduce the COX-2, PGE2 contents and TNF-α level. Moreover, all these treatments caused elevation in PPARγ levels and IL-10 levels. However, when the rats were pre-treated with GW-9662 (a selective PPARγ antagonist), all the anti-inflammation and alterations in the biochemical factors were antagonized. These results showed that PGL markedly enhanced the anti-inflammatory activity of IND and this effect mediated partly at least, through PPARγ. Possible mechanisms of the interaction were that PGL stimulates the PPARγ and inhibits COX-2 by those cytokines that trigger the PPARγ and also inhibit COX-2. This study suggests that combination therapy with pioglitazone and indomethacin may provide an alternative for the clinical control of inflammation especially in patients with diabetes.

  19. GLP-1 Receptor Agonists

    Science.gov (United States)

    ... in Balance › GLP-1 Receptor Agonists Fact Sheet GLP-1 Receptor Agonists May, 2012 Download PDFs English Espanol Editors Silvio ... are too high or too low. What are GLP-1 receptor agonist medicines? GLP-1 receptor agonist medicines, also called ...

  20. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart;

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  1. [Melatonin receptor agonist].

    Science.gov (United States)

    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.

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

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

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

  3. Melatonin agonists and insomnia.

    Science.gov (United States)

    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.

  4. Alleviating energy poverty: Indian experience

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Garima

    2010-09-15

    Energy services play an important role in human welfare. India faces acute energy poverty indicating lack of access of clean energy fuels. Access to electricity is limited to 56% households in India and about 89% of rural households depend on polluting energy sources. Energy poverty impacts income poverty as poor find it difficult to acquire high priced cleaner fuels. It also adversely impacts the socio economic conditions of women. The paper highlights the linkage of energy poverty with income poverty and gender inequality. It analyses measures taken to alleviate energy poverty and recommends regulatory and policy measures as way forward.

  5. Pharmacogenetics of β2-Agonists

    OpenAIRE

    Nobuyuki Hizawa

    2011-01-01

    Short-acting β2-agonists (SABAs) and long-acting β2-agonists (LABAs) are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD) because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target ...

  6. A natural history of "agonist".

    Science.gov (United States)

    Russo, Ruth

    2002-01-01

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

  7. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide...

  8. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...

  9. Harnessing motivation to alleviate neglect.

    Science.gov (United States)

    Russell, Charlotte; Li, Korina; Malhotra, Paresh A

    2013-01-01

    The syndrome of spatial neglect results from the combination of a number of deficits in attention, with patients demonstrating both spatially lateralized and non-lateralized impairments. Previous reports have hinted that there may be a motivational component to neglect and that modulating this might alleviate some of the debilitating symptoms. Additionally, recent work on the effects of reward on attention in healthy participants has revealed improvements across a number of paradigms. As the primary deficit in neglect has been associated with attention, this evidence for reward's effects is potentially important. However, until very recently there have been few empirical studies addressing this potential therapeutic avenue. Here we review the growing body of evidence that attentional impairments in neglect can be reduced by motivation, for example in the form of preferred music or anticipated monetary reward, and discuss the implications of this for treatments for these patients. Crucially these effects of positive motivation are not observed in all patients with neglect, suggesting that the consequences of motivation may relate to individual lesion anatomy. Given the key role of dopaminergic systems in motivational processes, we suggest that motivational stimulation might act as a surrogate for dopaminergic stimulation. In addition, we consider the relationship between clinical post stroke apathy and lack of response to motivation.

  10. Harnessing motivation to alleviate neglect

    Directory of Open Access Journals (Sweden)

    Charlotte eRussell

    2013-06-01

    Full Text Available The syndrome of spatial neglect results from the combination of a number of deficits in attention, with patients demonstrating both spatially lateralised and non-lateralised impairments. Previous reports have hinted that there may be a motivational component to neglect and that modulating this might alleviate some of the debilitating symptoms. Additionally, recent work on the effects of reward on attention in healthy participants has revealed improvements across a number of paradigms. As the primary deficit in neglect has been associated with attention, this evidence for reward’s effects is potentially important. However, until very recently there have been few empirical studies addressing this potential therapeutic avenue. Here we review the growing body of evidence that attentional impairments in neglect can be reduced by motivation, for example in the form of preferred music or anticipated monetary reward, and discuss the implications of this for treatments for these patients. Crucially these effects of positive motivation are not observed in all patients with neglect, suggesting that the consequences of motivation may relate to individual lesion anatomy. Given the key role of dopaminergic systems in motivational processes, we suggest that motivational stimulation might act as a surrogate for dopaminergic stimulation. In addition, we consider the relationship between clinical post stroke apathy and lack of response to motivation.

  11. Usefulness of HeLa cells to evaluate inverse agonistic activity of antihistamines.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Sasaki, Yohei; Fukui, Hiroyuki

    2013-03-01

    Antihistamines are thought to antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). However, recent studies indicate that antihistamines are classified into two groups, i.e., inverse agonists and neutral antagonists on the basis of their ability to down-regulate the constitutive activity of H1R. As H1R is an allergy-sensitive gene whose expression influences the severity of allergic symptoms, inverse agonists should more potently alleviate allergic symptoms than neutral antagonists by inhibiting H1R constitutive activity. Therefore, it is important to assess inverse agonistic activity of antihistamines. Here we report a novel assay method using HeLa cells expressing H1R endogenously for evaluation of inverse agonistic activity of antihistamines. Pretreatment with inverse agonists down-regulated H1R gene expression below to its basal level. On the other hand, basal H1R mRNA expression was unchanged by neutral antagonist pretreatment. Both inverse agonists and neutral antagonists suppressed histamine-induced H1R mRNA elevation. Classification of antihistamines on the basis of their suppressive activity of basal H1R gene expression was consistent with that of inositol phosphate accumulation in H1R-overexpressed cells. Our data suggest that the assay method using HeLa cells is more convenient and useful than the existing methods and may contribute to develop new antihistamines with inverse agonistic activity.

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

    Science.gov (United States)

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

    2016-07-01

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

  13. Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Song YanXia

    2011-09-01

    Full Text Available Abstract Helminth infection may modulate the expression of Toll like receptors (TLR in dendritic cells (DCs and modify the responsiveness of DCs to TLR ligands. This may regulate aberrant intestinal inflammation in humans with helminthes and may thus help alleviate inflammation associated with human inflammatory bowel disease (IBD. Epidemiological and experimental data provide further evidence that reducing helminth infections increases the incidence rate of such autoimmune diseases. Fine control of inflammation in the TLR pathway is highly desirable for effective host defense. Thus, the use of antagonists of TLR-signaling and agonists of their negative regulators from helminths or helminth products should be considered for the treatment of IBD.

  14. Pharmacogenetics of β2-Agonists

    Directory of Open Access Journals (Sweden)

    Nobuyuki Hizawa

    2011-01-01

    Full Text Available Short-acting β2-agonists (SABAs and long-acting β2-agonists (LABAs are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target therapies in highly responsive patients, especially for more expensive therapies or those with increased risk of side effects. Variation in response to both SABAs and LABAs has been observed in patients with polymorphisms in the β2 adrenoceptor gene (ADRB2. This review summarizes results from various studies on the possible relationship between ADRB2 polymorphisms and the bronchodilator or bronchoprotective effects of inhaled β2-agonists. By assessing the ADRB2 genotype, the hope is that it will be possible to predict the responsiveness to chronic administration of β2-agonists. Genetic testing, however, is of limited usefulness at this stage for ADRB2 because the common variants identified thus far account for only a small proportion of the variation observed for given responses. Carefully performed and adequately powered clinical trials continue to be important for achieving the goal of pharmacogenetic approaches to therapy.

  15. Elderly poverty alleviation through living with family.

    Science.gov (United States)

    Rendall, M S; Speare, A

    1995-11-01

    "We estimate here the extent of United States elderly poverty alleviation through living with family. These estimates are motivated by public-policy concern about the well-being of the elderly, and by the relevance of the process for fertility under the old-age-security hypothesis. An inter-temporal poverty-measurement model is estimated with 1984 Survey of Income and Program Participation income and wealth data. Without extended-family co-residence, and assuming no bequests, poverty rates would increase 42% over observed rates. Female elderly account for almost all the alleviated poverty. As a population, their impoverishment with age is effectively prevented by co-residence. Proportionately more black than white elderly are beneficiaries of poverty alleviation through living with family, but white elderly are more likely to be beneficiaries if at risk."

  16. Cannabinoids alleviate experimentally induced intestinal inflammation by acting at central and peripheral receptors.

    Directory of Open Access Journals (Sweden)

    Jakub Fichna

    Full Text Available In an attempt to further investigate the role of cannabinoid (CB system in the pathogenesis of inflammatory bowel diseases, we employed two recently developed ligands, AM841 (a covalently acting CB agonist and CB13 (a peripherally-restricted CB agonist to establish whether central and peripheral CB sites are involved in the anti-inflammatory action in the intestine.AM841 (0.01, 0.1 and 1 mg/kg, i.p. significantly decreased inflammation scores in dextran sulfate sodium (DSS- and 2,4,6-trinitrobenzene sulfonic acid (TNBS-treated mice when administered before induction of colitis or as a treatment of existing intestinal inflammation. The effect was absent in CB1, CB2 and CB(1/2-deficient mice. A peripherally-restricted agonist CB13 did not alleviate colitis when given i.p. (0.1 mg/kg, but significantly decreased inflammation score after central administration (0.1 µg/animal.This is the first evidence that central and peripheral CB receptors are responsible for the protective and therapeutic action of cannabinoids in mouse models of colitis. Our observations provide new insight to CB pharmacology and validate the use of novel ligands AM841 and CB13 as potent tools in CB-related research.

  17. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...... significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly...

  18. Integration of family planning with poverty alleviation.

    Science.gov (United States)

    Peng, P

    1996-12-01

    The Chinese Communist Central Committee and the State Council aim to solve food and clothing problems among impoverished rural people by the year 2000. This goal was a priority on the agenda of the recent October 1996 National Conference on Poverty Alleviation and Development and the 1996 National Conference of the State Family Planning Commission. Poverty is attributed to rapid population growth and underdevelopment. Poverty is concentrated in parts of 18 large provinces. These provinces are characterized by Family Planning Minister Peng as having high birth rates, early marriage and childbearing, unplanned births, and multiple births. Overpopulation is tied to overconsumption, depletion of resources, deforestation, soil erosion, pollution, shortages of water, decreases in shares of cultivated land, degraded grasslands, and general destruction of the environment. Illiteracy in poor areas is over 20%, compared to the national average of 15%. Mortality and morbidity are higher. Family planning is harder to enforce in poor areas. Pilot programs in Sichuan and Guizhou provinces are promoting integration of family planning with poverty alleviation. Several conferences have addressed the integrated program strategies. Experience has shown that poverty alleviation occurs by controlled population growth and improved quality of life. Departments should "consolidate" their development efforts under Communist Party leadership at all levels. Approaches should emphasize self-reliance and public mobilization. The emphasis should be on women's participation in development. Women's income should be increased. Family planning networks at the grassroots level need to be strengthened simultaneously with increased poverty alleviation and development. The government strategy is to strengthen leadership, mobilize the public, and implement integrated programs.

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

    Science.gov (United States)

    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.

  20. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

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

  1. Selective agonists for serotonin 7 (5-HT7) receptor and their applications in preclinical models: an overview.

    Science.gov (United States)

    Di Pilato, Pantaleo; Niso, Mauro; Adriani, Walter; Romano, Emilia; Travaglini, Domenica; Berardi, Francesco; Colabufo, Nicola A; Perrone, Roberto; Laviola, Giovanni; Lacivita, Enza; Leopoldo, Marcello

    2014-01-01

    The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT7 receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.

  2. AGONISTIC BEHAVIOR OF LABORATORY MICE

    Directory of Open Access Journals (Sweden)

    D. Cinghiţă

    2005-01-01

    Full Text Available In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between individuals. Each member of a group has its own place on the ierarchical scale depending on resultes of fhights – it can be leader or it can be subsurvient, depending on if it wines or looses the fight. Once hierarchical scale made, every animal will adjust its behavior. After analyzing the obtained data we have enough reasons to believe that after fights the winner, usually, is the massive mouse, but it is also very important the sexual ripeness, so the immature male will be beaten. The leader male had a big exploring area and it checks up all territory.The females can be more aggressive, its fights are more brutal, than male fights are, when they fight for supremacy, but in this case fights are not as frequent as in the case of males. Always the superior female, on hierarchical scale, shows males its own statute, so the strongest genes will be perpetuated.

  3. Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-selective inverse agonists.

    Science.gov (United States)

    Martínez-Cué, Carmen; Delatour, Benoît; Potier, Marie-Claude

    2014-10-01

    Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible for cognitive deficits observed throughout their lives. A change in the excitatory/inhibitory balance in adulthood would alter synaptic plasticity, potentially triggering learning and memory deficits. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system and binds to GABAA receptors, opens a chloride channel, and reduces neuronal excitability. In this review we discuss methods to alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn mouse, using either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the α5-subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic transmission, could rescue learning and memory deficits in Ts65Dn mice. We also discuss safety issues since modulation of the excitatory-inhibitory balance to improve cognition without inducing seizures remains particularly difficult when using GABA antagonists.

  4. Alleviating soil acidity through plant organic compounds

    Directory of Open Access Journals (Sweden)

    Meda Anderson R.

    2001-01-01

    Full Text Available A laboratory experiment was conducted to evaluate the effects of water soluble plant extracts on soil acidity. The plant materials were: black oat, oil seed radish, white and blue lupin, gray and dwarf mucuna, Crotalaria spectabilis and C. breviflora, millet, pigeon pea, star grass, mato grosso grass, coffee leaves, sugar cane leaves, rice straw, and wheat straw. Plant extracts were added on soil surface in a PVC soil column at a rate of 1.0 ml min-1. Both soil and drainage water were analyzed for pH, Ca, Al, and K. Plant extracts applied on the soil surface increased soil pH, exchangeable Ca ex and Kex and decreased Al ex. Oil seed radish, black oat, and blue lupin were the best and millet the worst materials to alleviate soil acidity. Oil seed radish markedly increased Al in the drainage water. Chemical changes were associated with the concentrations of basic cations in the plant extract: the higher the concentration the greater the effects in alleviating soil acidity.

  5. Beta-agonists and animal welfare

    Science.gov (United States)

    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...

  6. Alleviating Media Bias Through Intelligent Agent Blogging

    CERN Document Server

    Diaz-Aviles, Ernesto

    2009-01-01

    Consumers of mass media must have a comprehensive, balanced and plural selection of news to get an unbiased perspective; but achieving this goal can be very challenging, laborious and time consuming. News stories development over time, its (in)consistency, and different level of coverage across the media outlets are challenges that a conscientious reader has to overcome in order to alleviate bias. In this paper we present an intelligent agent framework currently facilitating analysis of the main sources of on-line news in El Salvador. We show how prior tools of text analysis and Web 2.0 technologies can be combined with minimal manual intervention to help individuals on their rational decision process, while holding media outlets accountable for their work.

  7. Alleviate Cellular Congestion Through Opportunistic Trough Filling

    Directory of Open Access Journals (Sweden)

    Yichuan Wang

    2014-04-01

    Full Text Available The demand for cellular data service has been skyrocketing since the debut of data-intensive smart phones and touchpads. However, not all data are created equal. Many popular applications on mobile devices, such as email synchronization and social network updates, are delay tolerant. In addition, cellular load varies significantly in both large and small time scales. To alleviate network congestion and improve network performance, we present a set of opportunistic trough filling schemes that leverage the time-variation of network congestion and delay-tolerance of certain traffic in this paper. We consider average delay, deadline, and clearance time as the performance metrics. Simulation results show promising performance improvement over the standard schemes. The work shed lights on addressing the pressing issue of cellular overload.

  8. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  9. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg

    2007-01-01

    Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  10. Wakeful rest alleviates interference-based forgetting.

    Science.gov (United States)

    Mercer, Tom

    2015-01-01

    Retroactive interference (RI)--the disruptive influence of events occurring after the formation of a new memory--is one of the primary causes of forgetting. Placing individuals within an environment that postpones interference should, therefore, greatly reduce the likelihood of information being lost from memory. For example, a short period of wakeful rest should diminish interference-based forgetting. To test this hypothesis, participants took part in a foreign language learning activity and were shown English translations of 20 Icelandic words for immediate recall. Half of the participants were then given an 8-min rest before completing a similar or dissimilar interfering distractor task. The other half did not receive a rest until after the distractor task, at which point interference had already taken place. All participants were then asked to translate the Icelandic words for a second time. Results revealed that retention was significantly worse at the second recall test, but being allowed a brief rest before completing the distractor task helped reduce the amount of forgetting. Taking a short, passive break can shield new memories from RI and alleviate forgetting.

  11. An Online Alternative to Alleviate Communication Apprehension

    Directory of Open Access Journals (Sweden)

    Seyit Ahmet Çapan

    2013-05-01

    Full Text Available Anxiety is an affective factor commonly associated with one’s overall performance in a foreign language. As a component of foreign language anxiety, communication apprehension specifically correlates with successful oral production. A plethora of research (Bailey, Onwuegbuzie & Daley, 2003; Foss & Reitzel, 1988 has indicated that high levels of communication apprehension negatively affects one’s L2 communication abilities. Thus, this study intends to remedy negative effects of communication apprehension on EFL learners by virtual meetings held through computer-mediated communication. The participants (N: 18 in this study were selected through purposive sampling. The study employed both quantitative and qualitative techniques. To analyze the data collected, a non-parametric test, Wilcoxon Signed Rank Test, was utilized. The results indicated that computer-mediated communication via voice over IP tools made a significant contribution to alleviate communication apprehension levels in the participants with varying degrees of apprehension levels. The study yielded the most drastic reduction in the high apprehension group, since the participants in this group made a significant progress and ended up with moderate levels of communication apprehension. Also, the participants’ self-reports revealed that computer-mediated communication yielded remarkably positive changes in their attitudes towards communicating in the target language. Moreover, the study revealed that computer-mediated communication helped to increase their intercultural awareness. Finally, participants provided a bunch of practical suggestions as possible solutions for reducing communication apprehension. Keywords: apprehension, communication, computer-mediated, attitudes

  12. Lactobacillus plantarum CCFM639 alleviates aluminium toxicity.

    Science.gov (United States)

    Yu, Leilei; Zhai, Qixiao; Liu, Xiaoming; Wang, Gang; Zhang, Qiuxiang; Zhao, Jianxin; Narbad, Arjan; Zhang, Hao; Tian, Fengwei; Chen, Wei

    2016-02-01

    Aluminium (Al) is the most abundant metal in the earth's crust. Al exposure can cause a variety of adverse physiological effects in humans and animals. Our aim was to demonstrate that specific probiotic bacteria can play a special physiologically functional role in protection against Al toxicity in mice. Thirty strains of lactic acid bacteria (LAB) were tested for their aluminium-binding ability, aluminium tolerance, their antioxidative capacity, and their ability to survive the exposure to artificial gastrointestinal (GI) juices. Lactobacillus plantarum CCFM639 was selected for animal experiments because of its excellent performance in vitro. Forty mice were divided into four groups: control, Al only, Al plus CCFM639, and Al plus deferiprone (DFP). CCFM639 was administered at 10(9) CFU once daily for 10 days, followed by a single oral dose of aluminium chloride hexahydrate at 5.14 mg aluminium (LD50) for each mouse. The results showed that CCFM639 treatment led to a significant reduction in the mortality rates with corresponding decrease in intestinal aluminium absorption and in accumulation of aluminium in the tissues and amelioration of hepatic histopathological damage. This probiotic treatment also resulted in alleviation of hepatic, renal, and cerebral oxidative stress. The treatment of L. plantarum CCFM639 has potential as a therapeutic dietary strategy against acute aluminium toxicity.

  13. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    Anna C. Calkin

    2008-01-01

    Full Text Available 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, PPAR 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 PPAR agonists, and more recently dual PPAR/ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR 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.

  14. PPAR Agonists and Cardiovascular Disease in Diabetes

    Science.gov (United States)

    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

  15. PPAR Agonists and Cardiovascular Disease in Diabetes.

    Science.gov (United States)

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

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

  16. Dihydrocodeine / Agonists for Alcohol Dependents

    Directory of Open Access Journals (Sweden)

    Albrecht eUlmer

    2012-03-01

    Full Text Available 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 addict-ed patients, later, also Buprenorphine, Clomethiazole (>6 weeks, Baclofen and in one case Amphetamine, each on individual indication. This paper focuses on the data with DH, 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-step 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.Conclusions: 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 ¼ of the patients already. Many further

  17. Agent Reward Shaping for Alleviating Traffic Congestion

    Science.gov (United States)

    Tumer, Kagan; Agogino, Adrian

    2006-01-01

    Traffic congestion problems provide a unique environment to study how multi-agent systems promote desired system level behavior. What is particularly interesting in this class of problems is that no individual action is intrinsically "bad" for the system but that combinations of actions among agents lead to undesirable outcomes, As a consequence, agents need to learn how to coordinate their actions with those of other agents, rather than learn a particular set of "good" actions. This problem is ubiquitous in various traffic problems, including selecting departure times for commuters, routes for airlines, and paths for data routers. In this paper we present a multi-agent approach to two traffic problems, where far each driver, an agent selects the most suitable action using reinforcement learning. The agent rewards are based on concepts from collectives and aim to provide the agents with rewards that are both easy to learn and that if learned, lead to good system level behavior. In the first problem, we study how agents learn the best departure times of drivers in a daily commuting environment and how following those departure times alleviates congestion. In the second problem, we study how agents learn to select desirable routes to improve traffic flow and minimize delays for. all drivers.. In both sets of experiments,. agents using collective-based rewards produced near optimal performance (93-96% of optimal) whereas agents using system rewards (63-68%) barely outperformed random action selection (62-64%) and agents using local rewards (48-72%) performed worse than random in some instances.

  18. Arctigenin alleviates ER stress via activating AMPK

    Institute of Scientific and Technical Information of China (English)

    Yuan GU; Xiao-xiao SUN; Ji-ming YE; Li HE; Shou-sheng YAN; Hao-hao ZHANG; Li-hong HU; Jun-ying YUAN; Qiang YU

    2012-01-01

    Aim:To investigate the protective effects of arctigenin (ATG),a phenylpropanoid dibenzylbutyrolactone lignan from Arctium lappa L (Compositae),against ER stress in vitro and the underlying mechanisms.Methods:A cell-based screening assay for ER stress regulators was established.Cell viability was measured using MTT assay.PCR and Western blotting were used to analyze gene and protein expression.Silencing of the CaMKKβ,LKB1,and AMPKα1 genes was achieved by RNA interference (RNAi).An ATP bioluminescent assay kit was employed to measure the intracellular ATP levels.Results:ATG (2.5,5,and 10 μmol/L) inhibited cell death and unfolded protein response (UPR) in a concentration-dependent manner in cells treated with the ER stress inducer brefeldin A (100 nmol/L).ATG (1,5,and 10 μmol/L) significantly attenuated protein synthesis in cells through inhibiting mTOR-p7OS6K signaling and eEF2 activity,which were partially reversed by silencing AMPKα1 with RNAi.ATG (1-50 μmol/L) reduced intracellular ATP level and activated AMPK through inhibiting complex I-mediated respiration.Pretreatment of cells with the AMPK inhibitor compound C (25 μmol/L) rescued the inhibitory effects of ATG on ER stress.Furthermore,ATG (2.5 and 5μmol/L) efficiently activated AMPK and reduced the ER stress and cell death induced by palmitate (2 mmol/L) in INS-1 β cells.Conclusion:ATG is an effective ER stress alleviator,which protects cells against ER stress through activating AMPK,thus attenuating protein translation and reducing ER load.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Tomer Israely

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

  1. The World Shares Chinese Experience of Poverty Alleviation

    Institute of Scientific and Technical Information of China (English)

    Wang Rengui

    2015-01-01

    As the 2nd China Poverty Alleviation Day and the 23rd International Day for the Eradication of Poverty is approaching,Chinese President Xi Jinping delivered a keynote speech at the 2015 Global Poverty Reduction and Development Forum in Beijing on October 16th and elaborated Chinese Government’s resolute measures on comprehensively promoting poverty alleviation campaign in the process of building a moderately prosperous society in an all suspects,showing China’s

  2. EFFECTS OF SILICON ON ALLEVIATING ARSENIC TOXICITY IN MAIZE PLANTS

    OpenAIRE

    Airon José da Silva; Clístenes Williams Nascimento; Artur da Silva Gouveia Neto; Elias Arcanjo Silva Junior

    2015-01-01

    Arsenic is a metalloid highly toxic to plants and animals, causing reduced plant growth and various health problems for humans and animals. Silicon, however, has excelled in alleviating stress caused by toxic elements in plants. The aim of this study was to investigate the effects of Si in alleviating As stress in maize plants grown in a nutrient solution and evaluate the potential of the spectral emission parameters and the red fluorescence (Fr) and far-red fluorescence (FFr) ratio obtained ...

  3. Entrepreneurship Development and Poverty Alleviation: An Empirical Review

    OpenAIRE

    Mohammad Delwar Hussain; Rosni Bakar; Abul Bashar Bhuiyan

    2014-01-01

    The main purpose of this paper is to corroborate the relationship between entrepreneurship development and poverty alleviation constructed on empirical reviews. In this study, we conducted general search to accumulate empirical literatures by the name of entrepreneurship development and poverty alleviation in different online database sources such as Google Scholars, Springer Link, Wiley, Science Direct, JSTOR, Emerald full text, Scopus, and EBSCO HOST etc. We found innovation, entrepreneursh...

  4. Muscimol as an ionotropic GABA receptor agonist.

    Science.gov (United States)

    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.

  5. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim

    2016-01-01

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

  6. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  7. Exploring prospects of β3-adrenoceptor agonists and inverse agonists for colon mobility control

    Directory of Open Access Journals (Sweden)

    Maria Grazia Perrone

    2013-07-01

    Full Text Available Inverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with non-endogenous agonist induced activity (constitutive or basal activity. SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor inverse agonists [EC50=181 nM (IA=- 64% and 136 nM (IA=-73%, respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89 and 8.16, respectively. The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h and inverse agonists (SP-1e and SP-1g on rat proximal colon motility and a confirmation of their inverse agonist nature in a more complex system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and pA2 of inverse agonists were determined. SP- 1a-d, SP-1f and SP-1h in rat colon have a muscle relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, respectively. In conclusion, experiments carried out by using isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility.

  8. Research Progress of Tourism-oriented Poverty Alleviation in China

    Institute of Scientific and Technical Information of China (English)

    Guoqing; HUANG; Pengfei; XIE

    2013-01-01

    Through systematic summary of domestic research documents about China’s tourism-oriented poverty alleviation in recent 10 years,it is found that researches mainly focus on 5 aspects:effect of tourism-oriented poverty alleviation,model and development strategy,benefit of poverty stricken people,practice of tourism-oriented poverty alleviation in specific region,and other related problems.At present,academic circle mainly has weak points of research content,method,object and region in tourism-oriented poverty alleviation.Finally,it points out key research interests:(1)Strengthening combination of qualitative and quantitative researches;(2)Expanding research fields and scope and promoting in-depth researches;(3)Analyzing benefiting mechanism of poverty-stricken people participating in tourism development in depth with poverty-stricken people as research objects;(4)Increasing scale development of perception research on effect of tourism-oriented poverty alleviation and research on measurement testing,to make subsequent research have reliability and comparability.

  9. [Effective prevention of indomethacin-induced gastroduodenal mucosal lesions with roxatidine acetate].

    Science.gov (United States)

    Dammann, H G; Wolf, N; Burkhardt, F

    1995-08-01

    In this randomized single-blind cross-over study the gastroduodenal damaging effect of indometacin 75 mg bid alone and in combination with roxatidine acetate (CAS 78628-28-1, Roxit) 75 mg nocte or 75 mg bid was evaluated in 12 healthy male volunteers. Prior to the start of the three therapeutic periods subjects underwent endoscopic examination to exclude gastroduodenal mucosa lesions. On days 7 and 14 of therapy 2 h after the application of the last indometacin dose subjects underwent endoscopy again. The 7- and 14-days administration of indometacin 75 mg bid, indometacin 75 mg bid plus roxatidine 75 mg nocte and indometacin 75 mg bid plus roxatidine 75 mg bid led to gastroduodenal mucosa lesion scores of 1.67 +/- 0.40 and 2.00 +/- 0.35, 1.33 +/- 0.28 and 1.50 +/- 0.29, 0.42 +/- 0.23 and 1.00 +/- 0.33 (mean +/- SEM), respectively. These differences were statistically significant when comparing indometacin 75 mg bid versus indometacin 75 mg bid plus roxatidine 75 mg bid (p roxatidine acetate represents an effective alternative in the prophylaxis of NSAID-induced gastroduodenal mucosa lesions.

  10. CT measurement of indomethacin-induced cerebral hemodynamic changes in the newborn piglet

    Science.gov (United States)

    Brown, Derek W.; Hadway, Jennifer; Lee, Ting-Yim

    2003-05-01

    Patent ductus arteriosus (PDA), a common condition among preterm infants, increases the risk of intraventricular hemorrhage, bronchopulmonary dysplasia, and death in afflicted individuals. Current clinical treatment of PDA relies on use of the drug indomethacin to close the ductus arteriosus. In the present study, we have investigated the effect of indomethacin on cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral mean transit time (MTT) in newborn piglets using computed tomography (CT) perfusion. Twenty newborn piglets divided by age into two groups, less than 12 hours of age (n = 10) and greater than 12 hours of age (n = 10) were studied. Five piglets in each group received indomethacin treatment (0.2 mg/kg infused over 30 min) while remaining piglets served as controls. No significant changes in CBF were observed in control groups. In both indomethacin treated groups, average CBF decreased 32.3% and 34.3% (P > 0.05) below baseline immediately post infusion in piglets less than and greater than 12 hours of age respectively. Piglets less than 12hours of age treated with indomethacin also exhibited a delayed increase in CBF, maximum average increase of 41.7% (P > 0.05) above baseline at 210 min post infusion, a response not observed in the corresponding group of piglets greater than 12 hours of age. The observed age dependent response may be due to functional/anatomical closure of the PDA.

  11. Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats

    Institute of Scientific and Technical Information of China (English)

    Xin Zhang; Koyuki Tajima; Kiyoto Kageyama; Takashi Kyoi

    2008-01-01

    AIM: To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats.METHODS: Gastric mucosal injury was induced in male Hos:Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg.One hour before indomethacin treatment,animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg,3 mg/kg or 10 mg/kg.Four hours after indomethacin administration,the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-α (TNF-α),interleukin-1β(IL-1β),IL-8 and myeloperoxidase (MPO) in mucosal tissues.RESULTS: Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin.Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dosedependent manner.The mucosal concentrations of proinflammatory cytokines (TNF-β,IL-1β,and IL-8)and MPO,which indicates the degree of mucosal infiltration by neutrophils,increased concomitantly with the occurrence of gastric injury in the indomethacintreated rats.Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin.CONCLUSION: The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration,leading to suppression of mucosal inflammation and subsequent tissue destruction.

  12. Anti-ulcerogenic mechanism of magnesium in indomethacin induced gastric ulcer in rats.

    Science.gov (United States)

    Adewoye, E O; Salami, A T

    2013-12-20

    The gastric mucosa is continuously exposed to various agents like food condiments, spices, alcohol, acids and drugs, some of which are implicated in the pathogenesis of gastric ulcer. Magnesium compounds commonly used as laxatives and antacids have been reported to prevent ulcer formation but the mechanisms underlying this potential is unknown. This study therefore seeks to evaluate the gastro-protective mechanism of magnesium in the stomach through its effect on the parietal and mucus cells. Thirty-six male albino rats divided into 6 groups of 6 rats each were used. Group 1 was control, Group 2 was ulcer induced and untreated, Group 3 was treated with 500mg/kg b.w magnesium alone, Group 4 was pre-treated with 500mg/kg b.w magnesium before inducing ulcer, Group 5 was pre-treated with 500mg/kg b.w magnesium and 20mg/kg omeprazole 4 hours before inducing ulcer, Group 6 was treated with 20mg/kg omeprazole 4 hours before inducing ulcer. Animals were sacrificed 6 hours after ulcer induction and their stomachs were removed for ulcer scoring and histological analysis. A significant reduction was observed in the ulcer scoring of magnesium pre-treated ulcerated rats (9.4±0.8) compared with ulcerated untreated (20.8±0.9) groups. Parietal cell count of magnesium pre treated ulcerated group significantly decreased (169.7±18.9) compared with ulcerated untreated group (310.5±34.7). Mucous cell count of magnesium pre-treated ulcerated group (264.6±8.3) significantly increased compared with ulcerated untreated group (170.0±17.7). This study shows that magnesium possesses anti-ulcerogenic properties due to its ability to reduce the number of parietal cell and increase mucous cell counts.

  13. Multiple indomethacin-induced jejunal ulcerations with perforation: a case report with histology.

    Science.gov (United States)

    Risty, Gina M; Najarian, Melissa M; Shapiro, Stephen B

    2007-04-01

    Gastric and duodenal inflammation and ulceration are well-known complications of nonsteroidal anti-inflammatory (NSAID) usage. However, small bowel ulceration and perforation secondary to NSAID use is uncommon and has rarely been reported in the literature. We describe a perforated jejunal ulcer that developed in a patient using indomethacin for treatment of ankylosing spondylitis. We performed a literature review of NSAID-induced small bowel injury and compared the histology of NSAID-related injury with more familiar causes of small bowel perforation.

  14. Anti-plasticizing effect of amorphous indomethacin induced by specific intermolecular interactions with PVA copolymer.

    Science.gov (United States)

    Ueda, Hiroshi; Aikawa, Shohei; Kashima, Yousuke; Kikuchi, Junko; Ida, Yasuo; Tanino, Tadatsugu; Kadota, Kazunori; Tozuka, Yuichi

    2014-09-01

    The mechanism of how poly(vinyl alcohol-co-acrylic acid-co-methyl methacrylate) (PVA copolymer) stabilizes an amorphous drug was investigated. Solid dispersions of PVA copolymer, poly(vinyl pyrrolidone) (PVP), and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA) with indomethacin (IMC) were prepared. The glass transition temperature (Tg)-proportion profiles were evaluated by differential scanning calorimetry (DSC). General Tg profiles decreasing with the IMC ratio were observed for IMC-PVP and IMC-PVPVA samples. An interesting antiplasticizing effect of IMC on PVA copolymer was observed; Tg increased up to 20% IMC ratio. Further addition of IMC caused moderate reduction with positive deviation from theoretical values. Specific hydrophilic and hydrophobic interactions between IMC and PVA copolymer were revealed by infrared spectra. The indole amide of IMC played an important role in hydrogen bonding with PVA copolymer, but not with PVP and PVPVA. X-ray diffraction findings and the endotherm on DSC profiles suggested that PVA copolymer could form a semicrystalline structure and a possibility of correlation of the crystallographic nature with its low hygroscopicity was suggested. PVA copolymer was able to prevent crystallization of amorphous IMC through both low hygroscopicity and the formation of a specific intermolecular interaction compared with that with PVP and PVPVA.

  15. Protective effect of Cupressus sempervirens extract against indomethacin-induced gastric ulcer in rats

    Directory of Open Access Journals (Sweden)

    Koriem Khaled M. M.

    2015-03-01

    Full Text Available Cupressus sempervirens (C. sempervirens belongs to the family Cupressaceae. It is widspread in Northern Africa, Greece, Turkey, North America, Cyprus and Syria. Cupressuflavone is the major ingredient of the plant leave extract. The aim of the present study was to evaluate the antiulcerogenic activity of the extract of C. sempervirens leaves in gastric ulcer tissues induced by indomethacin. The results of the present study revealed that indomethacin significantly decreased glutathione S-transferase (GST, glutathione peroxidase (GPx, catalase (CAT, reduced glutathione (GSH, glutathione reductase (GR and superoxide dismutase (SOD levels, while it increased significantly lipid peroxidation (MDA, nitric oxide (NO and protein carbonyl (PC levels in gastric tissue. Furthermore, indomethacin decreased p53 expression, while it increased bcl-2 expression in gastric tissue. Pretreatment with 5%, 10% & 20% of the LD50 of C. sempervirens and cupressuflavone of indomethacin-treated rats restored all the above parameters to approach normal values. C. sempervirens at the highest dose was more effective than the two lower doses. C. sempervirens proved more potent than cupressuflavone. In conclusion, C. sempervirens exerted antiulcerogenic activity and the effect was dose-dependent and related to the cupressuflavone ingredient of the plant leave extract.

  16. Protective effect of Cupressus sempervirens extract against indomethacin-induced gastric ulcer in rats.

    Science.gov (United States)

    Koriem, Khaled M M; Gad, Islam B; Nasiry, Zayenab K

    2015-03-01

    Cupressus sempervirens (C. sempervirens) belongs to the family Cupressaceae. It is widspread in Northern Africa, Greece, Turkey, North America, Cyprus and Syria. Cupressuflavone is the major ingredient of the plant leave extract. The aim of the present study was to evaluate the antiulcerogenic activity of the extract of C. sempervirens leaves in gastric ulcer tissues induced by indomethacin. The results of the present study revealed that indomethacin significantly decreased glutathione S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR) and superoxide dismutase (SOD) levels, while it increased significantly lipid peroxidation (MDA), nitric oxide (NO) and protein carbonyl (PC) levels in gastric tissue. Furthermore, indomethacin decreased p53 expression, while it increased bcl-2 expression in gastric tissue. Pretreatment with 5%, 10% & 20% of the LD50 of C. sempervirens and cupressuflavone of indomethacin-treated rats restored all the above parameters to approach normal values. C. sempervirens at the highest dose was more effective than the two lower doses. C. sempervirens proved more potent than cupressuflavone. In conclusion, C. sempervirens exerted antiulcerogenic activity and the effect was dose-dependent and related to the cupressuflavone ingredient of the plant leave extract.

  17. Sensor comparison study for load alleviating wind turbine pitch control

    DEFF Research Database (Denmark)

    Kragh, Knud Abildgaard; Hansen, Morten Hartvig; Henriksen, Lars Christian

    2014-01-01

    measurement types yield similar load reductions, but for varying inflow conditions, the LiDAR sensor-based controller yields larger load reductions than the two others. The results also show that the performance of the LiDAR sensor-based controller is very sensitive to uncertainties relating to the inflow......As the size of wind turbines increases, the load alleviating capabilities of the turbine controller are becoming increasingly important. Load alleviating control schemes have traditionally been based on feedback from load sensor; however, recent developments of measurement technologies have enabled...... root loads. In many existing studies, the performance of an advanced controller is compared with the performance of a simpler controller. In this study, the effect of three measurement types on the load alleviating performance of the same cyclic pitch control design is studied. By using a baseline...

  18. Dynamic decoupling nonlinear control method for aircraft gust alleviation

    Science.gov (United States)

    Lv, Yang; Wan, Xiaopeng; Li, Aijun

    2008-10-01

    A dynamic decoupling nonlinear control method for MIMO system is presented in this paper. The dynamic inversion method is used to decouple the multivariable system. The nonlinear control method is used to overcome the poor decoupling effect when the system model is inaccurate. The nonlinear control method has correcting function and is expressed in analytic form, it is easy to adjust the parameters of the controller and optimize the design of the control system. The method is used to design vertical transition mode of active control aircraft for gust alleviation. Simulation results show that the designed vertical transition mode improves the gust alleviation effect about 34% comparing with the normal aircraft.

  19. Poverty alleviation committee considers population among major issues.

    Science.gov (United States)

    1998-01-01

    This article presents a meeting of the Committee on Socioeconomic Measures in Poverty Alleviation, whose main purpose is to review and analyze global and regional trends and developments concerning poverty and to recommend policy options and program strategies to improve the situation. The Committee urged the Economic and Social Commission for Asia and the Pacific (ESCAP) secretariat to play a catalytic role in formulating approaches to the alleviation of poverty by conducting research, collecting information, providing training, organizing workshops, and maintaining professional and institutional networks. They also encouraged ESCAP to continue helping countries formulate and implement their population and development programs, including those related to reproductive health.

