FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / Moringa oleifera Lam. à uma planta nativa do nordeste da Ãndia muito utilizada na medicina popular devido Ãs suas vÃrias propriedades farmacolÃgicas. Estudos etnofarmacolÃgicos tÃm demonstrado atividade hipoglicemiante de compostos oriundos de partes dessa planta, principalmente de suas folhas, em modelos de animais diabÃticos e, tambÃm, em humanos, embasando sua utilizaÃÃo na medicina popular para o tratamento do diabetes. A aÃÃo hipoglicemiante de compostos de folhas de M. oleifera tem sido creditada a componentes oriundos do metabolismo secundÃrio vegetal, sendo escassos trabalhos abordando a participaÃÃo de proteÃnas nessa aÃÃo farmacolÃgica. O objetivo deste trabalho foi obter uma fraÃÃo proteica a partir de folhas de M. oleifera e verificar seu efeito hipoglicemiante em modelos de animais diabÃticos. Para isso, foi realizada extraÃÃo de proteÃnas a partir de folhas de M. oleifera, seguida de precipitaÃÃo com sulfato de amÃnio (0-90%). ApÃs diÃlise exaustiva, o material foi liofilizado para obtenÃÃo da fraÃÃo proteica denominada Mo-FPF. Como modelo de animal experimental, foram utilizados camundongos com diabetes quimicamente induzido por aloxano. Inicialmente, doses de 100, 300 e 500 mg/Kg de peso corpÃreo de Mo-FPF foram administradas intraperitonealmente, tendo sido a dose de 500 mg/Kg de peso corpÃreo a mais efetiva na reduÃÃo glicÃmica apÃs 1, 3 e 5 horas da administraÃÃo. Tal efeito hipoglicemiante nÃo foi verificado pela rota intragÃstrica. AlÃm disso, esse efeito sofreu reduÃÃo quando Mo-FPF foi previamente fervida e administrada por via intraperitoneal. Mo-FPF, administrada diariamente pela rota intraperitoneal, na dose de 500 mg/Kg, durante 20 dias, resultou em reduÃÃo glicÃmica, alÃm de ter exercido efeito hipocolesterolemiante e antioxidante. O perfil eletroforÃtico de Mo-FPF mostrou uma diversidade de bandas proteicas, que foram suscetÃveis à aÃÃo da pepsina e tripsina em ensaio de digestibilidade in vitro. AtravÃs de imunoensaio por Dot Blot, foi verificada reaÃÃo cruzada entre o anticorpo anti-insulina humana e Mo-FPF, sugerindo a existÃncia de epÃtopos antigÃnicos do tipo insulina em proteÃnas de folhas de M. oleifera. Assim, o conjunto de dados obtidos mostra que proteÃnas oriundas de folhas de M. oleifera contribuem para o efeito hipoglicemiante demonstrado neste trabalho. / Moringa oleifera is a plant native to northeastern India widely used in Indian folk medicine due to its various pharmacological properties. Ethnopharmacological studies have demonstrated that compounds derived from parts of this plant, especially leaves, have hypoglycemic activity in diabetic animal models and in humans, allowing its use in folk medicine. The hypoglycemic action of M. oleifera leaves has been attributed to compounds from plant secondary metabolism, however studies showing the involvement of proteins as antidiabetic substances are scarce. The aim of this study was to obtain a protein fraction of M. oleifera leaves and evaluate its hypoglycemic effects on diabetic animal models. For this, the leaf proteins were extracted followed by ammonium sulfate precipitation (0-90%). After exhaustive dialysis, this material was lyophilized to obtain the protein fraction named Mo-PFL. As experimental animal model, alloxan-induced diabetic mice were used. Initially Mo-PFL was intraperitoneally administered at doses of 100, 300 and 500 mg/Kg body weight. The dose of 500 mg/Kg body weight was more effective in reducing blood glucose after 1, 3 and 5 hours of Mo-PFL administration. This hypoglycemic effect was not observed by the intragastric route. This effect was also reduced when boiled Mo-PFL was intraperitoneally administered. Daily intraperitoneal administration of Mo-PFL at a dose of 500 mg/Kg body weight for 20 days caused a significant reduction in blood glucose level and also exerted antioxidant and hypocholesterolemic effects. Electrophoretic pattern of Mo-PFL showed a variety of protein bands, which were susceptible to in vitro pepsin and trypsin digestion. A Dot Blot immunoassay showed cross reactivity between human anti-insulin antibody and Mo-PFL, suggesting the presence of insulin-like epitopes in M. oleifera leaf protein. Overall, these data show that some proteins derived from M. oleifera leaves may contribute to the hypoglycemic effect observed in the present work.

