Isolamento de isobruceina B e neosergeolida de Picrolemma sprucei Hook. f. em escala-grama

Quassinoids neosergeolide and isobrucein B, obtained from Picrolemma sprucei, have proven in vitro antitumor, antimalarial, anthelminthic, cytotoxic, insecticide and leishmanicidal activities. There is interest in the in vivo pharmacological study of these natural compounds and their semi-synthetic derivatives, however, the quantities obtained in previous extraction processes have been shown to be a limiting factor for continuation of these studies. Herein, we describe a method for obtaining grams of these quassinoids whose purification relies only on recrystallization.Os quassinóides neosergeolida e isobruceína B, obtidos de Picrolemma sprucei, possuem atividades antitumoral, antimalárica, anti-helmíntica, citotóxica, inseticida e anti-leishmania comprovadas em estudos in vitro. Há interesse no estudo farmacológico in vivo dessas substâncias naturais e de seus derivados semi-sintéticos, porém a quantidade obtida nos processos de extração tem se mostrado um fator limitante à continuação desses estudos. No presente trabalho, descrevemos um método para obtenção de gramas desses quassinóides cuja purificação depende apenas de cristalização fracionada

Physical Exercise Decreases Fasting Hyperglycemia In Diabetic Mice Through Ampk Activation [exercício Físico Reduz A Hiperglicemia De Jejum Em Camundongos Diabéticos Através Da Ativação Da Ampk]

The deficiency in glucose uptake in peripheral tissues and increased hepatic gluconeogenesis are physiopathological phenomena observed in type 2 diabetes patients. Physical exercise plays an important role in the improvement of glycemic profile in diabetic patients; however, the mechanisms involved in these processes have not been fully elucidated. Objective: to assess the role of AMPk protein in the glycemic control of diabetic mice after exercise. Methods: During fasting condition, the insulin tolerance test (ITT) and Western blot technique, were combined to assess the glucose homeostasis in diabetic mice (ob/ob and db/db) after a single swimming session. Results: Fasting hyperglycemia, severe insulin resistance and deficiency in the AMPk/ACC signaling in muscle and liver observed in the diabetic mice were reversed after the exercise session. The restoration of AMPk/ACC signaling reduced the expression of the gluconeogenic enzyme, PEPCk in the liver, and increased the translocation of GLUT4 in the skeletal muscle. These data indicate that the activation of AMPk/ACC pathway induced by physical exercise is important to reduce fasting glucose levels in experimental models of type 2 diabetes. These data open new insights for determination of physical activity control on the glucose homeostasis in diabetic patients.153179184Cherrington, A.D., Control of glucose uptake and release by the liver in vivo (1999) Diabetes, 48, pp. 1198-214. , Banting Lecture 1997Herman, M.A., Kahn, B.B., Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony (2006) J Clin Invest, 116, pp. 1767-75Pauli, J.R., Ropelle, E.R., Cintra, D.E., Carvalho Filho, M.A., Moraes, J.C., de Souza, C.T., Acute physical exercise reverses S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt in dietary induced obese Wistar rats (2007) J Physiol, 586, pp. 659-71Ropelle, E.R., Pauli, J.R., Prada, P.O., de Souza, C.T., Picardi, P.K., Faria, M.C., Reversal of diet- induced insulin resistance with a single bout of exercise in the rat: The role of PTP1B and IRS-1 serine phosphorylation (2006) J Physiol, 577, pp. 997-1007Sriwijitkamol, A., Coletta, D.K., Wajcberg, E., Balbontin, G.B., Reyna, S.M., Barrientes, J., Effect of acute exercise on AMPk signaling in skeletal muscle of subjects with type 2 diabetes: A time-course and dose-response study (2007) Diabetes, 56, pp. 836-48Barnes, B.R., Zierath, J.R., Role of AMP-activated protein kinase in the control of glucose homeostasis (2005) Curr Mol Med, 5, pp. 341-8Kahn, B.B., Alquier, T., Carling, D., Hardie, D.G., AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism (2005) Cell Metab, 1, pp. 15-25Hardie, D.G., Minireview: The AMP-activated protein kinase cascade: The key sensor of cellular energy status (2003) Endocrinology, 144, pp. 5179-83Carling, D., Ampk (2004) Curr Biol, 14, pp. R220Hardie, D.G., Carling, D., The AMP-activated protein kinase - Fuel gauge of the mammalian cell? 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Acute Exercise Decreases Trb3 Protein Levels In The Hypothalamus Of Obese Rats