  20. Expression profiling in APP23 mouse brain: inhibition of Aβ amyloidosis and inflammation in response to LXR agonist treatment

    Directory of Open Access Journals (Sweden)

    Mangelsdorf David

    2007-10-01

    Full Text Available Abstract Background Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver X Receptor agonist T0901317 (T0 to APP transgenic and non-transgenic mice decreases the level of Aβ42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. In this study we applied T0 to APP23 mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from wild type and LXR knockout mice subjected to various LXR agonist treatments and inflammatory stimuli. Results We demonstrate an upregulation of genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Downregulated genes are involved in immune response and inflammation, cell death and apoptosis. Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Aβ. In primary LXRwt but not in LXRα-/-β-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Aβ. Conclusion The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of Aβ aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.

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

    Science.gov (United States)

    Bishop, Michael J

    2007-01-01

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

  2. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  3. Agonistic and reproductive interactions in Betta splendens.

    Science.gov (United States)

    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.

  4. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose

    Science.gov (United States)

    Seeman, P

    2016-01-01

    Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects. PMID:27754480

  5. Signal Use by Octopuses in Agonistic Interactions.

    Science.gov (United States)

    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.

  6. A congestion alleviated scheme in optical burst switching network

    Institute of Scientific and Technical Information of China (English)

    Gang Wang; Hongxiang Wang; Yuefeng Ji

    2008-01-01

    An optical burst switching (OBS) network platform is established with a ring topology of three nodes. A congestion alleviated scheme using advanced token protocol and wavelength tunable receivers is demonstrated to optimize the network platform. Experimental results testify that this scheme can resist collision at the level of 0.1% congestion rate.

  7. Training Teachers as Key Players in Poverty Alleviation

    Science.gov (United States)

    Benavente, Ana; Ralambomanana, Stangeline; Mbanze, Jorge

    2008-01-01

    This article presents several questions, reflections and suggestions on pre-service and in-service teacher training that arose during the project "Curricular innovation and poverty alleviation in sub-Saharan Africa". While recognizing that the situation in the nine countries taking part in the project, and in many other countries in the southern…

  8. The Role of NGOsin Poverty Alleviation in China

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    正Editor's Note: CAFIU's Secretary-General Ni Jian took part in the UN Sustainable Development Conference (Rio+20) held in Rio de Janeiro, Brazil from June 16 to 21. During the Conference, he also attended and addressed a side meeting of "Poverty-Alleviation and Sustainable Development: Chinese NGOs in Action" hosted by China NGO Network for International Exchanges.

  9. Helping Alleviate Statistical Anxiety with Computer Aided Statistical Classes

    Science.gov (United States)

    Stickels, John W.; Dobbs, Rhonda R.

    2007-01-01

    This study, Helping Alleviate Statistical Anxiety with Computer Aided Statistics Classes, investigated whether undergraduate students' anxiety about statistics changed when statistics is taught using computers compared to the traditional method. Two groups of students were questioned concerning their anxiety about statistics. One group was taught…

  10. Ganokendra: An Innovative Model for Poverty Alleviation in Bangladesh

    Science.gov (United States)

    Alam, Kazi Rafiqul

    2006-01-01

    Ganokendras (people's learning centers) employ a literacy-based approach to alleviating poverty in Bangladesh. They give special attention to empowering rural women, among whom poverty is widespread. The present study reviews the Ganokendra-approach to facilitating increased political and economic awareness and improving community conditions in…

  11. Alleviation Effects of Rare Earth on Cd Stress to Rape

    Institute of Scientific and Technical Information of China (English)

    马建军; 张淑侠; 朱京涛; 吴贺平

    2004-01-01

    Using rapes as test materials, the fastness expression and alleviation effect of rapes were studied under Cd stress condition, as the rapeseeds were dipped in the single element(La, Ce, Nd, Pr)and mixed rare earth(RE). The results indicate that, under Cd stress, the dry and fresh weight are increased by both the single element and mixed rare earth treatment, and the fastness of rape is improved.The single element of rare earth decreases the Cd content in rape roots and transmits Cd to the edible parts above the ground in which the alleviation effect of Ce is most significant.La treatment takes the second place, so that the poisonous effect of heavy metal Cd is eased.The mixed rare earth doesn't alleviate the assimilation of Cd in rape roots, but accelerates the transfer of Cd to the parts above the ground. The research puts forward that the alleviation of rare earth on Cd stress has connection with the decrease of Ca content.

  12. Urban agriculture and urban poverty alleviation: South African debates

    OpenAIRE

    Christian M. Rogerson

    1998-01-01

    Growing international attention has focussed on the potential role of urban agriculture in poverty alleviation. The aim in this paper is to analyse the existing challenge of urban poverty in South Africa and examine the potential role of urban agriculture as a component of a pro-poor urban development strategy.

  13. Anti-hyperalgesic effects of a novel TRPM8 agonist in neuropathic rats: a comparison with topical menthol.

    Science.gov (United States)

    Patel, Ryan; Gonçalves, Leonor; Leveridge, Mathew; Mack, Stephen R; Hendrick, Alan; Brice, Nicola L; Dickenson, Anthony H

    2014-10-01

    Menthol has historically been used topically to alleviate various pain conditions. At low concentrations, this non-selective TRPM8 agonist elicits a cooling sensation, however higher concentrations result in cold hyperalgesia in normal subjects and paradoxically analgesia in neuropathic patients. Through behavioural and electrophysiological means, we examined whether this back-translated into a pre-clinical rodent model. Menthol was applied topically to the hind paws of naive and spinal nerve-ligated (SNL) rats. In behavioural assays, menthol did not affect withdrawal thresholds to mechanical stimulation and 10% and 40% menthol rarely sensitised withdrawals to innocuous cooling in naïve rats. However, in SNL rats, 10% and 40% menthol alleviated cold hypersensitivity. This was partly corroborated by in vivo electrophysiological recordings of dorsal horn lamina V/VI neurones. As several studies have implicated TRPM8 in analgesia, we examined whether a novel systemically available TRPM8 agonist, M8-Ag, had more potent anti-hyperalgesic effects than menthol in neuropathic rats. In vitro, M8-Ag activates TRPM8, expressed in HEK293 cells, with an EC50 of 44.97 nM. In vivo, M8-Ag inhibited neuronal responses to innocuous and noxious cooling in SNL rats with no effect in sham-operated rats. This effect was modality selective; M8-Ag did not alter neuronal responses to mechanical, heat or brush stimulation. In addition, M8-Ag attenuated behavioural hypersensitivity to innocuous cooling but not mechanical stimulation. These data suggest that menthol induced hyperalgesia is not consistently replicable in the rat and that the analgesic properties are revealed by injury. Systemic TRPM8 agonists might be beneficial in neuropathy without affecting normal cold sensitivity.

  14. Agonist trigger: what is the best approach? Agonist trigger and low dose hCG

    DEFF Research Database (Denmark)

    Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2012-01-01

    Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)......Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)...

  15. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

  16. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose...... potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale...

  17. SNC 80 and related delta opioid agonists.

    Science.gov (United States)

    Calderon, S N; Coop, A

    2004-01-01

    The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, was a major advance in the field of delta-opioid ligands. Much research has been performed to uncover the structure-activity relationships (SAR) of this class of ligands and also to compare the diarylmethylpiperazines with the traditional morphinan-based delta opioids. This review focuses on the development of the SAR of this unique series of ligands, and discusses questions which remain unanswered.

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

    Science.gov (United States)

    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.

  19. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    OpenAIRE

    Maharjan Anu S; Pilling Darrell; Gomer Richard H

    2010-01-01

    Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fi...

  20. The Role of Forests in Poverty Alleviation: Dealing with Multiple Millennium Development Goals

    NARCIS (Netherlands)

    Wiersum, K.F.; Ros-Tonen, Mirjam A.F.

    2005-01-01

    This policy brief summarises the present state of scientific understanding of the potential contribution of tropical forests to poverty alleviation and highlights the implications of this knowledge for forest-based poverty alleviation policies

  1. FISHERMEN ALLEVIATION POVERTY MODEL IN THE NORTH COASTAL EAST JAVA

    Directory of Open Access Journals (Sweden)

    Roziana Ainul Hidayati

    2011-12-01

    Full Text Available Poverty is a multidimensional problem that the approach to eradicate poverty must also be multidimensional. The study aims to formulate a model of poverty alleviation in coastal fishing in the North Coast of East Java. Grounded research approach used to determine the causes, impacts and implications of poverty fishermen. The results showed that the main cause of poverty that occurred in the three districts in East Java's north coast is different from one another. In Gresik district, the major cause of poverty is law enforcements that do not support fishermen and overfishing. While Lamongan more due to low fish prices and capital problems. While in Tuban fishermen due to limited infrastructure and lazy and extravagant lifestyle of the fishermen. These differences lead to different coping strategies so that later can form a concept model of poverty alleviation North Coast fishermen in East Java.

  2. Alleviating alpha quenching by solar wind and meridional flow

    CERN Document Server

    Mitra, Dhrubaditya; Tavakol, Reza; Brandenburg, Axel

    2010-01-01

    We study the ability of magnetic helicity expulsion to alleviate catastrophic $\\alpha$-quenching in mean field dynamos in two--dimensional spherical wedge domains. Motivated by the physical state of the outer regions of the Sun, we consider $\\alpha^2\\Omega$ mean field models with a dynamical $\\alpha$ quenching. We include two mechanisms which have the potential to facilitate helicity expulsion, namely advection by a mean flow (``solar wind'') and meridional circulation. We find that a wind alone can prevent catastrophic quenching, with the field saturating at finite amplitude. In certain parameter ranges, the presence of a large-scale meridional circulation can reinforce this alleviation. However, the saturated field strengths are typically below the equipartition field strength. We discuss possible mechanisms that might increase the saturated field.

  3. Alleviating α quenching by solar wind and meridional flows

    Science.gov (United States)

    Mitra, D.; Moss, D.; Tavakol, R.; Brandenburg, A.

    2011-02-01

    Aims: We study the ability of magnetic helicity expulsion to alleviate catastrophic α-quenching in mean field dynamos in two-dimensional spherical wedge domains. Methods: Motivated by the physical state of the outer regions of the Sun, we consider α^2Ω mean field models with a dynamical α quenching. We include two mechanisms which have the potential to facilitate helicity expulsion, namely advection by a mean flow ("solar wind") and meridional circulation. Results: We find that a wind alone can prevent catastrophic quenching, with the field saturating at finite amplitude. In certain parameter ranges, the presence of a large-scale meridional circulation can reinforce this alleviation. However, the saturated field strengths are typically below the equipartition field strength. We discuss possible mechanisms that might increase the saturated field.

  4. Focused grooming networks and stress alleviation in wild female baboons.

    Science.gov (United States)

    Wittig, Roman M; Crockford, Catherine; Lehmann, Julia; Whitten, Patricia L; Seyfarth, Robert M; Cheney, Dorothy L

    2008-06-01

    We examine the relationship between glucocorticoid (GC) levels and grooming behavior in wild female baboons during a period of instability in the alpha male rank position. All females' GC levels rose significantly at the onset of the unstable period, though levels in females who were at lower risk of infanticide began to decrease sooner in the following weeks. Three factors suggest that females relied on a focused grooming network as a coping mechanism to alleviate stress. First, all females' grooming networks became less diverse in the weeks following the initial upheaval. Second, females whose grooming had already focused on a few predictable partners showed a less dramatic rise in GC levels than females whose grooming network had been more diverse. Third, females who contracted their grooming network the most experienced a greater decrease in GC levels in the following week. We conclude that close bonds with a few preferred partners allow female baboons to alleviate the stress associated with social instability.

  5. Islamic Microfinance: an Interest free Microfinance Model for Poverty Alleviation

    Directory of Open Access Journals (Sweden)

    Amit Kumar Chakrabarty

    2015-01-01

    Full Text Available This theoretical paper deals with Islamic microfinance and its rationality in Indian context as a panacea of Muslim poverty. Conventional microfinance system is very effective to alleviate poverty of developing countries. But it could not touch all community of people because of ‘interest’ component in debt and high degree of interest. Muslims dislike that microfinance which is based on ‘interest’ as it is strictly prohibited in Islam. Therefore the motto of financial inclusion is out of reach through conventional microfinance. An alternative interest free microfinance model has been developed in some part of world to include all Muslim poor people within the banking system. India is yet to adopt Islamic microfinance though 20% of total population is Muslim. The author strongly opines that India should adopt Islamic microfinance as a tool for poverty alleviation of Muslims as well as other communities.

  6. FISHERMEN ALLEVIATION POVERTY MODEL IN THE NORTH COASTAL EAST JAVA

    OpenAIRE

    Roziana Ainul Hidayati; Mu'minatus Sholichah

    2011-01-01

    Poverty is a multidimensional problem that the approach to eradicate poverty must also be multidimensional. The study aims to formulate a model of poverty alleviation in coastal fishing in the North Coast of East Java. Grounded research approach used to determine the causes, impacts and implications of poverty fishermen. The results showed that the main cause of poverty that occurred in the three districts in East Java's north coast is different from one another. In Gresik district, the major...

  7. Non-farm wages and poverty alleviation in developing countries

    OpenAIRE

    Jatta, Sylvester

    2013-01-01

    Abstract This paper is about rural non-farm income and poverty alleviation in sub-Saharan Africa and the determinants of differentials access to rural non-farm incomes, with an overview of trends in the magnitude, and location of rural poverty. It also offers evidence that advances our understanding of rural poverty, by presenting quantitative analysis of the determinants of rural income from farm and non-farm sources, drawing on data from Rural Income Generating Activities data b...

  8. Staircase effect alleviation based on multiscale analysis of Laplacian Pyramid

    Science.gov (United States)

    Chen, Wenjie; Ye, Yutang; Huang, Yonglin

    2012-01-01

    Image denoising with second order partial differential equations (PDEs) often leads to undesirable staircase effect, namely, the transformation of smooth regions into piecewise constant regions. In this paper, staircase effect is analyzed in spatial frequency domain which is different from previous studies. A method of nonlinear diffusion based on Laplacian Pyramid is proposed. The experimental results show that the proposed method alleviates the staircase effect and leads to more natural restored images.

  9. Application of Active Flow Control Technique for Gust Load Alleviation

    Institute of Scientific and Technical Information of China (English)

    XU Xiaoping; ZHU Xiaoping; ZHOU Zhou; FAN Ruijun

    2011-01-01

    A new gust load alleviation technique is presented in this paper based on active flow control.Numerical studies are conducted to investigate the beneficial effects on the aerodynamic characteristics of the quasi “Global Hawk” airfoil using arrays of jets during the gust process.Based on unsteady Navier-Stokes equations,the grid-velocity method is introduced to simulate the gust influence,and dynamic response in vertical gust flow perturbation is investigated for the airfoil as well.An unsteady surface transpiration boundary condition is enforced over a user specified portion of the airfoil's surface to emulate the time dependent velocity boundary conditions.Firstly,after applying this method to simulate typical NACA0006 airfoil gust response to a step change in the angle of attack,it shows that the indicial responses of the airfoil make good agreement with the exact theoretical values and the calculated values in references.Furthermore,gust response characteristic for the quasi “Global Hawk” airfoil is analyzed.Five kinds of flow control techniques are introduced as steady blowing,steady suction,unsteady blowing,unsteady suction and synthetic jets.The physical analysis of the influence on the effects of gust load alleviation is proposed to provide some guidelines for practice.Numerical results have indicated that active flow control technique,as a new technology of gust load alleviation,can affect and suppress the fluid disturbances caused by gust so as to achieve the purpose of gust load alleviation.

  10. EFFECTS OF SILICON ON ALLEVIATING ARSENIC TOXICITY IN MAIZE PLANTS

    Directory of Open Access Journals (Sweden)

    Airon José da Silva

    2015-02-01

    Full Text Available Arsenic is a metalloid highly toxic to plants and animals, causing reduced plant growth and various health problems for humans and animals. Silicon, however, has excelled in alleviating stress caused by toxic elements in plants. The aim of this study was to investigate the effects of Si in alleviating As stress in maize plants grown in a nutrient solution and evaluate the potential of the spectral emission parameters and the red fluorescence (Fr and far-red fluorescence (FFr ratio obtained in analysis of chlorophyll fluorescence in determination of this interaction. An experiment was carried out in a nutrient solution containing a toxic rate of As (68 μmol L-1 and six increasing rates of Si (0, 0.25, 0.5, 1.0, 1.5, and 2.0 mmol L-1. Dry matter production and concentrations of As, Si, and photosynthetic pigments were then evaluated. Chlorophyll fluorescence was also measured throughout plant growth. Si has positive effects in alleviating As stress in maize plants, evidenced by the increase in photosynthetic pigments. Silicon application resulted in higher As levels in plant tissue; therefore, using Si for soil phytoremediation may be a promising choice. Chlorophyll fluorescence analysis proved to be a sensitive tool, and it can be successfully used in the study of the ameliorating effects of Si in plant protection, with the Fr/FFr ratio as the variable recommended for identification of temporal changes in plants.

  11. B vitamins alleviate indices of neuropathic pain in diabetic rats.

    Science.gov (United States)

    Jolivalt, Corinne G; Mizisin, Leah M; Nelson, Austin; Cunha, Joice M; Ramos, Khara M; Bonke, Dieter; Calcutt, Nigel A

    2009-06-10

    There are sporadic reports that assorted combinations of B vitamins can alleviate pain in diabetic patients, but there is neither agreement on the relative efficacy of individual B vitamins nor understanding of the mechanisms involved. We therefore investigated the efficacy of a cocktail of the vitamins B1, B6 and B12 in alleviating behavioral indices of sensory dysfunction such as allodynia and hyperalgesia in diabetic rats and also the relative contribution of individual components of the cocktail. Repeated daily treatment with the cocktail of B vitamins for 7-9 days ameliorated tactile allodynia and formalin-evoked hyperalgesia in a dose-dependent manner and also improved sensory nerve conduction velocity in diabetic rats. Investigation of the contribution of individual B vitamins suggested that all three participated with variable efficacy in the alleviation of allodynia after protracted, but not single dose treatment. Only vitamin B6 improved sensory nerve conduction velocity slowing in diabetic rats when given alone. To address potential mechanisms of action, we measured markers of oxidative stress (lipid and protein oxidation) and inflammation (cyclooxygenase-2 (COX-2) and TNFalpha protein) in the nerve but treatment with the vitamin B cocktail did not significantly affect any of these parameters. The positive effects of B vitamins on functional and behavioral disorders of diabetic rats suggest a potential for use in treating painful diabetic neuropathy.

  12. Poverty alleviation programmes in India: a social audit.

    Science.gov (United States)

    K Yesudian, C A

    2007-10-01

    The review highlights the poverty alleviation programmes of the government in the post-economic reform era to evaluate the contribution of these programmes towards reducing poverty in the country. The poverty alleviation programmes are classified into (i) self-employment programmes; (ii) wage employment programmes; (iii) food security programmes; (iv) social security programmes; and (v) urban poverty alleviation programmes. The parameter used for evaluation included utilization of allocated funds, change in poverty level, employment generation and number or proportion of beneficiaries. The paper attempts to go beyond the economic benefit of the programmes and analyzes the social impact of these programmes on the communities where the poor live, and concludes that too much of government involvement is actually an impediment. On the other hand, involvement of the community, especially the poor has led to better achievement of the goals of the programmes. Such endeavours not only reduced poverty but also empowered the poor to find their own solutions to their economic problems. There is a need for decentralization of the programmes by strengthening the panchayat raj institutions as poverty is not merely economic deprivation but also social marginalization that affects the poor most.

  13. Effective alleviation of aluminum phytotoxicity by manure-derived biochar.

    Science.gov (United States)

    Qian, Linbo; Chen, Baoliang; Hu, Dingfei

    2013-03-19

    The alleviation of aluminum phytotoxicity to wheat plants in a hydroponic system through the amendment of biochar is investigated to explore the possibility of applying biochar in acidic soil amelioration. Biochar derived from cattle manure pyrolyzed at 400 °C (CM400) and the CM400 biochar washed with distilled-deionized water to remove alkalinity (WCM400) were prepared to determine the roles of the liming effect and adsorption during the alleviation of Al toxicity. Upon addition of 0.02% (W/V) CM400 to the exposure solution, the inhibition of plant growth by Al was significantly reduced while the toxic threshold was extended from 3 to 95 μmol/L Al(3+). Due to the biochar liming effect, the aluminum species were converted to Al(OH)(2+) and Al(OH)2(+) monomers, which were strongly adsorbed by biochar; furthermore, the highly toxic Al(3+) evolved to less toxic Al(OH)3 and Al(OH)4(-) species. Adsorption of Al by the biochar is dominated by surface complexation of the carboxyl groups with Al(OH)(2+)/Al(OH)2(+) rather than through electrostatic attraction of Al(3+) with negatively charged sites. Compared to the liming effect, the adsorption by biochar exhibited a sustainable effect on the alleviation of Al toxicity. Therefore, the biochar amendment appears to be a novel approach for aluminum detoxification in acidic soils.

  14. Alleviation of chromium toxicity by hydrogen sulfide in barley.

    Science.gov (United States)

    Ali, Shafaqat; Farooq, Muhammad Ahsan; Hussain, Sabir; Yasmeen, Tahira; Abbasi, G H; Zhang, Guoping

    2013-10-01

    A hydroponic experiment was carried out to examine the effect of hydrogen sulfide (H2 S) in alleviating chromium (Cr) stress in barley. A 2-factorial design with 6 replications was selected, including 3 levels of NaHS (0 μM, 100 μM, and 200 μM) and 2 levels of Cr (0 μM and 100 μM) as treatments. The results showed that NaHS addition enhances plant growth and photosynthesis slightly compared with the control. Moreover, NaHS alleviated the inhibition in plant growth and photosynthesis by Cr stress. Higher levels of NaHS exhibited more pronounced effects in reducing Cr concentrations in roots, shoots, and leaves. Ultrastructural examination of plant cells supported the facts by indication of visible alleviation of cell disorders in both root and leaf with exogenous application of NaHS. An increased number of plastoglobuli, disintegration, and disappearance of thylakoid membranes and starch granules were visualized inside the chloroplast of Cr-stressed plants. Starch accumulation in the chloroplasts was also noticed in the Cr-treated cells, with the effect being much less in Cr + NaHS-treated plants. Hence, it is concluded that H2 S produced from NaHS can improve plant tolerance under Cr stress.

  15. Factors Influencing Poverty Alleviation amongst Microfinance Adopting Households in Zambia

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    Mavhungu Abel Mafukata

    2016-01-01

    Full Text Available The main objective of this paper is to investigate the factors having the most influence on the alleviation of poverty amongst the households adopting microfinance in Zambia. Ninety nine (n=99 respondents were randomly and purposively selected from amongst 340 microfinance adopters of the so-called Micro Bankers Trust programme operating a microfinance business in the Makululu Compound of Kabwe, Zambia. Socio-demographic primary data were collected through face-to-face interviews based on a semi-structured questionnaire instrument. The data were entered into an excel spreadsheet for analysis. The descriptive data were thereafter exported and fitted to an empirical model. The descriptive results revealed that the majority of the respondents were married, unemployed, fairly educated younger women from larger-sized poor households who drew their household income mainly from microfinance activities. The majority of the respondents thought microfinance had improved their well-being in some crucial areas. The results of the empirical model found that some respondents were indeed alleviated from poverty through microfinance. Conclusion drawn in this paper is that microfinance does alleviate poverty of the poor.

  16. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

    Rørth, Rasmus; Fosbøl, Emil L; Mogensen, Ulrik M;

    2015-01-01

    PURPOSE: β2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of β2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain...

  17. Estrogen receptor beta agonists in neurobehavioral investigations.

    Science.gov (United States)

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research.

  18. Poverty Alleviation and Sustainable Development: The Role of Social Capital

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    Ali Asadi

    2008-01-01

    Full Text Available Developing countries are facing dilemmas such as un-sustainability, and poverty, (especially rural poverty. Poor people are often seen as compelled to exploit their surrounding for short-term survival and are assumed to be the ones most exposed to natural resources degradation. In order that at the first; we review the extensive theoretical literature on social capital, poverty and sustainability and demonstrate the nuanced treatment these concepts have received in this literature. Problem Statement: Current research and observations indicate that (these dilemmas un-sustainability and rural poverty are linked. The only feasible way out of current crisis is to integrate resources. The linkage among environment/agriculture, poverty and social capital are complex and in many cases, poorly understood. The developing countries have been criticized for their inability to reduce poverty and contribute to sustainable agricultural development. Approach: there is a need for improving of social capital to integrate environment and people to alleviate poverty and receive to sustainable development. Social capital has come to be defined in a variety of ways, all of which have been linked to collective norms, values and relationships reflecting the involvement of human individuals in a common life based on family and community. Results: This study argue that social capital as a concept has over the last decade or more been gaining significance in relation to a number of linked fields of analyses, including the identification of factors influencing educational attainment, explanations of differing levels of participation, rural development and poverty alleviation. Conclusions/Recommendations: social capital enhancement appears to have direct links with farmer education in that community development is generally defined as a social learning process which serves to empower people and to involve them as citizens in collective activities aimed at socio- economic

  19. Alleviating stress in the workplace: advice for nurses.

    Science.gov (United States)

    Wright, Kerri

    Stress is an inherent and arguably essential aspect of the nurse's role, with ongoing challenges associated with providing care for patients and their families. However, the level of stress currently being experienced in health care exceeds the capacity of many nurses, resulting in ill health and burnout. This stress can undermine the care and compassion nurses are able to give, a vital concern in health care which was highlighted by the Francis inquiry. This article explores the factors that contribute to stress and the strategies that can be used to alleviate the stresses inherent in nursing.

  20. Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.

    Science.gov (United States)

    Wecker, L; Engberg, M E; Philpot, R M; Lambert, C S; Kang, C W; Antilla, J C; Bickford, P C; Hudson, C E; Zesiewicz, T A; Rowell, Peter P

    2013-10-01

    Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.

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

    Science.gov (United States)

    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.

  2. Gynura procumbens Extract Alleviates Postprandial Hyperglycemia in Diabetic Mice

    Science.gov (United States)

    Choi, Sung-In; Park, Mi Hwa; Han, Ji-Sook

    2016-01-01

    This study was designed to investigate the inhibitory effect of Gynura procumbens extract against carbohydrate digesting enzymes and its ability to ameliorate postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. G. procumbens extract showed prominent α-glucosidase and α-amylase inhibitory effects. The half-maximal inhibitory concentration (IC50) of G. procumbens extract against α-glucosidase and α-amylase was 0.092±0.018 and 0.084±0.027 mg/mL, respectively, suggesting that the α-amylase inhibition activity of the G. procumbens extract was more effective than that of the positive control, acarbose (IC50=0.164 mg/mL). The increase in postprandial blood glucose levels was more significantly alleviated in the G. procumbens extract group than in the control group of STZ-induced diabetic mice. Moreover, the area under the curve significantly decreased with G. procumbens extract administration in STZ-induced diabetic mice. These results suggest that G. procumbens extract may help alleviate postprandial hyperglycemia by inhibiting carbohydrate digesting enzymes. PMID:27752493

  3. Alleviation of Al Toxicity in Barley by Addition of Calcium

    Institute of Scientific and Technical Information of China (English)

    GUO Tian-rong; CHEN Ying; ZHANG Yan-hua; JIN Ye-fei

    2006-01-01

    The potential mechanism by which Ca alleviates Al toxicity was investigated in barley seedlings. It was found that 100 μM Al-alone treatment inhibited barley plant growth and thereby reduced shoot height and root length, and dry weights of root, shoot and leaf; promoted Al accumulation but inhibited Ca absorption in plant tissues; and induced an increase in the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) and in the level of lipid peroxidation (MDA content) in leaves. Except for the increase in Ca concentration in plant tissues, treatment with 0.5 mM Ca in the absence of Al had less effect on the above-mentioned parameters, compared with the control. Addition of Ca efficiently reduced Al toxicity, which is reflected by the promotion of plant growth, reduction in Al concentration and MDA content,increase in Ca concentration and in SOD, POD, and CAT activities compared with the Al-alone-treatment; with increase in Ca level (3.0 mM), the ameliorative effect became more dominant. This indicated that the alleviation of aluminum toxicity in barley seedlings with Ca supplementation could be associated with less absorption of Al and the enhancement of the protective ability of the cell because of increased activity of the antioxidative enzyme.

  4. Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord

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    Ming Liu

    2014-01-01

    Full Text Available Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

  5. Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes.

    Science.gov (United States)

    Daverey, Amita; Agrawal, Sandeep K

    2016-10-01

    Oxidative stress plays a critical role in various neurodegenerative diseases, thus alleviating oxidative stress is a potential strategy for therapeutic intervention and/or prevention of neurodegenerative diseases. In the present study, alleviation of oxidative stress through curcumin is investigated in A172 (human glioblastoma cell line) and HA-sp (human astrocytes cell line derived from the spinal cord) astrocytes. H2O2 was used to induce oxidative stress in astrocytes (A172 and HA-sp). Data show that H2O2 induces activation of astrocytes in dose- and time-dependent manner as evident by increased expression of GFAP in A172 and HA-sp cells after 24 and 12h respectively. An upregulation of Prdx6 was also observed in A172 and HA-sp cells after 24h of H2O2 treatment as compared to untreated control. Our data also showed that curcumin inhibits oxidative stress-induced cytoskeleton disarrangement, and impedes the activation of astrocytes by inhibiting upregulation of GFAP, vimentin and Prdx6. In addition, we observed an inhibition of oxidative stress-induced inflammation, apoptosis and mitochondria fragmentation after curcumin treatment. Therefore, our results suggest that curcumin not only protects astrocytes from H2O2-induced oxidative stress but also reverses the mitochondrial damage and dysfunction induced by oxidative stress. This study also provides evidence for protective role of curcumin on astrocytes by showing its effects on attenuating reactive astrogliosis and inhibiting apoptosis.

  6. Role of magnesium in alleviation of aluminium toxicity in plants.

    Science.gov (United States)

    Bose, Jayakumar; Babourina, Olga; Rengel, Zed

    2011-04-01

    Magnesium is pivotal for activating a large number of enzymes; hence, magnesium plays an important role in numerous physiological and biochemical processes affecting plant growth and development. Magnesium can also ameliorate aluminium phytotoxicity, but literature reports on the dynamics of magnesium homeostasis upon exposure to aluminium are rare. Herein existing knowledge on the magnesium transport mechanisms and homeostasis maintenance in plant cells is critically reviewed. Even though overexpression of magnesium transporters can alleviate aluminium toxicity in plants, the mechanisms governing such alleviation remain obscure. Possible magnesium-dependent mechanisms include (i) better carbon partitioning from shoots to roots; (ii) increased synthesis and exudation of organic acid anions; (iii) enhanced acid phosphatase activity; (iv) maintenance of proton-ATPase activity and cytoplasmic pH regulation; (v) protection against an aluminium-induced cytosolic calcium increase; and (vi) protection against reactive oxygen species. Future research should concentrate on assessing aluminium toxicity and tolerance in plants with overexpressed or antisense magnesium transporters to increase understanding of the aluminium-magnesium interaction.

  7. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

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    Maharjan Anu S

    2010-11-01

    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  8. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.

    2011-01-01

    /13) pathway. The recognition pattern of wFw-Isn-NH(2) with the ghrelin receptor also differed significantly from that of all previously characterized unbiased agonists. Most importantly, wFw-Isn-NH(2) was not dependent on GluIII:09 (Glu3.33), which otherwise is an obligatory TM III anchor point residue...... orientation as compared with, for example, the wFw peptide agonists. It is concluded that the novel peptide-mimetic ligand wFw-Isn-NH(2) is a biased ghrelin receptor agonist and that the selective signaling pattern presumably is due to its unique receptor recognition pattern lacking interaction with key...

  9. "Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.

    Science.gov (United States)

    Nordstrom, Eric J; Bittner, Katie C; McGrath, Michael J; Parks, Clinton R; Burton, Frank H

    2015-12-10

    The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.

  10. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

    Full Text Available BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist and reducing smoking satisfaction (acting as an antagonist. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist' in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialized register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs, using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people

  11. Dexmedetomidine alleviates anxiety-like behaviors and cognitive impairments in a rat model of post-traumatic stress disorder.

    Science.gov (United States)

    Ji, Mu-Huo; Jia, Min; Zhang, Ming-Qiang; Liu, Wen-Xue; Xie, Zhong-Cong; Wang, Zhong-Yun; Yang, Jian-Jun

    2014-10-03

    Post-traumatic stress disorder (PTSD) is a psychiatric disease that has substantial health implications, including high rates of health morbidity and mortality, as well as increased health-related costs. Although many pharmacological agents have proven the effects on the development of PTSD, current pharmacotherapies typically only produce partial improvement of PTSD symptoms. Dexmedetomidine is a selective, short-acting α2-adrenoceptor agonist, which has anxiolytic, sedative, and analgesic effects. We therefore hypothesized that dexmedetomidine possesses the ability to prevent the development of PTSD and alleviate its symptoms. By using the rat model of PTSD induced by five electric foot shocks followed by three weekly exposures to situational reminders, we showed that the stressed rats displayed pronounced anxiety-like behaviors and cognitive impairments compared to the controls. Notably, repeated administration of 20μg/kg dexmedetomidine showed impaired fear conditioning memory, decreased anxiety-like behaviors, and improved spatial cognitive impairments compared to the vehicle-treated stressed rats. These data suggest that dexmedetomidine may exert preventive and protective effects against anxiety-like behaviors and cognitive impairments in the rats with PTSD after repeated administration.

  12. PRX-00023, a selective serotonin 1A receptor agonist, reduces ultrasonic vocalizations in infant rats bred for high infantile anxiety.

    Science.gov (United States)

    Brunelli, Susan A; Aviles, Jessica A; Gannon, Kimberly S; Branscomb, Aron; Shacham, Sharon

    2009-11-01

    To address the development of early anxiety disorders across the lifespan, the High USV line of rats was bred based on rates of infant ultrasonic vocalization in the 40-50 kHz range of predominant frequencies (USV) to maternal separation at postnatal day (P) 10. In this study, rates of USV in High line infants (pups: Postnatal Day 11+/-1) were compared to those of randomly-bred controls in response to EPIX compound PRX-00023, a unique serotonin (5-HT) agonist, acting exclusively at the 5-HT1A receptor, or buspirone, a nonspecific 5HT1A agonist. After testing, pups were examined for sedation and other drug-related effects. The results indicated that all doses of buspirone reduced USV rates in isolation, consistent with other reports. PRX-00023 significantly reduced USV rates at the lowest doses (0.01-0.05 mg/kg). None of the PRX-00023 doses produced sedation, whereas all but the lowest dose of buspirone (0.1 mg/kg) produced sedation effects. The results suggest that this compound alleviates infantile anxiety-like behavior with great specificity in rats bred for high anxiety/depressive phenotypes by selectively targeting 5-HT1A receptors, possibly by both pre- and post-synaptic mechanisms.

  13. MELATONIN DAN MELATONIN RECEPTOR AGONIST SEBAGAI PENANGANAN INSOMNIA PRIMER KRONIS

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    Ni Luh Putu Ayu Maha Iswari

    2013-04-01

    Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

  14. Appeasing pheromone inhibits cortisol augmentation and agonistic behaviors during social stress in adult miniature pigs.

    Science.gov (United States)

    Yonezawa, Tomohiro; Koori, Miyuki; Kikusui, Takefumi; Mori, Yuji

    2009-11-01

    Pairing and physical confrontation In adult sows causes social stress reactions and aggressive behaviors. Recently, maternal pig skin secretions were Isolated and a mixture containing several fatty acids, now called pig appeasing pheromone (PAP), was synthesized. In this study, we Investigated the effects of PAP on social and Immune stress response In adult female miniature pigs. PAP or vehicle solvents were sprayed Into the pens of Individually housed adult sows. A two-week exposure to the pheromone did not alter basal salivary Cortisol levels or clrcadlan rhythms. Following this treatment, the animals were paired and placed In a new pen that was divided with a wire-mesh fence. Although salivary cortisol Increased markedly In the vehicle-treated group, the PAP-treated group exhibited a drastic Inhibition of cortisol secretion. This effect was sustained even after they were allowed to physically Interact following fence removal. Moreover, the latency time of agonistic behaviors, such as escaping or biting, was significantly extended after PAP exposure. When lipopolysaccharide was Injected Intramuscularly, Cortisol levels, rectal temperatures, and lying time lengths Increased substantially. No differences were observed between the pheromone-treated and untreated groups. These results suggest that this synthetic pheromone alleviates social stress In adult pigs, although It does not affect Immune stress responses. Our findings demonstrate the potential benefit of this pheromone In field applications and clinical disciplines relating to adult female pigs.

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

    Science.gov (United States)

    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.

  16. Toll-like receptor agonists in cancer therapy

    OpenAIRE

    Adams, Sylvia

    2009-01-01

    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 recen...

  17. Significant alleviation of Darier's disease with fractional CO2 laser.

    Science.gov (United States)

    Benmously, Rym; Litaiem, Noureddine; Hammami, Houda; Badri, Talel; Fenniche, Samy

    2015-04-01

    Darier's disease (DD) is a dominantly inherited genodermatosis with highly variable expression. It is characterized by symmetrical hyperkeratotic papules affecting seborrheic areas and extremities. The existence of unsightly lesions could lead to discomfort and social handicap. Conventional treatment consists of topical and systemic steroids and/or retinoids alleviating DD. Ablative lasers also have been used to treat these conditions with variable results and side effects. To the best of our knowledge, fractional CO2 laser has never been used to treat DD. We present a case of a 36-year-old woman with verrucous and hyperkeratotic plaques of the forehead significantly improved after two sessions of fractional CO2 laser treatment. Neither scars nor pigmentary disorders were noted.

  18. Gust Load Alleviation with Robust Control for a Flexible Wing

    Directory of Open Access Journals (Sweden)

    Xiang Liu

    2016-01-01

    Full Text Available Traditional methods for gust alleviation of aircraft are mostly proposed based on a specific flight condition. In this paper, robust control laws are designed for a large flexible wing with uncertainty in Mach number and dynamic pressure. To accurately describe the aeroelastic model over a large flight envelope, a nonlinear parameter-varying model is developed which is a function of both Mach number and dynamic pressure. Then a linear fractional transformation is established accordingly and a modified model order reduction technique is applied to reduce the size of the uncertainty block. The developed model, in which the statistic nature of the gust is considered by using the Dryden power spectral density function, enables the use of μ-synthesis procedures for controller design. The simulations show that the μ controller can always effectively reduce the wing root shear force and bending moment at a given range of Mach number and dynamic pressure.

  19. Personality and Coping in Peruvian volunteers for poverty alleviation

    Directory of Open Access Journals (Sweden)

    Camila Gastelumendi Gonçalves

    2013-06-01

    Full Text Available This study explores the relationship between coping styles and strategies, and personality styles in a sample of 41 young volunteers of an institution that alleviates poverty in Lima. Peruvian adaptations of COPE and MIPS scales were administered. The results show that volunteers have higher scores on adaptive coping strategies. High scores in some particular personality styles were reported, which allowed to establish a personality profile of this group. According with theoretical framework, most coping strategies correlated with most personality styles, revealing four particular tendencies in these volunteers: they wish to have contact with other people, they usually see positive aspects of situations, they look forward for challenges, and they developed adaptive coping strategies.

  20. Non-pharmacological approaches to alleviate distress in dementia care.

    Science.gov (United States)

    Mitchell, Gary; Agnelli, Joanne

    2015-11-25

    Distress is one of the most common clinical manifestations associated with dementia. Pharmacological intervention may be appropriate in managing distress in some people. However, best practice guidelines advocate non-pharmacological interventions as the preferred first-line treatment. The use of non-pharmacological interventions encourages healthcare professionals to be more person-centred in their approach, while considering the causes of distress. This article provides healthcare professionals with an overview of some of the non-pharmacological approaches that can assist in alleviating distress for people living with dementia including: reminiscence therapy, reality orientation, validation therapy, music therapy, horticultural therapy, doll therapy and pet therapy. It provides a summary of their use in clinical practice and links to the relevant literature.