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-04-27T15:30:59Z No. of bitstreams: 1 daniellemariadeoliveiraaragao.pdf: 4293901 bytes, checksum: 9fe0e48b323213abc9a30b33ba1f90db (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-12T15:50:14Z (GMT) No. of bitstreams: 1 daniellemariadeoliveiraaragao.pdf: 4293901 bytes, checksum: 9fe0e48b323213abc9a30b33ba1f90db (MD5) / Made available in DSpace on 2017-05-12T15:50:14Z (GMT). No. of bitstreams: 1 daniellemariadeoliveiraaragao.pdf: 4293901 bytes, checksum: 9fe0e48b323213abc9a30b33ba1f90db (MD5) Previous issue date: 2015-02-27 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Diabetes melito engloba uma série de alterações metabólicas que acarretam um estado crônico de hiperglicemia. Buscando novas alternativas para seu tratamento, muitas espécies de plantas conhecidas na medicina popular pelas propriedades hipoglicemiantes têm sido avaliadas. Entre essas espécies está Cecropia pachystachya Trécul (URTICACEAE), uma planta nativa do Brasil, cujos nomes populares são embaúba, imbaíba, umbaúba, árvore-de-preguiça, barbeira, torém. Nesse contexto, o presente estudo teve como objetivo avaliar o potencial hipoglicemiante, antioxidante e toxicológico das folhas de Cecropia pachystachya. Inicialmente foram preparados dois extratos das folhas dessa espécie, metanólico (EM) e em acetato de etila (EAE). Ambos os extratos foram submetidos à análise quantitativa dos marcadores moleculares e, posteriormente, foi avaliado o efeito hipoglicemiante de cada um deles. EAE foi ncorporado a uma formulação farmacêutica líquida (FF). EM, EAE e FF foram utilizados para o tratamento de ratos da linhagem Wistar normais e induzidos ao diabetes por estreptozotocina. A evolução desses tratamentos foi avaliada através de medidas mensais de glicemias de jejum, além de acompanhamento de peso corporal e consumos de água e ração. Ao final de seis meses, os animais foram eutanasiados e amostras de sangue e órgãos foram coletadas para análises bioquímicas, antioxidante e histopatológica. Foram ainda avaliados os efeitos de FF após a interrupção do tratamento e o efeito do pré-tratamento com FF na indução de ratos com estreptozocina. A análise do perfil cromatográfico de EM e EAE revelou a presença de três marcadores moleculares, ácido clorogênico, isoorientina e orientina. Na análise quantitativa foram observados maiores teores dos flavonoides isoorientina e orientina em EAE. Os extratos padronizados foram administrados em ratos diabéticos ao longo de seis meses, mostrando reduções significativas tanto para EM (56%) quanto para EAE (69%). No entanto, EAE apresentou redução significativa da glicemia já no primeiro mês de tratamento, além de apresentar resultados relevantes em todos os parâmetros antioxidantes avaliados. O tratamento crônico com FF proporcionou uma redução de aproximadamente 70% da glicemia de jejum, ao final dos seis meses, em relação à glicemia inicial desses mesmos animais. Após a interrupção desse tratamento, as glicemias de animais diabéticos foram mantidas em níveis normais. Além disso, o pré-tratamento de ratos normais com FF promoveu proteção sobre as células B-pancreáticas durante a indução do diabetes utilizando estreptozocina. Os resultados mostraram que a FF desenvolvida a partir da espécie Cecropia pachystachya pode ser indicada na preparação de um fitoterápico para auxiliar no tratamento do diabetes melito. / Diabetes mellitus comprises a series of metabolic changes that lead to a chronic state of hyperglycemia. Seeking new alternatives for their treatment, many species of plants known in folk medicine for hypoglycemic properties have been evaluated. Among these species is Cecropia pachystachya Trécul (Urticaceae), a plant native to Brazil, whose common names are embaúba, imbaíba, umbaúba, tree-of-laziness, barbeira, Torem. In this context, the present study aimed to evaluate the potential hypoglycemic, antioxidant and toxicology of Cecropia leaves pachystachya. Initially were prepared two extracts from the leaves of this species, methanol (EM) and ethyl acetate (EAE). Both extracts were subjected to quantitative analysis of molecula markers and subsequently evaluated the hypoglycemic effect of each. EAE was incorporated into a liquid pharmaceutical formulation (FF). MS, EAE and FF were used for the treatment of normal Wistar rats and streptozotocin-induced diabetes. The evolution of these treatments was evaluated through monthly measurements of fasting glucose, and body weight monitoring and water and feed consumption. After six months, the animals were euthanized and blood samples and organs were collected for biochemical, antioxidant and histopathological analysis. We also assessed the effects of FF after discontinuation of treatment and the effect of pretreatment with inducing FF in rats with streptozocin. Analysis of the chromatographic profile of MS and EAE showed the presence of three molecular markers, chlorogenic, orientin and isoorientina acid. The quantitative analysis showed higher levels of flavonoids orientin isoorientina and in EAE. Standardized extracts were administered to diabetic rats over six months, showing significant reductions for both MS (56%) and against EAE (69%). However, EAE had a significant reduction of blood glucose in the first month of treatment, and provide relevant results in all evaluated parameters antioxidants. Chronic treatment with FF was reduced by approximately 70% of fasting glucose at the end of six months from the initial blood glucose of those animals. After discontinuation of treatment, the glycemia of diabetic animals were maintained at normal levels. In addition, pretreatment of mice with normal FF provided protection for pancreatic B-cells in diabetes induced using streptozotocin. The results show that FF developed from Cecropia pachystachya species can be indicated in a herbal preparation to aid in the treatment of diabetes mellitus.

