A Brief View of Molecular Modeling Approaches to P2 Receptors

Purinergic receptors are a class of receptors distributed into two groups, P1 and P2. P1 receptors are activated by nucleosides, like adenosine, while nucleotides active P2 receptors. In turn, P2 receptors comprise two families, metabotropic P2Y and ionotropic P2X. P2Y receptors consist in eight members, namely, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, described in mammals, while P2X includes seven members, numbered P2X1 to P2X7. These receptors have been described as expressed in practically all cells studied to date. In this context, P2 receptors are suggested as participating in certain diseases. The general approach applied in the discovery of new drugs is expensive and lengthy. Alternatively, in the last 20 years, molecular modeling has emerged as an exciting tool for the design of new drugs, in less time and at low costs. These tools allow for in silico testing of thousands of molecules against a target protein, as well as toxicity, absorption, distribution, metabolism, and constant affinity predictions of a given interaction. Thus, molecular modeling algorithms emerge as an increasingly important tool for the design of drugs targeting purinergic receptors as therapeutic targets of many diseases, including cancer, pain, inflammation, cardiovascular, and endocrine conditions

Analysis of factors associated with extremity ulceration in diabetic subjects with peripheral neuropathy

Peripheral neuropathy is the main risk factor for foot ulceration in diabetic subjects. This study examined the association of peripheral arterial disease (PAD) with foot ulceration in a sample of diabetic subjects with peripheral neuropathy, and also if inflammatory markers would be associated with this event. We evaluated 32 type 2 diabetic individuals with abnormal 10-g monofilament exam, who were stratified in 2 groups according to history or presence of lower extremities ulcer. The group with ulcer (n = 18) included the ones that had active or cicatrized ulcer, or some lower-extremity amputation due to ulcer complications. In addition to the neurological examination and monofilament test, they were submitted to biothesiometry, lower extremity vascular assessment with Doppler, and laboratory determinations. No difference between the groups was found concerning sex distribution, mean age, and duration of diabetes diagnosis. The group with ulcer showed higher mean values of height (1.70 ± 0.06 vs. 1.63 ± 0.11 m, p = 0.044), vibration perception threshold measured in medial malleolli (40.9 ± 13.0 vs. 30.6 ± 12.3 V, p = 0.040) than the group without ulcer. The groups did not differ regarding the mean values of the inflammatory markers. Response to patellae reflex was worse in the group with ulcer (p = 0.047), in which a higher proportion of individuals with abnormal toe-brachial index (p = 0.030) was observed as compared to those without ulcer. We concluded that PAD is associated with the presence of ulcer in neuropathic subjects. The assessment of digital arteries flow in lower limbs (in great toe) contributed to detect such association. Association of diabetic foot ulcers and inflammatory markers was not observed, but cannot be excluded due to limitations of sample size. Prospective studies should examine the sensitivity of the toe-brachial index to identify PAD in diabetic individual at risk of ulceration.A neuropatia periférica é o principal fator de risco para ulceração em pé de indivíduos diabéticos. Este estudo testou a associação de doença arterial periférica (DAP) à ulceração do pé em amostra de pacientes com neuropatia sensório-motora simétrica distal e se marcadores inflamatórios subclínicos também se associariam a esse evento. Foram avaliados 32 indivíduos diabéticos tipo 2 com exame do monofilamento de 10 g alterado, estratificados em 2 grupos segundo a história ou presença de úlcera nas extremidades inferiores. O grupo com úlcera (n = 18) incluiu aqueles que apresentavam úlcera ativa ou cicatrizada, ou que tiveram alguma amputação em membro inferior decorrente de complicações da úlcera. Além do exame neurológico e monofilamento, foram submetidos a bioestesiometria, avaliação vascular com Doppler e exames laboratoriais. Os grupos foram semelhantes quanto à distribuição dos sexos, média de idade e tempo de diabetes. O grupo com úlcera apresentou valores médios de altura (1,70 ± 0,06 vs. 1,63 ± 0,11 m; p = 0,044) e limiar de percepção vibratória no maléolo medial (40,9 ± 13,0 vs. 30,6 ± 12,3 V; p = 0,040) mais elevados que o sem a úlcera. Os grupos não diferiram entre si quanto à média dos marcadores inflamatórios. A resposta do reflexo patelar foi também pior no grupo com úlcera (p = 0,047), no qual se observou maior proporção de indivíduos com o índice hálux-braquial alterado (p = 0,030) quando comparado ao sem úlcera. Conclui-se que a DAP está associada à presença de úlcera (atual ou pregressa) em membros inferiores de indivíduos diabéticos neuropatas. A pesquisa de alteração de fluxo de artérias digitais de membro inferior (no hálux) contribuiu para detectar tal associação. Associação de neuropatia ulcerada a marcadores inflamatórios não foi observada, não sendo possível excluí-la devido às limitações do tamanho da amostra. Estudos prospectivos deverão examinar a sensibilidade do índice hálux-braquial para identificar DAP em indivíduos diabéticos sob risco de ulceração.Universidade Federal de São Paulo (UNIFESP) Programa de Pós-Graduação em Ciências EndocrinológicasUniversidade Federal de São Paulo (UNIFESP) Programa de Pós-Graduação em Cirurgia VascularUniversidade de São Paulo Faculdade de Saúde Pública Departamento de NutriçãoUNIFESP, Programa de Pós-Graduação em Ciências EndocrinológicasUNIFESP, Programa de Pós-Graduação em Cirurgia VascularSciEL