  1. Statins alleviate experimental nerve injury-induced neuropathic pain.

    Science.gov (United States)

    Shi, Xiang Qun; Lim, Tony K Y; Lee, Seunghwan; Zhao, Yuan Qing; Zhang, Ji

    2011-05-01

    The statins are a well-established class of drugs that lower plasma cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase. They are widely used for the treatment of hypercholesterolemia and for the prevention of coronary heart disease. Recent studies suggest that statins have anti-inflammatory effects beyond their lipid-lowering properties. We sought to investigate whether statins could affect neuropathic pain by mediating nerve injury-associated inflammatory responses. The effects of hydrophilic rosuvastatin and lipophilic simvastatin were examined in the mouse partial sciatic nerve ligation model. Systemic daily administration of either statin from days 0 to 14 completely prevented the development of mechanical allodynia and thermal hyperalgesia. When administered from days 8 to 14 after injury, both statins dose-dependently reduced established hypersensitivity. After treatment, the effects of the statins were washed out within 2 to 7 days, depending on dose. Effects of both statins in alleviating mechanical allodynia were further confirmed in a different injury-associated neuropathic pain model, mental nerve chronic constriction, in rats. Both statins were able to abolish interleukin-1β expression in sciatic nerve triggered by nerve ligation. Additionally, quantitative analysis with Iba-1 and glial fibrillary acid protein immunoreactivity demonstrated that rosuvastatin and simvastatin significantly reduced the spinal microglial and astrocyte activation produced by sciatic nerve injury. The increase of interleukin-1β mRNA in the ipsilateral side of spinal cords was also reduced by the treatment of either statin. We identified a potential new application of statins in the treatment of neuropathic pain. The pain-alleviating effects of statins are likely attributable to their immunomodulatory effects.

  2. Wake vortex alleviation using rapidly actuated segmented Gurney flaps

    Science.gov (United States)

    Matalanis, Claude G.

    All bodies that generate lift also generate circulation. The circulation generated by large commercial aircraft remains in their wake in the form of trailing vortices. These vortices can be hazardous to following aircraft due to their strength and persistence. To account for this, airports abide by spacing rules which govern the frequency with which aircraft can use their runways when operating in instrument flight rules. These spacing rules are the limiting factor on increasing airport capacity. We conducted an experimental and computational study to assess the potential for using rapidly actuated segmented Gurney flaps, also known as Miniature Trailing Edge Effectors (MiTEs), for active wake vortex alleviation. Wind tunnel tests were performed on a half-span model NACA 0012 wing equipped with an array of 13 independent MITE pairs. The chord-based Reynolds number was around 350,000. Each MiTE could extend 0.015 chord lengths perpendicular to the freestream on the pressure side of the wing. Pressure profiles and a five-hole probe survey in the near wake were used to examine the influence that the MiTEs had upon the wing aerodynamics and the vortex rollup process. Particle image velocimetry was used to measure the static and time-dependent response of the vortex in the intermediate wake to various MiTE actuation schemes. These results were used to form complete initial conditions for vortex filament computations of the far wake evolution. Results from these computations showed that the perturbations created by MiTEs could be used to excite a variety of three-dimensional inviscid vortex instabilities. Finally, the research performed on MiTEs led to the invention of a more practical wake alleviation device: the spanwise actuating Gurney flap. Prototype tests showed that this device could produce similar perturbations to the MiTEs.

  3. Short-Acting Beta-Agonist Research: A Perspective

    Directory of Open Access Journals (Sweden)

    Malcolm R Sears

    2001-01-01

    Full Text Available Asthma mortality increased sharply in New Zealand in 1977, prompting a national investigation into circumstances of asthma deaths. Subsequent observations of improved asthma control in subjects withdrawn from regular beta2-agonist treatment raised the question of whether asthma severity and, therefore, mortality could relate to frequent beta-agonist use. A randomized controlled trial of regular inhaled fenoterol versus as-needed bronchodilator use showed worsened asthma control during regular treatment despite concomitant use of inhaled corticosteroids. Assessment of these findings led to delay in the publishing of the American Asthma Guidelines, which were modified to suggest caution in using beta2-agonist treatments. Simultaneously, case control studies in New Zealand suggested that prescription of fenoterol was a substantial risk factor for asthma mortality. The causal association was hotly debated, but increasing evidence pointed to an adverse effect of fenoterol on asthma severity and, hence, mortality. This was supported by dramatic decreases in both morbidity and mortality when fenoterol was effectively withdrawn from use in New Zealand. The link between worsening asthma morbidity and mortality, and the use of potent short-acting beta2-agonists fulfills the Bradford Hill criteria for attributing causality. Application of evidence from randomized, controlled trials of short-acting beta-agonist use has led to a major shift in therapy in asthma to the recommendation of as-needed use only of short-acting beta-agonists and decreased patient reliance on regular bronchodilator therapy.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Sams-Dodd, F

    1998-01-01

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

  6. Cytisine-based nicotinic partial agonists as novel antidepressant compounds.

    Science.gov (United States)

    Mineur, Yann S; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L; Gündisch, Daniela; Picciotto, Marina R

    2009-04-01

    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

  7. Are Dopamine Agonists Neuroprotective in Parkinson‘s disease?

    Institute of Scientific and Technical Information of China (English)

    乐卫东; Jank.J

    2002-01-01

    Dopamine(DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson's disease(PD) and in PD patient with levodopa(L-DO-PA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoylasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer's disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinal trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as18F-L-DOPA PET and123I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.

  8. Are Dopamine Agonists Neuroprotective in Parkinson′s Disease?

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Dopamine (DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson′s disease (PD) and in PD patient with levodopa (L-DOPA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer′s disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinical trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as 18 F-L-DOPA PET and 123 I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.``

  9. Romiplostim: a second-generation thrombopoietin agonist.

    Science.gov (United States)

    Cohn, Claudia S; Bussel, James B

    2009-03-01

    in bone marrow reticulin have been reported. Other TPO nonpeptide mimetics have been created by using a similar strategy with libraries of nonpeptide molecules that can stimulate TPO-dependent cell lines. Eltrombopag and AKR-501 are two drugs of this type that have shown positive results in clinical trials. In addition, antibodies that can stimulate the c-Mpl receptor are being engineered to act as potent TPO agonists. These and other drugs in preclinical development represent a new line of therapy for thrombocytopenic patients.

  10. Active gust load alleviation system for flexible aircraft: Mixed feedforward/feedback approach

    DEFF Research Database (Denmark)

    Alam, Mushfiqul; Hromcik, Martin; Hanis, Tomas

    2015-01-01

    Lightweight flexible blended-wing-body (BWB) aircraft concept seems as a highly promising configuration for future high capacity airliners which suffers from reduced stiffness for disturbance loads such as gusts. A robust feedforward gust load alleviation system (GLAS) was developed to alleviate ...

  11. Role of dopamine agonists in Parkinson's disease: an update.

    Science.gov (United States)

    Bonuccelli, Ubaldo; Pavese, Nicola

    2007-10-01

    At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.

  12. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    Science.gov (United States)

    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.

  13. Aeroelastic scaling laws for gust load alleviation control system

    Directory of Open Access Journals (Sweden)

    Tang Bo

    2016-02-01

    Full Text Available Gust load alleviation (GLA tests are widely conducted to study the effectiveness of the control laws and methods. The physical parameters of models in these tests are aeroelastic scaled, while the scaling of GLA control system is always unreached. This paper concentrates on studying the scaling laws of GLA control system. Through theoretical demonstration, the scaling criterion of a classical PID control system has been come up and a scaling methodology is provided and verified. By adopting the scaling laws in this paper, gust response of the scaled model could be directly related to the full-scale aircraft theoretically under both open-loop and closed-loop conditions. Also, the influences of different scaling choices of an important non-dimensional parameter, the Froude number, have been studied in this paper. Furthermore for practical application, a compensating method is given when the theoretical scaled actuators or sensors cannot be obtained. Also, the scaling laws of some non-linear elements in control system such as the rate and amplitude saturations in actuator have been studied and examined by a numerical simulation.

  14. Probucol alleviates atherosclerosis and improves high density lipoprotein function

    Directory of Open Access Journals (Sweden)

    Zhong Jian-Kai

    2011-11-01

    Full Text Available Abstract Background Probucol is a unique hypolipidemic agent that decreases high density lipoprotein cholesterol (HDL-C. However, it is not definite that whether probucol hinders the progression of atherosclerosis by improving HDL function. Methods Eighteen New Zealand White rabbits were randomly divided into the control, atherosclerosis and probucol groups. Control group were fed a regular diet; the atherosclerosis group received a high fat diet, and the probucol group received the high fat diet plus probucol. Hepatocytes and peritoneal macrophages were isolated for [3H] labeled cholesterol efflux rates and expression of ABCA1 and SR-B1 at gene and protein levels; venous blood was collected for serum paraoxonase 1, myeloperoxidase activity and lipid analysis. Aorta were prepared for morphologic and immunohistochemical analysis after 12 weeks. Results Compared to the atherosclerosis group, the paraoxonase 1 activity, cholesterol efflux rates, expression of ABCA1 and SR-BI in hepatocytes and peritoneal macrophages, and the level of ABCA1 and SR-BI in aortic lesions were remarkably improved in the probucol group, But the serum HDL cholesterol concentration, myeloperoxidase activity, the IMT and the percentage plaque area of aorta were significantly decreased. Conclusion Probucol alleviated atherosclerosis by improving HDL function. The mechanisms include accelerating the process of reverse cholesterol transport, improving the anti-inflammatory and anti-oxidant functions.

  15. Effectiveness of Zakah Targeting in Alleviating Poverty in Indonesia

    Directory of Open Access Journals (Sweden)

    Rahmatina A Kasri

    2016-07-01

    Full Text Available Zakah is a unique Islamic institution targeted to eight groups of recipients with the aim to redistribute income, reduce poverty and achieve social welfare. However, the impacts and effectiveness of zakah targeting in reducing poverty is rarely measured. This is the main objective of the study. To achieve it, a survey was conducted to collect primary data from zakah recipients in Greater Jakarta Indonesia. The data were subsequently analysed by using descriptive and poverty index analyses. The main results suggest that the incidence, depth and severity of poverty amongst the recipients have decreased due to the contributions from zakah organizations. There are also indications that zakah has been distributed to the most disadvantaged people such as the uneducated and unemployed. The findings provide empirical evidence regarding positive contribution and effectiveness of zakah targeting in reducing poverty in Indonesia. Some policy implications of the findings are also highlighted to enrich discourses on the role of zakah in alleviating poverty in Muslim societies.DOI: 10.15408/aiq.v8i2.3005

  16. Alleviating energy poverty for the world's poor

    Energy Technology Data Exchange (ETDEWEB)

    Sagar, Ambuj D. E-mail: ambuj_sagar@harvard.edu

    2005-07-01

    Improving energy services for poor households in developing countries remains one of the most pressing challenges facing the development community. The dependence of these households on traditional forms of energy leads to significant health impacts as well as other major disbenefits, yet there has been little progress in meeting this challenge. This viewpoint argues for an 'energy-poverty alleviation' fund to help provide modern energy services to these households. It also proposes an approach through which to create such a fund, namely by introducing an incremental levy on petroleum. Notably, this scheme does not need a global agreement since a levy could be introduced by major oil-exporting countries. The implementation of this mechanism would result in a climate-friendly outcome (even before taking into account the elimination of products of incomplete combustion resulting from the traditional household use of biomass-based fuels) while providing immense socio-economic benefits to the world's poor. Such an approach would allow significant progress on the sustainable development front while reducing global greenhouse gas emissions, and therefore is very much consistent with the United Nations Framework Convention on Climate Change.

  17. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs.

    Science.gov (United States)

    Stoltz, David A; Rokhlina, Tatiana; Ernst, Sarah E; Pezzulo, Alejandro A; Ostedgaard, Lynda S; Karp, Philip H; Samuel, Melissa S; Reznikov, Leah R; Rector, Michael V; Gansemer, Nicholas D; Bouzek, Drake C; Abou Alaiwa, Mahmoud H; Hoegger, Mark J; Ludwig, Paula S; Taft, Peter J; Wallen, Tanner J; Wohlford-Lenane, Christine; McMenimen, James D; Chen, Jeng-Haur; Bogan, Katrina L; Adam, Ryan J; Hornick, Emma E; Nelson, George A; Hoffman, Eric A; Chang, Eugene H; Zabner, Joseph; McCray, Paul B; Prather, Randall S; Meyerholz, David K; Welsh, Michael J

    2013-06-01

    Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.

  18. Alleviating bias leads to accurate and personalized recommendation

    Science.gov (United States)

    Qiu, Tian; Wang, Tian-Tian; Zhang, Zi-Ke; Zhong, Li-Xin; Chen, Guang

    2013-11-01

    Recommendation bias towards objects has been found to have an impact on personalized recommendation, since objects present heterogeneous characteristics in some network-based recommender systems. In this article, based on a biased heat conduction recommendation algorithm (BHC) which considers the heterogeneity of the target objects, we propose a heterogeneous heat conduction algorithm (HHC), by further taking the heterogeneity of the source objects into account. Tested on three real datasets, the Netflix, RYM and MovieLens, the HHC algorithm is found to present better recommendation in both the accuracy and diversity than two benchmark algorithms, i.e., the original BHC and a hybrid algorithm of heat conduction and mass diffusion (HHM), while not requiring any other accessorial information or parameter. Moreover, the HHC algorithm also elevates the recommendation accuracy on cold objects, referring to the so-called cold-start problem. Eigenvalue analyses show that, the HHC algorithm effectively alleviates the recommendation bias towards objects with different level of popularity, which is beneficial to solving the accuracy-diversity dilemma.

  19. Coumarin pretreatment alleviates salinity stress in wheat seedlings.

    Science.gov (United States)

    Saleh, Ahmed Mahmoud; Madany, M M Y

    2015-03-01

    The potentiality of COU to improve plant tolerance to salinity was investigated. Wheat grains were primed with COU (50 ppm) and then grown under different levels of NaCl (50, 100, 150 mM) for two weeks. COU pretreatment improved the growth of wheat seedling under salinity, relative to COU-untreated seedlings, due to the accumulation of osmolytes such as soluble sugars and proline. Moreover, COU treatment significantly improved K(+)/Na(+) ratio in the shoots of both salt stressed and un-stressed seedlings. However, in the roots, this ratio increased only under non-salinity. In consistent with phenylalanine ammonia lyase (PAL), phenolics and flavonoids were accumulated in COU-pretreated seedlings under the higher doses of salinity, relative to COU-untreated seedlings. COU primed seedlings showed higher content of the coumarin derivative, scopoletin, and salicylic, chlorogenic, syringic, vanillic, gallic and ferulic acids, under both salinity and non-salinity conditions. Salinity stress significantly improved the activity of peroxidase (POD) in COU-pretreated seedlings. However, the effect of COU on the total antioxidant capacity (TAC) was only obtained at the highest dose of NaCl (150 mM). The present results suggest that COU pretreatment could alleviate the adverse effect of salinity on the growth of wheat seedlings through enhancing, at least partly, the osmoregulation process and antioxidant defense system.

  20. 扶贫研究概述%On Poverty Alleviation

    Institute of Scientific and Technical Information of China (English)

    肖立新

    2011-01-01

    贫困是一个伴随着人类生存和发展的历史性问题;同时,贫困也是一个存在于发达国家和发展中国家的世界性问题。2011年起,我国对农村低收入人口全面实施扶贫政策,实行新的扶贫标准,新标准提高到人均1500元,扶贫对象覆盖9000万人左右,标志着我国扶贫开发进入一个新阶段。但这也意味着我国扶贫工作的长期性、艰巨性。为此,作者对贫困、扶贫的国内外研究现状进行梳理,以期为相关的研究和扶贫实践提供理论借鉴和实践借鉴。%Poverty is a historical problem that accompanied by survival and development of humankind.Meanwhile,poverty is also a world-wide problem that exists in developed and developing countries.Since 2011,China has carried out policies of poverty alleviation on

  1. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.

    Science.gov (United States)

    Xiong, Zheng-Mei; Choi, Ji Young; Wang, Kun; Zhang, Haoyue; Tariq, Zeshan; Wu, Di; Ko, Eunae; LaDana, Christina; Sesaki, Hiromi; Cao, Kan

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

  2. Aeroelastic scaling laws for gust load alleviation control system

    Institute of Scientific and Technical Information of China (English)

    Tang Bo; Wu Zhigang; Yang Chao

    2016-01-01

    Gust load alleviation (GLA) tests are widely conducted to study the effectiveness of the control laws and methods. The physical parameters of models in these tests are aeroelastic scaled, while the scaling of GLA control system is always unreached. This paper concentrates on studying the scaling laws of GLA control system. Through theoretical demonstration, the scaling criterion of a classical PID control system has been come up and a scaling methodology is provided and veri-fied. By adopting the scaling laws in this paper, gust response of the scaled model could be directly related to the full-scale aircraft theoretically under both open-loop and closed-loop conditions. Also, the influences of different scaling choices of an important non-dimensional parameter, the Froude number, have been studied in this paper. Furthermore for practical application, a compen-sating method is given when the theoretical scaled actuators or sensors cannot be obtained. Also, the scaling laws of some non-linear elements in control system such as the rate and amplitude sat-urations in actuator have been studied and examined by a numerical simulation.

  3. Gust alleviation of highly flexible UAVs with artificial hair sensors

    Science.gov (United States)

    Su, Weihua; Reich, Gregory W.

    2015-04-01

    Artificial hair sensors (AHS) have been recently developed in Air Force Research Laboratory (AFRL) using carbon nanotube (CNT). The deformation of CNT in air flow causes voltage and current changes in the circuit, which can be used to quantify the dynamic pressure and aerodynamic load along the wing surface. AFRL has done a lot of essential work in design, manufacturing, and measurement of AHSs. The work in this paper is to bridge the current AFRL's work on AHSs and their feasible applications in flight dynamics and control (e.g., the gust alleviation) of highly flexible aircraft. A highly flexible vehicle is modeled using a strain-based geometrically nonlinear beam formulation, coupled with finite-state inflow aerodynamics. A feedback control algorithm for the rejection of gust perturbations will be developed. A simplified Linear Quadratic Regulator (LQR) controller will be implemented based on the state-space representation of the linearized system. All AHS measurements will be used as the control input, i.e., wing sectional aerodynamic loads will be defined as the control output for designing the feedback gain. Once the controller is designed, closed-loop aeroelastic simulations will be performed to evaluate the performance of different controllers with the force feedback and be compared to traditional controller designs with the state feedback. From the study, the feasibility of AHSs in flight control will be assessed. The whole study will facilitate in building a fly-by-feel simulation environment for autonomous vehicles.

  4. Alleviating the tension at low multipole through Axion Monodromy

    CERN Document Server

    Meerburg, P Daniel

    2014-01-01

    There exists some tension on large scales between the Planck data and the LCDM concordance model of the Universe, which has been amplified by the recently claimed discovery of non-zero tensor to scalar ratio $r$. At the same time, the current best-fit value of $r$ suggests large field inflation delta phi>M_p, which requires a UV complete description of inflation. A very promising working example that predicts large tensor modes and can be UV completed is axion monodromy inflation. This realization of inflation naturally produces oscillating features, as consequence of a broken shift symmetry. We analyse a combination of Planck, ACT, SPT, WMAP low l polarization and BICEP2 data, and show a long wavelength feature from a periodic potential can alleviate the tension at low multipoles with an improvement delta chi^2 ~2.5-4 per degree of freedom, depending on the level of foreground subtraction. As with an introduction of running, one expects that any scale dependence should lead to a worsened fit at high multipol...

  5. Chronic spinal infusion of loperamide alleviates postsurgical pain in rats.

    Science.gov (United States)

    Kumar, Rakesh; Reeta, K H; Ray, Subrata Basu

    2014-04-01

    Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain-related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 microL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels.

  6. Effects of nicotinic acetylcholine receptor agonists in assays of acute pain-stimulated and pain-depressed behaviors in rats.

    Science.gov (United States)

    Freitas, Kelen C; Carroll, F Ivy; Negus, S Stevens

    2015-11-01

    Agonists at nicotinic acetylcholine receptors (nAChRs) constitute one drug class being evaluated as candidate analgesics. Previous preclinical studies have implicated α4β2 and α7 nAChRs as potential mediators of the antinociceptive effects of (–)-nicotine hydrogen tartrate (nicotine) and other nAChR agonists; however, these studies have relied exclusively on measures of pain-stimulated behavior, which can be defined as behaviors that increase in frequency, rate, or intensity after presentation of a noxious stimulus. Pain is also associated with depression of many behaviors, and drug effects can differ in assays of pain-stimulated versus pain-depressed behavior. Accordingly, this study compared the effects of nicotine, the selective α4/6β2 agonist 5-(123I)iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), and the selective α7 agonist N-(3R)-1-azabicyclo(2.2.2)oct-3-yl-4-chlorobenzamide in assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to either stimulate a stretching response or depress the operant responding, which is maintained by electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Nicotine produced a dose-dependent, time-dependent, and mecamylamine-reversible blockade of both acid-stimulated stretching and acid-induced depression of ICSS. 5-I-A-85380 also blocked both acid-stimulated stretching and acid-induced depression of ICSS, whereas N-(3R)-1-azabicyclo(2.2.2)oct-3-yl-4-chlorobenzamide produced no effect in either procedure. Both nicotine and 5-I-A-85380 were ≥10-fold more potent in blocking the acid-induced depression of ICSS than in blocking the acid-induced stimulation of stretching. These results suggest that stimulation of α4β2 and/or α6β2 nAChRs may be especially effective to alleviate the signs of pain-related behavioral depression in rats; however, nonselective behavioral effects

  7. In silico discovery of novel Retinoic Acid Receptor agonist structures

    Directory of Open Access Journals (Sweden)

    Samuels Herbert H

    2001-06-01

    Full Text Available Abstract Background Several Retinoic Acid Receptors (RAR agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually to the structure of the receptor with the Internal Coordinates Mechanics (ICM program. Thirty ligand candidates were tested in vitro. Conclusions Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

  8. Compulsive eating and weight gain related to dopamine agonist use.

    Science.gov (United States)

    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.

  9. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh

    2014-04-01

    Full Text Available Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine and GABA. After the term chemoreceptor emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.

  10. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter;

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to inve......AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim...

  11. Partial agonistic action of endomorphins in the mouse spinal cord.

    Science.gov (United States)

    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.

  12. PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals.

    Science.gov (United States)

    Zakaria, Esraa M; El-Bassossy, Hany M; El-Maraghy, Nabila N; Ahmed, Ahmed F; Ali, Abdelmoneim A

    2016-11-15

    Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNF-α) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4-AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNF-α and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms.

  13. Biomass energy: Employment generation and its contribution to poverty alleviation

    Energy Technology Data Exchange (ETDEWEB)

    Openshaw, Keith [2430 Shenandoah St., Vienna, VA 22180 (United States)

    2010-03-15

    Studies were undertaken in Malawi from 1995 to 1997 and 2007 to 2008 to estimate the supply and demand of household energy. Because little is known about the supply chain for biomass, surveys were carried out for urban areas on its production, transport and trade as well as sustainable supply. Also, because biomass is used by all people for a multitude of purposes, a complete picture was made of regional and urban biomass supply and demand. The results indicated that biomass is not only the principal energy, accounting for 89 percent of demand, but also the main traded energy in the two time periods accounting for 56-59 percent of commercial demand. Petroleum products supplied 26-27 percent, electricity 8-12 percent and coal 6-10 percent. The market value of traded woodfuel was US$ 48.8 million and US$ 81.0 million in 1996 and 2008 respectively, about 3.5 percent of gross domestic product (GDP). The study found that in 1996 and 2008 respectively, the equivalent of 93,500 and 133,000 full-time people was employed in the biomass supply chain, approximately 2 percent of the potential workforce. In contrast, about 3400 and 4600 people were employed in the supply chain of other fuels in these years. If the Malawi findings are applied to the current estimated wood energy consumption in sub-Saharan Africa, then approximately 13 million people could be employed in commercial biomass energy; this highlights its importance as a means to assist with sustainable development and poverty alleviation. (author)

  14. Towards a virtual observatory for ecosystem services and poverty alleviation

    Science.gov (United States)

    Buytaert, W.; Baez, S.; Cuesta, F.; Veliz Rosas, C.

    2010-12-01

    Over the last decades, near real-time environmental observation, technical advances in computer power and cyber-infrastructure, and the development of environmental software algorithms have increased dramatically. The integration of these evolutions, which is commonly referred to as the establishment of a virtual observatory, is one of the major challenges of the next decade for environmental sciences. Worldwide, many coordinated activities are ongoing to make this integration a reality. However, far less attention is paid to the question of how these developments can benefit environmental services management in a poverty alleviation context. Such projects are typically faced with issues of large predictive uncertainties, limited resources, limited local scientific capacity. At the same time, the complexity of the socio-economic contexts requires a very strong bottom-up oriented and interdisciplinary approach to environmental data collection and processing. In this study, we present three natural resources management cases in the Andes and the Amazon basin, and investigate how "virtual observatory" technology can improve ecosystem management. Each of these case studies present scientific challenges in terms of model coupling, real-time data assimilation and visualisation for management purposes. The first project deals with water resources management in the Peruvian Andes. Using a rainfall-runoff model, novel visualisations are used to give farmers insight in the water production and regulation capacity of their catchments, which can then be linked to land management practices such as conservation agriculture, wetland protection and grazing density control. In a project in the Amazonian floodplains, optimal allocation of the nesting availability and quality of the giant freshwater turtle are determined using a combined hydraulic model and weather forecasts. Finally, in the rainforest of the Yasuní Biosphere Reserve, Ecuador, biodiversity models are used to

  15. INTRATHYMIC INOCULATION OF LIVER SPECIFIC ANTIGEN ALLEVIATES LIVER TRANSPLANT REJECTION

    Institute of Scientific and Technical Information of China (English)

    贾长库; 郑树森; 朱有法

    2004-01-01

    Objective To study the effects of liver specific antigen (LSA) on liver allotransplantation rejection. Methods Orthotopic liver transplantation was performed in this study. Group Ⅰ: syngeneic control (Wistar-to-Wistar); Group Ⅱ: acute rejection (SD-to-Wistar). Group Ⅲ: thymic inoculation of SD rat LSA day 7 before transplantation. The observation of general condition and survival time, rejection grades and the NF-κB activity of splenocytes were used to analyze severity of acute rejection and immune state of animals in different groups. Results The general condition of group Ⅰ was fair post transplantation with no sign of rejection. All recipients of group Ⅱ died within days 9 to 13 post transplantation with median survival time of 10.7 ±1.37 days. As for group Ⅲ, 5 out of 6 recipients survived for a long period with remarkably better general condition than that of group Ⅱ. Its rejection grades were significantly lower than group Ⅱ (P< 0.05).NF-κB activity was only detected in group Ⅰ between days 5 and 7 after transplantation, whereas high activity of NF-κB was detected at all points in group Ⅱ and low NF-κB activity was detected in group Ⅲ which was significantly lower than that of group Ⅱ (P < 0.05). Conclusions LSA is an important transplantation antigen directly involved in the immunorejection of liver transplantation. Intrathymic inoculation of LSA can alleviate the rejection of liver allotransplantation,grafts survive for a period of time thereby, allowing a novel way to liver transplantation immunotolerance.

  16. Nesfatin-1 alleviates extrahepatic cholestatic damage of liver in rats

    Directory of Open Access Journals (Sweden)

    Ali Solmaz

    2016-11-01

    Full Text Available Obstructive jaundice (OJ can be defined as cessation of bile flow into the small intestine due to benign or malignant changes. Nesfatin-1, recently discovered anorexigenic peptide derived from nucleobindin-2 in hypothalamic nuclei, was shown to have anti-inflammatory and antiapoptotic effects. This study is aimed to investigate the therapeutic effects of nesfatin-1 on OJ in rats. Twenty-four adult male Wistar-Hannover rats were randomly assigned to three groups: sham (n = 8, control (n = 8, and nesfatin (n = 8. After bile duct ligation, the study groups were treated with saline or nesfatin-1, for 10 days. Afterward, blood and liver tissue samples were obtained for biochemical analyses, measurement of cytokines, determination of the oxidative DNA damage, DNA fragmentation, and histopathologic analyses. Alanine aminotransferase and gamma-glutamyl transferase levels were decreased after the nesfatin treatment; however, these drops were statistically non-significant compared to control group (p = 0.345, p = 0.114. Malondialdehyde levels decreased significantly in nesfatin group compared to control group (p = 0.032. Decreases in interleukin-6 and tumor necrosis factor-α levels from the liver tissue samples were not statistically significant in nesfatin group compared to control group. The level of oxidative DNA damage was lower in nesfatin group, however this result was not statistically significant (p = 0.75. DNA fragmentation results of all groups were similar. Histopathological examination revealed that there was less neutrophil infiltration, edema, bile duct proliferation, hepatocyte necrosis, basement membrane damage, and parenchymal necrosis in nesfatin compared to control group. The nesfatin-1 treatment could alleviate cholestatic liver damage caused by OJ due to its anti-inflammatory and antioxidant effects.

  17. Alleviation of podophyllotoxin toxicity using coexisting flavonoids from Dysosma versipellis.

    Directory of Open Access Journals (Sweden)

    Juan Li

    Full Text Available Podophyllotoxin (POD is a lignan-type toxin existing in many herbs used in folk medicine. Until now, no effective strategy is available for the management of POD intoxication. This study aims to determine the protective effects of flavonoids (quercetin and kaempferol on POD-induced toxicity. In Vero cells, both flavonoids protected POD-induced cytotoxicity by recovering alleviating G2/M arrest, decreasing ROS generation and changes of membrane potential, and recovering microtubule structure. In Swiss mice, the group given both POD and flavonoids group had significantly lower mortality rate and showed less damages in the liver and kidney than the group given POD alone. As compared to the POD group, the POD plus flavonoids group exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde levels, and increases in superoxide dismutase and glutathione levels. Histological examination of the liver and kidney showed less pathological changes in the treatment of POD plus flavonoids group. The protective mechanisms were due to the antioxidant activity of flavonoids against the oxidative stress induced by POD and the competitive binding of flavonoids against POD for the same colchicines-binding sites. The latter binding was confirmed by the tubulin assembly assay in combination with molecular docking analyses. In conclusion, this study for the first time demonstrated that the coexisting flavonoids have great protective effects against the POD toxicity, and results of this study highlighted the great potential of searching for effective antidotes against toxins based on the pharmacological clues.

  18. Stratification requirements for seed dormancy alleviation in a wetland weed.

    Science.gov (United States)

    Boddy, Louis G; Bradford, Kent J; Fischer, Albert J

    2013-01-01

    Echinochloaoryzicola(syn.E. phyllopogon) is an exotic weed of California rice paddies that has evolved resistance to multiple herbicides. Elimination of seedlingsthroughcertain weed control methods can limit the spread of this weed, but is contingent on accurate predictions of germination and emergence timing, which are influenced by seed dormancy levels.In summer annuals, dormancy can often be relieved through stratification, a period of prolonged exposure to cold and moist conditions.We used population-based threshold models to quantify the effects of stratification on seed germination of four E. Oryzicola populations at a range of water potential (Ψ) and oxygen levels. We also determined how stratification temperatures, moisture levels and durations contributed to dormancy release. Stratification released dormancy by decreasing base Ψ and hydrotimerequired for germination and by eliminating any germination sensitivity to oxygen. Stratification also increased average germination rates (GR), which were used as a proxy for relative dormancy levels. Alternating temperatures nearly doubled GR in all populations, indicating that seeds could be partially dormant despite achieving high final germination percentages. Stratification at Ψ = 0 MPa increased GR compared to stratification at lower water potentials, demonstrating that Ψ contributed to regulating dormancy release. Maximum GR occurred after 2-4 weeks of stratification at 0 MPa; GR were often more rapid for herbicide-resistant than for herbicide-susceptible seeds, implying greater dormancy in the latter. Manipulation of field conditions to promote dormancy alleviation of E. oryzicola seeds might improve the rate and uniformity of germination for seed bank depletion through seedling weed control. Our results suggest field soil saturation in winter would contribute towards E. oryzicola dormancy release and decrease the time to seedling emergence.

  19. Cellular recycling of proteins in seed dormancy alleviation and germination

    Directory of Open Access Journals (Sweden)

    Krystyna Oracz

    2016-07-01

    Full Text Available Each step of the seed-to-seed cycle of plant development including seed germination is characterized by a specific set of proteins. The continual renewal and/or replacement of these biomolecules are crucial for optimal plant adaptation. As proteins are the main effectors inside the cells, their levels need to be tightly regulated. This is partially achieved by specific proteolytic pathways via multicatalytic protease complexes defined as 20S and 26S proteasomes. In plants, the 20S proteasome is responsible for degradation of carbonylated proteins, while the 26S being a part of ubiquitin-proteasome pathway (UPP is known to be involved in proteolysis of phytohormone signaling regulators. On the other hand, the role of translational control of plant development is also well documented, especially in the context of pollen tube growth and light signaling. Despite the current progress that has been made in seed biology, the sequence of cellular events that determine if the seed can germinate or not are still far from complete understanding. The role and mechanisms of regulation of proteome composition during processes occurring in the plant’s photosynthetic tissues have been well characterized since many years, but in nonphotosynthetic seeds it has emerged as a tempting research task only since the last decade. This review discusses the recent discoveries providing insights into the role of protein turnover in seed dormancy alleviation, and germination, with a focus on the control of translation and proteasomal proteolysis. The presented novel data of translatome profiling in seeds highlighted that post-transcriptional regulation of germination results from a timely regulated initiation of translation. In addition, the importance of 26S proteasome in the degradation of regulatory elements of cellular signaling and that of the 20S complex in proteolysis of specific carbonylated proteins in hormonal- and light-dependent processes occurring in seeds is

  20. Fostering Informed Choice: Alleviating the Trauma of Genetic Abortions.

    Science.gov (United States)

    Asbury, Bret D

    2015-01-01

    Each year, thousands of pregnant women learn of fetal abnormalities through prenatal genetic analysis. This discovery--made after a woman has initially declined to exercise her right to abort an unwanted pregnancy—raises the difficult and heart-wrenching question of whether to terminate on genetic grounds. Women considering a genetic abortion rely on information and support from health care providers to assist them in making their choice. Though intended to be objective and nondirective, the support women receive frequently provides them within complete and incomprehensible information having the effect of encouraging them to abort genetically anomalous fetuses. As a result, genetic terminations--which cause severe and long-standing psychological impacts such as pathological grief, depression and post-traumatic stress—are often the result of something other than a fully informed choice.Congress and eleven states have recognized the importance of better informing choice by passing legislation aimed at providing clearer and more balanced information to expectant mothers learning of fetal genetic abnormalities. But existing legislative remedies do not adequately address this problem, and this inadequacy will become more pronounced in future years as increases in access to prenatal genetic analysis further stretch the capabilities of the available support services.This Article describes the unique characteristics of terminations for a fetal abnormality, their troubling and persistent psychological impacts,and the reasons why they will become more common in future years. It then offers proposals for how to reconfigure the prenatal genetic counseling landscape in order to reduce the incidence of genetic terminations based on incomplete or misleading information, thereby alleviating their distinct psychological costs. Its overall objective is to ensure that women learning of prenatal genetic abnormalities have access to complete and comprehensible information prior to

  1. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    Science.gov (United States)

    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.

  2. The Approaches of Islamic and Conventional Microfinancing for Poverty Alleviation and Sustainable Livelihood

    Directory of Open Access Journals (Sweden)

    Abul Bashar Bhuiyan

    2012-01-01

    Full Text Available Poverty is the main illness for sustainable livelihood because it destroyed human basic rights for surviving with minimum opportunities especially political, social stability and economic processes, literature and environment. The aims of this study are to discuss about existing approaches of poverty alleviation and sustainable livelihood. The study found throughout the discussion of the theoretical sources i.e., participatory approaches have determined as a good way of poverty alleviation and sustainable livelihood especially zakat based Islamic mode of financing and Qard-al-Hasan on the basis of spiritual values as an alternative model for poverty alleviation and ensuring sustainable livelihood."

  3. Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

    Science.gov (United States)

    Zeng, Qingchun; Song, Rui; Fullerton, David A.; Ao, Lihua; Zhai, Yufeng; Li, Suzhao; Ballak, Dov B.; Cleveland, Joseph C.; Reece, T. Brett; McKinsey, Timothy A.; Xu, Dingli; Dinarello, Charles A.; Meng, Xianzhong

    2017-01-01

    Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease. PMID:28137840

  4. Melatonin agonists for treatment of sleep and depressive disorders

    Directory of Open Access Journals (Sweden)

    Seithikurippu R. Pandi-Perumal

    2011-06-01

    Full Text Available Melatonin the hormone secreted by the pineal gland has been effective in improving sleep both in normal sleepers and insomniacs and has been used successfully in treating sleep and circadian rhythm sleep disorders. The lack of consistency in the reports published by the authors is attributed to the differential bioavailabilty and short half-life of melatonin. Sleep disturbances are also prominent features of depressive disorders. To overcome this problem, melatonergic agonists with sleep promoting properties have been introduced in clinical practice. Ramelteon, the MT1/ MT2 melatonergic agonist, has been used in a large number of clinical trials involving chronic insomniacs and has been found effective in improving the total sleep time and sleep efficiency of insomniacs and has not manifested serious adverse effects. The development of another MT1/MT2 melatonergic agonist agomelatine with antagonsim to 5-HT2c serotonin receptors has been found useful not only in treating sleep problems of patients but also as a first line antidepressant with earlier onset of actions in patients with major depressive disorder. An agonist for MT3 melatonin receptor has also been found effective in animal models of depression. [J Exp Integr Med 2011; 1(3.000: 149-158

  5. [Alpha 2-adrenoceptor agonists for the treatment of chronic pain].

    Science.gov (United States)

    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.

  6. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.;

    2011-01-01

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk...

  7. Use of ß-adrenergic agonists in hybrid catfish

    Science.gov (United States)

    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...

  8. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian;

    2012-01-01

    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metaboli...

  9. Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Bushby, S.A.; Kamenecka, T.A.; He, Y.; Nettles, K.W.; Griffin, P.R.

    2009-05-28

    Binding to helix 12 of the ligand-binding domain of PPAR{gamma} is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPAR{gamma} with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPAR{gamma} transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

  10. Principles of agonist recognition in Cys-loop receptors

    DEFF Research Database (Denmark)

    Lynagh, Timothy Peter; Pless, Stephan Alexander

    2014-01-01

    diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework...

  11. Consumption of Pistacia lentiscus foliage alleviates coccidiosis in young goats.

    Science.gov (United States)

    Markovics, A; Cohen, I; Muklada, H; Glasser, T A; Dvash, L; Ungar, E D; Azaizeh, H; Landau, S Y

    2012-05-25

    Coccidiosis near weaning is a major cause of diarrhea, ill-thrift, and impaired performance in small ruminants. A recent survey showed that in villages of the Samaria Hills, Israel, shepherds treat young, weaned goat kids afflicted with diarrhea by cutting and feeding them the foliage of Pistacia lentiscus L. (lentisk) or by tethering them close to lentisk bushes which they browse. The aim of the present study was to assess whether lentisk leaves do indeed have anti-coccidial value, and, if positive, to ascertain the role of tannins in this effect. We monitored for 24 (Experiment 1) and 30 (Experiment 2) days the effect of lentisk feeding on the development of naturally occurring coccidiosis in weaned kids artificially infected with parasitic nematodes. In Experiment 1, kids were infected with nematodes and fed lentisk foliage (PIS) or cereal hay (HAY). Coccidiosis developed at the early stage of the nematode infection, when dietary treatments were initiated. Kids in the PIS group had a lower (P<0.02) concentration of oocysts per gram feces (opg). In Experiment 2, aimed at verifying if tannins are the active component in lentisk foliage, coccidiosis occurred at the peak of the nematode infection, before experimental diets were initiated. Dietary treatments were: cereal hay (HAY), or lentisk foliage consumed without (PIS) or with (PISPEG) a 20-g daily supplement of polyethylene glycol (PEG; MW 4000), a molecule that impairs tannin-bonding with proteins. Goats fed the PIS diet had lower fecal opg counts than counterparts of the HAY (P<0.001) and PISPEG (P<0.002) treatments. Fecal opg counts for the HAY and PISPEG treatments did not differ, suggesting that the anti-coccidial moiety in lentisk was indeed tannins. Our results strongly suggest that: (i) in agreement with the ethno-veterinary anecdotal evidence, exposure of young, weaned goat kids to lentisk foliage alleviates coccidiosis; and (ii) this positive effect is associated with tannins. As coccidiosis is a major

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

    Science.gov (United States)

    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. Predictive Gust Load Alleviation Control Using Leading Edge Stagnation Point Sensor Project

    Data.gov (United States)

    National Aeronautics and Space Administration — ZONA Technology, Inc proposes an R&D effort to develop a Gust Load Alleviation (GLA) control system using a novel Leading Edge Stagnation Point (LESP) sensor...

