Schistosoma Mansoni: Evaluation Of An Rnai-based Treatment Targeting Hgprtase Gene

Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) is an essential gene of the parasite Schistosoma mansoni and it is well conserved in its hosts (mouse and human) at the protein but not at the RNA level. This feature prompted us to assess RNA interference (RNAi) to combat schistosomiasis. Small interfering RNAs (siRNAs) were produced against HGPRTase, injected in infected mice and the number of worms was counted six days after injection. The total number of parasites was reduced by approximately 27% after treatment. RT-PCR analyzes showed a significant reduction in parasite target mRNA but not in host's homologue. The use of low doses of molecules did not oversaturate si- or miRNA pathways as mice survival rates were not affected by siRNAs. This is the first successful in vivo demonstration of a RNAi-based treatment against schistosomiasis. We believe that improvements in molecule delivery and an increase on siRNA dose could rapidly eliminate parasite. © 2007 Elsevier Inc. All rights reserved.1184619623Boyle, J.P., Wu, X.J., Shoemaker, C.B., Yoshino, T.P., Using RNA interference to manipulate endogenous gene expression in Schistosoma mansoni sporocysts (2003) Molecular and Biochemical Parasitology, 128, pp. 205-215Bumcrot, D., Manoharan, M., Koteliansky, V., Sah, D.W., RNAi therapeutics: a potential new class of pharmaceutical drugs (2006) Nature Chemical Biology, 12, pp. 711-719Craig III, S.P., McKerrow, J.H., Newport, G.R., Wang, C.C., Analysis of cDNA encoding the hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) of Schistosoma mansonia putative target for chemotherapy (1988) Nucleic Acids Research, 16, pp. 7087-7101Donze, O., Picard, D., RNA interference in mammalian cells using siRNAs synthesized with T7 RNA polymerase (2002) Nucleic Acids Research, 30, pp. e46Gitlin, L., Karelsky, S., Andino, R., Short interfering RNA confers intracellular antiviral immunity in human cells (2002) Nature, 418, pp. 430-434Grimm, D., Streetz, K.L., Jopling, C.L., Storm, T.A., Pandey, K., Davis, C.R., Marion, P., Kay, M.A., Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways (2006) Nature, 441, pp. 537-541Gryseels, B., Polman, K., Clerinx, J., Kestens, L., Human schistosomiasis (2006) Lancet, 368, pp. 1106-1118Harder, A., Chemotherapeutic approaches to schistosomes: current knowledge and outlook (2002) Parasitology Research, 88, pp. 395-397Kemp, H.A., Hunter III, G.W., Wilkins, O.P., Smalley, H., Dashiell, M.A., Studies on schistosomiasis. 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Antiproliferative Activity And Induction Of Apoptosis In Pc-3 Cells By The Chalcone Cardamonin From Campomanesia Adamantium (myrtaceae) In A Bioactivity-guided Study