Chan Siu-Wah. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 173-200). / Abstracts in English and Chinese; appendix in Chinese. / Table of Contents --- p.i / Abstract --- p.v / 論文摘要 --- p.ix / Acknowledgments --- p.xii / Table of Figures --- p.xiii / Table of Tables --- p.xvii / Chapter Chapter 1. --- Introduction --- p.1 / Chapter Chapter 2. --- Literature Review --- p.3 / Chapter 2.1 --- Diabetes Mellitus (DM)： Overview --- p.3 / Chapter 2.1.1 --- Diagnosis and Diagnostic Criteria --- p.4 / Chapter 2.1.2 --- Classifications of Diabetes Mellitus --- p.8 / Chapter 2.1.3 --- Management of Type 2 Diabetes Mellitus --- p.15 / Chapter 2.2 --- Diabetes Mellitus Complications： Overview --- p.25 / Chapter 2.2.1 --- Microvascular Complications --- p.26 / Chapter 2.2.2 --- Macrovascular Complications --- p.31 / Chapter 2.3 --- Type 2 Diabetes Mellitus - A Rising Global Burden --- p.32 / Chapter 2.3.1 --- Prevalence of Type 2 Diabetes Mellitus --- p.32 / Chapter 2.3.2 --- Prevalence of Type 2 Diabetes Mellitus in Hong Kong --- p.36 / Chapter 2.3.3 --- Mortality and Morbidity of Type 2 Diabetes Mellitus in Hong Kong --- p.40 / Chapter 2.4 --- cost of Type 2 Diabetes Mellitus - Under-explored Area in Hong Kong and Asia --- p.46 / Chapter 2.4.1 --- Cost of Type 2 Diabetes Mellitus in the USA --- p.48 / Chapter 2.4.2 --- Cost of Type 2 Diabetes Mellitus in Europe --- p.57 / Chapter 2.4.3 --- Cost of Type 2 Diabetes Mellitus in Asia-Pacific --- p.61 / Chapter 2.5 --- Hong Kong Healthcare System --- p.65 / Chapter 2.5.1 --- Hospital Authority in Hong Kong (Public Healthcare Sector) --- p.67 / Chapter 2.5.2 --- Hong Kong Healthcare Financing System --- p.73 / Chapter 2.6 --- New Emerging Drug Treatment for Type 2 DM in Hong Kong Chinese - Rosiglitazone --- p.77 / Chapter 2.6.1 --- Clinical Efficacy and Tolerability of Rosiglitazone --- p.77 / Chapter 2.6.2 --- Cost-effectiveness of Rosiglitazone --- p.78 / Chapter Chapter 3. --- Hypothesis and Objectives --- p.81 / Chapter 3.1 --- Cost of Type 2 Diabetes Mellitus in Hong Kong Chinese --- p.81 / Chapter 3.1.1 --- Hypothesis --- p.81 / Chapter 3.1.2 --- Objectives --- p.81 / Chapter 3.2 --- Cost-effectiveness Analysis of Metformin + Rosiglitazone vs. Metformin + Glibenclamide for Type 2 DM Patient Whose Diabetes is not Adequately Controlled by Metformin Alone from a Payer's Perspective --- p.82 / Chapter 3.2.1 --- Hypothesis --- p.82 / Chapter 3.2.2 --- Objectives --- p.83 / Chapter Chapter 4. --- Cost of Type 2 Diabetes Mellitus in Hong Kong Chinese --- p.84 / Chapter 4.1 --- Subjects and Methods --- p.84 / Chapter 4.1.1 --- Subjects --- p.84 / Chapter 4.1.2 --- Methods --- p.85 / Chapter 4.1.3 --- Validity and Reliability of the Chinese Questionnaire --- p.96 / Chapter 4.2 --- Results --- p.96 / Chapter 4.2.1 --- Subjects' Characteristics --- p.96 / Chapter 4.2.3 --- Comorbidity --- p.102 / Chapter 4.2.4 --- Complications --- p.102 / Chapter 4.2.5 --- Costs of Type 2 DM --- p.104 / Chapter 4.3 --- Discussions --- p.123 / Chapter Chapter 5 --- Cost-effectiveness Analysis of Metformin + Rosiglitazone vs. Metformin + Glibenclamide for Type 2 DM Patient Whose Diabetes is not Adequately Controlled by Metformin Alone from a Payer's Perspective --- p.134 / Chapter 5.1 --- Methods --- p.134 / Chapter 5.1.1 --- Model Overview --- p.134 / Chapter 5.1.2 --- "Success, Failure and Discontinuation Rates" --- p.138 / Chapter 5.1.3 --- Resources Use and Costs --- p.142 / Chapter 5.1.4 --- Health-Related Quality of Life (HRQOL) --- p.148 / Chapter 5.1.5 --- Base Case Analysis --- p.149 / Chapter 5.1.6 --- Sensitivity Analyses --- p.149 / Chapter 5.2 --- Results --- p.150 / Chapter 5.2.1 --- Base Case Model - CE Analysis: cost per controlled Type 2 DM patient --- p.150 / Chapter 5.2.2 --- Sensitivity Analysis- CE Analysis: cost per controlled Type 2 DM patient --- p.151 / Chapter 5.2.3 --- Base Case Model - CE Analysis: cost per EQ5D utility score --- p.154 / Chapter 5.2.4 --- Sensitivity Analysis- CE Analysis: cost per EQ5D utility score --- p.155 / Chapter 5.3 --- Discussions --- p.158 / Chapter Chapter 6. --- Conclusions --- p.163 / Appendix --- p.165 / References

<p>Gliklazid je jedan od najče&scaron;će kori&scaron;ćenih lekova u terapiji dijabetes melitusa tip 2. U poslednje vreme, utvrđeno je da gliklazid ispoljava i druge pozitivne farmakolo&scaron;ke efekte kao &scaron;to su imunomodulatorni i anti-koagulacioni efekti, ukazujući na njegovu potencijalnu primenu u terapiji dijabetes melitusa tip 1. Gliklazid se odlikuje varijabilnim stepenom apsorpcije nakon peroralne primene i iz tog razloga pretpostavlja se da bi tehnike njegove ciljane isporuke, kao &scaron;to je mikroinkapsulacija, mogle da dovedu do pobolj&scaron;anja njegove apsorpcije i njegove potencijalne primene u terapiji T1DM. Pokazano je da različite žučne kiseline, uključujući i holnu, imaju stabilizacione efekte u domenu primene mikrovezikula i kontrolisanog osobađanja lekova, te je moguće da bi njihov dodatak u mikrovezikularnu formulaciju gliklazida mogao dodatno da pobolj&scaron;a oslobađanje gliklazida, njegovu apsorpciju i antidijabetičke efekte. S tim u