  14. Use Of Dynamic Distortion To Predict And Alleviate Loss Of Control Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The intent of this project is to develop and validate means to alert, constrain and thereby alleviate loss of control (LOC) associated with unfavorable pilot-vehicle...

  15. Use Of Dynamic Distortion To Predict And Alleviate Loss Of Control Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Improvements to aviation safety will be made by the development and validation of means to alleviate, alert, and inhibit loss of control associated with unfavorable...

  16. Seed storage-mediated dormancy alleviation in Fabaceae from campo rupestre

    Directory of Open Access Journals (Sweden)

    Naïla Nativel

    2015-09-01

    Full Text Available ABSTRACTWe studied the effects of seed storage on germination and dormancy alleviation in three species of Fabaceae endemic to campo rupestrein southeastern Brazil. Fresh seeds of Collaea cipoensis, Mimosa maguirei and Mimosa foliolosawere set to germinate and germination of seeds after four, five and 13 years of storage was tested. Seed viability was maintained for all species after the full storage period. Seed storage significantly increased germination percentage and decreased germination time for C. cipoensisand M. foliolosa, suggesting the alleviation of physical dormancy with storage. However, we did not find evidence of dormancy alleviation in M. maguirei since stored seeds showed a decrease in germination in comparison to that of fresh seeds. Our data indicate species-specific storage-mediated dormancy alleviation, which will have important implications for restoration of campo rupestre.

  17. Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools

    NARCIS (Netherlands)

    Van Rosmalen, Peter; Klemke, Roland; Westera, Wim

    2011-01-01

    Van Rosmalen, P., Klemke, R., & Westera, W. (2011, 20-21 October). Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools. Presentation at 5th European Conference on Games Based Learning, Athens, Greece.

  18. Differential mechanisms of action of the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1.

    Science.gov (United States)

    Feng, Xinghua; Xiong, Jian; Lu, Yungang; Xia, Xuefeng; Zhu, Michael X

    2014-12-01

    Mucolipin synthetic agonist 1 (ML-SA1) was recently identified to activate mammalian TRPML channels and shown to alleviate lipid accumulation in lysosomes of cellular models of lysosome storage diseases, mucolipidosis type IV (MLIV) and Niemann-Pick's disease type C (NPC). Owning to its potential use in complimenting genetic studies in Drosophila melanogaster to elucidate the cellular and physiological functions of TRPML channels, we examined the effect of ML-SA1 on Drosophila TRPML expressed in HEK293 cells using whole-cell, inside-out, and whole-lysosome electrophysiological recordings. We previously showed that when expressed in HEK293 cells, Drosophila TRPML was localized and functional on both plasma membrane and endolysosome. We show here that in both inside-out patches excised from the plasma membrane and whole-lysosome recordings from enlarged endolysosome vacuoles, ML-SA1 failed to activate TRPML unless exogenous phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] was applied. At 1 μM ML-SA1, the sensitivity of TRPML to PI(3,5)P2 increased approximately by 10-fold and at 10 μM ML-SA1, the deactivation of PI(3,5)P2-evoked TRPML currents was markedly slowed. On the other hand, constitutive activation of TRPML by a mutation that mimics the varitint-waddler (Va) mutation of mouse TRPML3 rendered the insect channel sensitive to activation by ML-SA1 alone. Moreover, different from the insect TRPML, mouse TRPML1 was readily activated by ML-SA1 independent of PI(3,5)P2. Thus, our data reveal that while ML-SA1 acts as a true agonist at mouse TRPML1, it behaves as an allosteric activator of the Drosophila TRPML, showing dependence on and the ability to stabilize open conformation of the insect channels.

  19. Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2

    DEFF Research Database (Denmark)

    Holm, Mai Marie; Lunn, Marie-Louise; Traynelis, Stephen F;

    2005-01-01

    Glutamate receptors (GluRs) are the most abundant mediators of the fast excitatory neurotransmission in the human brain. Agonists will, after activation of the receptors, induce different degrees of desensitization. The efficacy of agonists strongly correlates with the agonist-induced closure of ...

  20. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists ar

  1. Analysis of Poverty Alleviation Model of Advancing Entire Villages——A Case Study of Ningxia

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    This paper gives an overview of the development-oriented poverty alleviation of advancing entire villages in Ningxia, and then relates the implementation of "1 000-village poverty alleviation program" of Ningxia by stages as follows: at the first stage (2005-2006), 203 villages began to implement the first development-oriented poverty alleviation program of advancing entire villages; at the second stage (2007-2008), the second development-oriented poverty alleviation program of advancing entire villages was implemented. By empirical analysis, the main experience in the process of implementing poverty alleviation model of advancing entire villages is generalized as follows: strengthen the support and help degree and frame feasible implementation planning; develop characteristic industries and expand export of labor services; support poor areas by using technology. Through five years of support, the poverty alleviation model of advancing entire villages achieves initial results: the specific sample survey shows that in the poor villages with smooth development of advancing entire villages and great investments, the farmers’ income per capita in whole village can be increased by more than 50% within one year or two years; due to the improvement of road, communication and other conditions, many poor villages can explore new possibilities for production, and better give play to the comparative advantages; the improvement of infrastructure also promotes export of labor services in the poor villages, so as to indirectly increase the income of farmers in poor villages.

  2. PPAR GAMMA AGONISTS: AN EFFECTIVE STRATEGY FOR CANCER TREATMENT

    Directory of Open Access Journals (Sweden)

    Divya G.S

    2013-10-01

    Full Text Available PPAR-γ regulates cellular differentiation, development and metabolism. They play these essential roles by functioning as transcription factors regulating the expression of genes. The PPARs mainly are of three types α, β and γ. The PPAR-γ expressed in three forms γ1, γ2 and γ3 present in different tissues. When PPAR binds its ligand, transcription of target gene is increased or decreased. Tzds were able to induce cell differentiation and apoptosis or inhibit cell proliferation both in vitro and in vivo. However, widespread use of thiazolidinediones (TZDs, the clinically used synthetic PPAR gamma agonists, has been limited by adverse effects. So in this review we are suggesting some new molecules other than thiazolidine diones which can act as potential anticancer agents, after explaining the mechanism of action of PPAR-γ agonists as anticancer agents especially thiazolidinediones.

  3. Grooming, rank, and agonistic support in tufted capuchin monkeys.

    Science.gov (United States)

    Schino, Gabriele; Di Giuseppe, Francesca; Visalberghi, Elisabetta

    2009-02-01

    Studies investigating the relation between allogrooming and social rank in capuchin monkeys (genus Cebus) have yielded inconsistent results. In this study, we investigated the relation between grooming, agonistic support, aggression and social rank in a captive group of tufted capuchin monkeys (C. apella). Differently from most previous studies, we based our analyses on a relatively large database and studied a group with known genealogical relationships. Tufted capuchin females did not exchange grooming for rank-related benefits such as agonistic support or reduced aggression. Coherently with this picture, they did not groom up the hierarchy and did not compete for accessing high-ranking grooming partners. It is suggested that a small group size, coupled with a strong kin bias, may make the exchange of grooming for rank-related benefits impossible or unprofitable, thus eliminating the advantages of grooming up the hierarchy. We provide several possible explanations for the heterogeneity of results across capuchin studies that have addressed similar questions.

  4. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    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. (GSKPA)

    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.

  5. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    Science.gov (United States)

    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

  6. Agonistic Vocalisations in Domestic Cats : A Case Study

    OpenAIRE

    Schötz, Susanne

    2015-01-01

    Introducing a new cat to a home with resident cats may lead to stress, aggression and even fights. In this case study 468 agonistic cat vocalisations were recorded as one cat was introduced to three resident cats in her new home. Six vocalisation types were identified: growl, howl, howl-growl, hiss, spit and snarl. Numerous other intermediate and complex vocalisations were also observed. An acoustic analysis showed differences within and between all types. Future studies include further acous...

  7. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  8. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    Directory of Open Access Journals (Sweden)

    Fergus Keane

    2016-06-01

    Full Text Available 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.

  9. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: burristp@slu.edu [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)

    2015-05-08

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

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

    Science.gov (United States)

    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.

  11. Pharmacophore-driven identification of PPARγ agonists from natural sources

    Science.gov (United States)

    Petersen, Rasmus K.; Christensen, Kathrine B.; Assimopoulou, Andreana N.; Fretté, Xavier; Papageorgiou, Vassilios P.; Kristiansen, Karsten; Kouskoumvekaki, Irene

    2011-02-01

    In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.

  12. Pro-cognitive and antipsychotic efficacy of the alpha7 nicotinic partial agonist SSR180711 in pharmacological and neurodevelopmental latent inhibition models of schizophrenia.

    Science.gov (United States)

    Barak, Segev; Arad, Michal; De Levie, Amaya; Black, Mark D; Griebel, Guy; Weiner, Ina

    2009-06-01

    Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of alpha7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective alpha7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with alpha7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

  13. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74...... receptor was highly selective for GRO peptides, with IL-8 being 10,000-fold less potent. The constitutive stimulating activity of ORF-74 on phosphatidylinositol turnover was not influenced by, for example, IL-8 binding. In contrast, GRO peptides acted as potent agonists in stimulating ORF-74 signaling......, whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc...

  14. Economic contribution of participatory agroforestry program to poverty alleviation: a case from Sal forests, Bangladesh

    Institute of Scientific and Technical Information of China (English)

    K.K.Islam; Marjanke Hoogstra; M.O.Ullah; Noriko Sato

    2012-01-01

    In the Forest Department of Bangladesh,a Participatory Agroforestry Program (PAP) was initiated at a denuded Sal forests area to protect the forest resources and to alleviate poverty amongst the local poor population.We explored whether the PAP reduced poverty and what factors might be responsible for poverty alleviation.We used three poverty measurement methods:the Head Count Index,the Poverty Gap Index and the Foster-Greer-Thorbecke index to determine the extent poverty reduction.We used a linear regression model to determine the possible differences among factors in poverty reduction.Data were collected through semi-structured questionnaires and face to face interviews within the study area.PAP proved effective at poverty alleviation,considerably improving the local situation.The linear regression model showed that PAP output explained the income differences in poverty reduction. Participants identified bureaucracy and illegal money demands by forest department officials,an uncontrolled market system,and underdeveloped road infrastructure as the main obstacles to reduction of poverty.Overall,PAP is quite successful in alleviating poverty.So this program might be of interest at other degraded forest areas as a tool to alleviate poverty.

  15. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  16. NOD2 Agonist Promotes the Production of Inflammatory Cytokines in VSMC in Synergy with TLR2 and TLR4 Agonists

    Directory of Open Access Journals (Sweden)

    Jinghua Sun

    2012-01-01

    Full Text Available Objective. To investigate the expression of NOD2 in human VSMCs, its role in the production of inflammatory cytokines in VSMC and the possible interaction of NOD2-mediated signaling pathway with those mediated by TLR2 and TLR4. Methods. Human coronary artery smooth muscle cells were stimulated with NOD2 agonist MDP alone or in combination with either TLR2 agonist PAM3 or TLR4 agonist LPSs. The mRNA expression of NOD2 and FGF-2 were measured by RT-PCR. The concentration of IL-8 and TNF-α in the culture supernatants was determined by ELISA. VSMC proliferation ability was analyzed by MTT assay. Results. MDP up regulated the expression of NOD2 mRNA in VSMC in a time-dependent manner, up regulated the expression of FGF-2 mRNA in VSMC, induced the production of IL-8 and TNF-α, and promoted the proliferation of VSMC. Additionally, MDP synergied with LPS and PAM3 to promote the proliferation of VSMC and induce the production of IL-8 and TNF-α. Conclusion. The activation of NOD2-mediated innate immune signaling pathway can increase the proliferation ability of VSMC and induce the production of inflammatory cytokines in VSMC. It is also shown a synergistic effect with TLR2- and TLR4-mediated signaling pathways in this process.

  17. Alleviation of glucose repression of maltose metabolism by MIG1 disruption in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Klein, Christopher; Olsson, Lisbeth; Rønnow, B.

    1996-01-01

    The MIG1 gene was disrupted in a haploid laboratory strain (B224) and in an industrial polyploid strain (DGI 342) of Saccharomyces cerevisiae. The alleviation of glucose repression of the expression of MAL genes and alleviation of glucose control of maltose metabolism were investigated in batch...... cultivations on glucose-maltose mixtures. In the MIG1-disrupted haploid strain, glucose repression was partly alleviated; i.e., maltose metabolism was initiated at higher glucose concentrations than in the corresponding wild-type strain. In contrast, the polyploid Delta mig1 strain exhibited an even more...... of glucose repression of the SUC genes. The disruption of MIG1 was shown to bring about pleiotropic effects, manifested in changes in the pattern of secreted metabolites and in the specific growth rate....

  18. The role of forestry development in China in alleviating greenhouse effects

    Energy Technology Data Exchange (ETDEWEB)

    Liu Hong

    1996-12-31

    Forestry development in China has gained great achievements and made great progress in realizing sustainable forest management and alleviating global climate change. The main measures to mitigate greenhouse effects through the means of forestry development include afforestation to increase the forested area, fuel wood forest development, management improvement, wise utilization, international cooperation, investment increase, forest related scientific research, strengthening the forest law enforcement system. Climate change as well as how to alleviate the greenhouse effects is a hot topic at present. This paper describes the achievements of China`s forestry development and its role to alleviate the greenhouse effects, and puts forward the measures to mitigate greenhouse effects through the means of forestry development.

  19. Alleviating Border Effects in Wavelet Transforms for Nonlinear Time-varying Signal Analysis

    Directory of Open Access Journals (Sweden)

    SU, H.

    2011-08-01

    Full Text Available Border effects are very common in many finite signals analysis and processing approaches using convolution operation. Alleviating the border effects that can occur in the processing of finite-length signals using wavelet transform is considered in this paper. Traditional methods for alleviating the border effects are suitable to compression or coding applications. We propose an algorithm based on Fourier series which is proved to be appropriate to the application of time-frequency analysis of nonlinear signals. Fourier series extension method preserves the time-varying characteristics of the signals. A modified signal duration expression for measuring the extent of border effects region is presented. The proposed algorithm is confirmed to be efficient to alleviate the border effects in comparison to the current methods through the numerical examples.

  20. Alleviating Energy Poverty through innovation: The case of Jyotigram Yojana (rural lighting scheme) of Gujarat

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Pramod Kumar

    2010-09-15

    Access to electricity is important for alleviation energy poverty in rural areas of developing countries. In spite of rural electrification schemes people in numerous villages do not have access to electricity because of inadequate and erratic power supply. The Jyotigram Yojana (Rural Lighting Scheme) of Gujarat in India transformed the rural electricity distribution scenario creating immense opportunities for socio-economic development. It shows how vision and political will can transcend the boundaries of technical and financial expertise and systemic rigidities, and facilitate successful adoption of simple but innovative approaches for alleviation of energy poverty and bringing about socio-economic development.

  1. Alleviating Effect of Phenol Compounds on Cucumber Fusarium Wilt and Mechanism

    Institute of Scientific and Technical Information of China (English)

    YUAN Fei; ZHANG Chun-lan; SHEN Qi-rong

    2003-01-01

    The amount of phenol compounds in the soil increased after adding organic material into the soil. It was found that p-hydroxybenzoic acid, p-coumaric acid and frulic acid alleviated Fusarium wilt of cucumber, the alleviating effect of p-hydroxybenzoic acid was the best, followed by p-coumaric acid and frulic acid. The total amount of bacterial, actinomyces and fungus in high phenol compounds treatment decreased than that of control treatment, while the microorganisms' amount in low phenol compounds treatment increased. Phenol compounds inhibit the growth of pathogen.

  2. Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions

    DEFF Research Database (Denmark)

    Zibert, John Robert; Wallbrecht, Katrin; Schön, Margarete

    2011-01-01

    with epidermal expression of human TGF-ß1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM...... in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.......-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue...

  3. Do Economic Reforms Alleviate Subjective Well-Being Losses of Economic Crises?

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    2014-01-01

    Major economic crises tend to be followed by crises in subjective well-being. Following the financial and debt crises, politicians and social scientists have engaged in heated discussions of ways to alleviate such losses. In particular, should governments intervene more or less? This paper explores...... whether liberalizing economic institutions, a type of reform favoured by some economists, is likely to alleviate such loses. Estimating the effects of crises across European states 1975–2011 suggest that countries with relatively easy market regulations suffered smaller well-being losses....

  4. Identification of human dopamine receptors agonists from Chinese herbs

    Institute of Scientific and Technical Information of China (English)

    Yi-lin ZHANG; Hai-qing ZHANG; Xiao-yu LIU; Shi-neng HUA; Lu-bing ZHOU; Jun YU; Xue-hai TAN

    2007-01-01

    Aim: To find human dopamine receptors, especially D1-like receptor specific ago-nists from Chinese herbs as potential antihypertension drug leads. Methods: Two D1-like receptor cell lines carrying a β-lactamase reporter gene, and a D2 receptor cell line coexpressing a promiscuous G protein G15 were constructed using HEK293 cells. A natural compound library made from fractionated samples of herbal ex-tracts was used for high-throughput screening (HTS) against one of the cell lines,HEK/D5R/CRE-blax. The interested hits were evaluated for their activities against various dopamine receptors. Results: Fourteen hits were identified from primary screening, of which 2 of the better hit samples, HD0522 and HD0059, were selected for further material and activity analysis, and to obtain 2 compounds that ap-peared as 2 single peaks in HPLC, HD0522H01 and HD0059H01. HD0059H01 could activate D1, D2, and D5 receptors, with EC50 values of 2.28 μg/mL, 0.85 μg/mL, and 1.41 μg/mL, respectively. HD0522H01 could only activate D1R and D5R with EC50 values of 2.95 μg/mL and 8.38 μg/mL. Conclusion: We established cell-based assays for 3 different human dopamine receptors and identified specific agonists HD0522H01 and HD0059H01 through HTS. The specific agonist to D1-like receptors, HD0522H01, may become a new natural product-based drug lead for antihypertension treatment.

  5. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    Science.gov (United States)

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD.

  6. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    Science.gov (United States)

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  7. Biased signaling by peptide agonists of protease activated receptor 2.

    Science.gov (United States)

    Jiang, Yuhong; Yau, Mei-Kwan; Kok, W Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A; Suen, Jacky Y; Fairlie, David P

    2017-02-07

    Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.

  8. Ramelteon: A melatonin receptor agonist for the treatment of insomnia

    Directory of Open Access Journals (Sweden)

    Devi V

    2008-01-01

    Full Text Available Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use> 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon′s properties.

  9. Discovery of a potent and selective GPR120 agonist.

    Science.gov (United States)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

  10. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    Science.gov (United States)

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

  11. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    Science.gov (United States)

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter.

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

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2012-09-14

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

  13. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment.

    Science.gov (United States)

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T; Abbruscato, Thomas J

    2015-06-03

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

  14. Exogenous calcium alleviates low night temperature stress on the photosynthetic apparatus of tomato leaves.

    Directory of Open Access Journals (Sweden)

    Guoxian Zhang

    Full Text Available The effect of exogenous CaCl2 on photosystem I and II (PSI and PSII activities, cyclic electron flow (CEF, and proton motive force of tomato leaves under low night temperature (LNT was investigated. LNT stress decreased the net photosynthetic rate (Pn, effective quantum yield of PSII [Y(II], and photochemical quenching (qP, whereas CaCl2 pretreatment improved Pn, Y(II, and qP under LNT stress. LNT stress significantly increased the non-regulatory quantum yield of energy dissipation [Y(NO], whereas CaCl2 alleviated this increase. Exogenous Ca2+ enhanced stimulation of CEF by LNT stress. Inhibition of oxidized PQ pools caused by LNT stress was alleviated by CaCl2 pretreatment. LNT stress reduced zeaxanthin formation and ATPase activity, but CaCl2 pretreatment reversed both of these effects. LNT stress caused excess formation of a proton gradient across the thylakoid membrane, whereas CaCl2 pretreatment decreased the said factor under LNT. Thus, our results showed that photoinhibition of LNT-stressed plants could be alleviated by CaCl2 pretreatment. Our findings further revealed that this alleviation was mediated in part by improvements in carbon fixation capacity, PQ pools, linear and cyclic electron transports, xanthophyll cycles, and ATPase activity.

  15. AVRDC- The World Vegetable Center: Role of horticulture in poverty alleviation

    OpenAIRE

    2006-01-01

    This presentation represents the mission of AVRDC as well as how it is implimented. The mission of AVRDC is to alleviate poverty and malnutrition in the developing world through increased production, marketing and consumption of safe vegetables. LTRA-5 (Agroforestry and Sustainable Vegetable Production)

  16. ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice

    DEFF Research Database (Denmark)

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar;

    2002-01-01

    we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals...

  17. Load alleviation potential of active flaps and individual pitch control in a full design load basis

    DEFF Research Database (Denmark)

    Barlas, Athanasios; Bergami, Leonardo; Hansen, Morten Hartvig;

    2015-01-01

    The load alleviation potential of the Controllable Rubber Trailing Edge Flap (CRTEF) is verified on a full Design Load Basis (DLB) setup using the aeroelastic code HAWC2, and by investigating a flap configuration for the NREL 5MW Reference Wind Turbine (RWT) model. The performance of the CRTEF co...

  18. Substitutive Competition: Virtual Pets as Competitive Buffers to Alleviate Possible Negative Influence on Pupils

    Science.gov (United States)

    Chen, Zhi-Hong; Chou, Chih-Yueh; Biswas, Gautam; Chan, Tak-Wai

    2012-01-01

    Although competition is regarded as a powerful motivator in game-based learning, it might have a negative influence, such as damage to confidence, on students who lose the competition. In this paper, we propose an indirect approach, substitutive competition, to alleviate such negative influences. The approach is used to develop a My-Pet v3 system,…

  19. Load alleviation potential of the Controllable Rubber Trailing Edge Flap (CRTEF) in the INDUFLAP project

    DEFF Research Database (Denmark)

    Barlas, Thanasis K.; Bergami, Leonardo; Hansen, Morten Hartvig

    The load alleviation potential of the Controllable Rubber Trailing Edge Flap (CRTEF) is verified on a full Design Load Base (DLB) setup using the aeroelastic code HAWC2, and by investigating a flap configuration for the NREL 5MW Reference Wind Turbine (RWT) model. The performance of the CRTEF...

  20. Novel Alleviation Mechanisms of Aluminum Phytotoxicity via Released Biosilicon from Rice Straw-Derived Biochars

    Science.gov (United States)

    Qian, Linbo; Chen, Baoliang; Chen, Mengfang

    2016-07-01

    Replacing biosilicon and biocarbon in soil via biochar amendment is a novel approach for soil amelioration and pollution remediation. The unique roles of silicon (Si)-rich biochar in aluminum (Al) phytotoxicity alleviation have not been discovered. In this study, the alleviation of Al phytotoxicity to wheat plants (root tips cell death) by biochars fabricated from rice straw pyrolyzed at 400 and 700 °C (RS400 and RS700) and the feedstock (RS100) were studied using a slurry system containing typical acidic soils for a 15-day exposure experiment. The distributions of Al and Si in the slurry solution, soil and plant root tissue were monitored by staining methods, chemical extractions and SEM-EDS observations. We found that the biological sourced silicon in biochars served dual roles in Al phytotoxicity alleviation in acidic soil slurry. On one hand, the Si particles reduced the amount of soil exchangeable Al and prevented the migration of Al to the plant. More importantly, the Si released from biochars synchronously absorbed by the plants and coordinated with Al to form Al-Si compounds in the epidermis of wheat roots, which is a new mechanism for Al phytotoxicity alleviation in acidic soil slurry by biochar amendment. In addition, the steady release of Si from the rice straw-derived biochars was a sustainable Si source for aluminosilicate reconstruction in acidic soil.

  1. Food Stamp and School Lunch Programs Alleviate Food Insecurity in Rural America. Fact Sheet

    Science.gov (United States)

    Smith, Kristin; Savage, Sarah

    2007-01-01

    The Food Stamp and the National School Lunch Programs play a vital role in helping poor, rural Americans obtain a more nutritious diet and alleviate food insecurity and hunger. This fact sheet looks at the extent to which rural America depends on these programs and describes characteristics of beneficiaries of these federal nutrition assistance…

  2. Economic contribution of participatory agroforestry program to poverty alleviation: a case from Sal forests, Bangladesh

    NARCIS (Netherlands)

    Islam, K.K.; Hoogstra, M.A.; Ullah, M.O.; Sato, N.

    2012-01-01

    In the Forest Department of Bangladesh, a Participatory Agroforestry Program (PAP) was initiated at a denuded Sal forests area to protect the forest resources and to alleviate poverty amongst the local poor population. We explored whether the PAP reduced poverty and what factors might be responsible

  3. Foreign direct investment and poverty alleviation : the case of Bulyanhulu and Geita gold mines, Tanzania

    NARCIS (Netherlands)

    Nyankweli, Emmanuel M.

    2012-01-01

    This PhD thesis seeks to quantify the economic, social and environmental effects of the gold mining sector as a component of foreign direct investments in Tanzania and its contribution to poverty alleviation. In addition to highlighting the socio-economic gains and losses, by exploring the corporate

  4. The Use of the Ombudsman's Services for Alleviating International Students' Difficulties

    Science.gov (United States)

    Katsara, Ourania

    2015-01-01

    This article offers some suggestions regarding the development of a support strategy by ombudsmen in order to alleviate international students' difficulties when studying in host universities. It is also shown how the Organisational Justice Theory can be used as a framework for understanding the role of ombudsman in higher education settings and…

  5. Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools

    NARCIS (Netherlands)

    Van Rosmalen, Peter; Klemke, Roland; Westera, Wim

    2011-01-01

    Van Rosmalen, P., Klemke, R., & Westera, W. (2011). Alleviating the Entrance to Serious Games by Exploring the Use of Commonly Available Tools. In D. Gouscos, & M. Meimaris (Eds.), Proceedings of the 5th European Conference on Games Based Learning (pp. 613-619), Athens, Greece. 20-21 October 2011.

  6. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy.

    Science.gov (United States)

    Klos, Kevin J; Bower, James H; Josephs, Keith A; Matsumoto, Joseph Y; Ahlskog, J Eric

    2005-09-01

    Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

  7. Long-acting beta(2)-agonists in management of childhood asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2000-01-01

    This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled......, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue...... medication instead of short-acting beta(2)-agonists for pediatric asthma management....

  8. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling.

    Science.gov (United States)

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar

    2016-04-26

    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  9. How does agonistic behaviour differ in albino and pigmented fish?

    Directory of Open Access Journals (Sweden)

    Ondřej Slavík

    2016-04-01

    Full Text Available In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics.

  10. The evolution of histamine H₃ antagonists/inverse agonists.

    Science.gov (United States)

    Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

    2011-01-01

    This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

  11. How does agonistic behaviour differ in albino and pigmented fish?

    Science.gov (United States)

    Slavík, Ondřej; Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics.

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  14. Identification of agonists for a group of human odorant receptors

    Directory of Open Access Journals (Sweden)

    Daniela eGonzalez-Kristeller

    2015-03-01

    Full Text Available Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10% have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs.

  15. Toll-Like Receptor 9 Agonists for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Davide Melisi

    2014-08-01

    Full Text Available The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  16. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  17. GLP-1 receptor agonist-induced polyarthritis: a case report.

    Science.gov (United States)

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo

    2014-08-01

    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  18. Melatonin and melatonin agonist for delirium in the elderly patients.

    Science.gov (United States)

    Chakraborti, Dwaipayan; Tampi, Deena J; Tampi, Rajesh R

    2015-03-01

    The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study.

  19. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  20. Discussion on the Work of Accurate Poverty Alleviation%做好精准扶贫工作的探讨

    Institute of Scientific and Technical Information of China (English)

    沈新忠

    2015-01-01

    Accurate poverty alleviation is one important content of deepening the reform and the work mechanism of innovative poverty alleviation development. In the article, it introduces the background of raising the accurate poverty alleviation, expounds the thought of doing the work of accurate poverty alleviation, and provides a reference for finding poor people, analyzing the causes of poverty, implementing the responsibility for helping, and doing accurate poverty alleviation.%精准扶贫是深化改革、创新扶贫开发工作机制的一项重要内容。介绍精准扶贫提出的背景,论述做好精准扶贫工作的思路,为找准贫困人口、分析致贫原因、落实帮扶责任、实施精准扶贫提供参考。

  1. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

    Directory of Open Access Journals (Sweden)

    Monica Puligheddu

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key

  2. Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists.

    Science.gov (United States)

    Maguire, David R; France, Charles P

    2014-11-01

    Cannabinoid receptor agonists, such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ(9)-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ(9)-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ(9)-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ(9)-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.

  3. Antinociceptive interactions between Mu-opioid receptor agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy.

    Science.gov (United States)

    Banks, Matthew L; Rice, Kenner C; Negus, S Stevens

    2010-11-01

    Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

  4. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice

    Science.gov (United States)

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P.; Wang, Nadan; Tang, Francesca; Knight, Morgan J.; Pan, Shi; Oliver, Brian; Deshpande, Deepak A.

    2017-01-01

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  5. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.

    2016-01-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  6. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    Science.gov (United States)

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  7. Synthesis of urea acetates as potential PPARα/γ,dual agonists

    Institute of Scientific and Technical Information of China (English)

    Chang Yan Zhao; Chang Qing Shi; Yuan Wei Chen

    2008-01-01

    In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia,we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists.The structure of the target compounds,intermediates were characterized by 1H NMR,HRMS.

  8. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    OpenAIRE

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  9. Sumatriptan (5-HT1D receptor agonist) does not exacerbate symptoms in obsessive compulsive disorder

    NARCIS (Netherlands)

    Pian, KLH; Westerberg, HGM; van Megen, HJGM; den Boer, JA

    1998-01-01

    The non-selective serotonin (5-HT) receptor agonist meta-chlorophenylpiperazine (mCPP) has been reported to elicit symptoms in patients with obsessive compulsive disorder (OCD). MK-212, another nonselective 5-HT receptor agonist, does not seem to induce obsessive compulsive symptoms in OCD patients.

  10. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis.

    NARCIS (Netherlands)

    Dekkers, O.M.; Lagro, J.; Burman, P.; Jorgensen, J.O.; Romijn, J.A.; Pereira, A.M.

    2010-01-01

    CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal

  11. The 5-HT(1F) receptor agonist lasmiditan as a potential treatment of migraine attacks

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer C; Olesen, Jes

    2012-01-01

    Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo...

  12. Efficacy and safety of the PPARγ partial agonist balaglitazone compared with pioglitazone and placebo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Byrjalsen, Inger; Qvist, Per;

    2011-01-01

    Treatment of patients with perioxisome proliferator-activated receptor-¿ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-¿ agonists has not been established in a clinical tri...

  13. Drug-induced Hypothermia by 5HT1A Agonists Provide Neuroprotection in Experimental Stroke

    DEFF Research Database (Denmark)

    Johansen, Flemming Fryd; Hasseldam, Henrik; Nybro Smith, Matthias;

    2014-01-01

    with .55°C ranging between .1-1.4°C. CONCLUSIONS: 5-hydroxytryptamine receptor 1A (5HT1A) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT1A agonists may be introduced to reduce body temperatures rapidly and prepare patients for further...

  14. Metabolic effects of beta2-agonists in relation to exercise performance

    DEFF Research Database (Denmark)

    Kalsen, Anders

    2015-01-01

    Beta2-agonists are frequently used in the treatment of asthma and exercise-induced bronchoconstriction in elite athletes. However, aside from a bronchodilatory effect, beta2-agonists have also been shown to improve exercise performance, which makes these substances subjected to misuse by elite...

  15. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

    Science.gov (United States)

    Sparks, Steven M; Chen, Grace; Collins, Jon L; Danger, Dana; Dock, Steven T; Jayawickreme, Channa; Jenkinson, Stephen; Laudeman, Christopher; Leesnitzer, M Anthony; Liang, Xi; Maloney, Patrick; McCoy, David C; Moncol, David; Rash, Vincent; Rimele, Thomas; Vulimiri, Padmaja; Way, James M; Ross, Sean

    2014-07-15

    The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

  16. A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Bergmann, Rikke; Sørensen, Pernille Louise

    2013-01-01

    We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate...

  17. Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related

    DEFF Research Database (Denmark)

    Shapiro, Bruce S; Andersen, Claus Yding

    2015-01-01

    . The agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger...

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

    Science.gov (United States)

    Museo, E; Wise, R A

    1990-03-01

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

  19. Use of thrombopoietin receptor agonists in childhood immune thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Angelica Maria Garzon

    2015-08-01

    Full Text Available Most children with immune thrombocytopenia (ITP will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA have been shown to be safe and efficacious in adults with ITP, and represent a new treatment option for children with chronic ITP. One TPO-RA, eltrombopag, is now approved for children. Clinical trials in children are ongoing and data is emerging on safety and efficacy. This review will focus on the physiology of TPO-RA, their clinical use in children, as well as the long term safety issues that need to be considered when using these agents

  20. N-methyl-D-aspartic acid receptor agonists

    DEFF Research Database (Denmark)

    Madsen, U; Frydenvang, Karla Andrea; Ebert, B

    1996-01-01

    (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy......) showed peak affinity for [3H]AMPA receptor sites (IC50 = 72 +/- 13 microM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 +/- 1.5 microM) than (S)-AMAA (9) (IC50 = 61 +/- 6.4 microM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly...

  1. Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra).

    Science.gov (United States)

    Simons, Rudy; Vincken, Jean-Paul; Mol, Loes A M; The, Susan A M; Bovee, Toine F H; Luijendijk, Teus J C; Verbruggen, Marian A; Gruppen, Harry

    2011-07-01

    The roots of licorice (Glycyrrhiza glabra) are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions, which were characterized by liquid chromatography-mass spectrometry and screened for activity in yeast estrogen bioassays. One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ERα and ERβ). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ERα. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E(2)). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20-60% by known ER antagonists, and no activity was found in yeast cells that did not express the ERα or ERβ subtype. Prolonged exposure of the yeast to the estrogenic fractions that showed superinduction did, contrary to E(2), not result in a decrease of the fluorescent response. Therefore, the superinduction was most likely the result of stabilization of the ER, yeast-enhanced green fluorescent protein, or a combination of both. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ERα-selective antagonism, similar to the ERα-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E(2) by approximately 80% at 6 × 10(-6) M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ERα.

  2. Agonist and antagonist effects of cytisine in vivo.

    Science.gov (United States)

    Radchenko, Elena V; Dravolina, Olga A; Bespalov, Anton Y

    2015-08-01

    Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects.

  3. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  4. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  5. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations.

    Science.gov (United States)

    Carris, Nicholas W; Taylor, James R; Gums, John G

    2014-12-01

    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  6. Alleviation Effect of Lanthanum on Cadmium Stress in Seedling Hydroponic Culture of Kidney Bean and Corn

    Institute of Scientific and Technical Information of China (English)

    Huang Xiaohua; Zhou Qing

    2006-01-01

    The seedling hydroponic culture experiment of kidney bean (Phaseolus vulgaris) and corn (Zea mays) was conducted to investigate the alleviation effect of lanthanum on Cd stress.It is found that growth is seriously inhibited and metabolism is maladjusted in the two crops under 30 and 300 μmol·L-1 Cd2+ stress.Plant height, taproot length, leaf area, and fresh or dry weight of root, stem, and leaf are all obviously decreased.Further, chlorophyll content decreases, membrane permeability, malonydialdehyde (MDA) content, activities of catalase (CAT) and peroxidase (POD) increases under Cd stress, as compared with the control.The damage to these two crops becomes more conspicuous with the prolongation of Cd stress.It is suggested that lanthanum might help kidney bean and corn seedlings alleviate Cd stress by improving the photosynthetic capacity, reducing membrane permeability and MDA content, and maintaining the activities of CAT and POD of these two crops.

  7. Initial Acceleration Suppression via Gust Alleviation Controller Using Prior Gust Information

    Science.gov (United States)

    Sato, Masayuki; Yokoyama, Nobuhiro

    This paper first shows the performance limit of gust alleviation controllers without prior gust information. Since control devices, such as elevator, aileron, and thrust, cannot be driven at the same time as their commands are given, the initial acceleration due to wind gust cannot be alleviated with any controllers which do not detect the wind gust a priori. However, if wind gust information is obtained a priori, then the initial acceleration can be suppressed with some controller, which is the second topic of this paper. Designing such controllers is formulated as a design problem of model predictive controllers, which is formulated as a convex Quadratic Programming (QP) problem and is easily solved numerically. Several numerical examples demonstrate the effectiveness of model predictive controllers to suppress the initial acceleration due to wind gust.

  8. Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway

    Science.gov (United States)

    Rani, Shilpa; Sreenivasaiah, Pradeep Kumar; Cho, Chunghee; Kim, Do Han

    2017-01-01

    Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit (p-eIF2)-α, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal (0.5 mg·kg−1·day−1) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling. PMID:28152298

  9. Integration of poverty alleviation with family planning: an interview with SFPC Vice Minister Yang Kuifu.

    Science.gov (United States)

    Zhu, H Z

    1996-08-01

    The Chinese Government, through its 1994-2000 National Program for Poverty Alleviation, plans to eradicate poverty for its 65 million impoverished citizens by 2000. Program strategies include providing tangible financial incentives to couples who accept the use of family planning. For example, family planning acceptors with per capita annual incomes of less than 530 yuan are given priority to obtain low-interest loans from local banks or credit cooperatives to launch and manage income-generating schemes. They also have priority over nonacceptors in being recruited to work in township and village enterprises, in purchasing farm supplies, and in obtaining land from village and township authorities upon which to build housing. Farm families need to be made to understand that family planning is in their own best interest. Providing children and adolescents in impoverished areas with more education is also important. The author notes how leaders in some impoverished areas do not understand the difference between poverty alleviation and poverty relief.

  10. CA-MAC: A Novel MAC Protocol to Alleviate Congestion in Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    WU, J.

    2013-11-01

    Full Text Available Even if the traffic pattern is known and the network topology is simple, a strong congestion can take place in wireless sensor networks (WSNs due to the data gathering effect and the duty-cycle operation. In this paper, we propose a novel medium access control (MAC protocol to alleviate the congestion, which is referred to as the congestion alleviation-MAC (CA-MAC. It adopts an adaptive contention window (ACW, which allows the nodes with more buffered packets to transmit with a higher probability, as well as an intelligent burst packet transmission when the congested nodes seize the channel. Simulations are performed in NS-2, and results show that the proposed CA-MAC protocol achieves a good performance in terms of the packet delivery ratio (PDR, power consumption, throughput, and average latency.