The Myrtaceae family is a common source of medicines used in the treatment of numerous diseases in South America. In Brazil, fruits of the Campomanesia species are widely used to make liqueurs, juices and sweets, whereas leaves are traditionally employedas a medicine for dysentery, stomach problems, diarrhea, cystitis and urethritis. Ethanol extracts of Campomanesia adamantium (Myrtaceae) leaves and fruits were evaluated against prostate cancer cells (PC-3). The compound (2E)-1-(2,4-dihydroxy-6-methoxyphenyl)-3- phenylprop-2-en-1-one, cardamonin) was isolated from ethanol extracts of C. adamantium leaves in a bioactivity-guided study and quantified by UPLC-MS/MS. In vitro studies showed that the isolated chalcone cardamonin inhibited prostate cancer cell proliferation and decreased the expression of NFkB1. Moreover, analysis by flow cytometry showed that this compound induced DNA fragmentation, suggesting an effect on apoptosis induction in the PC-3 cell line. © 2014 by the authors; licensee MDPI, Basel, Switzerland.19218431855Brandão, H.N., David, J.P., Couto, R.D., Nascimento, J.A.P., David, J.M., Química e farmacologia de quimioterápicos antineoplásicos derivados de plantas (2010) Quim. Nova, 33, pp. 1359-1369Newman, D.J., Cragg, G.M., Snader, K.M., Natural products as sources of new drugs over the period 1981-2002 (2003) J. Nat. Prod., 66, pp. 1022-1037Newman, D.J., Cragg, G.M., Snader, K.M., Natural products as sources of new drugs over the 30 years from 1981 to 2010 (2012) J. Nat. Prod., 75, pp. 311-335Stefanello, M.E.A., Pascoal, A.C.R.F., Salvador, M.J., Essential oils from neo-tropical myrtaceae: Chemical diversity and biological properties (2011) Chem. 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Commun., (6), pp. 969-972Ferreira, L.C., Grabe-Guimarães, A., De Paula, C.A., Michel, M.C.P., Guimarães, R.G., Rezende, S.A., De Souza-Filho, J.D., Guimarães, D.A.S., Anti-inflammatory and antinociceptive activities of campomanesia adamantium (2013) J. Ethnopharmacol., 145, pp. 100-108Zi, X., Simoneau, A.R., Flavokawain, A., A novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice (2005) Cancer Res., 65, pp. 3479-3486Solomon, V.R., Lee, H., Anti-breast cancer activity of heteroaryl chalcone derivatives (2012) Biomed. 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Gene Expression Profiling In Genetic Animal Models Of Provide Elements To Unveil The Molecular Mechanisms Underlying Epileptogenesis In Rodents [a Caracterização Do Perfil De Expressão Gênica Em Larga Escala Em Modelos Genéticos De Epilepsia Fornece Elementos Para Entender Os Mecanismos Envolvidos Na Epileptogênese Em Roedores]

Objective: The objective of this study was to characterize and compare the genetic profile of two rodent models of epilepsy (Wistar Audiogenic Rat - WAR and rats with generalized epilepsy with absence seizures-GEAS) using gene expression analysis Methods: We used microarray technology for gene expression analysis. Results: The analysis of gene expression profiles in WAR showed among genes up-regulated Neurod1, involved in the development of the cochlear duct. In addition, we found significant differences in gene expression of Apbb1, Foxg1 and Scn1A. GEAS rats had differentially expressed genes related to the development of central nervous system, as well as genes involved in the MAPK pathway, transcription factors, neuronal migration and apoptosis. Conclusion: This study may help to clarify the underlying molecular mechanism that leads to the predisposition to seizures in these animals. Our results indicate the activation of distinct molecular pathways in both models.1825052Aicard, J., Course and prognosis of certain chidhood epilepsies with predominantly myoclonic seizures (1980) Advances in Epileptology. The Xth Epilepsy International Symposim, pp. 159-163. , Wada JA, Penry JK e cols. New York: RavemAndré, E.S., Electrophysiological characterization of a new form of spontaneous epilepsy in Wistar rats (1999) Epilepsia, 40 (SUPPL. 2)Bruno-Neto, R., Caracterização de uma nova forma de epilepsia espontânea em ratos Wistar (1999) XIV FESBE, AnaisBruno-Neto, R., André, E.S., Pellarin, L., Hilário, F.K., Valle, A.C., Timo-Iaria, C., Electrophysiological characterization of a new form of spontaneous epilepsy in Wistar rats (1999) 23rd International Epilepsy Congress, Prague, Czech RepublicDoretto, M.C., Fonseca, C.G., Lobo, R.B., Terra, V.C., Oliveira, J.A., Garcia-Cairasco, N., Quantitative study of the response to genetic selection of the WistarAudiogenic Rat strain (WAR) (2003) Behav Genet, 33 (1), pp. 33-42Garcia-Cairasco, N., Sabbatini, R., Role of the substantianigra in audiogenic seizures: A neuroethological analysis in the rat (1983) Braz J Med Biol Res, 16 (2), pp. 171-183Gitaí, D.L., Martinelli, H.N., Valente, V., Pereira, M.G., Oliveira, J.A., Elias, C.F., Bittencourt, J.C., Paçó-Larson, M.L., Increased expression of GluR2-flip in the hippocampus of the Wistaraudiogenic rat strain after acute and kindled seizures (2010) Hippocampus, 20, pp. 125-133Jobe, P.C., Brown, R.D., Dailey, J.W., Effect of Ro 4-1284 on audiogenic seizure susceptibility and intensity in epilepsy-prone rats (1981) Life Sci, 28 (18), pp. 2031-2038Kovács, Z., Suppression of spike-wave discharge activity and c-fos expression by2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in vivo (2007) Neuroscience Letters, 423, pp. 73-77Mesquita, F., Aguiar, J.F., Oliveira, J.A., Garcia-Cairasco, N., Varanda, W.A., Electrophysiological properties of cultured hippocampal neurons from WistarAudiogenic rats (2005) Brain Res Bul, 65, pp. 177-183Moraes, M.F., Galvis-Alonso, O.Y., Garcia-Cairasco, N., Audiogenic kindling in the Wistar rat: A potential model for recruitment of limbic structures (2000) Epilepsy Research, 39, pp. 251-259Nunes, P.V., Valle, A.C., Timo-Iaria, C., Epileptogenic potentials recorded from the cerebellar cortex in rats (1999) Epilepsia, 40, p. 132. , 23th International Epilepsy Congress, Prague, Czech Republi