vezi, cilj ovog istraživanja je da se ispita hipoglikemijski efekat gliklazida primenjenog u obliku alginatnih mikrovezikula, sa ili bez dodatka holne kiseline na T1DM modelu pacova. Trideset &scaron;est pacova obolelih od T1DM indukovanog aloksanom i odgovarajuće zdrave kontrolne životinje su nasumično raspoređene u &scaron;est grupa (n=6) i tretirane jednokratnom dozom fiziolo&scaron;kog rastvora, suspenzijom gliklazida, gliklazidom u obliku alginatnih mikrovezikula, samo holnom kiselinom, i mikrovezikulama gliklazida sa ili baz dodatka holne kiseline. Uzorkovana je krv tokom 10 h nakon unete doze i merena je koncentracija glukoze u krvi I koncentracija gliklazida u serumu kori&scaron;ćenjem HPLC metode. Mikrovezikule gliklazida su ispoljile hipo-glikemijski efekat kod pacova obolelih od dijabetesa, uprkos njegovim smanjenim koncentracijama u serumu, dok je dodatak holne kiseline u mikrovezikularnu formulaciju smanjio hipoglikemijski efekat gliklazida. Ovo potvrđuje izostanak sinergističkog efekta između gliklazida i holne kiseline. Takođe, ni proces mikroinkapsulacije niti dodatak holne kiseline nisu doprineli pobolj&scaron;anju apsorpcije gliklazida, &scaron;to ukazuje na činjenicu da su njegovi hipoglikemijski efekti nezavisni od njegove apsorpcije i koncentracije u serumu. Stoga se može pretpostaviti da su hipoglikemijski efekti gliklazida pre pod uticajem crevno-metaboličke aktivacije nego ciljanog oslobađanja u digestivnom traktu sistemske apsorpcije. Mikrovezikule gliklazida ispoljavaju hipoglikemijski efekat kod pacova obolelih od T1DM nezavisno od insulina, te mogu imati potencijalnu primenu u terapiji T1DM. Ovaj rad su podržali: HORIZON 2020 MEDLEM projekat broj 690876; Projekat Sekretarijata naučnog i tehnolo&scaron;kog razvoja Vojvodine broj . 114-451-2072-/2016-02; Projekat Ministarstva obrazovanja, nauke i tehnolo&scaron;kog razvoja Republike Srbije broja 41012.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>mladen</o:Author> <o:Version>16.00</o:Version> </o:DocumentProperties> <o:OfficeDocumentSettings> <o:AllowPNG/> </o:OfficeDocumentSettings></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> 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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / IntroduÃÃo: A Cissus verticillata à uma planta, utilizada popularmente como antidiabÃtica e antiinflamatÃria, Objetivos: Investigar as atividades antidiabÃtica, analgÃsica, antiinflamatÃria e antioxidante da FraÃÃo SolÃvel em Metanol (FSM), FraÃÃo Rica em Tiramina (FRT) e tiramina (TIR) isolados de Cissus verticillata. Material e MÃtodos: Ratos Wistar, machos, foram tratados por via oral com a FSM (50 e 100 mg/kg), glibenclamida(GLI, 5 mg/kg), Ãgua destilada ou glicose), e o sangue coletado antes e 30, 60, 90 e 120 min apÃs à glicose (3g/kg) para medir a hipoglicemia. Na avaliaÃÃo da glicemia em ratos normais, os animais foram tratados com a FSM (100 mg/kg), GLI (5 mg/kg) ou Ãgua destilada e a glicemia medida antes e 5 dias depois do tratamento. O diabetes foi induzidos com aloxano (40 mg/kg, i.v) e apÃs 48 h, os animais foram tratados por via oral com a FSM (100 mg/kg), GLI (5 mg/kg) e TIR (2 e 4 mg/kg) e a glicemia determinada antes e 30, 60, 90 e 120 min apÃs à glicose. Outros grupos de animais diabÃticos foram tratados com a FSM (50 e 100 mg/kg), FRT (100 mg/kg), TIR (1- 4 mg/kg), GLI (2,5 e 5 mg/kg), MET (50 e 100 mg/kg) e 5 dias depois, o sangue foi coletado para avaliaÃÃo da glicemia, triglicerÃdios, VLDL, colesterol total, HDL, AST, ALT, urÃia e creatinina. Os animais que sobreviveram foram sacrificados, dissecados o pÃncreas e o fÃgado, e os ÃrgÃos foram usados para a avaliaÃÃo histopatolÃgica, sendo este Ãltimo tambÃm utilizado para avaliaÃÃo da atividade antioxidante (TBARS, GSH, catalase e nitritos/nitratos). Para determinaÃÃo da hemoglobina glicada in vitro foi utilizado sangue de ratos nÃo-diabÃticos incubados com D-glicose (50mM) e FSM ou TIR (50 &#61549;g/ml). Na dosagem do glicogÃnio hepÃtico, ratos diabÃticos foram tratados por 10 dias com a FSM. A avaliaÃÃo da atividade analgÃsica foi realizada em camundongos Swiss, machos, tratados com a FSM (50 e 100 mg/kg, v.o.), TIR (1,2 e 4 mg/kg), GLI ( 5 mg/kg) e MOR (10 mg/kg,.) no teste da formalina. A atividade antiinflamatÃria foi analisada com os modelos do edema de pata induzido por carragenina ou dextrano, em ratos e camundongos tratados com FSM (50 e 100 e 200 mg/kg), TIR (1- 4 mg/kg), GLI ( 5 mg/kg), INDO (5 mg/kg) e CIPRO (5 e 10 mg/kg,v.o.). Resultados: A FSM demonstrou pequena atividade hipoglicemiante no teste de tolerÃncia a glicose em ratos normais e foi ineficaz em diabÃticos. A FSM reduziu a glicemia em ratos normais, enquanto a TIR nÃo teve efeito. O tratamento de ratos diabÃticos durante 5 dias com a FSM, FRT, TIR, GLI e MET reduziu a glicemia, triglicerÃdios, VLDL, urÃia e creatinina. Nenhuma potencializaÃÃo do efeito hipoglicÃmico foi observado com a associaÃÃo de FSM + TIR ou GLI + TIR. Os estudos histopatolÃgicos mostraram regeneraÃÃo das lesÃes e aumento do nÃmero de cÃlulas &#61538; apÃs tratamento dos animais diabÃticos com a FSM, TIR e GLI. A FSM e TIR