  11. Quercetin alleviates high glucose-induced Schwann cell damage by autophagy

    Institute of Scientific and Technical Information of China (English)

    Ling Qu; Xiaochun Liang; Bei Gu; Wei Liu

    2014-01-01

    Quercetin can reverse high glucose-induced inhibition of neural cell proliferation, and therefore may have a neuroprotective effect in diabetic peripheral neuropathy. It is dififcult to obtain pri-mary Schwann cells and RSC96 cells could replace primary Schwann cells in studies of the role of autophagy in the mechanism underlying diabetic peripheral neuropathy. Here, we show that under high glucose conditions, there are fewer autophagosomes in immortalized rat RSC96 cells and primary rat Schwann cells than under control conditions, the proliferative activity of both cell types is signiifcantly impaired, and the expression of Beclin-1 and LC3, the molecular mark-ers for autophagy, is signiifcantly lower. After intervention with quercetin, the autophagic and proliferative activity of both cell types is rescued. These results suggest that quercetin can allevi-ate high glucose-induced damage to Schwann cells by autophagy.

  12. Metacognitive emotion regulation: children's awareness that changing thoughts and goals can alleviate negative emotions.

    Science.gov (United States)

    Davis, Elizabeth L; Levine, Linda J; Lench, Heather C; Quas, Jodi A

    2010-08-01

    Metacognitive emotion regulation strategies involve deliberately changing thoughts or goals to alleviate negative emotions. Adults commonly engage in this type of emotion regulation, but little is known about the developmental roots of this ability. Two studies were designed to assess whether 5- and 6-year-old children can generate such strategies and, if so, the types of metacognitive strategies they use. In Study 1, children described how story protagonists could alleviate negative emotions. In Study 2, children recalled times that they personally had felt sad, angry, and scared and described how they had regulated their emotions. In contrast to research suggesting that young children cannot use metacognitive regulation strategies, the majority of children in both studies described such strategies. Children were surprisingly sophisticated in their suggestions for how to cope with negative emotions and tailored their regulatory responses to specific emotional situations.

  13. Novel controller design demonstration for vibration alleviation of helicopter rotor blades

    Science.gov (United States)

    Ulker, Fatma Demet; Nitzsche, Fred

    2012-04-01

    This paper presents an advanced controller design methodology for vibration alleviation of helicopter rotor sys- tems. Particularly, vibration alleviation in a forward ight regime where the rotor blades experience periodically varying aerodynamic loading was investigated. Controller synthesis was carried out under the time-periodic H2 and H∞ framework and the synthesis problem was solved based on both periodic Riccati and Linear Matrix Inequality (LMI) formulations. The closed-loop stability was analyzed using Floquet-Lyapunov theory, and the controller's performance was validated by closed-loop high-delity aeroelastic simulations. To validate the con- troller's performance an actively controlled trailing edge ap strategy was implemented. Computational cost was compared for both formulations.

  14. Prophylactic proopiomelanocortin expression alleviates capsaicin-induced neurogenic inflammation in rat trachea.

    Science.gov (United States)

    Liu, Guei-Sheung; Huang, Hung-Tu; Lin, Che-Jen; Shi, Jhih-Yin; Liu, Li-Feng; Tseng, Rue-Tseng; Weng, Wen-Tsan; Lam, Hing-Chung; Wen, Zhi-Hong; Cheng, Tian-Lu; Hsu, Kuei-Sen; Tai, Ming-Hong

    2009-12-01

    Neurogenic inflammation frequently causes acute plasma leakage in airways and life-threatening pulmonary edema. However, limited strategies are available to alleviate neurogenic inflammation. Proopiomelanocortin (POMC) is the precursor of anti-inflammatory melanocortins, which have been proposed of therapeutic potential for various inflammatory diseases. The present study aimed to evaluate whether peripheral POMC expression ameliorated capsaicin-induced acute neurogenic inflammation in rat trachea. Prophylactic POMC expression was achieved by intravenous injection of adenovirus encoding POMC (Ad-POMC), which led to POMC expression in livers and elevated plasma adrenocorticotropin levels for approximately 60 days. After gene delivery for 7 days, neurogenic inflammation was induced in rats by capsaicin injection. The extent of capsaicin-evoked plasma leakage in trachea was alleviated in Ad-POMC-treated rats compared with animals of control groups (P neurogenic inflammation.

  15. Low dose of lipopolysaccharide pretreatment can alleviate the inflammatory response in wound infection mouse model

    Institute of Scientific and Technical Information of China (English)

    Dong Wang; Yang Liu; Yan-Rui Zhao; Jun-Lin Zhou

    2016-01-01

    Purpose:To assess the effects of lipopolysaccharide (LPS) pretreatment on wound infection mouse model and evaluate the biological safety of the optimal pretreatment dose in vivo.Methods:Mice were pretreated with LPS of different doses at 48 and 24 h before femoral medial longitudinal incision was made and infected with different bacteria.Results:It is showed that 0.5 mg/kg/time of LPS pretreatment can significantly alleviate the inflammation in mouse model infected with methicillin-resistances Staphylococcus aureus,methicillin-sensitive S.aureus,Pseudomonas aeruginosa,or Escherichia coli compared with doses of 0.25 mg/kg/time,1 mg/kg/time,and 1.5 mg/kg/time.Conclusions:LP5 pretreatment can alleviate the inflammation in mouse model and the optimal dose is 0.5 mg/kg/time,and meanwhile it does not damage organs' function.

  16. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.

    Science.gov (United States)

    Valdecantos, M Pilar; Pardo, Virginia; Ruiz, Laura; Castro-Sánchez, Luis; Lanzón, Borja; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Rupérez, Francisco J; Barbas, Coral; Konkar, Anish; Naylor, Jacqui; Hornigold, David; Santos, Ana Dos; Bednarek, Maria; Grimsby, Joseph; Rondinone, Cristina M; Valverde, Ángela M

    2017-03-01

    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49.

  17. Alleviating Poverty

    DEFF Research Database (Denmark)

    Svendsen, Gunnar L.H.; Svendsen, Gert Tinggaard

    2001-01-01

    Why do we find entrepreneurship within larger groups? This question has challenged the social sciences since Olson (1965) showed that it does not pay an individual to provide collective goods voluntarily, if the individual economic gain from doing this is negative. However, the fact that larger g...

  18. AVRDC- The World Vegetables Center: Role of horticulture in poverty alleviation

    OpenAIRE

    2006-01-01

    This presentation highlights the work of AVRDC- The World Vegetable Center, whose mission is to alleviate poverty and malnutrition in the developing world through increased production, marketing and consumption of safe vegetables. The presentation outlines the issue of poverty and nutrient deficiency in the world, and the economic and health benefits to producing vegetables in developing countries. It outlines the research currently being conducted at global stations, as well as achievements ...

  19. Drought Impact Is Alleviated in Sugar Beets (Beta vulgaris L.) by Foliar Application of Fullerenol Nanoparticles

    OpenAIRE

    Borišev, Milan; Borišev, Ivana; Župunski, Milan; Arsenov, Danijela; Pajević, Slobodanka; Ćurčić, Živko; Vasin, Jovica; Djordjevic, Aleksandar

    2016-01-01

    Over the past few years, significant efforts have been made to decrease the effects of drought stress on plant productivity and quality. We propose that fullerenol nanoparticles (FNPs, molecular formula C60(OH)24) may help alleviate drought stress by serving as an additional intercellular water supply. Specifically, FNPs are able to penetrate plant leaf and root tissues, where they bind water in various cell compartments. This hydroscopic activity suggests that FNPs could be beneficial in pla...

  20. An integration programme of poverty alleviation and development with family planning.

    Science.gov (United States)

    1997-04-01

    The State Council (the central government) recently issued a Circular for Speeding Up the Integration of Poverty Alleviation and Development with the Family Planning Programme during the Ninth Five-year Plan (1996-2000). The Circular was jointly submitted by the State Family Planning Commission and the Leading Group for Poverty Alleviation and Development. The document sets the two major tasks as solving the basic needs for food and clothing of the rural destitute and the control of over-rapid growth of China's population. Practice indicates that a close Integration Programme is the best way for impoverished farmers to alleviate poverty and become better-off. Overpopulation and low educational attainments and poor health quality of population in backward areas are the major factors retarding socioeconomic development. Therefore, it is inevitable to integrate poverty alleviation with family planning. It is a path with Chinese characteristics for a balanced population and sustainable socioeconomic development. The targets of the Integration Programme are as follows: The first is that preferential policies should be worked out to guarantee family planning acceptors, especially households with an only daughter or two daughters, are the first to be helped to eradicate poverty and become well-off. They should become good examples for other rural poor in practicing fewer but healthier births, and generating family income. The second target is that the population plans for the poor counties identified by the central government and provincial governments must be fulfilled. This should contribute to breaking the vicious circle of poverty leading to more children, in turn generating more poverty. The circular demands that more efforts should focus on the training of cadres for the Integrated Programme and on services for poor family planning acceptors.

  1. Poverty Alleviation through Ecotourism in the Three Parallel Rivers World Heritage Site, Yunnan China

    OpenAIRE

    Cho, (Jenny) Juhyung

    2011-01-01

    Based on the material gathered from two months of fieldwork, this thesis explores the relations between ecotourism and poverty alleviation in the villages within the Three Parallel Rivers of the Yangtze (Jinsha), the Mekong (Lancang) and the Salween (Nu) rivers (henceforth TPR) in north-west Yunnan, China. The purpose of this research is to examine the mechanism of community-based ecotourism activities (horseback riding, nongjiale) and the dynamics of collaboration in maintaining these ecotou...

  2. Contribution Of Human Development Index On Per Capita Income Growth And Poverty Alleviation In Indonesia

    OpenAIRE

    Sudarlan

    2015-01-01

    Abstract The development of a country usually determined by the human development index HDI. Per capita income education and health are the three most important components of human development index. The purpose of this research is to understand the relationship among human development index to income per capita growth and poverty alleviation in Indonesia with cross-section data from 30 provinces period 2002 2011 year. The result of this research were a income per capita growth was not sign...

  3. CDM. Is it a 'win-win' strategy for rural poverty alleviation in India?

    Energy Technology Data Exchange (ETDEWEB)

    Sirohi, Smita [Department of Dairy Economics, Statistics and Management, National Dairy Research Institute, Karnal, Haryana, 132001 (India)

    2007-09-15

    India is perceived to be one of the most attractive Non-Annex I countries for CDM project development. There are more than 350 projects in the CDM pipeline, largely in the areas of renewable energy, energy efficiency in industries and fossil fuel switching. This paper examines the socio-economic component of sustainable development commitments of the CDM projects to see if they can make any impact on rural poverty in India, since the goal of poverty alleviation lies at the core of the country's development priorities. The study concludes that CDM is not contributing to rural poverty alleviation to any notable extent. Nearly all the projects have a business orientation and are not directed to the development of rural poor. Even the renewable energy projects will have limited role in up-liftment of the masses below poverty line due to their weak resource base. For CDM to emerge as a 'win-win' strategy for poverty alleviation projects should be aimed at the rural communities and designed to accelerate agricultural growth in the rain-fed regions of the country.

  4. Mechanisms of silicon-mediated alleviation of heavy metal toxicity in plants: A review.

    Science.gov (United States)

    Adrees, Muhammad; Ali, Shafaqat; Rizwan, Muhammad; Zia-Ur-Rehman, Muhammad; Ibrahim, Muhammad; Abbas, Farhat; Farid, Mujahid; Qayyum, Muhammad Farooq; Irshad, Muhammad Kashif

    2015-09-01

    In present era, heavy metal pollution is rapidly increasing which present many environmental problems. These heavy metals are mainly accumulated in soil and are transferred to food chain through plants grown on these soils. Silicon (Si) is the second most abundant element in the soil. It has been widely reported that Si can stimulate plant growth and alleviate various biotic and abiotic stresses, including heavy metal stress. Research to date has explored a number of mechanisms through which Si can alleviate heavy metal toxicity in plants at both plant and soil levels. Here we reviewed the mechanisms through which Si can alleviate heavy metal toxicity in plants. The key mechanisms evoked include reducing active heavy metal ions in growth media, reduced metal uptake and root-to-shoot translocation, chelation and stimulation of antioxidant systems in plants, complexation and co-precipitation of toxic metals with Si in different plant parts, compartmentation and structural alterations in plants and regulation of the expression of metal transport genes. However, these mechanisms might be associated with plant species, genotypes, metal elements, growth conditions, duration of the stress imposed and so on. Further research orientation is also discussed.

  5. Cost-Effectiveness of Payments for Ecosystem Services with Dual Goals of Environment and Poverty Alleviation

    Science.gov (United States)

    Gauvin, Crystal; Uchida, Emi; Rozelle, Scott; Xu, Jintao; Zhan, Jinyan

    2010-03-01

    The goal of this article is to understand strategies by which both the environmental and poverty alleviation objectives of PES programs can be achieved cost effectively. To meet this goal, we first create a conceptual framework to understand the implications of alternative targeting when policy makers have both environmental and poverty alleviation goals. We then use the Grain for Green program in China, the largest PES program in the developing world, as a case study. We also use a data set from a survey that we designed and implemented to evaluate the program. Using the data set we first evaluate what factors determined selection of program areas for the Grain for Green program. We then demonstrate the heterogeneity of parcels and households and examine the correlations across households and their parcels in terms of their potential environmental benefits, opportunity costs of participating, and the asset levels of households as an indicator of poverty. Finally, we compare five alternative targeting criteria and simulate their performance in terms of cost effectiveness in meeting both the environmental and poverty alleviation goals when given a fixed budget. Based on our simulations, we find that there is a substantial gain in the cost effectiveness of the program by targeting parcels based on the “gold standard,” i.e., targeting parcels with low opportunity cost and high environmental benefit managed by poorer households.

  6. Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion.

    Science.gov (United States)

    Ma, Jing; Zhang, Jing; Hou, Wei Wei; Wu, Xiao Hua; Liao, Ru Jia; Chen, Ying; Wang, Zhe; Zhang, Xiang Nan; Zhang, Li San; Zhou, Yu Dong; Chen, Zhong; Hu, Wei Wei

    2015-01-01

    Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0-3), but not the late stage after rUCCAO (day 4-32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.

  7. Assessing poverty-alleviation outcomes of an enterprise-led approach to sanitation.

    Science.gov (United States)

    London, Ted; Esper, Heather

    2014-12-01

    Inadequate sanitation negatively affects the lives of billions of people in the base of the pyramid (BoP) in the developing world, and has a particularly substantial impact on the well-being of millions of young children. Given the magnitude of the challenge and the limitations of existing approaches, enterprise-led approaches to providing public goods are generating growing interest. Emphasizing convergent innovation, enterprises targeting the BoP are presented as potentially sustainable and scalable interventions that generate positive poverty-alleviation effects. Yet our understanding of who is affected, and how, remains limited. To begin to address this gap, we apply a multidimensional framework to an urban-based, sanitation-oriented BoP enterprise, focusing on its poverty-alleviation effects on young children. Our analysis indicates that the enterprise's effects include changes in capability, economic, and relationship well-being and that these changes can be positive or negative. We also find that the impact varies depending on the role of the stakeholder in the business model and the age of the child. Our results contribute to a better understanding of how to assess the effectiveness of a sanitation intervention and how to evaluate the poverty-alleviation implications of an enterprise-led approach.

  8. Policy Review on Watershed Protection and Poverty Alleviation by the Grain for Green Program in China

    Institute of Scientific and Technical Information of China (English)

    LIZhiyong

    2004-01-01

    The sustained growth of Chinese economy in the new century is a silver lining in the continuously depressed global economy. Meanwhile, the rapid development of Chinese economy is still confronted with constraints from deteriorating environment and rural poverty issues. It has become a significant policy option in maintaining high speed, efficiency and sound development of Chinese economy to rehabilitate forest resources, improve ecological conditions, increase farmers' income and get on a sustainable road featuring coordinated development of population, resources and environment. The Grain for Green Program, as a CDM activity of Chinese style, launched on trial in 1999 and implemented in 2002 across the country, is the biggest land use transition, watershed management and poverty alleviation program involving the largest population in Chinese history and across the globe. It covers 25 provinces/regions/cities and gets over 1600 counties, 15 million households and 60 million farmers were involved. Hence the Grain for Tree policy has a significant bearing on ecological protection and farmers' poverty alleviation in the soil and water erosion-prone region. A review and assessment of the background, essentials, effects, problems and trend of the Grain for Tree policy is of great significance for both China and the other developing countries in the world in their efforts to combat the deteriorating environment and alleviate poverty.

  9. A Phase 3 Placebo-Controlled, Double Blind, Multi-Site Trial of the alpha-2-adrenergic Agonist, Lofexidine, for Opioid Withdrawal

    Science.gov (United States)

    Yu, Elmer; Miotto, Karen; Akerele, Evaristo; Montgomery, Ann; Elkashef, Ahmed; Walsh, Robert; Montoya, Ivan; Fischman, Marian W.; Collins, Joseph; McSherry, Frances; Boardman, Kathy; Davies, David K.; O’Brien, Charles P.; Ling, Walter; Kleber, Herbert; Herman, Barbara H.

    2008-01-01

    Context Lofexidine is an alpha-2-A noradrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. Objective To demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally-defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. Design An inpatient, Phase 3, placebo-controlled, double blind, randomized multi-site trial with three phases: (1) Opioid Agonist Stabilization Phase (days 1–3), (2) Detoxification/Medication or Placebo Phase (days 4–8), and (3) Post Detoxification/Medication Phase (days 9–11). Subjects Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. Main Outcome Measure Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (2nd opioid detoxification treatment day). Results Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (Least squares means 19.5 ± 2.1 versus 30.9 ± 2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). Conclusions Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification. Trial Registration trial registry name A Phase 3 Placebo-Controlled, Double-Blind Multi-Site Trial of Lofexidine for Opiate Withdrawal, registration number NCT00032942, URL for the registry http://clinicaltrials.gov/ct/show/NCT00032942?order=4. PMID:18508207

  10. Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model.

    Directory of Open Access Journals (Sweden)

    Noriko Suzuki

    Full Text Available BACKGROUND: Cannabinoid (CB receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB(1 and CB(2 receptors, respectively. In a previous study, TAK-937, a novel potent and selective CB(1 and CB(2 receptor agonist, was shown to exert significant cerebroprotective effects accompanied by hypothermia after transient middle cerebral artery occlusion (MCAO in rats. Sustained hypothermia itself induces significant neuroprotective effects. In the present studies, we examined the relative contribution of hypothermia and CB(1 receptor activation to the cerebroprotective effects of TAK-937. METHODOLOGY/PRINCIPAL FINDINGS: Using a multichannel brain temperature controlling system we developed, the brain temperature of freely moving rats was telemetrically monitored and maintained between 37 and 38°C during intravenous infusion of TAK-937 (100 µg/kg/h or vehicle for 24 h after 2 h MCAO. AM251, a selective CB(1 receptor antagonist, was administered intraperitoneally at 30 mg/kg 30 min before starting intravenous infusion of TAK-937 (100 µg/kg/h for 24 h. Rats were sacrificed and their brains were isolated 26 h after MCAO in both experiments. When the hypothermic effect of TAK-937 was completely reversed by a brain temperature controlling system, the infarct-reducing effect of TAK-937 was attenuated in part, but remained significant. On the other hand, concomitant AM251 treatment with TAK-937 completely abolished the hypothermic and infarct-reducing effects of TAK-937. CONCLUSIONS/SIGNIFICANCE: We conclude that the cerebroprotective effects of TAK-937 were at least in part mediated by induction of hypothermia, and mainly mediated by CB(1 receptor activation.

  11. Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy.

    Science.gov (United States)

    Katz, N K; Ryals, J M; Wright, D E

    2015-01-29

    Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8 weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N(6)-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of

  12. In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.

    Science.gov (United States)

    Coe, Jotham W; Vetelino, Michael G; Bashore, Crystal G; Wirtz, Michael C; Brooks, Paige R; Arnold, Eric P; Lebel, Lorraine A; Fox, Carol B; Sands, Steven B; Davis, Thomas I; Schulz, David W; Rollema, Hans; Tingley, F David; O'Neill, Brian T

    2005-06-15

    The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.

  13. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  14. Potency and characterization of estrogen-receptor agonists in United Kingdom estuarine sediments.

    Science.gov (United States)

    Thomas, Kevin V; Balaam, Jan; Hurst, Mark; Nedyalkova, Zoya; Mekenyan, Ovanes

    2004-02-01

    The activity of estrogen-receptor (ER) agonists in sediments collected from the United Kingdom (UK) estuaries was assessed using the in vitro recombinant yeast estrogen screen (YES assay). The YES assay was successfully used to determine the in vitro ER agonist potency of pore waters and solvent extracts of sediments collected from UK estuaries. Estrogen-receptor agonists were detected in 66% of the pore water samples and in 91% of the sediment solvent extracts tested. The pore waters tested had ER agonist potencies from less than 2 to 68 ng 17beta-estradiol (E2) L(-1), whereas sediment extracts had potencies from less than 0.2 to 13 microg E2 kg(-1). A toxicity identification evaluation approach using bioassay-directed fractionation was used in an attempt to identify the ER agonists in extracts of sediments collected from the Tyne and Tees estuaries (UK). Gas chromatography-mass spectrometry was used to provide lists of compounds in the fractions obtained that were evaluated for known ER agonist activity using published data and an ER quantitative structure-activity relationship model. Toxicity identification evaluation characterization failed to identify any ER agonists in pore water extracts; however, three compounds in sediment solvent extracts were identified as ER agonists. Nonylphenol, cinnarizine, and cholesta-4,6-dien-3-one were identified in the sample collected from the Tyne estuary. Important ER agonist substances that contaminate marine sediments remain unidentified. The present study as well as previous work on effluents point toward the involvement of natural products in the estrogenic burdens of marine sediments. Further work is required to establish the relative contribution of natural products and anthropogenic chemicals to current environmental impacts in the context of the Oslo and Paris Commission strategy to eliminate hazardous substances by 2020.

  15. Binding Mode of Insulin Receptor and Agonist Peptide

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

  16. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    OpenAIRE

    Pertwee, R. G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor ago...

  17. Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte L; Kelstrup, Christian D; Lyngsø, Christina;

    2010-01-01

    , we performed a global quantitative phosphoproteomics analysis of the AT(1)R signaling network. We analyzed ligand-stimulated SILAC (stable isotope labeling by amino acids in cell culture) cells by high resolution (LTQ-Orbitrap) MS and compared the phosphoproteomes of the AT(1)R agonist angiotensin II......(q)-dependent and -independent AT(1)R signaling. This study provides substantial novel insight into angiotensin II signal transduction and is the first study dissecting the differences between a full agonist and a biased agonist from a 7TMR on a systems-wide scale. Importantly, it reveals a previously unappreciated diversity...

  18. Behavioural effects of the benzodiazepine receptor partial agonist RO 16-6028 in mice.

    Science.gov (United States)

    Belzung, C; Misslin, R; Vogel, E

    1989-01-01

    The imidazo-diazepinone RO 16-6028 is a benzodiazepine receptor partial agonist which exhibits some anti-conflict effects in the two-chambered light/dark test without significantly affecting the behaviour of mice confronted with the staircase test. In addition, this drug slightly reduced locomotion and more markedly rearing in a free exploration procedure. These results indicate that RO 16-6028 appears to produce some anxiolytic and sedative properties like full agonists, but with weaker magnitude. This could be related to the benzodiazepine partial agonistic profile of the compound.

  19. Determining the contribution of tourism to poverty alleviation in Mozambique : case studies of Praia Bilene and Macanetta / Berni Valentin

    OpenAIRE

    2014-01-01

    Understanding the role that tourism play in poverty alleviation globally has been a research focus of many studies in different countries. For an extended period the trickle down method of wealth distribution, where it was believed that riches find its way down the value chain to the poor in terms of taxes spent on welfare, infrastructure, grants etc., was globally accepted. In recent years though, focus on tourism as tool for increasing economic growth and poverty alleviation has been placed...

  20. Role of silicon in alleviation of iron deficiency and toxicity in hydroponically-grown rice (Oryza sativa L.) plants

    OpenAIRE

    A Abdol Zadeh; z Kiani Chalmardi

    2013-01-01

    Silicon (Si) nutrition may alleviate biotic and abiotic stresses including heavy metal deficiency and toxicity in plants. Iron deficiency and toxicity are important limiting factors in growth of rice. In the present study, role of Si nutrition on alleviation of iron deficiency and toxicity was investigated in rice plants. Plants were cultivated in greenhouse in hydroponics, using Yoshida solution, under different iron treatments (0, 2, 10, 20, 50, 100 and 250 mg/L as Fe- EDTA) and Si nutritio...

  1. Agonists and Antagonists of TGF-β Family Ligands.

    Science.gov (United States)

    Chang, Chenbei

    2016-08-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

  2. Ontogenesis of agonistic vocalizations in the cichlid fish Metriaclima zebra.

    Science.gov (United States)

    Bertucci, Frédéric; Scaion, Delphine; Beauchaud, Marilyn; Attia, Joël; Mathevon, Nicolas

    2012-08-01

    While acoustic communication has been described in adults of various fish species, our knowledge about the ontogeny of fish sound production is limited. In adults, sound signals are known to be involved during aggressive interactions. However, aggressive behaviour may appear early in the life of fishes due to the possible competition for food and space. If acoustic signals are used to send information to competitors, sounds are likely to play a role during interactions between juvenile fish as well. The apparition and evolution of sound production were monitored in a group of juveniles of the cichlid fish Metriaclima zebra from hatching to 4 months of age. In addition, the link between vocalizations and agonistic behaviour was studied during dyadic interactions at three different ages. Sounds production appeared to be present early in the development of this fish and increased along with the number of aggressive behaviours. Recorded sounds consisted, in juveniles, in isolated pulses showing a decrease in frequency and duration as the fish grew. In adults, sounds became bursts of pulses but the transition from isolated to repetitive pulses was not observed. These results are compared to the existing literature on sound production ontogeny in fishes.

  3. Basic understanding of gonadotropin-releasing hormone-agonist triggering.

    Science.gov (United States)

    Casper, Robert F

    2015-04-01

    A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.

  4. Acute and Chronic Effects of ß2-Adrenoceptor Agonists in Relation to Exercise Performance and Doping with Emphasis on Terbutaline

    DEFF Research Database (Denmark)

    Hostrup, Morten

    , the underlying mechanisms by which β2-agonists affect performance in humans are inadequately explored. The purpose of this PhD was to investigate acute and chronic effects of high dose administration of terbutaline and to examine underlying mechanisms by which terbutaline affects performance.......This thesis addresses the performance enhancing effects of β2-agonists (asthma medication) with emphasis on terbutaline in the context of doping. Given the high prevalence of asthma in the athletic population, β2-agonists are among the most used drugs in competitive sport. While there is consensus...... that therapeutic inhalation of β2-agonists is without performance enhancing effects, oral β2-agonists are considered performance-enhancing. Since the systemic uptake of inhaled β2-agonists is higher than after oral intake, it may be that high dose inhalation of β2-agonists is performance enhancing. Moreover...

  5. Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

    DEFF Research Database (Denmark)

    Schwartz, Thue W; Holst, Birgitte

    2007-01-01

    Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites...... different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery...... process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug....

  6. Gust response modeling and alleviation scheme design for an elastic aircraft

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Time-domain approaches are presented for analysis of the dynamic response of aeroservoelastic systems to atmospheric gust excitations. The continuous and discrete gust inputs are defined in the time domain. The time-domain approach to continuous gust response uses a state-space formulation that requires the frequency-dependent aerodynamic coefficients to be approximated with the rational function of a Laplace variable. A hybrid method which combines the Fourier transform and time-domain approaches is used to calculate discrete gust response. The purpose of this approach is to obtain a time-domain state-space model without using rational function approximation of the gust columns. Three control schemes are designed for gust alleviation on an elastic aircraft, and three control surfaces are used: aileron, elevator and spoiler. The signals from the rate of pitch angle gyroscope or angle of attack sensor are sent to the elevator while the signals from accelerometers at the wing tip and center of gravity of the aircraft are sent to the aileron and spoiler, respectively. All the control laws are based on classical control theory. The results show that acceleration at the center of gravity of the aircraft and bending-moment at the wing-root section are mainly excited by rigid modes of the aircraft and the accelerations at the wing-tip are mainly excited by elastic modes of the aircraft. All the three control schemes can be used to alleviate the wing-root moments and the accelerations. The gust response can be alleviated using control scheme 3, in which the spoiler is used as a control surface, but the effects are not as good as those of control schemes 1 and 2.

  7. Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury.

    Science.gov (United States)

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Xia, Mi-Zhen; Wang, Hua; Zhao, Hui; Xu, De-Xiang; Yu, De-Xin

    2015-08-01

    Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 μg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS-induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up-regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3-pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS-induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS-induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes.

  8. Lutein alleviates arsenic-induced reproductive toxicity in male mice via Nrf2 signaling.

    Science.gov (United States)

    Li, S G; Xu, S Z; Niu, Q; Ding, Y S; Pang, L J; Ma, R L; Jing, M X; Wang, K; Ma, X M; Feng, G L; Liu, J M; Zhang, X F; Xiang, H L; Li, F

    2016-05-01

    This study aims to investigate the mechanisms involved in the action of lutein (LU) alleviating arsenic-induced reproductive toxicity using mice model. Forty male Kunming mice were received following treatments by gavage: normal saline solution (control), arsenic trioxide (ATO; 5 mg/kg/day), LU (40 mg/kg/day), and ATO + LU (5 mg/kg/day + 40 mg/kg/day). At the end, the mice were killed by cervical dislocation and weighed. Pathological examination was done on the testis. The biomedical parameters including superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. The messenger RNA (mRNA) and protein expression of Nrf2, heme oxygenase 1 (HO-1), glutathione S-transferase (GST), nicotinamide adenine dinucleotide phosphate dehydrogenase, quinone 1 (NQO1) in testis were detected by real-time polymerase chain reaction and Western blot. We found that there was a decrease in sperm count; testis somatic index; the activities of SOD, GSH, total antioxidative capacity (p treated mice, while there was an increase in the levels of sperm abnormalities, MDA, and 8-OHdG than control (p treated with ATO + LU showed recovery of the measured parameters between those of ATO or saline-treated group. The antagonized interaction between ATO and LU was statistically significant (p treated with ATO + LU also showed greater mRNA expression of Nrf2, HO-1, NQO1, and GST than ATO or saline-treated groups. These findings suggest that LU alleviates reproductive toxicity induced by arsenic in male mice via Nrf2 signaling, which implicates a possible mechanism of LU in preventing the reproductive injury, and elucidates that consuming the rich plant sources of LU will alleviate the reproductive toxicity induced by chemicals.

  9. Alleviation of cadmium toxicity in Medicago sativa by hydrogen-rich water

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Weiti; Gao, Cunyi; Fang, Peng [College of Life Sciences, Nanjing Agricultural University, Nanjing 210095 (China); Lin, Guoqing [Laboratory Center of Life Sciences, Co. Laboratory of Nanjing Agricultural University and Carl Zeiss Far East, Nanjing Agricultural University, Nanjing 210095 (China); Shen, Wenbiao, E-mail: wbshenh@njau.edu.cn [College of Life Sciences, Nanjing Agricultural University, Nanjing 210095 (China)

    2013-09-15

    Highlights: • HRW can alleviate Cd-induced alfalfa seedling growth inhibition and DNA laddering. • HRW alleviates Cd-induced oxidative stress by activating antioxidant enzymes. • Cd uptake in alfalfa seedling roots was decreased by HRW. • HRW can re-establish glutathione homeostasis under Cd stress. -- Abstract: Hydrogen gas (H{sub 2}) induces plant tolerance to several abiotic stresses, including salinity and paraquat exposure. However, the role of H{sub 2} in cadmium (Cd)-induced stress amelioration is largely unknown. Here, pretreatment with hydrogen-rich water (HRW) was used to characterize physiological roles and molecular mechanisms of H{sub 2} in the alleviation of Cd toxicity in alfalfa plants. Our results showed that the addition of HRW at 10% saturation significantly decreased contents of thiobarbituric acid reactive substances (TBARS) caused by Cd, and inhibited the appearance of Cd toxicity symptoms, including the improvement of root elongation and seedling growth. These responses were related to a significant increase in the total or isozymatic activities of representative antioxidant enzymes, or their corresponding transcripts. In vivo imaging of reactive oxygen species (ROS), and the detection of lipid peroxidation and the loss of plasma membrane integrity provided further evidence for the ability of HRW to improve Cd tolerance significantly, which was consistent with a significant enhancement of the ratio of reduced/oxidized (homo)glutathione ((h)GSH). Additionally, plants pretreated with HRW accumulated less amounts of Cd. Together, this study suggested that the usage of HRW could be an effective approach for Cd detoxification and could be explored in agricultural production systems.

  10. Alleviation of Boron Stress through Plant Derived Smoke Extracts in Sorghum bicolor

    Directory of Open Access Journals (Sweden)

    Pirzada Khan

    2014-08-01

    Full Text Available Boron is an essential micronutrient necessary for plant growth at optimum concentration. However, at high concentrations boron affects plant growth and is toxic to cells. Aqueous extract of plant-derived smoke has been used as a growth regulator for the last two decades to improve seed germination and seedling vigor. It has been established that plant-derived smoke possesses some compounds that act like plant growth hormones. The present research was the first comprehensive attempt to investigate the alleviation of boron stress with plant-derived smoke aqueous extract on Sorghum (Sorghum bicolor seed. Smoke extracts of five plants, i.e. Cymbopogon jwarancusa, Eucalyptus camaldulensis, Peganum harmala, Datura alba and Melia azedarach each with six dilutions (Concentrated, 1:100, 1:200, 1:300, 1:400 and 1:500 were used. While boron solutions at concentrations of 5, 10, 15, 20 and 25 ppm were used for stress. Among the dilutions of smoke, 1:500 of E. camaldulensis significantly increased germination percentage, root and shoot length, number of secondary roots and fresh weight of root and shoot while, boron stress reduced growth of Sorghum. It was observed that combined effect of boron solution and E. camaldulensis smoke extract overcome inhibition and significantly improved plant growth. Present research work investigated that the smoke solution has the potential to alleviate boron toxicity by reducing the uptake of boron by maintaining integrity of plant cell wall. The present investigation suggested that plant derived smoke has the potential to alleviate boron stress and can be used to overcome yield losses caused by boron stress to plants.

  11. The Effects of Inhaled β-Adrenergic Agonists in Transient Tachypnea of the Newborn

    Directory of Open Access Journals (Sweden)

    Esengul Keleş MD

    2016-05-01

    Full Text Available Aim. To investigate the efficacy of an inhaled β-adrenergic agonists in transient tachypnea of the newborn (TTN. Method. We retrospectively analyzed a cohort of 51 term infants (Group 1 and 37 term infants (Group 2 monitored in the newborn intensive care unit diagnosed with TTN. Infants in Group 1 received humidified oxygen alone, and infants in Group 2 were administered the inhaled β-2 agonist plus humidified oxygen. Results. TTN clinical respiratory assessment, respiratory rate, oxygen saturation values, need for supplemental oxygen therapy, blood gas PH, PO2, and duration of hospitalization were significantly improved in infants in Group 2 as compared with infants in Group 1 (P .05. Conclusion. Inhaled β-adrenergic agonist added to humidified oxygen was found to improve clinical and laboratory parameters. We believe that further studies should be conducted with larger groups to demonstrate the efficacy of β-2 agonists in TTN patients.

  12. [Pramipexol: a new dopaminergic agonist for the treatment of Parkinson disease].

    Science.gov (United States)

    Grandas, F; Galiano, M L

    1999-05-01

    Pramipexol is a novel nonergot dopamine agonist which has high selectivity for intereacting with dopamine D2 receptors (especially with D3 receptor subtype). It has been effective in early Parkinson's disease as monotherapy and as adjunctive therapy with L-dopa in advanced stages of the disease. Clinical improvement can be observed after 3 or 4 weeks of treatment. The adverse events profile of pramipexol is similar, in general, to that of other dopamine receptor agonists, although it can be foreseen that pramipexol should not induce side effects related to the ergot chemical structure such as eritromelalgia, distal vasospasm, retroperitoneal fibrosis or pleural effusions. Nevertheless, the potential advantages of this promising dopamine agonist should be tested in well-designed prospective comparative studies with other available ergot and nonergot dopamine agonists.

  13. Two cases of takotsubo cardiomyopathy in patients treated with high doses of inhaled beta-2-agonists

    DEFF Research Database (Denmark)

    Thomsen, Camilla Fjord; Jeppesen, Jørgen Lykke; Stride, Nis Ottesen

    2016-01-01

    Takotsubo cardiomyopathy (TCM) is characterised by reversible left ventricular dysfunction in patients presenting with acute coronary syndrome (ACS). TCM is considered multifactorial, and the repetitive exposure to inhaled beta-2-agonists has been suspected to induce TCM in predisposed individuals...

  14. Inhibition of AMPA Receptors by Polyamine Toxins is Regulated by Agonist Efficacy and Stargazin

    DEFF Research Database (Denmark)

    Poulsen, Mette H; Lucas, Simon; Strømgaard, Kristian;

    2014-01-01

    The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels mediating the majority of fast excitatory synaptic transmission in the central nervous system (CNS). Polyamine toxins derived from spiders and wasps are use- and voltage-dependent...... explored the effect of the TARP γ-2 (also known as stargazin) on the inhibitory potency of three structurally different polyamine toxins at Ca(2+)-permeable homomeric GluA1 AMPARs expressed in oocytes. We find that polyamine toxin IC50 is differentially affected by presence of stargazin depending...... on the efficacy of the agonists used to activate GluA1. Co-assembly of GluA1 receptors with stargazin increases the potency of the polyamine toxins when activated by the weak partial agonist kainate, but has no effect in presence of full-agonist L-glutamate (Glu) and partial agonist (RS)-willardiine....

  15. Dopamine Agonist in Treatment of ADHD with Restless Legs Syndrome and ODD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-05-01

    Full Text Available A 6-year-old male with attention deficit hyperactivity disorder who responded poorly to methylphenidate (MPH was benefited following treatment with the dopamine agonist ropinirole, in a report from the Hopital Robert Debre, Paris, France.

  16. Ingestion of TRP channel agonists attenuates exercise-induced muscle cramps.

    Science.gov (United States)

    Craighead, Daniel H; Shank, Sean W; Gottschall, Jinger S; Passe, Dennis H; Murray, Bob; Alexander, Lacy M; Kenney, W Larry

    2017-02-13

    Exercise associated muscle cramping (EAMC) is a poorly understood problem that is neuromuscular in origin. Ingestion of transient receptor potential (TRP) channel agonists has been efficacious in attenuating electrically-induced muscle cramps.

  17. Synthesis of 2-(Benzodioxol-2-yl)acetic Acids as PPARδ Agonists

    Institute of Scientific and Technical Information of China (English)

    Jian Lei KANG; Zhi Bing ZHENG; Dan QIN; Li Li WANG; Song LI

    2006-01-01

    A new series of compounds, 2-(benzodioxol-2-yl)acetic acids, have been synthesized. Their structures were confirmed by MS and 1H-NMR. The preliminary pharmacological screening showed that these compounds exhibited potent human PPARδ agonist activities.

  18. Experimental investigation of wing fin configurations for alleviation of vortex wakes of aircraft

    Science.gov (United States)

    Rossow, V. J.

    1978-01-01

    A variety of fin configurations were tested on a model of the Boeing B747 in 40 by 80 foot wind tunnels. The test results confirmed that a reduction in wake rolling moment was brought about by the vortex shed by the fins so that a wide range of designs can be used to achieve wake alleviation. It was also found that the reduction in wake-induced rolling moments was especially sensitive to the location of the smaller fins on the wing and that the penalties in lift and drag can probably be made negligible by proper fin design.

  19. Dietary Supplementation of Seaweed (Ulva lactuca) to alleviate the Impact of Heat Stress in Growing Lambs

    OpenAIRE

    Kkalid A. Abdoun, Aly B. Okab, Ahmed M. El-Waziry, Emad M. Samara and Ahmed A. Al-Haidary

    2014-01-01

    Several environmental and nutritional management approaches have been used to mitigate heat stress and improve performance of farm animals in semi-arid and arid regions. The present study was designed with the intention to alleviate the negative effects of heat stress and to promote the performance of growing lambs reared under hot environmental conditions. The study was conducted on 18 male Naimey lambs with average body weight of 22.78±0.49 kg, and 4-5 months old. The animals were randomly...