Peripheral Sensitization Increases Opioid Receptor Expression And Activation By Crotalphine In Rats

Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE2) increases the mRNA and protein levels of the μ- and κ-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE 2, alone does not increase the activation of these opioid receptors but that in the presence of PGE2, the activation of specific opioid receptors by CRP and selective μ- and κ-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the δ-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase Cζ. This CRP effect was much more prominent when the cells were pretreated with PGE 2. These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids. © 2014 Zambelli et al.93Stein, C., Peripheral mechanisms of opioid analgesia (1993) Anesth Analg, 76, pp. 182-191Obara, I., Parkitna, J.R., Korostynski, M., Makuch, W., Kaminska, D., Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain (2009) Pain, 141, pp. 283-291Puehler, W., Zollner, C., Brack, A., Shaqura, M.A., Krause, H., Schafer, M., Stein, C., Rapid upregulation of mu opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction (2004) Neuroscience, 129 (2), pp. 473-479. , DOI 10.1016/j.neuroscience.2004.06.086, PII S030645220400627XMaekawa, K., Minami, M., Masuda, T., Satoh, M., Expression of mu- and kappa-, but not delta-, opioid receptor mRNAs is enhanced in the spinal dorsal horn of the arthritic rats (1996) Pain, 64 (2), pp. 365-371. , DOI 10.1016/0304-3959(95)00132-8Cahill, C.M., Morinville, A., Hoffert, C., O'Donnell, D., Beaudet, A., Up-regulation and trafficking of delta opioid receptor in a model of chronic inflammation: Implications for pain control (2003) Pain, 101 (1-2), pp. 199-208. , DOI 10.1016/S0304-3959(02)00333-0Hassan, A.H.S., Ableitner, A., Stein, C., Herz, A., Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue (1993) Neuroscience, 55 (1), pp. 185-195. , DOI 10.1016/0306-4522(93)90465-RZollner, C., Shaqura, M.A., Bopaiah, C.P., Mousa, S., Stein, C., Schafer, M., Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons (2003) Molecular Pharmacology, 64 (2), pp. 202-210. , DOI 10.1124/mol.64.2.202Shaqura, M.A., Zollner, C., Mousa, S.A., Stein, C., Schafer, M., Characterization of mu Opioid Receptor Binding and G Protein Coupling in Rat Hypothalamus, Spinal Cord, and Primary Afferent Neurons during Inflammatory Pain (2004) Journal of Pharmacology and Experimental Therapeutics, 308 (2), pp. 712-718. , DOI 10.1124/jpet.103.057257Antonijevic, I., Mousa, S.A., Schafer, M., Stein, C., Perineurial defect and peripheral opioid analgesia in inflammation (1995) J Neurosci, 15, pp. 165-172Mousa, S.A., Zhang, Q., Sitte, N., Ji, R.-R., Stein, C., beta-endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue (2001) Journal of Neuroimmunology, 115 (1-2), pp. 71-78. , DOI 10.1016/S0165-5728(01)00271-5, PII S0165572801002715Konno, K., Picolo, G., Gutierrez, V.P., Brigatte, P., Zambelli, V.O., Crotalphine, a novel potent analgesic peptide from the venom of the South American rattlesnake Crotalus durissus terrificus (2008) PeptidesGutierrez, V.P., Zambelli, V.O., Picolo, G., Chacur, M., Sampaio, S.C., The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats Behav Pharmacol, 23, pp. 