mostraram atividade antioxiodante, como aumento no nÃvel de GSH e reduÃÃo nos nÃveis de catalase e nitritos. A FRT aumentou somente o GSH. A FSM e TIR reduziram a hemoglobina glicada, demonstraram potente atividade analgÃsica, mas foram ineficazes como antiinflamatÃrias. A FSM e TIR nÃo reverteram a hiperglicemia induzida pelo diazÃxido, um bloqueador dos canais de potÃssio. MET e TIR reduziram a glicemia, triglicerÃdios, VLDL, urÃia e creatinina, e os efeitos hipoglicemiantes foram potencializados quando essas duas drogas foram associadas. ConclusÃo: Estes resultados confirmam a atividade hipoglicemiante da FSM. O mecanismo de aÃÃo nÃo parece ser similar aquele apresentado pelas sulfonilurÃias. A potencializaÃÃo do efeito hipoglicemiante da TIR foi observada apÃs sua associaÃÃo com MET, sugerindo que o mecanismo de aÃÃo dos constituintes hipoglicÃmicos de C. verticillata à similar ao das biguanidas. Posteriormente, a FSM e TIR apresentaram atividade antioxidante, reduzidos nÃveis de hemoglobina glicada, aumento do glicogÃnio hepÃtico, e no nÃmero de cÃlulas &#61538; pancreÃticas, sugerindo que essas drogas diminuem a toxicidade hepÃtica e pancreÃtica. Embora a atividade antiinflamatÃria tenha sido marginal, seu efeito foi potencializado pela associaÃÃo com TIR, indicando que a TIR à um dos principais constituintes bioativos de Cissus verticillata. / IntroduÃÃo: A Cissus verticillata à uma planta, utilizada popularmente como antidiabÃtica e antiinflamatÃria, Objetivos: Investigar as atividades antidiabÃtica, analgÃsica, antiinflamatÃria e antioxidante da FraÃÃo SolÃvel em Metanol (FSM), FraÃÃo Rica em Tiramina (FRT) e tiramina (TIR) isolados de Cissus verticillata. Material e MÃtodos: Ratos Wistar, machos, foram tratados por via oral com a FSM (50 e 100 mg/kg), glibenclamida(GLI, 5 mg/kg), Ãgua destilada ou glicose), e o sangue coletado antes e 30, 60, 90 e 120 min apÃs à glicose (3g/kg) para medir a hipoglicemia. Na avaliaÃÃo da glicemia em ratos normais, os animais foram tratados com a FSM (100 mg/kg), GLI (5 mg/kg) ou Ãgua destilada e a glicemia medida antes e 5 dias depois do tratamento. O diabetes foi induzidos com aloxano (40 mg/kg, i.v) e apÃs 48 h, os animais foram tratados por via oral com a FSM (100 mg/kg), GLI (5 mg/kg) e TIR (2 e 4 mg/kg) e a glicemia determinada antes e 30, 60, 90 e 120 min apÃs à glicose. Outros grupos de animais diabÃticos foram tratados com a FSM (50 e 100 mg/kg), FRT (100 mg/kg), TIR (1- 4 mg/kg), GLI (2,5 e 5 mg/kg), MET (50 e 100 mg/kg) e 5 dias depois, o sangue foi coletado para avaliaÃÃo da glicemia, triglicerÃdios, VLDL, colesterol total, HDL, AST, ALT, urÃia e creatinina. Os animais que sobreviveram foram sacrificados, dissecados o pÃncreas e o fÃgado, e os ÃrgÃos foram usados para a avaliaÃÃo histopatolÃgica, sendo este Ãltimo tambÃm utilizado para avaliaÃÃo da atividade antioxidante (TBARS, GSH, catalase e nitritos/nitratos). Para determinaÃÃo da hemoglobina glicada in vitro foi utilizado sangue de ratos nÃo-diabÃticos incubados com D-glicose (50mM) e FSM ou TIR (50 &#61549;g/ml). Na dosagem do glicogÃnio hepÃtico, ratos diabÃticos foram tratados por 10 dias com a FSM. A avaliaÃÃo da atividade analgÃsica foi realizada em camundongos Swiss, machos, tratados com a FSM (50 e 100 mg/kg, v.o.), TIR (1,2 e 4 mg/kg), GLI ( 5 mg/kg) e MOR (10 mg/kg,.) no teste da formalina. A atividade antiinflamatÃria foi analisada com os modelos do edema de pata induzido por carragenina ou dextrano, em ratos e camundongos tratados com FSM (50 e 100 e 200 mg/kg), TIR (1- 4 mg/kg), GLI ( 5 mg/kg), INDO (5 mg/kg) e CIPRO (5 e 10 mg/kg,v.o.). Resultados: A FSM demonstrou pequena atividade hipoglicemiante no teste de tolerÃncia a glicose em ratos normais e foi ineficaz em diabÃticos. A FSM reduziu a glicemia em ratos normais, enquanto a TIR nÃo teve efeito. O tratamento de ratos diabÃticos durante 5 dias com a FSM, FRT, TIR, GLI e MET reduziu a glicemia, triglicerÃdios, VLDL, urÃia e creatinina. Nenhuma potencializaÃÃo do efeito hipoglicÃmico foi observado com a associaÃÃo de FSM + TIR ou GLI + TIR. Os estudos histopatolÃgicos mostraram regeneraÃÃo das lesÃes e aumento do nÃmero de cÃlulas &#61538; apÃs tratamento dos animais diabÃticos com a FSM, TIR e GLI. A FSM e TIR mostraram atividade antioxiodante, como aumento no nÃvel de GSH e reduÃÃo nos nÃveis de catalase e nitritos. A FRT aumentou somente o GSH. A FSM e TIR reduziram a hemoglobina glicada, demonstraram potente atividade analgÃsica, mas foram ineficazes como antiinflamatÃrias. A FSM e TIR nÃo reverteram a hiperglicemia induzida pelo diazÃxido, um bloqueador dos canais de potÃssio. MET e TIR reduziram a glicemia, triglicerÃdios, VLDL, urÃia e creatinina, e os efeitos hipoglicemiantes foram potencializados quando essas duas drogas foram associadas. ConclusÃo: Estes resultados confirmam a atividade hipoglicemiante da FSM. O mecanismo de aÃÃo nÃo parece ser similar aquele apresentado pelas sulfonilurÃias. A potencializaÃÃo do efeito hipoglicemiante da TIR foi observada apÃs sua associaÃÃo com MET, sugerindo que o mecanismo de aÃÃo dos constituintes hipoglicÃmicos de C. verticillata à similar ao das biguanidas. Posteriormente, a FSM e TIR apresentaram atividade antioxidante, reduzidos nÃveis de hemoglobina glicada, aumento do glicogÃnio hepÃtico, e no nÃmero de cÃlulas &#61538; pancreÃticas, sugerindo que essas drogas diminuem a toxicidade hepÃtica e pancreÃtica. Embora a atividade antiinflamatÃria tenha sido marginal, seu efeito foi potencializado pela associaÃÃo com TIR, indicando que a TIR à um dos principais constituintes bioativos de Cissus verticillata.