  20. Low carbon development and poverty alleviation. Options for development cooperation in energy, agriculture and forestry

    Energy Technology Data Exchange (ETDEWEB)

    Funder, M.; Fjalland, J.; Munk Ravnborg, H.; Egelyng, H.

    2009-07-01

    This report presents the main findings of a desk study on 'Climate change mitigation and poverty reduction in developing countries: opportunities for development cooperation'. The main objective of the study is to identify options for combining low carbon development pathways with poverty reduction and economic growth in the Least Developed Countries (LDCs), as part of efforts to target development assistance to address both poverty and global warming problems. The report discusses the pros and cons of climate change mitigation measures that also support poverty alleviation and economic development within the energy, agriculture and forestry sectors. It concludes with a series of recommendations for development cooperation.

  1. Alleviation of salinity stress on Vicia faba L. plants via seed priming with melatonin

    OpenAIRE

    Mona Gergis Dawood

    2014-01-01

    Melatonin is an environmentally friendly-molecule with a potent free radical scavenger and antioxidant capacity. Two pot experiments were conducted during two successive winter seasons (2011/2012 and 2012/2013) at the wire-house of the National Research Centre, Dokki, Cairo, Egypt to study the potentiality of melatonin (100 mM and 500 mM) in alleviating the harmful effect of diluted sea water at a relatively low and high concentrations (3.85 dS/m and 7.69 dS/m, respectively) on the performanc...

  2. Extractive sector politics in Latin America and their impact on poverty alleviation

    DEFF Research Database (Denmark)

    Pacheco Cueva, Vladimir

    disappointing with an increasing number of countries suffering from environmental degradation and resource dependency. Still, governments pursuing export-led development strategies continue to encourage foreign investment in the industry by promising predictable legal frameworks and favorable fiscal...... and experiences of Mexico, Chile and Peru in regards to the nexus between non-renewable resource management and poverty alleviation. With that contextual background, the paper will present the most common developmental debates taking place in El Salvador, the province of Mendoza (Argentina) and the state of Baja...

  3. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children

    Directory of Open Access Journals (Sweden)

    Chenhong Zhang

    2015-08-01

    Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

  4. Economic growth and poverty alleviation in Africa - linking hard and soft economics

    DEFF Research Database (Denmark)

    Kuada, John

    2014-01-01

    This paper provides a quick glance at the dominant issues that have characterized the development economics debate during the past five decades. It is based on a review of a selection of literature that highlights the dominant perspectives in development economics. It draws a distinction between ...... soft and hard economics, arguing that economic growth must be converted into social change that benefits poor for it to be described as development-oriented. It provides a direction for future research into issues of economic growth and poverty alleviation in Sub-Sahara Africa...

  5. Tema 2: Ethel and her Telenoid: Toward using humanoids to alleviate symptoms of dementia

    Directory of Open Access Journals (Sweden)

    Jens Dinesen Strandbech

    2016-01-01

    Full Text Available This article elaborates on a longitudinal study investigating if conversations with the teleoperated humanoid robot Telenoid can alleviate symptoms of dementia. The article initially frames Telenoid in the field of social robotics and relevant dementia-initiatives before dwelling on the emerging relationship between Telenoid and a person with severe dementia. Here it is shown how persons with severe dementia can benefit greatly from interaction with Functionally Designed Anthropomorphic Robots such as Telenoid as a means of providing a temporary ‘conversational stepping stone’, working toward improving quality of life and regaining conversational and social confidence to seek and interact socially with others.

  6. Alleviation of additional phase noise in fiber optical parametric amplifier based signal regenerator.

    Science.gov (United States)

    Jin, Lei; Xu, Bo; Yamashita, Shinji

    2012-11-19

    We theoretically and numerically explain the power saturation and the additional phase noise brought by the fiber optical parametric amplifier (FOPA). An equation to calculate an approximation to the saturated signal output power is presented. We also propose a scheme for alleviating the phase noise brought by the FOPA at the saturated state. In simulation, by controlling the decisive factor dispersion difference term Δk of the FOPA, amplitude-noise and additional phase noise reduction of quadrature phase shift keying (QPSK) based on the saturated FOPA is studied, which can provide promising performance to deal with PSK signals.

  7. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test.

    Science.gov (United States)

    Isacson, Ruben; Nielsen, Elisabet; Dannaeus, Karin; Bertilsson, Göran; Patrone, Cesare; Zachrisson, Olof; Wikström, Lilian

    2011-01-10

    We have earlier shown that the glucagon-like peptide 1 receptor agonist exendin-4 stimulates neurogenesis in the subventricular zone and excerts anti-parkinsonian behavior. The aim of this study was to assess the effects of exendin-4 treatment on hippocampus-associated cognitive and mood-related behavior in adult rodents. To investigate potential effects of exendin-4 on hippocampal function, radial maze and forced swim test were employed. The time necessary to solve a radial maze task and the duration of immobility in the forced swim test were significantly reduced compared to respective vehicle groups if the animals had received exendin-4 during 1-2weeks before testing. In contrast to the positive control imipramine, single administration of exendin-4 1h before the challenge in the forced swim test had no effect. Immunohistochemical analysis showed that the incorporation of bromodeoxyuridine, a marker for DNA synthesis, as well as doublecortin expression was increased in the hippocampal dentate gyrus following chronic treatment with exendin-4 compared to vehicle-treated controls. The neurogenic effect of exendin-4 on hippocampus was confirmed by quantitative PCR showing an upregulation of mRNA expression for Ki-67, doublecortin and Mash-1. Since exendin-4 significantly improves hippocampus-associated behavior in adult rodents, it may be a candidate for alleviation of mood and cognitive disorders.

  8. An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

    Directory of Open Access Journals (Sweden)

    Xia Chen

    2012-01-01

    Full Text Available Various 2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several 2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three 2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498, one 1-selective GABAA agonists (zolpidem, and another full agonist (alprazolam were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV- relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD. SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the 2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the 2,3-selective GABA-A agonists, implying an improved therapeutic window.

  9. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.; (GSKNC); (GSKPA)

    2010-09-03

    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  10. Discovery of a novel series of potent S1P1 agonists.

    Science.gov (United States)

    Crosignani, Stefano; Bombrun, Agnes; Covini, David; Maio, Maurizio; Marin, Delphine; Quattropani, Anna; Swinnen, Dominique; Simpson, Don; Sauer, Wolfgang; Françon, Bernard; Martin, Thierry; Cambet, Yves; Nichols, Anthony; Martinou, Isabelle; Burgat-Charvillon, Fabienne; Rivron, Delphine; Donini, Cristina; Schott, Olivier; Eligert, Valerie; Novo-Perez, Laurence; Vitte, Pierre-Alain; Arrighi, Jean-François

    2010-03-01

    The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.

  11. Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

    OpenAIRE

    Maslov, Leonid N; Khaliulin, Igor; Oeltgen, Peter R; Naryzhnaya, Natalia V.; Pei, Jian‐Ming; Brown, Stephen A; Lishmanov, Yury B.; Downey, James M

    2016-01-01

    Abstract It has now been demonstrated that the μ, δ1, δ2, and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusi...

  12. Structural determinants of agonist-specific kinetics at the ionotropic glutamate receptor 2.

    Science.gov (United States)

    Holm, Mai Marie; Lunn, Marie-Louise; Traynelis, Stephen F; Kastrup, Jette S; Egebjerg, Jan

    2005-08-23

    Glutamate receptors (GluRs) are the most abundant mediators of the fast excitatory neurotransmission in the human brain. Agonists will, after activation of the receptors, induce different degrees of desensitization. The efficacy of agonists strongly correlates with the agonist-induced closure of the ligand-binding domain. However, the differences in desensitization properties are less well understood. By using high-resolution x-ray structure of the GluR2 flop (GluR2o) ligand-binding core protein in complex with the partial glutamate receptor agonist (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isothiazolyl)propionic acid [(S)-thio-ATPA], we show that (S)-thio-ATPA induces an 18 degrees closure of the binding core similar to another partial agonist, (S)-2-amino-3-(4-bromo-3-hydroxy-5-isoxazolyl)propionic acid [(S)-Br-HIBO]. Despite the similar closure of the ligand-binding domain, we find in electrophysiological studies that (S)-thio-ATPA induced a 6.4-fold larger steady-state current than (RS)-Br-HIBO, and rapid agonist applications show that (S)-thio-ATPA induces a 3.6-fold higher steady-state/peak ratio and a 2.2-fold slower desensitization time constant than (RS)-Br-HIBO. Structural comparisons reveal that (S)-Br-HIBO, but not (S)-thio-ATPA, induces a twist of the ligand-binding core compared with the apostructure, and the agonist-specific conformation of Leu-650 correlates with the different kinetic profiles pointing at a key role in defining the desensitization kinetics. We conclude that, especially for intermediate efficacious agonists, the desensitization properties are influenced by additional ligand-induced factors beyond domain closure.

  13. Identification of benzoxazole analogs as novel, S1P(3) sparing S1P(1) agonists.

    Science.gov (United States)

    Deng, Guanghui; Meng, Qinghua; Liu, Qian; Xu, Xuesong; Xu, Qiongfeng; Ren, Feng; Guo, Taylor B; Lu, Hongtao; Xiang, Jia-Ning; Elliott, John D; Lin, Xichen

    2012-06-15

    A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

  14. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist.

    Science.gov (United States)

    Sard, Howard; Kumaran, Govindaraj; Morency, Cynthia; Roth, Bryan L; Toth, Beth Ann; He, Ping; Shuster, Louis

    2005-10-15

    An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.

  15. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician?

    Science.gov (United States)

    Scheen, André J

    2013-12-01

    Pharmacological treatment of type 2 diabetes has been enriched during recent years, with the launch of incretin therapies targeting glucagon-like peptide-1 (GLP-1). Such medications comprise either GLP-1 receptor agonists, with short (one or two daily injections: exenatide, liraglutide, lixisenatide) or long duration (one injection once weekly: extended-released exenatide, albiglutide, dulaglutide, taspoglutide); or oral compounds inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that inactives GLP-1, also called gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin). Although both pharmacological approaches target GLP-1, important differences exist concerning the mode of administration (subcutaneous injection versus oral ingestion), the efficacy (better with GLP-1 agonists), the effects on body weight and systolic blood pressure (diminution with agonists versus neutrality with gliptins), the tolerance profile (nausea and possibly vomiting with agonists) and the cost (higher with GLP-1 receptor agonists). Both agents may exert favourable cardiovascular effects. Gliptins may represent a valuable alternative to a sulfonylurea or a glitazone after failure of monotherapy with metformin while GLP-1 receptor agonists may be considered as a good alternative to insulin (especially in obese patients) after failure of a dual oral therapy. However, this scheme is probably too restrictive and modalities of using incretins are numerous, in almost all stages of type 2 diabetes. Physicians may guide the pharmacological choice based on clinical characteristics, therapeutic goals and patient's preference.

  16. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

  17. Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. (Eastern Virginia Medical School, Norfolk (USA))

    1989-11-01

    Stimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14- tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-(14C)eicosatrienoate was two-to threefold that of 5,11,14-(14C)eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.

  18. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

    Directory of Open Access Journals (Sweden)

    Ling Yang

    2011-12-01

    Full Text Available The nociceptin/orphanin FQ (NOP receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR studies were carried out using comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.

  19. Fluorescence characteristics of hydrophobic partial agonist probes of the cholecystokinin receptor.

    Science.gov (United States)

    Harikumar, Kaleeckal G; Pinon, Delia I; Miller, Laurence J

    2006-04-01

    Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.

  20. PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARα Agonists.

    Science.gov (United States)

    Silswal, Neerupma; Parelkar, Nikhil K; Wacker, Michael J; Badr, Mostafa; Andresen, Jon

    2012-01-01

    We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists using isolated mouse aortas and middle cerebral arteries (MCAs). The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K(+) attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium (K(ATP)) channel blocker glibenclamide also impaired relaxations whereas the other K(+) channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC), and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved K(ATP) channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response.

  1. Radiolabelled D2 agonists as prolactinoma imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Otto, C.A.

    1989-08-01

    During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

  2. The Long-Term Effective Mechanism of Rural Poverty Alleviation in China from the Perspective of Ecological Management

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Based on the ecological environmental situation of poverty-stricken areas in China and the domestic and foreign research results,the long-term effective mechanism of sustainable poverty alleviation in China is established(the ideological premise is ecological culture,the material base is ecological economy and the basic guarantee is ecological system) from the perspective of ecological management.To be specific,ecological culture,the ideological premise of rural sustainable poverty alleviation in China,includes two aspects:the first one is upholding the Marxism,passing on the Chinese traditional ecological wisdom and fostering ecological consciousness;the second one is mirroring the thought of western modern ecological ethics,emphasizing ecological criticism and redoubling the ecological education.As for ecological economy,the material guarantee for sustainable poverty alleviation in Chinese rural poverty-stricken areas,also contents two aspects.The first one is promoting the way of "clean production" and developing ecological industry;the second one is building ecological concept of consumption and establishing the ecological lifestyle.In addition,ecological system,the basic guarantee of sustainable poverty alleviation in Chinese rural poverty-stricken areas,covers three terms.The first one is implementing the ecological policies and stipulating ecological plan;the second one is establishing perfect ecological legislation and ecological system and intensifying their implementation;the third one is enforcing ecological management in the process of sustainable poverty alleviation.Through the establishment of the above mechanism,we look forward to realizing sustainability of economic development and poverty alleviation effects in the process of poverty alleviation in Chinese rural areas,as well as ecological management of the poverty-stricken areas.

  3. AN APPROACH TO ALLEVIATE THE FALSE ALARM IN BUILDING CHANGE DETECTION FROM URBAN VHR IMAGE

    Directory of Open Access Journals (Sweden)

    J. Chen

    2016-06-01

    Full Text Available Building change detection from very-high-resolution (VHR urban remote sensing image frequently encounter the challenge of serious false alarm caused by different illumination or viewing angles in bi-temporal images. An approach to alleviate the false alarm in urban building change detection is proposed in this paper. Firstly, as shadows casted by urban buildings are of distinct spectral and shape feature, it adopts a supervised object-based classification technique to extract them in this paper. Secondly, on the opposite direction of sunlight illumination, a straight line is drawn along the principal orientation of building in every extracted shadow region. Starting from the straight line and moving toward the sunlight direction, a rectangular area is constructed to cover partial shadow and rooftop of each building. Thirdly, an algebra and geometry invariant based method is used to abstract the spatial topological relationship of the potential unchanged buildings from all central points of the rectangular area. Finally, based on an oriented texture curvature descriptor, an index is established to determine the actual false alarm in building change detection result. The experiment results validate that the proposed method can be used as an effective framework to alleviate the false alarm in building change detection from urban VHR image.

  4. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  5. Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats

    Science.gov (United States)

    Shin, Mal-Soon; Kim, Tae-Woon; Lee, Jae-Min; Ji, Eun-Sang; Lim, Baek-Vin

    2017-01-01

    Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats.

  6. Drought Impact Is Alleviated in Sugar Beets (Beta vulgaris L.) by Foliar Application of Fullerenol Nanoparticles

    Science.gov (United States)

    Borišev, Milan; Borišev, Ivana; Župunski, Milan; Arsenov, Danijela; Pajević, Slobodanka; Ćurčić, Živko; Vasin, Jovica; Djordjevic, Aleksandar

    2016-01-01

    Over the past few years, significant efforts have been made to decrease the effects of drought stress on plant productivity and quality. We propose that fullerenol nanoparticles (FNPs, molecular formula C60(OH)24) may help alleviate drought stress by serving as an additional intercellular water supply. Specifically, FNPs are able to penetrate plant leaf and root tissues, where they bind water in various cell compartments. This hydroscopic activity suggests that FNPs could be beneficial in plants. The aim of the present study was to analyse the influence of FNPs on sugar beet plants exposed to drought stress. Our results indicate that intracellular water metabolism can be modified by foliar application of FNPs in drought exposed plants. Drought stress induced a significant increase in the compatible osmolyte proline in both the leaves and roots of control plants, but not in FNP treated plants. These results indicate that FNPs could act as intracellular binders of water, creating an additional water reserve, and enabling adaptation to drought stress. Moreover, analysis of plant antioxidant enzyme activities (CAT, APx and GPx), MDA and GSH content indicate that fullerenol foliar application could have some beneficial effect on alleviating oxidative effects of drought stress, depending on the concentration of nanoparticles applied. Although further studies are necessary to elucidate the biochemical impact of FNPs on plants; the present results could directly impact agricultural practice, where available water supplies are often a limiting factor in plant bioproductivity. PMID:27832171

  7. Prophylactic treatment with growth hormone improves intestinal barrier function and alleviates bacterial translocation in stressed rats

    Institute of Scientific and Technical Information of China (English)

    丁连安; 黎介寿; 李幼生; 刘放南; 谭力

    2004-01-01

    Background Damage to the gut barrier often occurs during critical illnesses. In such cases, it is very important to alleviate impairment of the intestinal barrier and protect intestinal barrier function. This study investigated the protective effect of growth hormone on intestinal barrier function in rats under stress.Methods This study consisted of prospective, randomized, and controlled animal experiments. Twenty-five Sprague-Dawley rats served as total parenteral nutrition (TPN) models and were divided into three groups: TPN group, sepsis (Sep) group, and growth hormone (GH) group. Another 8 rats served as normal controls. Each group received different stress stimuli. Rats were fed for 7 days, and samples were taken for examination 24 hours after garaging with dual saccharides. Results The architecture of the small intestinal mucosa in the Sep group showed the most severe damage among all groups. Nitric oxide levels in blood plasma and immunoglobulin A levels in the intestinal mucosa of the GH group were significantly lower than in the Sep group (P<0.02). There were no significant changes in CD3 counts and in the CD4/CD8 ratio between the four groups. Dual sugar tests and bacteriological examinations revealed that intestinal permeability and rate of bacterial translocation in the GH group were lower than in the Sep group (P<0.01, respectively).Conclusion Prophylactic treatment with growth hormone can alleviate damage to intestinal barrier function caused by trauma and endotoxemia in rats under stress.

  8. Engineering Strategies and Industrial Processing Capacity for Poverty Alleviation in Nigeria

    Directory of Open Access Journals (Sweden)

    Oladejo, I. O.

    2013-05-01

    Full Text Available The paper attempts to identify, discuss and proffer solution to some of the engineering activities that might have contributed to the poverty problem. Engineering profession’s willingness to find some meaningful solutions to the nation’s poverty problem is understandable and laudable. The nature of businesses including public enterprises are increasingly technical and engineering profession is usually involved in their development and maintenance. These enterprises have a remarkable capacity to absorb labour and hence are fruitful sources of jobs and income. The dismay performance of them in recent times is undoubtedly a contributing factor to the current poverty problem in Nigeria. In this paper, it was observed that past approaches to poverty alleviation such as free education, adult education, rural electrification, operation feed the nation, etc has an impact, but they were not successful. In order for engineering to effectively contribute to poverty alleviation, the country does require long-term engineering solution through technological innovation, manufacturing sector, manufacturing Value Added and activities of Engineering professional bodies. Proposal are presented to enhance engineering vision through industries capacity for improve quality of life for the increasing population to survive the competitive international economy

  9. Drought Impact Is Alleviated in Sugar Beets (Beta vulgaris L.) by Foliar Application of Fullerenol Nanoparticles.

    Science.gov (United States)

    Borišev, Milan; Borišev, Ivana; Župunski, Milan; Arsenov, Danijela; Pajević, Slobodanka; Ćurčić, Živko; Vasin, Jovica; Djordjevic, Aleksandar

    2016-01-01

    Over the past few years, significant efforts have been made to decrease the effects of drought stress on plant productivity and quality. We propose that fullerenol nanoparticles (FNPs, molecular formula C60(OH)24) may help alleviate drought stress by serving as an additional intercellular water supply. Specifically, FNPs are able to penetrate plant leaf and root tissues, where they bind water in various cell compartments. This hydroscopic activity suggests that FNPs could be beneficial in plants. The aim of the present study was to analyse the influence of FNPs on sugar beet plants exposed to drought stress. Our results indicate that intracellular water metabolism can be modified by foliar application of FNPs in drought exposed plants. Drought stress induced a significant increase in the compatible osmolyte proline in both the leaves and roots of control plants, but not in FNP treated plants. These results indicate that FNPs could act as intracellular binders of water, creating an additional water reserve, and enabling adaptation to drought stress. Moreover, analysis of plant antioxidant enzyme activities (CAT, APx and GPx), MDA and GSH content indicate that fullerenol foliar application could have some beneficial effect on alleviating oxidative effects of drought stress, depending on the concentration of nanoparticles applied. Although further studies are necessary to elucidate the biochemical impact of FNPs on plants; the present results could directly impact agricultural practice, where available water supplies are often a limiting factor in plant bioproductivity.

  10. Grape Seed Proanthocyanidin Extract Alleviates Arsenic-induced Oxidative Reproductive Toxicity in Male Mice

    Institute of Scientific and Technical Information of China (English)

    LI Shu Gang; GUO Shu Xia; DING Yu Song; NIU Qiang; XU Shang Zhi; PANG Li Juan; MA Ru Lin; JING Ming Xia; FENG Gang Ling; LIU Jia Ming

    2015-01-01

    Objective To determine the ability of grape seed proanthocyanidin extract (GSPE) in alleviating arsenic-induced reproductive toxicity. Methods Sixty male Kunming mice received the following treatments by gavage: normal saline solution (control); arsenic trioxide (ATO; 4 mg/kg); GSPE (400 mg/kg); ATO+GSPE (100 mg/kg);ATO+GSPE (200 mg/kg) and ATO+GSPE (400 mg/kg). Thereafter, the mice were sacrificed and weighed, and the testis was examined for pathological changes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO1), glutathione S-transferase (GST), NAD(P)H dehydrogenase, and quinone 1 (NQO1) expression in the testis was detected by real-time PCR. Superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability (T-AOC), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. Results ATO-treated mice showed a significantly decreased sperm count and testis somatic index and activity levels of SOD, GSH, and T-AOC than control group. Compared to the ATO-treated group, ATO+GSPE group showed recovery of the measured parameters. Mice treated with ATO+high-dose GSPE showed the highest level of mRNA expression of Nrf2, HO, NQO1, and GST. Conclusion GSPE alleviates oxidative stress damage in mouse testis by activating Nrf2 signaling, thus counteracting arsenic-induced reproductive toxicity.

  11. Alleviating versus stimulating effects of bicarbonate on the growth of Vallisneria natans under ammonia stress.

    Science.gov (United States)

    Dou, Yanyan; Wang, Baozhong; Chen, Liangyan; Yin, Daqiang

    2013-08-01

    Bicarbonate plays a crucial role in limiting the growth of submersed aquatic macrophytes in eutrophic lakes, and high ammonia is often toxic to macrophytes. In order to evaluate the combined effect of HCO3 (-) and total ammonia (i.e., the total of NH3 and NH4 (+)) on submersed macrophytes Vallisneria natans, the growth and physiological response of V. natans in the presence of HCO3 (-) and ammonia were studied. The results showed that with the increase of ammonia, morphological parameters of V. natans declined. In contrast, increased HCO3 (-) concentration stimulated the growth of V. natans, especially when the NH4 (+)-N/NO3 (-)-N ratio was 1:7. High ammonia concentration induced excess free amino acids (FAA) accumulation and soluble carbohydrates (SC) depletion in plant tissues. However, the elevated HCO3 (-) promoted the synthesis of SC and rendered the decrease of FAA/SC ratio. The results also suggested that HCO3 (-) could partially alleviate the stress of ammonia, as evidenced by the decrease of FAA/SC ratio and the growth enhancement of V. natans when the ammonia concentration was 0.58 mg L(-1). Given the fact that HCO3 (-) is probably the dominant available carbon source in most eutrophic lakes, the ability of V. natans to use HCO3 (-) for SC synthesis may explain the alleviating effect of HCO3 (-) on V. natans under ammonia stress.

  12. Foliar application with nano-silicon alleviates Cd toxicity in rice seedlings.

    Science.gov (United States)

    Wang, Shihua; Wang, Fayuan; Gao, Shuangcheng

    2015-02-01

    Nanofertilizers may be more effective than regular fertilizers in improving plant nutrition, enhancing nutrition use efficiency, and protecting plants from environmental stress. A hydroponic pot experiment was conducted to study the role of foliar application with 2.5 mM nano-silicon in alleviating Cd stress in rice seedlings (Oryza sativa L. cv Youyou 128) grown in solution added with or without 20 μM CdCl2. The results showed that Cd treatment decreased the growth and the contents of Mg, Fe, Zn, chlorophyll a, and glutathione (GSH), accompanied by a significant increase in Cd accumulation. However, foliar application with nano-Si improved the growth, Mg, Fe, and Zn nutrition, and the contents of chlorophyll a of the rice seedlings under Cd stress and decreased Cd accumulation and translocation of Cd from root to shoot. Cd treatment produced oxidative stress to rice seedlings indicated by a higher lipid peroxidation level (as malondialdehyde (MDA)) and higher activities of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), and a lower GSH content. However, those nano-Si-treated plants had lower MDA but higher GSH content and different antioxidant enzyme activities, indicating a higher Cd tolerance in them. The results suggested that nano-Si application alleviated Cd toxicity in rice by decreasing Cd accumulation, Cd partitioning in shoot and MDA level and by increasing content of some mineral elements (Mg, Fe, and Zn) and antioxidant capacity.

  13. Poverty alleviation strategies in eastern China lead to critical ecological dynamics.

    Science.gov (United States)

    Zhang, Ke; Dearing, John A; Dawson, Terence P; Dong, Xuhui; Yang, Xiangdong; Zhang, Weiguo

    2015-02-15

    Poverty alleviation linked to agricultural intensification has been achieved in many regions but there is often only limited understanding of the impacts on ecological dynamics. A central need is to observe long term changes in regulating and supporting services as the basis for assessing the likelihood of sustainable agriculture or ecological collapse. We show how the analyses of 55 time-series of social, economic and ecological conditions can provide an evolutionary perspective for the modern Lower Yangtze River Basin region since the 1950s with powerful insights about the sustainability of modern ecosystem services. Increasing trends in provisioning ecosystem services within the region over the past 60 years reflect economic growth and successful poverty alleviation but are paralleled by steep losses in a range of regulating ecosystem services mainly since the 1980s. Increasing connectedness across the social and ecological domains after 1985 points to a greater uniformity in the drivers of the rural economy. Regime shifts and heightened levels of variability since the 1970s in local ecosystem services indicate progressive loss of resilience across the region. Of special concern are water quality services that have already passed critical transitions in several areas. Viewed collectively, our results suggest that the regional social-ecological system passed a tipping point in the late 1970s and is now in a transient phase heading towards a new steady state. However, the long-term relationship between economic growth and ecological degradation shows no sign of decoupling as demanded by the need to reverse an unsustainable trajectory.

  14. Role of Ulva lactuca Extract in Alleviation of Salinity Stress on Wheat Seedlings

    Directory of Open Access Journals (Sweden)

    Wael M. Ibrahim

    2014-01-01

    Full Text Available Seaweeds are potentially excellent sources of highly bioactive materials that could represent useful leads in the alleviation of salinity stress. The effects of presoaking wheat grains in water extract of Ulva lactuca on growth, some enzymatic activities, and protein pattern of salinized plants were investigated in this study. Algal presoaking of grains demonstrated a highly significant enhancement in the percentage of seed germination and growth parameters. The activity of superoxide dismutase (SOD and catalase (CAT increased with increasing the algal extract concentration while activity of ascorbate peroxidase (APX and glutathione reductase (GR was decreased with increasing concentration of algal extract more than 1% (w/v. The protein pattern of wheat seedling showed 12 newly formed bands as result of algal extract treatments compared with control. The bioactive components in U. lactuca extract such as ascorbic acid, betaine, glutathione, and proline could potentially participate in the alleviation of salinity stress. Therefore, algal presoaking is proved to be an effective technique to improve the growth of wheat seedlings under salt stress conditions.

  15. The abnormal Wnt/β-cateninsignalingpathway in injury induced by opioid dependence and alleviations of adanon

    Institute of Scientific and Technical Information of China (English)

    Shi-Chao Xu; Peng Huang

    2015-01-01

    Objective:The present research aimed to explore the abnormal Wnt/β-Catenin signaling pathway in injury induced by opioid dependence and alleviations of adanon.Methods:80 cases of opioid dependence patients who received adanon treatment in our hospital were analyzed. The expression of Wnt/β-Catenin signaling pathway key proteins and TNF-αα as well as IL2/4 was detected by western blotting. 40 cases of healthy subjects in our hospital were taken as the internal the control group.Results:The expression of Wnt4,β-Catenin, TNF-α as well as IL2/4 was up-regulated greatly in patients before treatment with a statistical difference. Those abnormalities were alleviated after medication of adanon which also signified a statistical difference when compared with the level before medication.Conclusion:Over-activated Wnt/β-Catenin and up-regulated TNF-α as well as IL2/4 were involved in the injury induced by opioid and adanon exerts injury restoration by normalizing these abnormal expressions.

  16. Trichoderma spp. alleviate phytotoxicity in lettuce plants (Lactuca sativa L.) irrigated with arsenic-contaminated water.

    Science.gov (United States)

    Caporale, Antonio G; Sommella, Alessia; Lorito, Matteo; Lombardi, Nadia; Azam, Shah M G G; Pigna, Massimo; Ruocco, Michelina

    2014-09-15

    The influence of two strains of Trichoderma (T. harzianum strain T22 and T. atroviride strain P1) on the growth of lettuce plants (Lactuca sativa L.) irrigated with As-contaminated water, and their effect on the uptake and accumulation of the contaminant in the plant roots and leaves, were studied. Accumulation of this non-essential element occurred mainly into the root system and reduced both biomass development and net photosynthesis rate (while altering the plant P status). Plant growth-promoting fungi (PGPF) of both Trichoderma species alleviated, at least in part, the phytotoxicity of As, essentially by decreasing its accumulation in the tissues and enhancing plant growth, P status and net photosynthesis rate. Our results indicate that inoculation of lettuce with selected Trichoderma strains may be helpful, beside the classical biocontrol application, in alleviating abiotic stresses such as that caused by irrigation with As-contaminated water, and in reducing the concentration of this metalloid in the edible part of the plant.

  17. An Approach to Alleviate the False Alarm in Building Change Detection from Urban Vhr Image

    Science.gov (United States)

    Chen, J.; Hou, J. L.; Deng, M.

    2016-06-01

    Building change detection from very-high-resolution (VHR) urban remote sensing image frequently encounter the challenge of serious false alarm caused by different illumination or viewing angles in bi-temporal images. An approach to alleviate the false alarm in urban building change detection is proposed in this paper. Firstly, as shadows casted by urban buildings are of distinct spectral and shape feature, it adopts a supervised object-based classification technique to extract them in this paper. Secondly, on the opposite direction of sunlight illumination, a straight line is drawn along the principal orientation of building in every extracted shadow region. Starting from the straight line and moving toward the sunlight direction, a rectangular area is constructed to cover partial shadow and rooftop of each building. Thirdly, an algebra and geometry invariant based method is used to abstract the spatial topological relationship of the potential unchanged buildings from all central points of the rectangular area. Finally, based on an oriented texture curvature descriptor, an index is established to determine the actual false alarm in building change detection result. The experiment results validate that the proposed method can be used as an effective framework to alleviate the false alarm in building change detection from urban VHR image.

  18. Biodiversity Conservation and Poverty Alleviation in the Niger Delta Area of Nigeria

    Directory of Open Access Journals (Sweden)

    Oghenerioborue Mary Agbogidi

    2006-09-01

    Full Text Available This paper established that biodiversity conservation can aid the alleviation of poverty among the people of the Niger Delta area of Nigeria. The benefits derived from biodiversity were discussed and the ways through which biodiversity can be applied as a tool in the reduction of poverty were emphasized as including bio-regional management approach to biodiversity conservation, ecotourism, community participation in biodiversity management, advocacy of sericulture and drawing from the experiences, knowledge and ideas of conservation bodies all over the world. The paper also maintained that the extension services of government and non–governmental organizations (NGOS should not be left out in this process as they are equipped with the teaching, communication and human relationship and rural sociological skills to live up to the tasks in the process of poverty alleviation through biodiversity conservation. Besides, the knowledge and ideas of other professionals including ecologists, conservationists, geographers, zoologists, botanists, taxonomists, and soil scientists should be tapped as biodiversity conservation requires a multi-disciplinary approach.

  19. Hydrogen Sulfide Alleviates Postharvest Senescence of Grape by Modulating the Antioxidant Defenses.

    Science.gov (United States)

    Ni, Zhi-Jing; Hu, Kang-Di; Song, Chang-Bing; Ma, Run-Hui; Li, Zhi-Rong; Zheng, Ji-Lian; Fu, Liu-Hui; Wei, Zhao-Jun; Zhang, Hua

    2016-01-01

    Hydrogen sulfide (H2S) has been identified as an important gaseous signal in plants. Here, we investigated the mechanism of H2S in alleviating postharvest senescence and rotting of Kyoho grape. Exogenous application of H2S released from 1.0 mM NaHS remarkably decreased the rotting and threshing rate of grape berries. H2S application also prevented the weight loss in grape clusters and inhibited the decreases in firmness, soluble solids, and titratable acidity in grape pulp during postharvest storage. The data of chlorophyll and carotenoid content suggested the role of H2S in preventing chlorophyll breakdown and carotenoid accumulation in both grape rachis and pulp. In comparison to water control, exogenous H2S application maintained significantly higher levels of ascorbic acid and flavonoid and total phenolics and reducing sugar and soluble protein in grape pulp. Meanwhile, H2S significantly reduced the accumulation of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide anion (O2 (∙-)) in grape pulp. Further investigations showed that H2S enhanced the activities of antioxidant enzymes ascorbate peroxidase (APX) and catalase (CAT) and decreased those of lipoxygenase (LOX) in both grape peels and pulp. In all, we provided strong evidence that H2S effectively alleviated postharvest senescence and rotting of Kyoho grape by modulating antioxidant enzymes and attenuating lipid peroxidation.

  20. Alleviating CTAC and Flu combined pollution damage in Chlorella vulgaris by exogenous nitric oxide.

    Science.gov (United States)

    Li, Qi; Liang, Zhijie; Ge, Fei; Xu, Yin; Yang, Liang; Zeng, Hui

    2014-02-01

    This study investigates the effect of sodium nitroprussiate (SNP), an exogenous NO-donor, on the joint toxicity of binary mixtures of cetyltrimethylammonium chloride (CTAC) and fluoranthene (Flu) (CTAC/Flu), which are representatives for surfactants and polycyclic aromatic hydrocarbons (PAHs) respectively, in a unicellular green alga Chlorella vulgaris (C. vulgaris). The results showed that the addition of low SNP (20μM) alleviated the CTAC/Flu combined pollution damage in C. vulgaris. Supplement of low SNP significantly increased the algae biomass, chlorophyll content, soluble protein content and the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) as compared to CTAC/Flu treatment alone. SNP also reduced the content of malondialdehyde (MDA) and the reactive oxygen species (ROS), as compared with CTAC/Flu treated alone. On the contrary, the above phenomena were reversed when high concentration of SNP (100μM) was added. Our study indicated that the damage of the joint action of surfactants and PAHs on hydrobios can be alleviated through protecting against oxidant substances and increasing the activity of antioxidant enzymes with an exogenous supply of NO in certain concentration range.

  1. Phase transfer function based method to alleviate image artifacts in wavefront coding imaging system

    Science.gov (United States)

    Mo, Xutao; Wang, Jinjiang

    2013-09-01

    Wavefront coding technique can extend the depth of filed (DOF) of the incoherent imaging system. Several rectangular separable phase masks (such as cubic type, exponential type, logarithmic type, sinusoidal type, rational type, et al) have been proposed and discussed, because they can extend the DOF up to ten times of the DOF of ordinary imaging system. But according to the research on them, researchers have pointed out that the images are damaged by the artifacts, which usually come from the non-linear phase transfer function (PTF) differences between the PTF used in the image restoration filter and the PTF related to real imaging condition. In order to alleviate the image artifacts in imaging systems with wavefront coding, an optimization model based on the PTF was proposed to make the PTF invariance with the defocus. Thereafter, an image restoration filter based on the average PTF in the designed depth of field was introduced along with the PTF-based optimization. The combination of the optimization and the image restoration proposed can alleviate the artifacts, which was confirmed by the imaging simulation of spoke target. The cubic phase mask (CPM) and exponential phase mask (EPM) were discussed as example.

  2. SOCIAL ENTERPRISES AND MICROFINANCE AS TOOLS FOR POVERTY ALLEVIATION IN ROMANIA

    Directory of Open Access Journals (Sweden)

    OANA-MIRELA COJOCARU (DIACONESCU

    2016-12-01

    Full Text Available Poverty is a dangerous indicator that situates Romania in top positions in many EU statistics: 40% of the population is at risk of poverty or social exclusion and 29% have severe material deprivation. Even though it has been stated on several occasions that funds for the eradication of poverty in Romania do exist, the lack of interest and focus on solving this problem have led to the mismanagement of these funds. In contrast with the previous EU financing programme, a new perspective on the policy creation regarding poverty alleviation has been recently developed and is presented as an integrated package. This wishes to bring together disparate programmes/projects and different stakeholders. This proposal is a very different approach from institutional/methodological point of view, and it has been said to mark “the start of an effective capacity building effort”. The purpose of this literature exploration is focused on the potential Romanian social enterprises and microfinance have in poverty alleviation, taking into consideration that these tools have been created especially for poverty eradication. Our conclusion has been that policy makers have to sustain the development of social enterprises through microfinance, which most of the times can be the single financial instrument available to them.

  3. Vicuña conservation and poverty alleviation? Andean communities and international fibre markets

    Directory of Open Access Journals (Sweden)

    Gabriela Lichtenstein

    2009-09-01

    Full Text Available Vicuna (Vicugna vicugna fiber is produced by extremely low-income communities that inhabit the harsh environment of the Andes in Argentina, Chile, Peru and Bolivia. At the other end of the social scale, affluent consumers are willing to pay high prices for vicuna-made accessories and clothes. Vicuna management projects follow the logic of community-based wildlife management. The rationale for seeking to conserve vicuñas through sustainable use is that commercial utilization of the fiber (obtained from live-shorn animals will generate sufficient economic benefits to outweigh the costs of conservation, and contribute to community development and poverty alleviation. However, although conservation efforts have been extremely successful with vicuñas having recovered from the brink of extinction, the socio-economic achievements have thus far proved modest. This paper explores multiple-objective projects that address vicuña conservation and poverty alleviation in Andean countries. In doing so it analyses the tensions that exist between these objectives, as well as the factors that limit a more equitable distribution of benefits among stakeholders. Examples are drawn from vicuna management under common-property in Peru and Bolivia, and vicuna captive management under private property in Argentina. These case studies enable us to illustrate the complex relationship between local communities and the global market, and the importance of community enterprises and supportive government policy in managing a common pool resource.

  4. Knockout of Ccr2 alleviates photoreceptor cell death in rodent retina exposed to chronic blue light.

    Science.gov (United States)

    Hu, Zizhong; Zhang, Yi; Wang, Junling; Mao, Pingan; Lv, Xuehua; Yuan, Songtao; Huang, Zhengru; Ding, Yuzhi; Xie, Ping; Liu, Qinghuai

    2016-11-10

    Age-related macular degeneration (AMD), the leading cause of visual loss after the age of 60 years, is a degenerative retinal disease involving a variety of environmental and hereditary factors. Although it has been implicated that immune system is involved in the disease progression, the exact role that microglia has is still unclear. Here we demonstrated that knockout of Ccr2 gene could alleviate photoreceptor cell death in mice retinas exposed to chronic blue light. In Ccr2(-/-) mice, a damaged microglia recruitment was shown in retina and this could protect the visual function in electroretinogram and alleviate the photoreceptor apoptosis, which thus helped attenuate the blue light-induced retinopathy. We further found an increased co-location of NLRP3, Iba-1, and IL-1β in fluorescence and a concomitant increased protein expression of NLRP3, caspase-1, and IL-1β in western blotting in chronic blue light-induced retinopathy. Moreover, the activation of microglia and their cellular NLRP3 inflammasomes occurred as an earlier step before the structural and functional damage of the mice retinas, which collectively supported that microglial NLRP3 inflammasome might be the key to the chronic blue light-induced retinopathy.