14-24Gutierrez, V.P., Konno, K., Chacur, M., Sampaio, S.C., Picolo, G., Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors (2008) Eur J Pharmacol, 594, pp. 84-92Granados-Soto, V., Rufino, M.D.O., Gomes, L.L.D., Ferreira, S.H., Evidence for the involvement of the nitric oxide-cGMP pathway in the antinociception of morphine in the formalin tests (1997) European Journal of Pharmacology, 340 (2-3), pp. 177-180. , DOI 10.1016/S0014-2999(97)01399-X, PII S001429999701399XSachs, D., Cunha, F.Q., Ferreira, S.H., Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway (2004) Proceedings of the National Academy of Sciences of the United States of America, 101 (10), pp. 3680-3685. , DOI 10.1073/pnas.0308382101Pacheco, D.F., Reis, G.M.L., Francischi, J.N., Castro, M.S.A., Perez, A.C., Duarte, I.D.G., delta-Opioid receptor agonist SNC80 elicits peripheral antinociception via delta1 and delta2 receptors and activation of the L-arginine/nitric oxide/cyclic GMP pathway (2005) Life Sciences, 78 (1), pp. 54-60. , DOI 10.1016/j.lfs.2005.04.032, PII S0024320505006697Amarante, L.H., Duarte, I.D.G., The kappa-opioid agonist (+/-)-bremazocine elicits peripheral antinociception by activation of the L-arginine/nitric oxide/cyclic GMP pathway (2002) European Journal of Pharmacology, 454 (1), pp. 19-23. , DOI 10.1016/S0014-2999(02)02275-6, PII S0014299902022756Cunha, T.M., Roman-Campos, D., Lotufo, C.M., Duarte, H.L., Souza, G.R., Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway Proc Natl Acad Sci U S A, 107, pp. 4442-4447Law, B.K., Waltner-Law, M.E., Entingh, A.J., Chytil, A., Aakre, M.E., Norgaard, P., Moses, H.L., Salicylate-induced growth arrest is associated with inhibition of p70s6k and down-regulation of c-Myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen (2000) Journal of Biological Chemistry, 275 (49), pp. 38261-38267. , DOI 10.1074/jbc.M005545200Belcheva, M.M., Clark, A.L., Haas, P.D., Serna, J.S., Hahn, J.W., Kiss, A., Coscia, C.J., Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes (2005) Journal of Biological Chemistry, 280 (30), pp. 27662-27669. , DOI 10.1074/jbc.M502593200Connor, M., Christie, M.J., Opioid receptor signalling mechanisms (1999) Clinical and Experimental Pharmacology and Physiology, 26 (7), pp. 493-499. , DOI 10.1046/j.1440-1681.1999.03049.xZimmermann, M., Ethical guidelines for investigations of experimental pain in conscious animals (1983) Pain, 16, pp. 109-110Picolo, G., Giorgi, R., Bernardi, M.M., Cury, Y., The antinociceptive effect of Crotalus durissus terrificus snake venom is mainly due to a supraspinally integrated response (1998) Toxicon, 36 (1), pp. 223-227. , DOI 10.1016/S0041-0101(97)00048-2, PII S0041010197000482Von Banchet, G.S., Scholze, A., Schaible, H.-G., Prostaglandin E2 increases the expression of the neurokinin1 receptor in adult sensory neurones in culture: A novel role of prostaglandins (2003) British Journal of Pharmacology, 139 (3), pp. 672-680Picolo, G., Giorgi, R., Cury, Y., delta-Opioid receptors and nitric oxide mediate the analgesic effect of Crotalus durissus terrificus snake venom (2000) European Journal of Pharmacology, 391 (1-2), pp. 55-62. , DOI 10.1016/S0014-2999(99)00934-6, PII S0014299999009346Gendron, L., Pintar, J.E., Chavkin, C., Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia (2007) Neuroscience, 150 (4), pp. 