Ikk? is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity

IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-KB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1Ser307phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.IKK epsilon (IKK?) is induced by the activation of nuclear factor-?B (NF-?B). Whole-body IKK? knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKK? is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKK? in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-?B activation in this tissue, relieving the inflammatory environment. Inhibition of IKK? activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. 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Sobotzik, J.M., Schultz, C., Schmitz, M.L., Specification of the NF-kappaB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon (2010) Nucleic Acids Res, 38, pp. 6029-6044Chiang, S.H., Bazuine, M., Lumeng, C.N., The protein kinase IKKepsilon regulates energy balance in obese mice (2009) Cell, 138, pp. 961-975Prada, P.O., Hirabara, S.M., De Souza, C.T., L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity (2007) Diabetologia, 50, pp. 1949-1959Prada, P.O., Ropelle, E.R., Mourão, R.H., EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice (2009) Diabetes, 58, pp. 2910-2919Prada, P.O., Quaresma, P.G., Caricilli, A.M., Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei (2013) Diabetes, 62, pp. 137-148Elias, C.F., Bittencourt, J.C., Study of the origins of melanin-concentrating hormone and neuropeptide El immunoreactive projections to the periaqueductal gray matter (1997) Brain Res, 755, pp. 255-271De Souza, C.T., Araujo, E.P., Bordin, S., Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus (2005) Endocrinology, 146, pp. 4192-4199Hotamisligil, G.S., Arner, P., Caro, J.F., Atkinson, R.L., Spiegelman, B.M., Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance (1995) J Clin Invest, 95, pp. 2409-2415García-Cáceres, C., Yi, C.X., Tschöp, M.H., Hypothalamic astrocytes in obesity (2013) Endocrinol Metab Clin North Am, 42, pp. 57-66Clark, K., Peggie, M., Plater, L., Novel cross-talk within the IKK family controls innate immunity (2011) Biochem J, 434, pp. 93-104Arkan, M.C., Hevener, A.L., Greten, F.R., IKK-beta links inflammation to obesity-induced insulin resistance (2005) Nat Med, 11, pp. 191-198Scheja, L., Heese, B., Seedorf, K., Beneficial effects of IKKε-deficiency on body weight and insulin sensitivity are lost in high fat diet-induced obesity in mice (2011) Biochem Biophys Res Commun, 407, pp. 288-294Obici, S., Zhang, B.B., Karkanias, G., Rossetti, L., Hypothalamic insulin signaling is required for inhibition of glucose production (2002) Nat Med, 8, pp. 1376-1382Pocai, A., Morgan, K., Buettner, C., Gutierrez-Juarez, R., Obici, S., Rossetti, L., Central leptin acutely reverses diet-induced hepatic insulin resistance (2005) Diabetes, 54, pp. 3182-3189Morton, G.J., Blevins, J.E., Kim, F., Matsen, M., Figlewicz, D.P., The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling (2009) Am J Physiol Endocrinol Metab, 297, pp. E202-E21