  5. Hydrogen Sulfide Alleviates Postharvest Senescence of Grape by Modulating the Antioxidant Defenses

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    Zhi-Jing Ni

    2016-01-01

    Full Text Available Hydrogen sulfide (H2S has been identified as an important gaseous signal in plants. Here, we investigated the mechanism of H2S in alleviating postharvest senescence and rotting of Kyoho grape. Exogenous application of H2S released from 1.0 mM NaHS remarkably decreased the rotting and threshing rate of grape berries. H2S application also prevented the weight loss in grape clusters and inhibited the decreases in firmness, soluble solids, and titratable acidity in grape pulp during postharvest storage. The data of chlorophyll and carotenoid content suggested the role of H2S in preventing chlorophyll breakdown and carotenoid accumulation in both grape rachis and pulp. In comparison to water control, exogenous H2S application maintained significantly higher levels of ascorbic acid and flavonoid and total phenolics and reducing sugar and soluble protein in grape pulp. Meanwhile, H2S significantly reduced the accumulation of malondialdehyde (MDA, hydrogen peroxide (H2O2, and superoxide anion (O2∙- in grape pulp. Further investigations showed that H2S enhanced the activities of antioxidant enzymes ascorbate peroxidase (APX and catalase (CAT and decreased those of lipoxygenase (LOX in both grape peels and pulp. In all, we provided strong evidence that H2S effectively alleviated postharvest senescence and rotting of Kyoho grape by modulating antioxidant enzymes and attenuating lipid peroxidation.

  6. Traditional Chinese medicine "Qing Yi Tang" alleviates oxygen free radical injury in acute necrotizing pancreatitis

    Institute of Scientific and Technical Information of China (English)

    1998-01-01

    AIM To observe the changes in oxygen free radical (OFR) and the curative effect of traditional Chinese medicine "Qing Yi Tang" in acute necrotizing pancreatitis (ANP).METHODS After induction of ANP by injection of sodium taurocholate into pancreatic duct, 16 dogs were randomly divided into control group and Chinese medicine group. Serum amylase, SOD and MDA were determined on postoperative day 1, 2, 4 and 7. The animals were sacrificed on day 7. SOD and MDA in organs were determined, and pathological changes in pancreas were observed.RESULTS As compared with control group, the serum level of amylase (734U/L vs 2783U/L) and MDA (7.8nmol/ml vs 14.8nmol/ml) in Chinese medicine group were decreased on day 7 (P<0.05), while SOD increased significantly (281nU/ml vs 55nU/ml, P<0.01), and similar changes occurred in MDA and SOD in organs, especially in the pancreas; the pathological changes in the pancreas were alleviated as well.CONCLUSION "Qing Yi Tang" is effective in clearing OFRs and alleviating pathological changes in ANP.

  7. Gonadotropin-releasing hormone agonist use in men without a cancer registry diagnosis of prostate cancer

    Directory of Open Access Journals (Sweden)

    Kuo Yong-fang

    2008-07-01

    Full Text Available Abstract Background Use of gonadotropin-releasing hormone (GnRH agonists has become popular for virtually all stages of prostate cancer. We hypothesized that some men receive these agents after only a limited work-up for their cancer. Such cases may be missed by tumor registries, leading to underestimates of the total extent of GnRH agonist use. Methods We used linked Surveillance, Epidemiology and End-Results (SEER-Medicare data from 1993 through 2001 to identify GnRH agonist use in men with either a diagnosis of prostate cancer registered in SEER, or with a diagnosis of prostate cancer based only on Medicare claims (from the 5% control sample of Medicare beneficiaries residing in SEER areas without a registered diagnosis of cancer. The proportion of incident GnRH agonist users without a registry diagnosis of prostate cancer was calculated. Factors associated with lack of a registry diagnosis were examined in multivariable analyses. Results Of incident GnRH agonist users, 8.9% had no diagnosis of prostate cancer registered in SEER. In a multivariable logistic regression model, lack of a registry diagnosis of prostate cancer in GnRH agonist users was significantly more likely with increasing comorbidity, whereas it was less likely in men who had undergone either inpatient admission or procedures such as radical prostatectomy, prostate biopsy, or transurethral resection of the prostate. Conclusion Reliance solely on tumor registry data may underestimate the rate of GnRH agonist use in men with prostate cancer.

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

    Science.gov (United States)

    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.

  9. The Effect of Coasting on Intracytoplasmic Sperm Injection Outcome in Antagonist and Agonist Cycle

    Directory of Open Access Journals (Sweden)

    İltemir Duvan Z.Candan,

    2017-01-01

    Full Text Available Background Coasting can reduce the ovarian hyperstimulation syndrome (OHSS risk in ovulation induction cycles before intracytoplasmic sperm injection (ICSI. This study aimed to investigate the effect of gonadotropin-releasing hormone (GnRH agonist and GnRH antagonist protocols to controlled ovarian hyperstimulation (COH cycles with coasting on the parameters of ICSI cycles and the outcome. Materials and Methods In a retrospective cohort study, 117 ICSI cycles were per- formed and coasting was applied due to hyperresponse, between 2006 and 2011. The ICSI outcomes after coasting were then compared between the GnRH agonist group (n=91 and the GnRH antagonist group (n=26. Results The duration of induction and the total consumption of gonadotropins were found to be similar. Estradiol (E2 levels on human chorionic gonadotropin (hCG day were found higher in the agonist group. Coasting days were similar when the two groups were compared. The number of mature oocytes and the fertilization rates were similar in both groups; however, the number of grade 1 (G1 embryos and the number of transferred embryos were higher in the agonist group. Implantation rates were significantly higher in the antagonist group compared to the agonist group. Pregnancy rates/embryo transfer rates were higher in the antagonist group; however, this difference was not statistically significant (32.8% for agonist group vs. 39.1% for antagonist group, P>0.05. Conclusion The present study showed that applying GnRH-agonist and GnRH-antago- nist protocols to coasted cycles did not result in any differences in cycle parameters and clinical pregnancy rates.

  10. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    Energy Technology Data Exchange (ETDEWEB)

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-11-16

    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  11. A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor

    Science.gov (United States)

    Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G

    2015-01-01

    Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

  12. Metabotropic glutamate receptor agonists modify the pyloric output of the crustacean stomatogastric ganglion.

    Science.gov (United States)

    Pérez-Acevedo, Nivia L; Krenz, Wulf D

    2005-11-16

    We have studied the effects of groups I, II, and III metabotropic glutamate receptor (mGluR) agonists and antagonists on pyloric activity in the stomatogastric ganglion (STG) of the Caribbean spiny lobster Panulirus argus. We have found that agonists for all three groups of mGluRs modify the pyloric output. The group I agonist, l-quisqualic acid (l-QA), activated the pyloric central pattern generator (CPG). When the pyloric rhythm was partially suppressed by sucrose-block of input fibers in the stomatogastric nerve (stn), l-QA accelerated the rhythmic activity. In addition, the number of spike discharges was increased in pyloric motoneurons: pyloric (PY), and lateral pyloric (LP). In completely blocked preparations, a slow pyloric rhythm was initiated by l-QA. Groups II and III agonists exerted an inhibitory effect on pyloric activity. The group II agonist, (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (L-CCG-I), decreased both the frequency of the pyloric rhythm and the number of spike discharges in the motoneurons: ventricular dilator (VD), PY, and LP. The effects of L-CCG-I were dose-dependent. The group III agonist, l-(+)-2-Amino-4-phosphonobutyric acid (l-AP4), slightly decreased the frequency of the pyloric rhythm and suppressed spike discharges in the VD neuron. All effects of mGluR agonists were reversible. The effect of l-QA was blocked by the broad spectrum mGluR antagonist (S)-Methyl-4-carboxyphenylglycine (MCPG). The inhibitory effect of L-CCG-I was prevented by MCPG and by the group II/III mGluR antagonist (RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG), and was partially blocked by the group II mGluR antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA). The inhibitory effect of l-AP4 was blocked by MPPG and partially blocked by APICA.

  13. Effects of PPARg agonist pioglitazone on rat hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Guang-Jin Yuan; Ming-Liang Zhang; Zuo-Jiong Gong

    2004-01-01

    dramatically compared with model group.CONCLUSION: PPARγ agonist pioglitazone greatly retards the progression of rat hepatic fibrosis induced by CCl4through inhibition of HSC activation and amelioration of hepatocyte necroinflammation in rats.

  14. Selective imidazoline agonist moxonidine in obese hypertensive patients.

    Science.gov (United States)

    Sanjuliani, A F; de Abreu, V G; Francischetti, E A

    2006-05-01

    Obesity is the major risk factor for the development of hypertension. This association accentuates the risk of cardiovascular disease, as it is frequently accompanied by the components of the metabolic syndrome. This randomised open parallel study evaluated the chronic effects of moxonidine--a selective imidazoline receptor agonist--on blood pressure, plasma catecholamines, leptin, insulin and components of the metabolic syndrome in obese hypertensives. Amlodipine was used as the control drug. Our results showed that moxonidine and amlodipine significantly reduced blood pressure when measured using the oscillometric method and 24-hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 +/- 2.4 to 142.1 +/- 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 +/- 1.3 to 89.7 +/- 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Moxonidine administration reduced the supine arterial plasma levels of adrenaline from 63.2 +/- 6.6 to 49.0 +/- 6.7 pg/ml (p < 0.005), the supine arterial plasma levels of noradrenaline from 187.9 +/- 10.7 to 149.7 +/- 13.2 pg/ml (p < 0.01) and the orthostatic venous plasma levels of noradrenaline from 258.6 +/- 25.0 to 190.3 +/- 16.4 pg/ml (p = 0.03). Those variables were not changed by amlodipine. The plasma levels of leptin and insulin 120 min after a glucose load decreased after moxonidine administration from 27.2 +/- 3.5 to 22.6 +/- 2.9 pg/ml (p < 0.05) and from 139.7 +/- 31.2 to 76.0 +/- 15.2 U/ml (p < 0.05), respectively. Amlodipine, however, did not modify those variables. This study showed a comparable reduction in blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin.

  15. Suplatast tosilate alleviates nasal symptoms through the suppression of nuclear factor of activated T-cells-mediated IL-9 gene expression in toluene-2,4-diisocyanate-sensitized rats.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Orimoto, Naoki; Kadota, Takuya; Kominami, Takahiro; Das, Asish K; Sawada, Akiho; Tamada, Misaki; Miyagi, Kohei; Adachi, Tsubasa; Matsumoto, Mayumi; Kosaka, Tomoya; Kitamura, Yoshiaki; Takeda, Noriaki; Fukui, Hiroyuki

    2016-03-01

    Histamine H1 receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.

  16. Quantitative encoding of a partial agonist effect on individual opioid receptors by multi-site phosphorylation and threshold detection

    OpenAIRE

    Lau, Elaine K.; Trester-Zedlitz, Michelle; Trinidad, Jonathan C.; Kotowski, Sarah J.; Krutchinsky, Andrew N.; Burlingame, Alma L; von Zastrow, Mark

    2011-01-01

    Many drugs act as partial agonists of seven-transmembrane signaling receptors when compared to endogenous ligands. Partial agonism is well described as a 'macroscopic' property manifest at the level of physiological systems or cell populations, but it is not known whether partial agonists encode discrete regulatory information at the 'microscopic' level of individual receptors. We addressed this question by focusing on morphine, a partial agonist drug for µ-type opioid peptide receptors, and ...

  17. Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.

    Science.gov (United States)

    Trotter, B Wesley; Nanda, Kausik K; Burgey, Christopher S; Potteiger, Craig M; Deng, James Z; Green, Ahren I; Hartnett, John C; Kett, Nathan R; Wu, Zhicai; Henze, Darrell A; Della Penna, Kimberly; Desai, Reshma; Leitl, Michael D; Lemaire, Wei; White, Rebecca B; Yeh, Suzie; Urban, Mark O; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T

    2011-04-15

    A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

  18. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    Directory of Open Access Journals (Sweden)

    Yiyi Sun

    Full Text Available Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (--arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.

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

    Science.gov (United States)

    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 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.

  20. Structure-Activity Relationship and Signaling of New Chimeric CXCR4 Agonists.

    Science.gov (United States)

    Mona, Christine E; Besserer-Offroy, Élie; Cabana, Jérôme; Lefrançois, Marilou; Boulais, Philip E; Lefebvre, Marie-Reine; Leduc, Richard; Lavigne, Pierre; Heveker, Nikolaus; Marsault, Éric; Escher, Emanuel

    2016-08-25

    The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode are unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls affinity, whereas position 7 (Tyr) acts as an efficacy switch. Chimeric molecules bearing aromatic residues in position 3 possess high binding affinities for CXCR4 and are Gαi full agonists with robust chemotactic properties. Fine-tuning of electron-poor aromatic rings in position 7 enhances receptor activation. To rationalize these results, a homology model of a receptor-ligand complex was built using the published crystal structures of CXCR4. Molecular dynamics simulations reveal further details accounting for the observed SAR for this series.

  1. Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.

    Science.gov (United States)

    Scott, Caitlin E; Ahn, Kwang H; Graf, Steven T; Goddard, William A; Kendall, Debra A; Abrol, Ravinder

    2016-01-25

    Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.

  2. Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis.

    Science.gov (United States)

    Fairbanks, Carolyn A; Stone, Laura S; Wilcox, George L

    2009-08-01

    Endogenous, descending noradrenergic fibers impose analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (alpha(2)ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express alpha(2A)AR and alpha(2C)AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal alpha(2)ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of the six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal alpha(2)AR agonists featured.

  3. Effects of glucagon-like peptide-1 receptor agonists on renal function

    Institute of Scientific and Technical Information of China (English)

    Theodosios; D; Filippatos; Moses; S; Elisaf

    2013-01-01

    Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

  4. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

    Science.gov (United States)

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-05-03

    Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

  5. Cocaine synergism with alpha agonists in rat aorta: computational analysis reveals an action beyond reuptake inhibition*

    Science.gov (United States)

    Lamarre, Neil S.; Raffa, Robert B.; Tallarida, Ronald J.

    2012-01-01

    BACKGROUND Cocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized. METHODS Cocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine. Synergy analysis begins with the predicted additive effect of the combination of two agonists, based upon dose equivalence theory. This case where one agonist (cocaine) has no effect when administered alone requires only a t-test to demonstrate that a departure from additivity has occurred. RESULTS At doses where cocaine alone produced no vasoconstriction, it potentiated the vasoconstriction produced by all three alpha agonists, a clear indication of synergism between cocaine and these agents. Higher doses of cocaine in combination with alpha adrenoceptor agents gave an inverted-U shaped (hormetic) dose-effect curve, i.e., dose-related relaxation at higher doses. The hormetic dose-effect relation was analyzed using computational methodology based on dose equivalence to derive the unknown second component of action that causes relaxation. CONCLUSIONS Cocaine exhibits both vasoconstricting and vasorelaxant effects. This relaxing component, possibly related to activation of myosin light chain phosphatase, was quantified as a dose-effect curve. Most important is the synergism between cocaine and alpha-adrenoceptor stimulation which cannot be explained as an action due to reuptake inhibition, and has not been previously described. PMID:23270987

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

    Energy Technology Data Exchange (ETDEWEB)

    Remmers, A.E.; Medzihradsky, F. (Univ. of Michigan Medical School, Ann Arbor (United States))

    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.

  7. Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.

    Science.gov (United States)

    Balboni, Gianfranco; Salvadori, Severo; Trapella, Claudio; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Neumeyer, John L

    2010-02-17

    Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.

  8. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

    Directory of Open Access Journals (Sweden)

    Martin B. Oleksiewicz

    2008-01-01

    Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

  9. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

    Science.gov (United States)

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.

  10. Adaptive trailing edge flaps for active load alleviation in a smart rotor configuration

    Energy Technology Data Exchange (ETDEWEB)

    Bergami, L.

    2013-08-15

    The work investigates the development of an active smart rotor concept from an aero-servo-elastic perspective. An active smart rotor is a wind turbine rotor that, through a combination of sensors, control units and actuators, is able to alleviate the fluctuating part of the aerodynamic loads it has to withstand. The investigation focuses on a specific actuator type: the Adaptive Trailing Edge Flap (ATEF), which introduces a continuous deformation of the aft part of the airfoil camber-line. An aerodynamic model that accounts for the steady and unsteady effects of the flap deflection on a 2D airfoil section is developed, and, considering both attached and separated flow conditions, is validated by comparison against Computational Fluid Dynamic solutions and a panel code method. The aerodynamic model is integrated in the BEM-based aeroelastic simulation code HAWC2, thus providing a tool able to simulate the response of a wind turbine equipped with ATEF. A load analysis of the NREL 5 MW reference turbine in its baseline configuration reveals that the highest contribution to the blade flapwise fatigue damage originates from normal operation above rated wind speed, and from loads characterized by frequencies below 1 Hz. The analysis also reports that periodic load variations on the turbine blade account for nearly 11 % of the blade flapwise lifetime fatigue damage, while the rest is ascribed to load variations from disturbances of stochastic nature. The study proposes a smart rotor configuration with flaps laid out on the outer 20 % of the blade span, from 77 % to 97% of the blade length. The configuration is first tested with a simplified cyclic control approach, which gives a preliminary indication of the load alleviation potential, and also reveals the possibility to enhance the rotor energy capture below rated conditions by using the flaps. Two model based control algorithms are developed to actively alleviate the fatigue loads on the smart rotor with ATEF. The first

  11. Dimension Reduction and Alleviation of Confounding for Spatial Generalized Linear Mixed Models

    CERN Document Server

    Hughes, John

    2010-01-01

    Non-gaussian spatial data are very common in many disciplines. For instance, count data are common in disease mapping, and binary data are common in ecology. When fitting spatial regressions for such data, one needs to account for dependence to ensure reliable inference for the regression coefficients. The spatial generalized linear mixed model (SGLMM) offers a very popular and flexible approach to modeling such data, but the SGLMM suffers from three major shortcomings: (1) uninterpretability of parameters due to spatial confounding, (2) variance inflation due to spatial confounding, and (3) high-dimensional spatial random effects that make fully Bayesian inference for such models computationally challenging. We propose a new parameterization of the SGLMM that alleviates spatial confounding and speeds computation by greatly reducing the dimension of the spatial random effects. We illustrate the application of our approach to simulated binary, count, and Gaussian spatial datasets, and to a large infant mortali...

  12. Does a sorghum-cowpea composite porridge hold promise for contributing to alleviating oxidative stress?

    Science.gov (United States)

    Apea-Bah, Franklin B; Minnaar, Amanda; Bester, Megan J; Duodu, Kwaku G

    2014-08-15

    The effect of compositing red non-tannin sorghum with cream-coloured cowpea and porridge preparation on phenolic profile and radical scavenging activity was studied. A maize-soybean composite porridge representing a similar product on the South African market was used as reference sample. UPLC-QToF-MS-ESI was used to determine phenolic composition of the grain flours, their composites and porridges. Total phenolic content was determined using Folin-Ciocalteu method while radical scavenging activity was determined using the ABTS, DPPH and NO radical scavenging assays. Four benzoic acid derivatives and five cinnamic acid derivatives were identified in the samples. The predominant flavonoid subclasses identified in sorghum were flavan-3-ols, flavanones and flavones while cowpea had mainly flavan-3-ols and flavonols with soybean having mainly isoflavones. Compositing the cereals with legumes significantly (pporridge showed better promise in contributing to alleviating radical induced oxidative stress than maize-soybean composite porridge.

  13. ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice

    DEFF Research Database (Denmark)

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar;

    2002-01-01

    we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals......Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study......, as evidenced by less muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that ADAM12 directly or indirectly contributes to muscle cell regeneration, stability, and survival....

  14. Intravenous phentolamine infusion alleviates the pain of abdominal visceral cancer, including pancreatic carcinoma.

    Science.gov (United States)

    Yasukawa, Masako; Yasukawa, Ken'ichi; Kamiizumi, You; Yokoyama, Ryouji

    2007-01-01

    This case report series describes eight patients (four patients with pancreatic carcinoma, one patient with hepatocellular carcinoma, one patient with gastric and rectal carcinoma, one with sigmoid colon cancer, and one with rectal cancer), whose abdominal cancer pain was treated with intravenous phentolamine infusion at 80 mg x day(-1) for 2 days. All but one of the patients had already been treated with opioids. All eight patients complained of severe abdominal pain; in five patients the pain radiated to the back, and there was associated anal pain in two patients. Analgesia was achieved in three patients; pain alleviation was obtained in four patients, but was not sustained in two of these four patients; and the treatment in one patient could not be judged for efficacy because epidural morphine was used together with the phentolamine. Adverse effects of phentolamine were tachycardia and/or hypotension.

  15. From inflation to dark energy through a dynamical Lambda: an attempt at alleviating fundamental cosmic puzzles

    CERN Document Server

    Basilakos, S; Solà, J

    2013-01-01

    After decades of successful hot big-bang paradigm, Cosmology still lacks a framework in which the early inflationary phase of the universe smoothly matches the radiation epoch and evolves to the present `quasi' de Sitter spacetime. No less intriguing is that the current value of the effective vacuum energy density is vastly smaller than the value that triggered inflation. In this Essay we propose a new class of cosmologies capable of overcoming, or highly alleviating, some of these acute cosmic puzzles. Powered by a decaying vacuum energy density, the spacetime emerges from a pure nonsingular de Sitter vacuum stage, "gracefully" exits from inflation to a radiation phase followed by dark matter and vacuum regimes, and, finally, evolves to a late time de Sitter phase.

  16. Money or mental health: the cost of alleviating psychological distress with monetary compensation versus psychological therapy.

    Science.gov (United States)

    Boyce, Christopher J; Wood, Alex M

    2010-10-01

    AbstractMoney is the default way in which intangible losses, such as pain and suffering, are currently valued and compensated in law courts. Economists have suggested that subjective well-being regressions can be used to guide compensation payouts for psychological distress following traumatic life events. We bring together studies from law, economic, psychology and medical journals to show that alleviating psychological distress through psychological therapy could be at least 32 times more cost effective than financial compensation. This result is not only important for law courts but has important implications for public health. Mental health is deteriorating across the world - improvements to mental health care might be a more efficient way to increase the health and happiness of our nations than pure income growth.

  17. Alleviation of chilling injury in tomato fruit by exogenous application of oxalic acid.

    Science.gov (United States)

    Li, Peiyan; Yin, Fei; Song, Lijun; Zheng, Xiaolin

    2016-07-01

    The effects of oxalic acid on the development of chilling injury (CI), energy metabolism and lycopene metabolism in tomato fruit (Solanum lycopersicum L.) were investigated. Mature green tomatoes were dipped in 10mmoll(-1) oxalic acid (OA) solution for 10min at 25°C. Tomatoes were subsequently stored at 4±0.5°C for 20days before being transferred to 25°C for 12days. Oxalic acid treatment apparently alleviated CI development and membrane damage; maintained higher levels of ATP and ADP; increased activities of succinic dehydrogenase (SDH), Ca(2+)-adenosine triphosphatase (Ca(2+)-ATPase) and H(+)-adenosine triphosphatase (H(+)-ATPase); and elevated lycopene accumulation associated with the upregulation of PSY1 and ZDS expression in tomatoes during a period at room temperature following exposure to chilling stress. Thus, oxalic acid treatment benefited the control of CI and the maintenance of fruit quality in tomatoes stored for long periods (approximately 32days).

  18. Foliar nickel application alleviates detrimental effects of glyphosate drift on yield and seed quality of wheat.

    Science.gov (United States)

    Kutman, Bahar Yildiz; Kutman, Umit Baris; Cakmak, Ismail

    2013-09-04

    Glyphosate drift to nontarget crops causes growth aberrations and yield losses. This herbicide can also interact with divalent nutrients and form poorly soluble complexes. The possibility of using nickel (Ni), an essential divalent metal, for alleviating glyphosate drift damage to wheat was investigated in this study. Effects of Ni applications on various growth parameters, seed yield, and quality of durum wheat ( Triticum durum ) treated with sublethal glyphosate at different developmental stages were investigated in greenhouse experiments. Nickel concentrations of various plant parts and glyphosate-induced shikimate accumulation were measured. Foliar but not soil Ni applications significantly reduced glyphosate injuries including yield losses, stunting, and excessive tillering. Both shoot and grain Ni concentrations were enhanced by foliar Ni treatment. Seed germination and seedling vigor were impaired by glyphosate and improved by foliar Ni application to parental plants. Foliar Ni application appears to have a great potential to ameliorate glyphosate drift injury to wheat.

  19. Novel medical bathing with traditional Chinese herb formula alleviates paraplegia spasticity.

    Science.gov (United States)

    Liu, Xin; Meng, Qingxi; Yu, Dapeng; Zhao, Xiwu; Zhao, Tingbao

    2014-06-01

    Paraplegia spasm is a kind of chronic disease which lacks effective treatment; the patients have to endure long-term pain, which is a tough problem for nursing practice. Lots of potential candidate medicines are under investigation, and a new Chinese herb formula is introduced in the current study. In the present study, we chose six different well-known Chinese herbs to form a formula, and boiled them into the water with an optimized ratio to make bath water; 80 paraplegic patients received this medicinal bath, and 80 patients received perfume water bath as placebo group. Compared with placebo control patients, the herb-treated patients have significant reduction in paraplegia spasm, visual analogue scale score, clinician global impression and sleep disorder. This novel six-combined formula traditional medicine could be beneficial for alleviating paraplegia spasm, but the underlying action mechanism deserves further study.

  20. Epigallocatechin-3-gallate inhibits lactase but is alleviated by salivary proline-rich proteins.

    Science.gov (United States)

    Naz, Shahina; Siddiqi, Rahmanullah; Dew, Tristan P; Williamson, Gary

    2011-03-23

    Lactase phlorizin hydrolase is a small intestinal brush border enzyme that catalyzes the hydrolysis of the milk sugar, lactose, and also many flavonoid glucosides. We demonstrate that epigallocatechin-3-gallate (EGCG), the principal flavonoid from green tea, inhibits in vitro hydrolysis of lactose by intestinal lactase. We then tested the hypothesis that salivary proline-rich proteins (PRPs) could modulate this inhibition and stabilize EGCG. Inhibition by EGCG of digestive enzymes (α-amylase>chymotrypsin>trypsin>lactase≫pepsin) was alleviated ∼2-6-fold by PRPs. Furthermore, PRPs appeared stable to proteolysis and also stabilized EGCG under digestive conditions in vitro. This is the first report on EGCG inhibition of lactase, and it quantifies the protective role of PRPs against EGCG inhibition of digestive enzymes.

  1. SNR Wall Effect Alleviation by Generalized Detector Employed in Cognitive Radio Networks

    Directory of Open Access Journals (Sweden)

    Modar Safir Shbat

    2015-07-01

    Full Text Available The most commonly used spectrum sensing techniques in cognitive radio (CR networks, such as the energy detector (ED, matched filter (MF, and others, suffer from the noise uncertainty and signal-to-noise ratio (SNR wall phenomenon. These detectors cannot achieve the required signal detection performance regardless of the sensing time. In this paper, we explore a signal processing scheme, namely, the generalized detector (GD constructed based on the generalized approach to signal processing (GASP in noise, in spectrum sensing of CR network based on antenna array with the purpose to alleviate the SNR wall problem and improve the signal detection robustness under the low SNR. The simulation results confirm our theoretical issues and effectiveness of GD implementation in CR networks based on antenna array.

  2. Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation.

    Science.gov (United States)

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Nafees, Sana; Seth, Amlesh; Ali, Nemat; Rashid, Summya; Sultana, Sarwat

    2012-01-25

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.

  3. Low molecular weight fucoidan modulates P-selectin and alleviates diabetic nephropathy.

    Science.gov (United States)

    Xu, Yingjie; Zhang, Quanbin; Luo, Dali; Wang, Jing; Duan, Delin

    2016-10-01

    Diabetic nephropathy (DN) is a serious microvascular complication that can lead to chronic and end-stage renal failure. It is understood that inflammation is associated with the onset and process of DN. Low molecular weight fucoidan (LMWF) isolated from Saccharina japonica has anti-inflammatory properties. Therefore, this study aimed to explore the mechanism of LMWF in DN model induced by streptozotocin. The biochemical indices levels showed LMWF reduced the DN diagnostic indices to protect renal function. The HE stained sections exhibited LMWF protected normal morphological structures and reduced inflammatory cell infiltration in the kidneys of DN rats. Furthermore, the levels of P-selectin and selectin-dependent inflammatory cytokines resulting from LMWF were obviously decreased at both the transcriptional and protein levels. Thus, our results found that LMWF protected the renal function in DN rats and alleviated inflammation through the modulation of P-selectin and inflammatory cytokines. LMWF may have therapeutic potential against DN.

  4. Optimality study of a gust alleviation system for light wing-loading STOL aircraft

    Science.gov (United States)

    Komoda, M.

    1976-01-01

    An analytical study was made of an optimal gust alleviation system that employs a vertical gust sensor mounted forward of an aircraft's center of gravity. Frequency domain optimization techniques were employed to synthesize the optimal filters that process the corrective signals to the flaps and elevator actuators. Special attention was given to evaluating the effectiveness of lead time, that is, the time by which relative wind sensor information should lead the actual encounter of the gust. The resulting filter is expressed as an implicit function of the prescribed control cost. A numerical example for a light wing loading STOL aircraft is included in which the optimal trade-off between performance and control cost is systematically studied.

  5. VPA alleviates neurological deficits and restores gene expression in a mouse model of Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Weixiang Guo

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that occurs once in every 10,000-15,000 live female births. Despite intensive research, no effective cure is yet available. Valproic acid (VPA has been used widely to treat mood disorder, epilepsy, and a growing number of other disorders. In limited clinical studies, VPA has also been used to control seizure in RTT patients with promising albeit somewhat unclear efficacy. In this study we tested the effect of VPA on the neurological symptoms of RTT and discovered that short-term VPA treatment during the symptomatic period could reduce neurological symptoms in RTT mice. We found that VPA restores the expression of a subset of genes in RTT mouse brains, and these genes clustered in neurological disease and developmental disorder networks. Our data suggest that VPA could be used as a drug to alleviate RTT symptoms.

  6. Toxic Effect of Cd2+ on Potamogeton crispus Alleviated by Exogenous Nd3+

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The mitigation of toxic effect of Cd2 + on Potamogeton crispus L. by exogenous Nd3 + was studied. The result shows that activity of antioxidase (SOD, CAT, POD) is decreased, and the content of MDA increased. The content of different concentrations of Nd3 + for 5 d significantly improved the activity of SOD, POD and CAT in comparison with toxicity of Cd2+ , and ranged from 14.0% ~ 30.0%, 8.8% ~ 47.3%, 4.6% ~ 15.1% respectively. The degradation of chlorophyll and protein is alleviated, and generation of MDA reduced . But with the higher concentration of Nd3 + , such ability of Nd3+ is weakened. The optimum concentration of Nd3+ is 10 ~ 15 mg·L-1.

  7. MMSE Multiuser Detector Alleviating Edge Effect in Asynchronous DS-CDMA Systems

    Institute of Scientific and Technical Information of China (English)

    WANGLing; JIAOLicheng; TAOHaihong; LIUFang

    2005-01-01

    Multiuser detection is a key technique in DS-CDMA systems. At the base station, the received signal is the compositive signal transmitted by active users in the system over asynchronous channels, the Multiple access interference (MAI) components of which is more serious than that in synchronous systems. In this paper, based on the compact matrix signal model of the asynchronous system, a MMSE (Minimum mean square error) Multiuser detector alleviating edge effect (MMSEAEE) with low complexity is proposed. The asymptotic efficiency, near-far effect resistance and computational complexity of the multiuser detector are analyzed qualitatively. Finally, the bit error rate is simulated via plentiful Monte Carlo numerical experiments. With performance analysis and numerical simulation, it is shown that MMSEAEE with low complexity offers significant performance improvement over some existing popular detectors in eliminating multiple access interference and near-far resistance.

  8. Cadmium Toxicity and Alleviating Effects of Exogenous Salicylic Acid in Iris hexagona.

    Science.gov (United States)

    Han, Ying; Chen, Gang; Chen, Yahua; Shen, Zhenguo

    2015-12-01

    Cadmium (Cd) toxictity and possible role of salicylic acid (SA) in alleviating Cd-induced toxicity were investigated on ornamental hydrophyte Iris hexagona. Compared to the control, treatments with 100 and 500 µM Cd for 7 days significantly decreased dry weight, the contents of chlorophyll, photosynthetic parameters, and increased the content of thiobarbituric acid reactive substance. Pretreatment of the roots of I. hexagona seedlings with 1 µM SA before Cd exposure may increase dry weight, photosynthetic rate, activities of antioxidant enzymes, improve the cell ultrastructure and protect plants from Cd-induced oxidative stress damage. However, SA pretreatment had no significant effect on Cd concentrations in the leaves and roots. It is suggested that SA-induced Cd tolerances in I. hexagona are likely associated with increases in antioxidant enzyme activities and vacuolar compartmentation, rather than Cd uptake.

  9. Ammonia tolerant enriched methanogenic cultures as bioaugmentation inocula to alleviate ammonia inhibition in continuous anaerobic reactors

    DEFF Research Database (Denmark)

    Fotidis, Ioannis; Wang, Han; Angelidaki, Irini

    tolerant methanogenic culture as potential bioaugmentation inoculum in a continuous stirred tank reactor (CSTR) operating under “inhibited steady-state”, triggered by high ammonia levels (5 g NH4+-N L-1). The results of the current study established for the first time that bioaugmentation of an enriched...... ammonia tolerant methanogen in a CSTR reactor could completely alleviate the ammonia inhibitory effect. Furthermore, it was found that bioaugmentation with the enriched culture resulted in 25% higher methane production compared to when the bioaugmentation was achieved with pure methanogenic strains....... The bioaugmentation was performed without pausing the continuous operation of the CSTR reactor and without excluding the ammonia-rich substrate from the feedstock. Thus, bioaugmentation with mixed methanogenic cultures could potentially support the development of an efficient and cost-effective biomethanation process...

  10. Experimental evidence for alleviating nociceptive hypersensitivity by single application of capsaicin.

    Science.gov (United States)

    Ma, Xiao-Li; Zhang, Fang-Xiong; Dong, Fei; Bao, Lan; Zhang, Xu

    2015-04-22

    The single application of high-concentration of capsaicin has been used as an analgesic therapy of persistent pain. However, its effectiveness and underlying mechanisms remain to be further evaluated with experimental approaches. The present study provided evidence showing that the single application of capsaicin dose-dependently alleviated nociceptive hypersensitivity, and reduced the action potential firing in small-diameter neurons of the dorsal root ganglia (DRG) in rats and mice. Pre-treatment with capsaicin reduced formalin-induced acute nocifensive behavior after a brief hyperalgesia in rats and mice. The inhibitory effects of capsaicin were calcium-dependent, and mediated by the capsaicin receptor (transient receptor potential vanilloid type-1). We further found that capsaicin exerted inhibitory effects on the persistent nociceptive hypersensitivity induced by peripheral inflammation and nerve injury. Thus, these results support the long-lasting and inhibitory effects of topical capsaicin on persistent pain, and the clinic use of capsaicin as a pain therapy.

  11. Modified μ-law Companding For LED Nonlinearity Alleviation in DCO-OFDM VLC System

    Science.gov (United States)

    Yan, Chaowen; Wang, Jianping; Lu, Huimin; Shi, Yinjia

    2016-10-01

    In this paper, the direct current (DC)-biased optical orthogonal frequency division multiplexing (DCO-OFDM) visible light communication (VLC) system using modified μ-law companding is modeled and investigated. The simulation results reveal that the high peak to average power ratio (PAPR) induced by multi-carrier modulation (MCM) and DC bias, can aggravate signal distortion that is caused by the nonlinear characteristic of light emitting diode (LED). Thus, a pre-distortion method based on modification of μ-law companding is proposed for DCO-OFDM VLC system to resolve this problem. With the proposed method, the system can achieve a good performance of PAPR reduction and bit error rate (BER), compared to the original DCO-OFDM VLC system. It is demonstrated that the modified μ-law companding is appropriate to alleviate LED nonlinearity without degradation of the signal quality in DCO-OFDM VLC system.

  12. SNR Wall Effect Alleviation by Generalized Detector Employed in Cognitive Radio Networks.

    Science.gov (United States)

    Shbat, Modar Safir; Tuzlukov, Vyacheslav

    2015-07-03

    The most commonly used spectrum sensing techniques in cognitive radio (CR) networks, such as the energy detector (ED), matched filter (MF), and others, suffer from the noise uncertainty and signal-to-noise ratio (SNR) wall phenomenon. These detectors cannot achieve the required signal detection performance regardless of the sensing time. In this paper, we explore a signal processing scheme, namely, the generalized detector (GD) constructed based on the generalized approach to signal processing (GASP) in noise, in spectrum sensing of CR network based on antenna array with the purpose to alleviate the SNR wall problem and improve the signal detection robustness under the low SNR. The simulation results confirm our theoretical issues and effectiveness of GD implementation in CR networks based on antenna array.

  13. 高职教育与精准扶贫的对接%Higher Vocational Education and Precision Poverty Alleviation

    Institute of Scientific and Technical Information of China (English)

    王红春; 宾扬帆

    2016-01-01

    本文通过对高职教育对于精准扶贫意义的分析,指出了高职教育精准扶贫所存在的问题,在此基础上探讨了高职教育精准的对接措施。%This article through the analysis of the significance of higher vocational education for the precision of poverty all-eviation, pointed out the problems existing in the precise poverty alleviation, and on this basis to explore the higher vocational education.

  14. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  15. Analysis on the Effect of Poverty Alleviation Based on Walnut Industry

    Directory of Open Access Journals (Sweden)

    Yang Binbin

    2015-06-01

    Full Text Available This study explores the poverty reduction effection of Lv-Ling model which based on walnut industry. The Walnut tree or Juglans is a plant genus of the family Juglandaceae; it is one of the famous nuts in the world and one of the important economic forest tree species in China. Because of development fastly, variety breeding can’t keep up with development needs, causing confusion species, affected the economic benefit seriously, some even did not play benefit into death, therefore, create excellent varieties, cultivated in the most suitable area and regionalization is an urgent problem of walnut production need to solve in Hebei province. This study uses a single case study method to research the model of the leading enterprises drives, which is choosing six countries as sample points and using questionnaire survey on 180 peasant households to interview, then using the semi-structured interview with company, base manager and technical director. Calm base than the standardized method, the year-on-year growth rate method is used to analyze the data. The results show that “Lv-ling company” by planting grass in the forest, breeding chicken in the grass, chicken manure input the fens, put the rubbish into the fields of "fruit, grass, livestock, marsh" "four in one" stereo ecological planting and breeding model and to popularize it, develop the walnut industry chain of circular economy. Farmer’s income, employment, green area increased significantly from 2008 to 2013, especially 2012. The local economic have promote, social and ecological benefits of coordinated development from Industry as a tool for poverty alleviation of Lv-Ling and can be used for reference for industrialization poverty alleviation in Taihang mountain area.