<p>Iako je dijabetes melitus (DM) tip 2 je hronično oboljenje čija se stopa značajno povećala poslednjih decenija, podaci o odnosu pacijenta prema leku i lečenju dijabetes melitusa su retki i odnose se na pojedine aspekte terapije. Glavni kamen spoticanja u lečenju dijabetesa jeste nepridržavanje pacijenata propisanim lekovima, &scaron;to otežava održavanje normalne glikoregulacije i doprinosi razvoju te&scaron;kih komplikacija koje značajno utiču na kvalitet života pacijenata sa DM. Raspolaganje tačnim podacima o upotrebi antidijabetičnim lekova, kao i uvidom u realno stanje o odnosu pacijenata prema leku u lečenju DM tipa 2, omogućava pobolj&scaron;anje farmakoterapijske prakse i kreiranje intervencije za pobolj&scaron;anje adherencije pacijenata Ciljevi ovog istraživanja bili su: 1) analiza obima potro&scaron;nje i strukture antidijabetičnih lekova na teritoriji Republike Srpske i njihovo poređenje sa upotrebom i strukturom propisivanja u okolnim zemljama kao i državama sa razvijenom farmakoterapijskom praksom; 2) analiza obima potro&scaron;nje i strukture antidijabetičnih lekova u op&scaron;tini Foča i poređenje sa savremenim farmakoterapijskim smernicama; 3) određivanje procenta pokrivenosti antidijabetičnom terapijom pacijenata sa DM tip 2 tokom jedne godine u op&scaron;tini Foča; 4) određivanje adherencije pacijenata sa DM tipa 2 prema antidijabetičnoj terapiji metodom brojanja tableta/doza insulina i putem validiranog upitnika; 5) određivanje kvaliteta života povezanog sa zdravljem pacijenata sa DM tipa 2 u op&scaron;tini Foča primenom validiranog upitnika SF-36v2; 6) određivanje prediktora neadherenije kod primene obe metode merenja adherencije u odnosu na karakteristike i kvalitet života pacijenata sa DM tip 2 u op&scaron;tini Foča. Ispitivanje se sastojalo iz dva dela. U prvom delu sprovedeno je retrospektivno farmakoepidemiolo&scaron;ko praćenje upotrebe antidijabetičnih lekova kao i određivanje strukture ovih lekova na teritoriji Republike Srpske u periodu od 01.01.2013. do 31.12.2013.godine i izvr&scaron;eno je poređenje sa upotrebom i strukturom propisivanja u okolnim zemljama kao i državama sa razvijenom farmakoterapijskom praksom. U drugom delu ispitivanja sprovedeno je farmakoepidemiolo&scaron;ko ispitivanje primene antidijabetičnih lekova na nivou same op&scaron;tine Foča u okviru koje je pored analize obima potro&scaron;nje i strukture antidijabetičnih lekova u istom periodu kao i na teritoriji Republike Srpske i poređenja sa savremenim farmakoterapijskim smernicama, određivan i procenta pokrivenosti antidijabetičnom terapijom mereno redovno&scaron;ću ponovnih popunjavanja recepata od strane lekara op&scaron;te prakse tokom jednogodi&scaron;njeg perioda. Takođe je sprovedeno i ispitivanje adherencije prema antidijabetičnim lekovima primenom dve različite metode merenja kao i kvalitet života pacijenata sa DM tip 2 između 01.01.2015. i 31.12.2015.godine. Ukupna upotreba antidijabetika za lečenje dijabetesa tip 1 i tip 2 na teritoriji Republike Srpske iznosila je 38,29 DDD/1000st/dan. Upotreba insulina i analoga iznosila je 11,28 DDD/1000st/dan. Ukupna upotreba oralnih lekova koji snižavaju glukozu i krvi, isključujući insuline iznosila je 27,01 DDD/1000st/dan, a metformin je najče&scaron;će kori&scaron;ćeni predstavnik. Sličan obim i struktura upotrebe antidijabetičnih lekova utvrđena je i u op&scaron;tini Foča. Procenat pokrivenosti antidijabetičnom terapijom pacijenata sa DM tip 2 tokom jedne godine u op&scaron;tini Foča iznosio je vi&scaron;e od 94,91%. Adherencija određivana metodom brojanja tableta/doza insulina iznosila je 52,3%, a merena primenom validiranog upitnikom iznosila je svega 44,9%. Statistički značajni prediktori neadherencije određivane primenom metode brojanja tableta/doza insulina su doplata cena leka kao i niži skor dimenzije mentalnog zdravlja kada je u pitanju kvalitet života. Prediktori neadherencije merene primenom validiranog upitnikom bili su mu&scaron;ki pol, kao i niži skor dimenzije mentalnog kao i fizičkog zdravlja kada je u pitanju kvalitet života. Na osnovu ovih saznanja, intervencije za pobolj&scaron;anje adherencije pacijenata bi bile usmerene na edukaciju pacijenata mu&scaron;kog pola, zatim na smanjivanje izdataka pacijenata za lekove, &scaron;to će doprineti i boljem kvalitetu života ovih pacijenata.