807-817. , DOI 10.1016/j.neuroscience.2007.09.060, PII S0306452207012365Lomas, L.M., Barrett, A.C., Terner, J.M., Lysle, D.T., Picker, M.J., Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats (2007) Psychopharmacology, 191 (2), pp. 273-285. , DOI 10.1007/s00213-006-0663-1Ji, Y., Murphy, A.Z., Traub, R.J., Estrogen modulation of morphine analgesia of visceral pain in female rats is supraspinally and peripherally mediated (2007) J Pain, 8, pp. 494-502. , JPicolo, G., Cury, Y., Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a delta- and kappa-opioid receptor agonist (2004) Life Sciences, 75 (5), pp. 559-573. , DOI 10.1016/S0024-3205(04)00292-9, PII S0024320504002929Randall, L.O., Selitto, J.J., A method for measurement of analgesia activity on inflamed tissue (1957) Arch Inst Pharmacodyn, 111, pp. 209-219Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding (1976) Anal Biochem, 72, pp. 248-254Gupta, A., Decaillot, F.M., Gomes, I., Tkalych, O., Heimann, A.S., Conformation state sensitive antibodies to G-protein coupled receptors (2006) J Biol ChemCunha, T.M., Souza, G.R., Domingues, A.C., Carreira, E.U., Lotufo, C.M., Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kgamma/AKT/nNOS/NO signaling pathway Mol Pain, 8, p. 10Bruchas, M.R., Chavkin, C., Kinase cascades and ligand-directed signaling at the kappa opioid receptor Psychopharmacology, 210, pp. 137-147. , BerlBerra, E., Diaz-Meco, M.T., Dominguez, I., Municio, M.M., Sanz, L., Lozano, J., Chapkin, R.S., Moscat, J., Protein kinase C zeta isoform is critical for mitogenic signal transduction (1993) Cell, 74 (3), pp. 555-563Kwong, K., Lee, L.-Y., Prostaglandin E2 potentiates a TTX-resistant sodium current in rat capsaicin-sensitive vagal pulmonary sensory neurones (2005) Journal of Physiology, 564 (2), pp. 437-450. , DOI 10.1113/jphysiol.2004.078725Southall, M.D., Vasko, M.R., Prostaglandin receptor subtypes, EP3C and EP4, mediate the prostaglandin E2-induced cAMP production and sensitization of sensory neurons (2001) J Biol Chem, 276, pp. 16083-16091Ferreira, S.H., Lorenzetti, B.B., Prostaglandin hyperalgesia, IV: A metabolic process (1981) Prostaglandins, 21, pp. 789-792Stein, C., Millan, M.J., Shippenberg, T.S., Peter, K., Herz, A., Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors (1989) Journal of Pharmacology and Experimental Therapeutics, 248 (3), pp. 1269-1275Mousa, S.A., Machelska, H., Schafer, M., Stein, C., Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain (2002) Journal of Neuroimmunology, 126 (1-2), pp. 5-15. , DOI 10.1016/S0165-5728(02)00049-8, PII S0165572802000498Furst, S., Riba, P., Friedmann, T., Timar, J., Al-Khrasani, M., Obara, I., Makuch, W., Schmidhammer, H., Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat (2005) Journal of Pharmacology and Experimental Therapeutics, 312 (2), pp. 609-618. , DOI 10.1124/jpet.104.075176Nunez, S., Lee, J.-S., Zhang, Y., Bai, G., Ro, J.Y., Role of peripheral mu-opioid receptors in inflammatory orofacial muscle pain (2007) Neuroscience, 146 (3), pp. 1346-1354. , DOI 10.1016/j.neuroscience.2007.02.024, PII S030645220700173XSchafer, M., Imai, Y., Uhl, G.R., Stein, C., Inflammation enhances peripheral mu-opioid receptor-mediated analgesia, but not mu-opioid receptor transcription in dorsal root ganglia (1995) Eur J Pharmacol, 279, pp. 165-169Zhou, L., Zhang, Q., Stein, C., Schafer, M., Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia (1998) Journal of Pharmacology and Experimental Therapeutics, 286 (2), pp. 1000-1006Lecat, S., Bucher, B., Mely, Y., Galzi, J.