PURPOSE: To evaluate the effects of acute exercise on the TRB3 protein levels and interaction between TRB3/Akt proteins in the hypothalamus of obese rats. In addition, we evaluated the relationship between TRB3 and endoplasmic reticulum stress (ER stress) and verified whether an acute exercise session is able to influence these processes.METHODS: In the first part of the study, the rats were divided into three groups: control (lean) - fed with a standard rodent chow, DIO - fed with a high fat diet and DIO submitted to a swimming acute exercise protocol (DIO-EXE). In the second part of the study, we used other three groups: control (lean) receiving an intracerebroventricular (i.c.v.) infusion of vehicle, lean receiving an i.c.v. infusion of thapsigargin, and lean receiving an i.c.v infusion of thapsigargin and performing an acute exercise session. Four hours after the exercise session, the food intake was measured and the hypothalamus was dissected and separated for subsequent protein analysis by immunoblotting and Real Time PCR.RESULTS: The acute exercise session reduced the TRB3 protein levels, disrupted the interaction between TRB3/Akt proteins, increased the phosphorylation of Foxo1 and restored the anorexigenic effects of insulin in the hypothalamus of DIO rats. Interestingly, the suppressive effects of acute exercise on TRB3 protein levels may be related, at least in part, to the decrease of ER stress (evaluated though pancreatic ER kinase phosphorylation - pPERK and C/EBP homologous protein - CHOP protein levels) in the hypothalamus.CONCLUSION: In conclusion, the reduction of hypothalamic TRB3 protein levels mediated by exercise may be associated with the reduction of ER stress. These data provided a new mechanism by which an acute exercise session improves insulin sensitivity in hypothalamus and restores food intake control in obesity

Exercise Training Decreases Mitogen-activated Protein Kinase Phosphatase-3 Expression And Suppresses Hepatic Gluconeogenesis In Obese Mice

Insulin plays an important role in the control of hepatic glucose production. Insulin resistant states are commonly associated with excessive hepatic glucose production, which contributes to both fasting hyperglycaemia and exaggerated postprandial hyperglycaemia. In this regard, increased activity of phosphatases may contribute to the dysregulation of gluconeogenesis. Mitogen-activated protein kinase phosphatase-3 (MKP-3) is a key protein involved in the control of gluconeogenesis. MKP-3-mediated dephosphorylation activates FoxO1 (a member of the forkhead family of transcription factors) and subsequently promotes its nuclear translocation and binding to the promoters of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In this study, we investigated the effects of exercise training on the expression of MKP-3 and its interaction with FoxO1 in the livers of obese animals. We found that exercised obese mice had a lower expression of MKP-3 and FoxO1/MKP-3 association in the liver. Further, the exercise training decreased FoxO1 phosphorylation and protein levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and gluconeogenic enzymes (PEPCK and G6Pase). These molecular results were accompanied by physiological changes, including increased insulin sensitivity and reduced hyperglycaemia, which were not caused by reductions in total body mass. Similar results were also observed with oligonucleotide antisense (ASO) treatment. However, our results showed that only exercise training could reduce an obesity-induced increase in HNF-4α protein levels while ASO treatment alone had no effect. These findings could explain, at least in part, why additive effects of exercise training treatment and ASO treatment were not observed. 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CMS Physics Technical Design Report: Addendum on High Density QCD with Heavy Ions

This report presents the capabilities of the CMS experiment to explore the rich heavy-ion physics programme offered by the CERN Large Hadron Collider (LHC). The collisions of lead nuclei at energies $\sqrt{s_{NN}}= 5.5\,{\rm TeV}$ , will probe quark and gluon matter at unprecedented values of energy density. The prime goal of this research is to study the fundamental theory of the strong interaction \u2014 Quantum Chromodynamics (QCD) \u2014 in extreme conditions of temperature, density and parton momentum fraction (low- x ). This report covers in detail the potential of CMS to carry out a series of representative Pb-Pb measurements. These include "bulk" observables, (charged hadron multiplicity, low p T inclusive hadron identified spectra and elliptic flow) which provide information on the collective properties of the system, as well as perturbative probes such as quarkonia, heavy-quarks, jets and high p T hadrons which yield "tomographic" information of the hottest and densest phases of the reaction