</p> / <p>Although diabetes mellitus (DM) type 2 is a chronic disease whose rate has increased significantly in recent decades, data on the patient&#39;s attitudes towards the medicine and the treatment of diabetes mellitus are rare and relate to individual aspects of the therapy. The main stumbling block in the treatment of diabetes is not taking prescribed drugs regularly, which makes it difficult to maintain normal glycoregulation and contribute to the development of severe complications that significantly affect the quality of life of patients with DM. The disposition of accurate data on the use of antidiabeticdrugs, as well as the insight into the real state of the patient&#39;s relationship with the medication in the treatment of DM type 2, enables the improvement of pharmacotherapeutic practice and the creation of an intervention to improve patient adherence.<br />The objectives of this research were:<br />1) analysis of the volume of consumption and structure of anti-diabetic medicines on the territory of the Republic of Srpska and their comparison with the use and structure of prescribing in the surrounding countries as well as countries with developed pharmacotherapeutic practice;<br />2) analysis of the volume of consumption and structure of antidiabetic drugs in the municipality of Foča and comparison with modern pharmacotherapeutic guidelines;<br />3) determining the percentage of coverage with antidiabetic therapy of patients with DM type 2 during one year in the municipality of Foča;<br />4) determining the adherence of patients with DM type 2 in antidiabetic therapy by the method of pill counts /volume of insulin and by validated questionnaire;<br />5) determining the quality of life associated with the health of patients with DM type 2 in the municipality of Foča using the validated questionnaire SF-36v2;<br />6) determination of the predictor of nonadherence in the application of both methods of adherence measurement in relation to the characteristics and quality of life of patients with DM type 2 in the municipality of Foča.<br />The investigation consisted of two parts.<br />In the first part, a retrospective pharmacoepidemiological monitoring of the use of antidiabetic drugs was carried out, as well as determining the structure of these drugs in the territory of the Republic of Srpska in the period from January, 1st 2013 until December, 31st 2013, and a comparison was made with the use and prescription structure in neighboring countries as well as countries with developed pharmacotherapeutic practices. In the second part of the study, a pharmacoepidemiological study was carried out on the use of antidiabetic drugs at the level of the municipality of Foča itself, in which, besides analyzing the volume of consumption and structure of anti-diabetic drugs in the same period as in the territory of the Republic of Srpska and comparison with modern pharmacotherapeutic guidelines, the percentage of coverage by antidiabetic therapy was measured by the regularity of the prescription prescribed by the general practitioner over a one-year period. Medication adherence to antidiabetic drugs was also carried out using two different methods of measurement as well as the quality of life of patients with DM type 2 between January, 1st 2015 and December, 31st 2015. The total use of antidiabetic for the treatment of type 1 diabetes and type 2 in the territory of the Republic of Srpska was 38.29 DDD / 1000st / day. The use of insulin and analogs was 11.28 DDD / 1000st / day. The total use of blood glucose lowering drugs , excluding insulins, was 27.01 DDD / 1000st / day, and metformin is the most commonly used representative. A similar volume and structure of the use of anti-diabetic drugs was also determined in the municipality of Foča. The percentage of coverage of antidiabetic therapy of patients with DM type 2 during one year in the municipality of Foca amounted to more than 94.91%. Adherence determined by the pill counts and the volume of insulin method was 52.3%, and measured by applying the validated questionnaire was only 44.9%. Statistically significant predictors of nonadherence determined by the method of pill counts/volume of insulin are copayment, a fix fee for prescription made by patients as well as the lower score of the mental health dimension when it comes to quality of life. The non-adherence predictors measured using the validated questionnaire were the male sex, as well as a lower score of the mental dimension as well as physical health when it comes to quality of life. Based on these findings, interventions to improve patient adherence would focus on health education of male patients, and policy changes regarding availability of antidiabetic medication through copayment reductions , which will contribute to a better quality of life for these patients.</p>