-L., Mutations in the extracellular amino-terminal domain of the NK2 neurokinin receptor abolish cAMP signaling but preserve intracellular calcium responses (2002) Journal of Biological Chemistry, 277 (44), pp. 42034-42048. , DOI 10.1074/jbc.M203606200Decaillot, F.M., Befort, K., Filliol, D., Yue, S.Y., Walker, P., Kieffer, B.L., Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation (2003) Nature Structural Biology, 10 (8), pp. 629-636. , DOI 10.1038/nsb950Selley, D.E., Breivogel, C.S., Childers, S.R., Modification of G protein-coupled functions by low-pH pretreatment of membranes from NG108-15 cells: Increase in opioid agonist efficacy by decreased inactivation of G proteins (1993) Molecular Pharmacology, 44 (4), pp. 731-741Belcheva, M.M., Vogel, Z., Ignatova, E., Avidor-Reiss, T., Zippel, R., Levy, R., Young, E.C., Coscia, C.J., Opioid modulation of extracellular signal-regulated protein kinase activity is ras-dependent and involves G(betagamma) subunits (1998) Journal of Neurochemistry, 70 (2), pp. 635-645Bohn, L.M., Belcheva, M.M., Coscia, C.J., Mitogenic signaling via endogenous kappa-opioid receptors in C6 glioma cells: Evidence for the involvement of protein kinase C and the mitogen- activated protein kinase signaling cascade (2000) Journal of Neurochemistry, 74 (2), pp. 564-573. , DOI 10.1046/j.1471-4159.2000.740564.xBruchas, M.R., Macey, T.A., Lowe, J.D., Chavkin, C., Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes (2006) Journal of Biological Chemistry, 281 (26), pp. 18081-18089. , http://www.jbc.org/cgi/reprint/281/26/18081, DOI 10.1074/jbc.M513640200Sweatt, J.D., Mitogen-activated protein kinases in synaptic plasticity and memory (2004) Curr Opin Neurobiol, 14, pp. 311-317Thomas, G.M., Huganir, R.L., MAPK cascade signalling and synaptic plasticity (2004) Nature Reviews Neuroscience, 5 (3), pp. 173-183Carlezon Jr., W.A., Duman, R.S., Nestler, E.J., The many faces of CREB (2005) Trends in Neurosciences, 28 (8), pp. 436-445. , DOI 10.1016/j.tins.2005.06.005, PII S016622360500158XBruchas, M.R., Xu, M., Chavkin, C., Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2 (2008) Neuroreport, 19, pp. 1417-1422Kreibich, A.S., Blendy, J.A., cAMP response element-binding protein is required for stress but not cocaine-induced reinstatement (2004) Journal of Neuroscience, 24 (30), pp. 6686-6692. , DOI 10.1523/JNEUROSCI.1706-04.2004Bruchas, M.R., Yang, T., Schreiber, S., DeFino, M., Kwan, S.C., Li, S., Chavkin, C., Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase (2007) Journal of Biological Chemistry, 282 (41), pp. 29803-29811. , http://www.jbc.org/cgi/reprint/282/41/29803, DOI 10.1074/jbc.M705540200Melief, E.J., Miyatake, M., Bruchas, M.R., Chavkin, C., Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling (2010) Proc Natl Acad Sci U S A, 107, pp. 11608-11613Velazquez, K.T., Mohammad, H., Sweitzer, S.M., Protein kinase C in pain: Involvement of multiple isoforms (2007) Pharmacological Research, 55 (6), pp. 578-589. , DOI 10.1016/j.phrs.2007.04.006, PII S104366180700084