  16. Alleviation of salinity stress on Vicia faba L. plants via seed priming with melatonin

    Directory of Open Access Journals (Sweden)

    Mona Gergis Dawood

    2014-12-01

    Full Text Available Melatonin is an environmentally friendly-molecule with a potent free radical scavenger and antioxidant capacity. Two pot experiments were conducted during two successive winter seasons (2011/2012 and 2012/2013 at the wire-house of the National Research Centre, Dokki, Cairo, Egypt to study the potentiality of melatonin (100 mM and 500 mM in alleviating the harmful effect of diluted sea water at a relatively low and high concentrations (3.85 dS/m and 7.69 dS/m, respectively on the performance of faba bean plant. The results revealed that irrigation of faba bean plants with diluted sea water reduced growth parameters (plant height, leaves number/plant, fresh and dry weights /plant, relative water content (RWC, photosynthetic pigments (chlorophylls a, b and carotenoids, indole acetic acid, total carbohydrate, K+,Ca+2, as well as the ratios of K+/Na+ and Ca+2/Na+ .Thiswasaccompanied by significant increases in phenolic content, compatible solutes (total soluble carbohydrate, free amino acids, proline, Na+ and Cl- , relative to the control plants (untreated plants. On the other hand, melatonin treatments improved growth parameters, RWC, photosynthetic pigments, total carbohydrate, total phenolic content, indole acetic acid, K+,Ca+2 as well as K+/Na+ and Ca+2/Na+ ratios, either in the plants irrigated with tap water or with diluted sea water, as compared with corresponding controls. Meanwhile, melatonin treatments reduced the levels of compatible solutes, as well as Na+ and Cl-  contents, relative to those of corresponding controls. Salinity stress and/ or melatonin treatments induced the production of new protein bands that did not occur in the control plants. Melatonin at 500 mM had a more pronounced effect in alleviating the adverse effects of the two salinity levels under study on the performance of faba bean plants than 100 mM melatonin.

  17. Does going to an amusement park alleviate low back pain? A preliminary study

    Directory of Open Access Journals (Sweden)

    Sakakibara T

    2012-10-01

    Full Text Available Toshihiko Sakakibara, Zhuo Wang, Yuichi KasaiDepartment of Spinal Surgery and Medical Engineering, Mie University Graduate School of Medicine, Tsu City, Mie Prefecture, JapanBackground: Low back pain is often called nonspecific pain. In this type of low back pain, various emotions and stress are known to strongly affect pain perception. The purpose of this study is to investigate how the degree of low back pain changes in people with chronic mild low back pain when they are inside and outside of an amusement park where people are supposed to have physical and psychological enjoyment.Methods: The subjects were 23 volunteers (13 males and 10 females aged 18 to 46 years old with a mean age of 24.0 years who had chronic low back pain. Visual analog scale (VAS scores of low back pain and salivary amylase levels (kIU/L of all subjects were measured at five time points: immediately after getting on the bus heading for the amusement park; 10 minutes, 1 hour (immediately after boarding the roller coaster, and 3 hours (immediately after exiting the haunted house after arriving at the amusement park; and immediately before getting off the bus returning from the park.Results: The three VAS values in the amusement park (10 minutes, 1 hour, and 3 hours after arriving at the amusement park measured were significantly lower (P < 0.05 when compared with the other two values measured immediately after getting on the bus heading for the amusement park and immediately before getting off the return bus. In salivary amylase levels, there were no statistically significant differences among the values measured at the five time points.Conclusion: Low back pain was significantly alleviated when the subjects were in the amusement park, which demonstrated that enjoyable activities, though temporarily, alleviated their low back pain.Keywords: low back pain, emotion, salivary alpha-amylase activity, enjoyment activities, psychological stress

  18. Hydrogen sulfide in posthemorrhagic shock mesenteric lymph drainage alleviates kidney injury in rats

    Energy Technology Data Exchange (ETDEWEB)

    Han, B.; Zhao, Z.G.; Zhang, L.M.; Li, S.G.; Niu, C.Y. [Institute of Microcirculation, Hebei North University, Hebei Zhangjiakou (China)

    2015-04-28

    Posthemorrhagic shock mesenteric lymph (PHSML) is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H{sub 2}S) in PHSML drainage in alleviating acute kidney injury (AKI) by administering D,L-propargylglycine (PPG) and sodium hydrosulfide hydrate (NaHS) to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage), and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage). Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H{sub 2}S, cystathionine-γ-lyase (CSE), Toll-like receptor 4 (TLR4), interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H{sub 2}S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H{sub 2}S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H{sub 2}S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H{sub 2}S and H{sub 2}S-mediated inflammation.

  19. Strategies to alleviate the incidence of ascites in broilers: a review

    Directory of Open Access Journals (Sweden)

    U Aftab

    2005-12-01

    Full Text Available Ascites is a complex problem caused by many interacting factors such as genetics, environment and management. Many nutritional, medicinal and management strategies have been proposed to alleviate the problem. Higher levels of dietary vitamin C and E along with selenium yeast might be beneficial, presumably because of their role in improving cellular integrity. Oils rich in n-3 fatty acids have been shown to reduce pulmonary hypertension and, consequently, ascites incidence. The potential use of flax oil has already been demonstrated, whereas the effects of other oils rich in n-3 fatty acids (fish, linseed and canola oils remain to be investigated. The assessment of the effects of dietary electrolyte balance on ascites incidence seems to be a promising field of research in broiler nutrition. In general, reducing the dietary level of salt (NaCl and adding bicarbonates to the diet and drinking water have been proposed as potential "cost-effective" methods to reduce ascites incidence. The use of nutrients/drug agents that increase the vascular capacity of the lungs or decrease the pulmonary vascular resistance may help to alleviate the problem, but economic and local feed regulations might restrict such use. Diuretics have also shown positive effects, presumably because there is a reduction of sodium and fluid retention in the body; litter humidity however must be closely monitored if diuretics are continuously administered. As the high metabolic rate (fast growth is a major factor contributing to the susceptibility of broilers to ascites, early-age feed or nutrient restriction (qualitative or quantitative or light restriction in order to slow down the growth rate seem practically viable methods, since final body weight is not compromised. Optimization of the house temperature and ventilation in cold weather seem helpful practices to decrease ascites incidence. Under practical conditions, it might be interesting to test the additive effects of

  20. East Indian Sandalwood Oil (EISO) Alleviates Inflammatory and Proliferative Pathologies of Psoriasis

    Science.gov (United States)

    Sharma, Manju; Levenson, Corey; Clements, Ian; Castella, Paul; Gebauer, Kurt; Cox, Michael E.

    2017-01-01

    Psoriasis, a chronic inflammatory skin disease marked by hyper proliferation and aberrant differentiation of keratinocytes, affects 2–3% of the world’s population. Research into the pathogenesis of psoriasis has been hampered by the lack of models that accurately reflect the biology of the psoriatic phenotype. We have previously reported that East Indian Sandalwood oil (EISO) has significant anti-inflammatory properties in skin models and hypothesized that EISO might provide therapeutic benefit to psoriasis patients due to its anti-inflammatory and anti-proliferative properties. Here we present interim results from an on-going proof-of-concept Phase 2 clinical trial in which topically applied EISO is demonstrating to be well tolerated and helpful in alleviating mild to moderate psoriasis symptoms. This led us to evaluate the ability of EISO to affect the psoriatic phenotype using MatTek Corporation reconstituted organotypic psoriatic and normal human skin models. EISO had no impact on the phenotype of the normal skin tissue model, however, EISO treatment of the psoriasis tissue model reverted psoriatic pathology as demonstrated by histologic characterization and expression of keratinocyte proliferation markers, Ki67 and psoriasin. These phenotypic affects correlated with suppressed production of ENA-78, IL-6, IL-8, MCP-1, GM-CSF, and IL-1β. Demonstration of the ability of EISO to abrogate these psoriasis symptoms in well-characterized in vitro psoriatic tissue models, supports the hypothesis that the clinically observed symptom alleviation is due to suppression of intrinsic tissue inflammation reactions in afflicted lesions. This study presents a systematic approach to further study the underlying mechanisms that cause psoriasis, and presents data supporting the potential of EISO as a new ethnobotanical therapeutic concept to help direct and accelerate the development of more effective therapies. PMID:28360856

  1. Rural-to-urban migration and its implications for poverty alleviation.

    Science.gov (United States)

    Skeldon, R

    1997-03-01

    This article examines rural-urban migration, its role in poverty alleviation in Thailand, and policy implications. The empirical research literature suggests that the poorest tend be left behind by wealthier migrants moving to urban areas. The youngest tend to migrate. The impact of remittances tends to appear more positive in international migration, but the impact of remittances among rural internal migrant families can also be substantial and be responsible for wealth differences within rural communities. Return migrants contribute to communities by bringing back new ideas and new attitudes toward family size. Migration can also produce negative impacts for sending communities, but the total analysis appears to favor positive impacts. The urban sector becomes another resource base for rural populations that can sustain rural populations during rapid change processes. The migrant population tends to be wealthier and better educated than rural populations, but poorer and less educated than urban populations. Informal sectors in urban areas may offer migrants flexible working hours, no taxes or deductions, less bureaucratic structures, and only 9% less income than the formal sector. Social networks reinforce migrant work in the informal sector and segmentation of the labor force. Social networks may be formalized into associations and help in securing migrant's housing and living. Migrants are integrated in a variety of ways into city life. Migrant communities are a source of energy, organizational skills, and talent. The incidence of poverty appears to be the greatest among women. Women migrants and women left behind by migrants must adjust to new conditions. Migration policies tend to focus on regulating the volume of migration. The author concludes that migration alleviates poverty and that policies should address city management, migrant adjustment processes, and training programs for nonmigrants.

  2. Does going to an amusement park alleviate low back pain? A preliminary study

    Science.gov (United States)

    Sakakibara, Toshihiko; Wang, Zhuo; Kasai, Yuichi

    2012-01-01

    Background Low back pain is often called nonspecific pain. In this type of low back pain, various emotions and stress are known to strongly affect pain perception. The purpose of this study is to investigate how the degree of low back pain changes in people with chronic mild low back pain when they are inside and outside of an amusement park where people are supposed to have physical and psychological enjoyment. Methods The subjects were 23 volunteers (13 males and 10 females) aged 18 to 46 years old with a mean age of 24.0 years who had chronic low back pain. Visual analog scale (VAS) scores of low back pain and salivary amylase levels (kIU/L) of all subjects were measured at five time points: immediately after getting on the bus heading for the amusement park; 10 minutes, 1 hour (immediately after boarding the roller coaster), and 3 hours (immediately after exiting the haunted house) after arriving at the amusement park; and immediately before getting off the bus returning from the park. Results The three VAS values in the amusement park (10 minutes, 1 hour, and 3 hours after arriving at the amusement park) measured were significantly lower (P amusement park and immediately before getting off the return bus. In salivary amylase levels, there were no statistically significant differences among the values measured at the five time points. Conclusion Low back pain was significantly alleviated when the subjects were in the amusement park, which demonstrated that enjoyable activities, though temporarily, alleviated their low back pain. PMID:23118550

  3. Co-administration of cyclosporine A alleviates thioacetamide-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Sabrina Fan; Ching-Feng Weng

    2005-01-01

    AIM: To investigate the effects of cyclosporine A (CsA)on thioacetamide (TAA)-induced liver injury.METHODS: CsA was co-administrated (7.5 μg/kg body weight per day, i.p.) into rat to investigate the role of CsA on TAA-(200 mg/kg body weight per 3 d for 30 d, i.p.)induced liver injury.RESULTS: The data show that TAA caused liver fibrosis in rat after 30 d of treatment. CsA alleviates the morphological changes of TAA-induced fibrosis in rat liver. The blood glutamyl oxaloacetic transaminase (GOT)/glutamyl pyruvic transaminase (GPT) in the TAA-injury group is elevated compared to that of the normal rat. Compared with the TAA-injury group, the blood GOT/GPT and TGFβ1 (by RT-PCR analysis) are reduced in the CsA plus TAA-treated rat. The level of the transforming growth factor receptor I (TGFβ-R1) in the CsA plus TAA-treated group shows higher than that in the TAA only group, but shows a lower level of the fibroblast growth factor receptor 4 (FGFR4)in the CsA plus TAA-treated group, when using the Western blot analysis. After immunostaining of the frozen section,TGFβ-R1 and FGFR4 are more concentrated in rat liver after CsA plus TAA injury.CONCLUSION: This result suggests that CsA has an alleviated effect on TAA-induced liver injury by increasing the multidrug resistance P-glycoprotein and could be through the regulation of TGFβ-R1 and FGFR4.

  4. Arbuscular mycorrhizal symbiosis influences strigolactone production under salinity and alleviates salt stress in lettuce plants.

    Science.gov (United States)

    Aroca, Ricardo; Ruiz-Lozano, Juan Manuel; Zamarreño, Angel María; Paz, José Antonio; García-Mina, José María; Pozo, María José; López-Ráez, Juan Antonio

    2013-01-01

    Arbuscular mycorrhizal (AM) symbiosis can alleviate salt stress in plants. However the intimate mechanisms involved, as well as the effect of salinity on the production of signalling molecules associated to the host plant-AM fungus interaction remains largely unknown. In the present work, we have investigated the effects of salinity on lettuce plant performance and production of strigolactones, and assessed its influence on mycorrhizal root colonization. Three different salt concentrations were applied to mycorrhizal and non-mycorrhizal plants, and their effects, over time, analyzed. Plant biomass, stomatal conductance, efficiency of photosystem II, as well as ABA content and strigolactone production were assessed. The expression of ABA biosynthesis genes was also analyzed. AM plants showed improved growth rates and a better performance of physiological parameters such as stomatal conductance and efficiency of photosystem II than non-mycorrhizal plants under salt stress since very early stages - 3 weeks - of plant colonization. Moreover, ABA levels were lower in those plants, suggesting that they were less stressed than non-colonized plants. On the other hand, we show that both AM symbiosis and salinity influence strigolactone production, although in a different way in AM and non-AM plants. The results suggest that AM symbiosis alleviates salt stress by altering the hormonal profiles and affecting plant physiology in the host plant. Moreover, a correlation between strigolactone production, ABA content, AM root colonization and salinity level is shown. We propose here that under these unfavourable conditions, plants increase strigolactone production in order to promote symbiosis establishment to cope with salt stress.

  5. Kinetin applications alleviate salt stress and improve the antioxidant composition of leaf extracts in Salvia officinalis.

    Science.gov (United States)

    Tounekti, Taïeb; Hernández, Iker; Müller, Maren; Khemira, Habib; Munné-Bosch, Sergi

    2011-10-01

    A pot experiment was carried out under glasshouse conditions with common sage (Salvia officinalis L.) to investigate the interactive effects of salt stress and kinetin on growth attributes and the abundance of pigments, ions, phenolic diterpenes and α-tocopherol in leaf extracts of this species. The plants were subjected to the following four treatments: (i) control (nutrient solution), (ii) control + 10 μM kinetin, (iii) salt stress (nutrient solution + 100 mM NaCl), and (iv) salt stress + 10 μM kinetin. Kinetin was applied as a foliar fertilizer. Salt stress reduced water contents, photosynthetic activity and pigment contents of sage leaves. In addition, it increased Na(+) contents, and reduced those of Ca(2+) and K(+) in leaves. Salt stress reduced carnosic acid and 12-O-methyl carnosic acid contents in leaves, while it did not affect carnosol and α-tocopherol contents. Foliar applications of kinetin seemed to counterbalance or alleviate the stress symptoms induced by salinity, improving ion and pigment contents, while leaf phenolic diterpene (mainly carnosol) and α-tocopherol contents also increased in both control and NaCl-treated plants; still this effect was much more obvious in salt-treated plants. A similar effect was also obtained when plants were sprayed with KNO(3) or Ca(NO(3))(2), thus suggesting that kinetin effects were at least partly due to an improvement of ion homeostasis. Kinetin applications resulted in increased transcript levels of the isoprenoid and tocopherol biosynthetic genes, DXPRI and VTE2 and VTE4 in control plants, but not in NaCl-treated plants. We conclude that kinetin can alleviate the negative impact of salt on sage plants cultivated under arid environments with salinity problems.

  6. Silicon alleviates deleterious effects of high salinity on the halophytic grass Spartina densiflora.

    Science.gov (United States)

    Mateos-Naranjo, Enrique; Andrades-Moreno, Luis; Davy, Anthony J

    2013-02-01

    The non-essential element silicon is known to improve plant fitness by alleviating the effects of biotic and abiotic stresses, particularly in crops. However, its possible role in the exceptional tolerance of halophytes to salinity has not been investigated. This study reports the effect of Si supply on the salinity tolerance of the halophytic grass Spartina densiflora; plants were treated with NaCl (0-680 mM), with or without silicon addition of 500 μM, in a glasshouse experiment. Plant responses were examined using growth analysis, combined with measurements of gas exchange, chlorophyll fluorescence and photosynthetic pigment concentrations. In addition, tissue concentrations of aluminium, calcium, copper, iron, potassium, magnesium, sodium, phosphorus and silicon were determined. Although high salinity decreased growth, this effect was alleviated by treatment with Si. Improved growth was associated with higher net photosynthetic rate (A), and greater water-use efficiency (WUE). Enhanced A at high salinity could be explained by beneficial effects of Si on the photochemical apparatus, and on chlorophyll concentrations. Ameliorative effects of Si were correlated with reduced sodium uptake, which was unrelated to a reduction in the transpiration rate, since Si-supplemented plants had higher stomatal conductances (G(s)). These plants also had higher tissue concentrations of essential nutrients, suggesting that Si had a positive effect on the mineral nutrient balance in salt-stressed plants. Si appears to play a significant role in salinity tolerance even in a halophyte, which has other, specific salt-tolerance mechanisms, through diverse protective effects on the photosynthetic apparatus, water-use efficiency and mineral nutrient balance.

  7. Pulmonary oligemia maneuver can alleviate pulmonary artery injury during pulmonary thromboendarterectomy procedure

    Institute of Scientific and Technical Information of China (English)

    GAN Hui-li; ZHANG Jian-qun; LU Jia-kai; DONG Xiu-hua; HOU Xiao-tong; GAO Yuan-ming; ZHU Guang-fa

    2013-01-01

    Background Pulmonary thromboendarterectomy (PTE) has evolved as a treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH).This study aimed to characterize if pulmonary oligemia maneuver (POM) can alleviate pulmonary artery injury during PTE procedure.Methods A total of 112 cases of CTEPH admitted to Beijing Anzhen Hospital from March 2002 to August 2011 received PTE procedure.They were retrospectively classified as non-POM group (group A,n=55) or POM group (group B,n=57).Members from group B received POM during rewarming period,whereas members from group A did not.Results There were three (5.45%) early deaths in group A,no death in group B (0) (Fisher's exact test,P=-0.118).Six patients in group A needed extracorporeal membrane oxygenation (ECMO) as life support after the PTE procedure,no patients in group B needed ECMO (Fisher's exact test,P=0.013).The patients in group B had a shorter intubation and ICU stay,lower mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR),higher partial pressure of oxygen in artery (PaO2) and arterial oxygen saturation (SaO2) and less medical expenditure than patients in group A.With a mean follow-up time of (58.3 ± 30.6) months,two patients in group A and one patient in group B died.The difference of the actuarial survival after the procedure between the two groups did not reach statistical significance.Three months post the PTE procedure,the difference of residual occluded pulmonary segment between the two groups did not reach statistical significance (P=-0.393).Conclusion POM can alleviate pulmonary artery injury,shorten ICU stay and intubation time,and lower down the rate of ECMO after PTE procedure.

  8. Hydrogen sulfide in posthemorrhagic shock mesenteric lymph drainage alleviates kidney injury in rats.

    Science.gov (United States)

    Han, B; Zhao, Z G; Zhang, L M; Li, S G; Niu, C Y

    2015-07-01

    Posthemorrhagic shock mesenteric lymph (PHSML) is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H2S) in PHSML drainage in alleviating acute kidney injury (AKI) by administering D,L-propargylglycine (PPG) and sodium hydrosulfide hydrate (NaHS) to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage), and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage). Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H2S, cystathionine-γ-lyase (CSE), Toll-like receptor 4 (TLR4), interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H2S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H2S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H2S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H2S and H2S-mediated inflammation.

  9. Hydrogen sulfide in posthemorrhagic shock mesenteric lymph drainage alleviates kidney injury in rats

    Directory of Open Access Journals (Sweden)

    B. Han

    2015-07-01

    Full Text Available Posthemorrhagic shock mesenteric lymph (PHSML is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H2S in PHSML drainage in alleviating acute kidney injury (AKI by administering D,L-propargylglycine (PPG and sodium hydrosulfide hydrate (NaHS to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage, and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage. Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H2S, cystathionine-γ-lyase (CSE, Toll-like receptor 4 (TLR4, interleukin (IL-10, IL-12, and tumor necrosis factor (TNF-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H2S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H2S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H2S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H2S and H2S-mediated inflammation.

  10. An evaluation of the integrated poverty alleviation and housing scheme in Botswana, case of Ramotswa village

    Directory of Open Access Journals (Sweden)

    Ikgopoleng Horatio Gaogakwe

    2011-01-01

    Full Text Available This article evaluates the effectiveness of the Integrated Poverty Alleviation and Housing Scheme (IPAHS in Ramotswa; an urban village located 32 km south-east of the capital city of Botswana, Gaborone. This study emanates from the fact that low income urban and rural residents with no formal employment were left out of the Self Help Housing Scheme (SHHA. The SHHA was mandated to facilitate the acquisition of subsidised land and loan to purchase building materials. One of the major conditions to qualify for SHHA is that applicants should have formal employment.; the IPAHS was specifically introduced to facilitate economic empowerment to poor households who do not qualify under the SHHA scheme. The IPAHS scheme is a twothronged approach mandated to equip the residents with skills to build/improve houses for themselves and create employment for themselves through molding of bricks for sale in an effort to alleviate poverty. This paper is based on documentary and field research. The field research has a participatory component involving discussion and open ended interviews with relevant government departments. It also involves the administration of structured questionnaire survey to 30 beneficiaries of the scheme. Results show that despite high uptake of the scheme within the country, there are several challenges such as insufficient income to build or improve their houses, signs of poverty in living environments of beneficiaries, uncoordinated roles of various institutions which are major stakeholders in the implementation of the scheme. The scheme requires pragmatic policies geared to meet the needs and aspirations of the poor. There is a need for policy interventions through Government commitment to principles such as the right to housing by every citizen, coordination of roles played by different stakeholders to support the sustainability of the scheme.

  11. Green tea epigallocatechin-3-gallate alleviates Porphyromonas gingivalis-induced periodontitis in mice.

    Science.gov (United States)

    Cai, Yu; Chen, ZhiBin; Liu, Hao; Xuan, Yan; Wang, XiaoXuan; Luan, QingXian

    2015-12-01

    Porphyromonas gingivalis causes inflammation, and leads to the periodontitis in gingival tissue damage and bone resorption. Epigallocatechin-3-gallate (EGCG) is a major polyphenol extract from green tea with plenty of pharmacological functions. The aim of this study was to determine whether continuous oral intake of EGCG would alleviate P. gingivalis-induced periodontitis. Eight-week BALB/c mice were administered with EGCG (0.02%) or vehicle in drinking water. They were fed normal food and orally infected with P. gingivalis every 2days, up to a total of 20 times, and then sacrificed at 15weeks of age. The P. gingivalis-challenged group markedly increased alveolar bone resorption of the maxillae in BALB/c mice by Micro-CT detection, and administration of EGCG resulted in a significant reduction in bone loss. Inflammation cytokine antibody array and enzyme linked immunosorbent assay revealed that some inflammatory mediators in serum were increased by P. gingivalis infection, but were lowered after EGCG treatment. High positive areas of IL-17 and IL-1β in the gingival tissue were observed in the P. gingivalis-challenged mice, and were reduced by EGCG treatment. Real-time polymerase chain reaction (PCR) analyses also showed the expressions of IL-1β, IL-6, IL-17, IL-23, TNF-α and other mediators in gingival tissue were higher in P. gingivalis-challenged mice, and were down-regulated with EGCG treatment, except IL-23. Our results suggest that EGCG, as a natural healthy substance, probably alleviates P. gingivalis-induced periodontitis by anti-inflammatory effect.

  12. Identification of PPARgamma partial agonists of natural origin (I: development of a virtual screening procedure and in vitro validation.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists.

  13. Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner.

    Science.gov (United States)

    Blume, Lawrence C; Leone-Kabler, Sandra; Luessen, Deborah J; Marrs, Glen S; Lyons, Erica; Bass, Caroline E; Chen, Rong; Selley, Dana E; Howlett, Allyn C

    2016-11-01

    Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB1 Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1 R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1 R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1 R by a dynamin- and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1 R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30-120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB1 Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)-mediated increase in cell surface CB1 Rs, which is postulated to be as a result of rimonabant effects on 'non-agonist-driven' internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface.

  14. Mitigation of indomethacin-induced gastrointestinal damages in fat-1 transgenic mice via gate-keeper action of ω-3-polyunsaturated fatty acids

    Science.gov (United States)

    Han, Young-Min; Park, Jong-Min; Kang, Jing X.; Cha, Ji-Young; Lee, Ho-Jae; Jeong, Migeyong; Go, Eun-Jin; Hahm, Ki Baik

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastrointestinal (GI) epithelial cell membranes by inducing several signals through lipid raft organization after membrane incorporation, whereas ω-3 polyunsaturated fatty acids (PUFAs) relieve inflammation, reduce oxidative stress, and provide cytoprotection, consequent to lipid raft disorganization. Therefore, we hypothesized that ω-3 PUFAs can protect the GI from NSAID-induced damages by initiating the gatekeeper action of cell membranes, subsequent to anti-inflammatory and anti-oxidative actions. Administration of indomethacin (IND) leads to the formation of lipid rafts and activation of caveolin-1; however, no such observations were made upon co-administration of eicosapentaenoic acid (EPA) and IND. In addition, the EPA-induced lipid raft disorganization, caveolin-1 inactivation, and cellular cytotoxicity were inhibited when target cells were knocked-out using G-protein coupled receptor 120 (GPR 120). EPA significantly attenuated IND-induced oxidative damage and apoptosis. IND administration induced significant ulceration, bleeding, and oedema in the stomach or small intestine of wild-type (WT) mice; however, such severe damages to the GI significantly decreased in fat-1 transgenic (TG) mice (P < 0.001), which exhibited decreased cyclooxygenase-2 expression and apoptosis, decreased interleukin-1β and FAS concentrations, and increased heme oxygenase-1 concentration. Our study indicates that the gatekeeper function of ω-3 PUFAs improves GI safety when administered with NSAID. PMID:27658533

  15. SCREENING THE EFFICACY OF FORTY MEDICINAL PLANTS NORTH EAST HIMALAYAS OF INDIAN SUBCONTINENT IN INDOMETHACIN INDUCED GASTRIC ULCER IN ALBINO RATS

    Directory of Open Access Journals (Sweden)

    PRASANTA KUMAR MITRA

    2014-05-01

    Full Text Available Objective: To know anti gastric ulcer effect, if any, of 40 medicinal plants. Method: Gastric ulcer was induced in rats by indomethacin and anti gastric ulcer activity of medicinal plants was evaluated. Result: Nine medicinal plants showed anti gastric ulcer activity under the experimental conditions. Conclusion: Active compounds of these planst may be included in future in the list of anti gastric ulcer drugs.

  16. Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds.

    Science.gov (United States)

    Vendramini-Costa, Débora Barbosa; Monteiro, Karin Maia; Iwamoto, Leilane Hespporte; Jorge, Michelle Pedroza; Tinti, Sirlene Valério; Pilli, Ronaldo Aloise; de Carvalho, João Ernesto

    2014-12-01

    Goniothalamin (GTN), a styryl-lactone, is a secondary metabolite naturally found in its enantiomeric form (R) in plants of the genus Goniothalamus (Annonaceae). The antiproliferative activity against human tumor cell lines reported in several studies suggest that the α,β-unsaturated δ-lactone moiety emerges as a key Michael acceptor for cysteine residues or other nucleophilic biological molecules. Our group reported on the in vivo activity of (R)- and (S)-GTN as well as its racemic form (rac-GTN) in both Ehrlich solid tumor and carrageenan-induced paw edema in mice, without side effects in the effective doses. Despite the rich body of data on the in vitro GTN biological activity, much less is known about its in vivo pharmacological action. Herein we describe the gastroprotective activity of rac-GTN on chemical-induced gastric ulcers models in rats. GTN has a potent gastroprotective effect on ethanol-induced ulcers (effective dose50=18mg/kg) and this activity is dependent on sulfhydryl compounds and prostaglandins generation, but independent of nitric oxide (NO), gastric secretion and mucus production. We hypothesize that goniothalamin may act as a mild irritant, inducing the production of sulfhydryl compounds and prostaglandins, in a process known as adaptive cytoprotection. This hypothesis is supported by the fact that Michael acceptors are the most potent inducers of antioxidant response (as activation of Nrf2 pathway) through generation of mild oxidative stress and that gastroprotective activity of goniothalamin is inhibited after pre-treatment with NEM (N-ethylmaleimide) and NSAID (non-steroidal anti-inflammatory drugs), highlighting the importance of sulfhydryl compounds and prostaglandins on GTN activity.

  17. The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives

    DEFF Research Database (Denmark)

    Humaidan, Peter; Papanikolaou, E G; Kyrou, D;

    2012-01-01

    is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal...... phase - the phase after egg transfer - necessitating hormonal support with vaginally applied progesterone to obtain ongoing pregnancies. With the introduction of the gonadotrophin-releasing hormone (GnRH) antagonist protocol (short protocol) it became possible to perform final oocyte maturation...... with a GnRH agonist instead of human chorionic gonadotrophin (HCG). The first studies applying this concept, however, showed a very poor pregnancy rate, despite standard luteal-phase support with progesterone. This review discusses the reason for the poor results and the newest studies, using GnRH agonist...

  18. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    Science.gov (United States)

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

  19. 2-Thiazolylethylamine, a selective histamine H1 agonist, decreases seizure susceptibility in mice.

    Science.gov (United States)

    Yokoyama, H; Onodera, K; Iinuma, K; Watanabe, T

    1994-03-01

    The effects of intracerebroventricular (ICV) administration of histamine and its selective agonists on electrically and pentylenetetrazole-induced convulsions in mice were studied. The ICV administration of histamine decreased seizure susceptibility on electrically and pentylenetetrazole-induced convulsions significantly and dose-dependently. The inhibitory effects of histamine were well antagonized by centrally acting histamine H1 antagonists such as pyrilamine (or mepyramine) and ketotifen, but not by a peripherally acting histamine H1 antagonist, astemizole, or a centrally acting H2 antagonist, zolantidine. The ICV administration of 2-thiazolylethylamine, a selective histamine H1 agonist, also decreased seizure susceptibility, which could be antagonized by centrally acting histamine H1 antagonists, whereas dimaprit, a selective histamine H2 agonist, did not affect seizure susceptibility. These findings strengthened the idea that the central histaminergic neuron system plays an inhibitory role in convulsions.

  20. Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands.

    Science.gov (United States)

    Vardanyan, Ruben; Kumirov, Vlad K; Nichol, Gary S; Davis, Peg; Liktor-Busa, Erika; Rankin, David; Varga, Eva; Vanderah, Todd; Porreca, Frank; Lai, Josephine; Hruby, Victor J

    2011-10-15

    Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.

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

    Science.gov (United States)

    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.

  2. Small-molecule agonists for the glucagon-like peptide 1 receptor

    DEFF Research Database (Denmark)

    Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min;

    2007-01-01

    described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor...... and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also......The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been...

  3. Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange......, with CO2 reduced for CO2 from fermentation processes, and nitrogen excretion in urine. The beta-agonist had no effect on the level of rumen fermentation as indicated by the same methane production for control and treated animals. Heat Production (HE, RQx) increased by the treatment of beta......-agonist corresponding to the increment in the protein retention. OXP/HE,RQx was reduced to about 10% in treated animals, indicating that in order to supply amino acids for an increased protein deposition oxidation of protein is decreased. OXF/HE,RQx were markedly higher in treated animals, but as indicated by the same...

  4. Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

    DEFF Research Database (Denmark)

    Mehlsen, J; Trap-Jensen, J

    1986-01-01

    Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...... and pindolol, a non-selective beta-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single......, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural...

  5. An aryloxypropanolamine hβ3-adrenoceptor agonist as bladder smooth muscle relaxant.

    Science.gov (United States)

    Tasler, Stefan; Baumgartner, Roland; Behr-Roussel, Delphine; Oger-Roussel, Stephanie; Gorny, Diane; Giuliano, Francois; Ney, Peter

    2012-08-15

    The relaxant effect of an aryloxypropanolamine β3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy-3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2-(hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as hβ3-AR agonists have been evaluated and discussed thoroughly. A ranking of hβ3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such.

  6. Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons

    Science.gov (United States)

    Zheng, F.; Gallagher, J. P.

    1992-01-01

    We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.

  7. New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.

    Science.gov (United States)

    Visentin, Sonja; Rolando, Barbara; Di Stilo, Antonella; Fruttero, Roberta; Novara, Monica; Carbone, Emilio; Roussel, Christian; Vanthuyne, Nicolas; Gasco, Alberto

    2004-05-06

    A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.

  8. Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

    Science.gov (United States)

    Buonsanti, M Federica; Bertinaria, Massimo; Stilo, Antonella Di; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2007-10-04

    The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15b at micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol.

  9. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes.

    Science.gov (United States)

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan

    2015-07-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.

  10. Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity.

    Science.gov (United States)

    Ursu, Daniel; Knopp, Kelly; Beattie, Ruth E; Liu, Bin; Sher, Emanuele

    2010-09-01

    TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

  11. Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

    Science.gov (United States)

    Riese, David J.

    2010-01-01

    Introduction Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. Areas covered Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. Expert opinion While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and –independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics. PMID:21532939

  12. Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

    Science.gov (United States)

    Guo, Song; Lu, Xiaowei; Gu, Ruihuan; Zhang, Di; Sun, Yijuan; Feng, Yun

    2017-01-01

    Purpose Adenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH) agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis. Methods Neonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each). The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR). Results The litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; Ppregnancy outcome of adenomyosis in a mouse model. Besides pituitary down-regulation, other possible mechanisms such as the regulation of cell proliferation may play a role in this. These new insights into GnRH agonist mechanisms will be useful for future adenomyosis treatment. PMID:28331289

  13. Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists.

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    Mays, Suzanne G; Okafor, C Denise; Whitby, Richard J; Goswami, Devrishi; Stec, Józef; Flynn, Autumn R; Dugan, Michael C; Jui, Nathan T; Griffin, Patrick R; Ortlund, Eric A

    2016-12-02

    Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. Although preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth nor do they expand the pocket like phospholipids. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable face-to-face π-π-stacking with the LRH-1 residue His-390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies.

  14. Partial nicotinic acetylcholine (α4β2 agonists as promising new medications for smoking cessation

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    Singh J

    2008-01-01

    Full Text Available Objective: To review the pharmacology, clinical efficacy and safety of partial agonists of a4β 2 nicotinic acetylcholine receptor. Data Sources: Primary literature and review articles were obtained via a PUBMED search (1988-August 2006 using the key terms smoking cessation, partial agonist alpha4beta2 nicotinic acetylcholine receptor, varenicline, cytisine and SSR591813. Additional studies and abstracts were identified from the bibliographies of reviewed literature. Study Selection and Data Extraction: Studies and review articles related to varenicline, cytisine and the partial agonist alpha4beta2 nicotinic acetylcholine receptor were reviewed. Data Synthesis: Smoking is widely recognized as a serious health problem. Smoking cessation has major health benefits. According to the US Public Health Services, all patients attempting to quit smoking should be encouraged to use one or more effective pharmacotherapy. Currently, along with nicotine replacement therapy, bupropion, nortriptyline and clonidine, are the mainstay of pharmacotherapy. More than ¾ of patients receiving treatment for smoking cessation return to smoking within the first year. Nicotine, through stimulating α4β 2 nAChR, releases dopamine in the reward pathway. Partial agonist of α4β 2 nAChR elicits moderate and sustained release of dopamine, which is countered during the cessation attempts; it simultaneously blocks the effects of nicotine by binding with α4β 2 receptors during smoking. Recently, varenicline, a partial agonist at α4β 2 nAChR, has been approved by the FDA (Food and Drug Administration for smoking cessation. Conclusion: Partial agonist α4β 2 nAChR appears to be a promising target in smoking cessation. Varenicline of this group is approved for treatment of smoking cessation by the FDA in May 2006.

  15. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    Energy Technology Data Exchange (ETDEWEB)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland); Erchegyi, Judit; Rivier, Jean E. [The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA (United States)

    2010-08-15

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst{sub 1}-sst{sub 5}) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst{sub 2} and sst{sub 3} internalization in vitro in HEK293 cells stably expressing the human sst{sub 2} or sst{sub 3} receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst{sub 2} internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst{sub 3} internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst{sub 3} receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  16. STING agonists induce an innate antiviral immune response against hepatitis B virus.

    Science.gov (United States)

    Guo, Fang; Han, Yanxing; Zhao, Xuesen; Wang, Jianghua; Liu, Fei; Xu, Chunxiao; Wei, Lai; Jiang, Jian-Dong; Block, Timothy M; Guo, Ju-Tao; Chang, Jinhong

    2015-02-01

    Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.

  17. PPARγ agonists promote oligodendrocyte differentiation of neural stem cells by modulating stemness and differentiation genes.

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    Saravanan Kanakasabai

    Full Text Available Neural stem cells (NSCs are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS. Peroxisome proliferator-activated receptor gamma (PPARγ is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF and basic fibroblast growth factor (bFGF induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA and PPARγ agonist ciglitazone or 15-Deoxy-Δ(12,14-Prostaglandin J(2 (15d-PGJ2 resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3-7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3-7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.

  18. Adenosine-A1 receptor agonist induced hyperalgesic priming type II.

    Science.gov (United States)

    Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D

    2016-03-01

    We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that, as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N-cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced type II hyperalgesic priming. In this study, we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms, as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor.

  19. Time-Dependent Protection of CB2 Receptor Agonist in Stroke.

    Directory of Open Access Journals (Sweden)

    Seong-Jin Yu

    Full Text Available Recent studies have indicated that type 2 cannabinoid receptor (CB2R agonists reduce neurodegeneration after brain injury through anti-inflammatory activity. The purpose of this study was to examine the time-dependent interaction of CB2R and inflammation in stroke brain. Adult male rats were subjected to right middle cerebral artery occlusion (MCAo. CB2R mRNA expression was significantly elevated >20 fold on day 2, peaked >40-fold on day 5, and normalized on day 10 post-stroke. Inflammatory markers IBA1 and TLR4 were significantly upregulated 15 fold until day 5 after MCAo. Because of the delayed upregulation of CB2R and IBA1, we next treated animals daily with CB2R agonist AM1241 or anti-inflammatory PPAR-γ agonist pioglitazone from 2 to 5 days after MCAo. Delayed treatment with pioglitazone significantly reduced abnormal neurological scores and body asymmetry as well as brain infarction in stroke animals. No behavioral improvement or reduction in brain infarction was found in animals receiving AM1241. Pioglitazone, but not AM1241, significantly reduced IBA1 expression in the stroke cortex, suggesting that delayed treatment with AM1241 failed to alter ischemia-mediated IBA-1 upregulation. In contrast, pretreatment with AM1241 significantly reduced brain infarction and neurological deficits. In conclusion, our data support a time-dependent neuroprotection of CB2 agonist in an animal model of stroke. Delayed post- treatment with PPAR-γ agonist induced behavioral recovery and microglial suppression; early treatment with CB2R agonist suppressed neurodegeneration in stroke animals.

  20. Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists.

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    Ramirez, Servio H; Reichenbach, Nancy L; Fan, Shongshan; Rom, Slava; Merkel, Steven F; Wang, Xu; Ho, Wen-Zhe; Persidsky, Yuri

    2013-05-01

    Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB₂ can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB₂ agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB₂ expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB₂ surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up-regulation of CB₂ may allow for the use of synthetic CB₂ agonist to limit HIV-1 infection. Two commercially available CB₂ agonists, JWH133 and GP1a, and a resorcinol-based CB₂ agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB₂ agonist was present. Furthermore, CB₂ activation also partially inhibited the expression of HIV-1 pol. CB₂ agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB₂-mediated suppression in viral replication. However, CB₂ may affect the HIV-1 replication machinery. Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB₂ ligands. Together, these results indicate that CB₂ may offer a means to limit HIV-1 infection in macrophages.