PAULA, Paulo Carvalho de. Propriedade hipoglicemiante, hipocolesterolêmica e antioxidante de proteínas de folhas de Moringa oleifera Lam. 2012. 131 f. Dissertação (Mestrado em Bioquímica) - Universidade Federal do Ceará, Fortaleza-CE, 2012. / Submitted by Eric Santiago (erichhcl@gmail.com) on 2016-06-27T13:58:24Z No. of bitstreams: 1 2012_dis_pcpaula.pdf: 1990621 bytes, checksum: eca00b313255b123d7e0371df4b0233f (MD5) / Approved for entry into archive by José Jairo Viana de Sousa (jairo@ufc.br) on 2016-08-02T20:10:31Z (GMT) No. of bitstreams: 1 2012_dis_pcpaula.pdf: 1990621 bytes, checksum: eca00b313255b123d7e0371df4b0233f (MD5) / Made available in DSpace on 2016-08-02T20:10:31Z (GMT). No. of bitstreams: 1 2012_dis_pcpaula.pdf: 1990621 bytes, checksum: eca00b313255b123d7e0371df4b0233f (MD5) Previous issue date: 2012 / Moringa oleifera is a plant native to northeastern India widely used in Indian folk medicine due to its various pharmacological properties. Ethnopharmacological studies have demonstrated that compounds derived from parts of this plant, especially leaves, have hypoglycemic activity in diabetic animal models and in humans, allowing its use in folk medicine. The hypoglycemic action of M. oleifera leaves has been attributed to compounds from plant secondary metabolism, however studies showing the involvement of proteins as antidiabetic substances are scarce. The aim of this study was to obtain a protein fraction of M. oleifera leaves and evaluate its hypoglycemic effects on diabetic animal models. For this, the leaf proteins were extracted followed by ammonium sulfate precipitation (0-90%). After exhaustive dialysis, this material was lyophilized to obtain the protein fraction named Mo-PFL. As experimental animal model, alloxan-induced diabetic mice were used. Initially Mo-PFL was intraperitoneally administered at doses of 100, 300 and 500 mg/Kg body weight. The dose of 500 mg/Kg body weight was more effective in reducing blood glucose after 1, 3 and 5 hours of Mo-PFL administration. This hypoglycemic effect was not observed by the intragastric route. This effect was also reduced when boiled Mo-PFL was intraperitoneally administered. Daily intraperitoneal administration of Mo-PFL at a dose of 500 mg/Kg body weight for 20 days caused a significant reduction in blood glucose level and also exerted antioxidant and hypocholesterolemic effects. Electrophoretic pattern of Mo-PFL showed a variety of protein bands, which were susceptible to in vitro pepsin and trypsin digestion. A Dot Blot immunoassay showed cross reactivity between human anti-insulin antibody and Mo-PFL, suggesting the presence of insulin-like epitopes in M. oleifera leaf protein. Overall, these data show that some proteins derived from M. oleifera leaves may contribute to the hypoglycemic effect observed in the present work. / Moringa oleifera Lam. é uma planta nativa do nordeste da Índia muito utilizada na medicina popular devido às suas várias propriedades farmacológicas. Estudos etnofarmacológicos têm demonstrado atividade hipoglicemiante de compostos oriundos de partes dessa planta, principalmente de suas folhas, em modelos de animais diabéticos e, também, em humanos, embasando sua utilização na medicina popular para o tratamento do diabetes. A ação hipoglicemiante de compostos de folhas de M. oleifera tem sido creditada a componentes oriundos do metabolismo secundário vegetal, sendo escassos trabalhos abordando a participação de proteínas nessa ação farmacológica. O objetivo deste trabalho foi obter uma fração proteica a partir de folhas de M. oleifera e verificar seu efeito hipoglicemiante em modelos de animais diabéticos. Para isso, foi realizada extração de proteínas a partir de folhas de M. oleifera, seguida de precipitação com sulfato de amônio (0-90%). Após diálise exaustiva, o material foi liofilizado para obtenção da fração proteica denominada Mo-FPF. Como modelo de animal experimental, foram utilizados camundongos com diabetes quimicamente induzido por aloxano. Inicialmente, doses de 100, 300 e 500 mg/Kg de peso corpóreo de Mo-FPF foram administradas intraperitonealmente, tendo sido a dose de 500 mg/Kg de peso corpóreo a mais efetiva na redução glicêmica após 1, 3 e 5 horas da administração. Tal efeito hipoglicemiante não foi verificado pela rota intragástrica. Além disso, esse efeito sofreu redução quando Mo-FPF foi previamente fervida e administrada por via intraperitoneal. Mo-FPF, administrada diariamente pela rota intraperitoneal, na dose de 500 mg/Kg, durante 20 dias, resultou em redução glicêmica, além de ter exercido efeito hipocolesterolemiante e antioxidante. O perfil eletroforético de Mo-FPF mostrou uma diversidade de bandas proteicas, que foram suscetíveis à ação da pepsina e tripsina em ensaio de digestibilidade in vitro. Através de imunoensaio por Dot Blot, foi verificada reação cruzada entre o anticorpo anti-insulina humana e Mo-FPF, sugerindo a existência de epítopos antigênicos do tipo insulina em proteínas de folhas de M. oleifera. Assim, o conjunto de dados obtidos mostra que proteínas oriundas de folhas de M. oleifera contribuem para o efeito hipoglicemiante demonstrado neste trabalho.

No description available.

No / Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments (i) metformin induces PP2A activity before and at lower levels than AMPK activity and (ii) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-alpha4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.

No / AIMS/HYPOTHESIS: We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity. METHODS: Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. RESULTS: HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. CONCLUSIONS/INTERPRETATION: Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.