Faraday rotation in graphene

We study magneto--optical properties of monolayer graphene by means of quantum field theory methods in the framework of the Dirac model. We reveal a good agreement between the Dirac model and a recent experiment on giant Faraday rotation in cyclotron resonance. We also predict other regimes when the effects are well pronounced. The general dependence of the Faraday rotation and absorption on various parameters of samples is revealed both for suspended and epitaxial graphene.Comment: 10 pp; v2: typos corrected and references added, v3, v4: small changes and more reference

Role of dynamical particle-vibration coupling in reconciliation of the d3/2d_{3/2} puzzle for spherical proton emitters

It has been observed that decay rate for proton emission from $d_{3/2}$ single particle state is systematically quenched compared with the prediction of a one dimensional potential model although the same model successfully accounts for measured decay rates from $s_{1/2}$ and $h_{11/2}$ states. We reconcile this discrepancy by solving coupled-channels equations, taking into account couplings between the proton motion and vibrational excitations of a daughter nucleus. We apply the formalism to proton emitting nuclei $^{160,161}$Re to show that there is a certain range of parameter set of the excitation energy and the dynamical deformation parameter for the quadrupole phonon excitation which reproduces simultaneously the experimental decay rates from the 2$d_{3/2}$, 3$s_{1/2}$ and 1$h_{11/2}$ states in these nuclei.Comment: RevTex, 12 pages, 4 eps figure

3-amino-1,2,4-triazole induces quick and strong fat loss in mice with high fat-induced metabolic syndrome

BACKGROUND: Obesity is a growing epidemic with limited effective treatments and an important risk factor for several diseases such as metabolic syndrome (MetS). In this study, we aimed to investigate the effect of 3-amino-1,2,4-triazole (ATZ), an inhibitor of catalase and heme synthesis, in a murine model for MetS. METHODS: Male C57BL/6 mice with high-fat diet-induced MetS received ATZ (500 mg·kg(-1)·24 h(-1)) for 12 weeks. RESULTS: The HFD group showed increased blood pressure and body weight, enhanced fat deposition accompanied by an increase in adipocyte diameter, and decreased lipolysis in white adipose tissue (WAT). The expression of genes related to inflammation was increased in WAT of the HFD group. Concurrently, these mice exhibited an increase in leptin, nonesterified fatty acid (NEFA), insulin, and glucose in plasma, coupled with glucose intolerance and insulin resistance. Strikingly, ATZ prevented the increase in blood pressure and the HFD-induced obesity as observed by lower body weight, WAT index, triglycerides, NEFA, and leptin in plasma. ATZ treatment also prevented the HFD-induced increase in adipocyte diameter and even induced marked atrophy and the accumulation of macrophages in this tissue. ATZ treatment also improved glucose metabolism by increasing glucose tolerance and insulin sensitivity, GLUT4 mRNA expression in WAT in parallel to decreased insulin levels. CONCLUSIONS: In the context of HFD-induced obesity and metabolic syndrome, the fat loss induced by ATZ is probably due to heme synthesis inhibition, which blocks adipogenesis by probably decreased RevErbα activity, leading to apoptosis of adipocytes and the recruitment of macrophages. As a consequence of fat loss, ATZ elicits a beneficial systemic antiobesity effect and improves the metabolic status

SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis.

Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases

Theoretical description of deformed proton emitters: nonadiabatic coupled-channel method

The newly developed nonadiabatic method based on the coupled-channel Schroedinger equation with Gamow states is used to study the phenomenon of proton radioactivity. The new method, adopting the weak coupling regime of the particle-plus-rotor model, allows for the inclusion of excitations in the daughter nucleus. This can lead to rather different predictions for lifetimes and branching ratios as compared to the standard adiabatic approximation corresponding to the strong coupling scheme. Calculations are performed for several experimentally seen, non-spherical nuclei beyond the proton dripline. By comparing theory and experiment, we are able to characterize the angular momentum content of the observed narrow resonance.Comment: 12 pages including 10 figure