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Piperine, the major alkaloid derived from black pepper corns, has played an important role in traditional medicine worldwide. Current research has demonstrated piperine to have several anti-inflammatory properties, however, little is known concerning the effect of piperine on B cells. Spleen-derived murine B cells were cultured in the presence or absence of piperine during T-dependent or T-independent activation. Piperine reversibly inhibited B cell proliferation in a dose-dependent manner. This was due to a G0/1-phase cell cycle arrest, and was associated with a reduction in phospho-ERK, phospho-AKT, and Cyclin D1, D2, and D3. Piperine also inhibited antibody and cytokine production. Furthermore, piperine treatment diminished B cell-mediated antigen presentation determined by measuring OT-II transgenic T cell proliferation in response to OVA, which was attributed to the decreased MHC-II ad co-stimulatory molecule expression observed. This in vitro study shows that piperine has potent immuno-suppressive effects on B cell activation and effector function.

Piperine, a pungent alkaloid found in the fruits of long and black pepper plants, has diverse physiological effects, including anti-inflammatory and anti-cancer activities. The effect of piperine on the function of T cells and endothelial cells, two important elements of inflammation, have not been examined previously and were the focus of this study. Piperine inhibited the proliferation of human endothelial cells, murine T cells, and IL-2-dependent CTLL-2 T cells, without affecting cell viability. Progression into the S phase of the cell cycle was inhibited in all three cell types. In T cells, piperine inhibited expression of the early activation marker CD25, production of IFN-?, IL-2, IL-4, and IL-17A, and the generation of cytotoxic effector cells. In endothelial cells, piperine inhibited migration and tubule formation in vitro and ex vivo, as well as breast cancer cell-induced angiogenesis in chick embryos. Piperine inhibited Akt phosphorylation in signaling pathways associated with growth factor receptors on endothelial cells, T cell receptor and CD28 on T cells, and IL-2 receptor on CTLL-2 cells. Additionally, piperine inhibited ERK1/2 and I?B phosphorylation in activated T cells, as well as STAT3, STAT5, and ERK1/2 phosphorylation in IL-2-stimulated CTLL-2 cells. However, piperine is not a broad-spectrum inhibitor of phosphorylation as it did not inhibit ZAP-70 phosphorylation in activated T cells or phosphorylation of JAK1 and JAK3 in IL-2-stimulated CTLL-2 cells. Piperine-mediated inhibition of T cell activation and IL-2 receptor signaling suppresses T cell proliferation and effector cell differentiation, suggesting possible utility in treating T cell-mediated autoimmune and chronic inflammatory conditions. Additionally, the potent anti-angiogenic activity of piperine warrants further study for the prevention of inflammation- and cancer-promoting angiogenesis.

A piperina e a piplartina são alcalóides isolados de espécies do gênero Piper. A escolha destas moléculas para este estudo foi baseada em suas atividades biológicas, em especial pelo seu potencial antitumoral. Tendo em vista a procura de meios alternativos para o estudo do metabolismo de novos fármacos, especialmente aqueles provenientes de produtos naturais, este trabalho teve como objetivo avaliar o perfil oxidativo da piperina e da piplartina através de diferentes metaloporfirinas, que biomimetizam o metabolismo do citocromo P450. Para a realização deste trabalho, a piperina e a piplartina foram expostas à oxidação em meio homogêneo, utilizando o iodosilbenzeno (PhIO) como doador de oxigênio e metaloporfirinas sintéticas de primeira e segunda geração como catalisadores da reação, que foram [Fe(TPP)]Cl, [Mn(TPP)]Cl, [Fe(TFPP)]Cl e [Mn(TFPP)]Cl. Como solvente para os meios reacionais foram utilizados 1,2-dicloroetano e acetonitrila. Os padrões e os meios reacionais contendo os produtos de oxidação foram analisados por cromatografia gasosa acoplada à espectrometria de massas (CG-EM) com ionização por elétrons (IE), e por espectrometria de massas tandem com ionização por electrospray em modo positivo. Através das análises dos espectros obtidos por CG-EM e IES-EM, foi possível observar a presença de produtos de oxidação, formados com todas as metaloporfirinas testadas, especialmente as fluoradas. Apesar de ter sido detectada pequena formação de produto oxidado na piperina, este foi praticamente insignificante. A piplartina mostrou-se um substrato mais reativo frente aos catalisadores testados. Na piperina foi verificada a presença do produto hidroxilado. Na piplartina os produtos de oxidação observados foram as substâncias desmetoxilada, monohidroxilada e dihidroxiladada, sendo os dois últimos observados apenas através da técnica de electrospray. As estruturas foram propostas baseadas nas vias de fragmentação apresentadas nos espectros de IE-EM de baixa resolução, e também através de IES-EM/EM de alta resolução em modo positivo. Os resultados deste trabalho são promissores para a obtenção de derivados oxidados de piperina e piplartina através das metaloporfirinas. / Piperine and piplartine are alkaloids isolated from species of Piper genus. The choice of these molecules for this study was based on the promising biological activities presented by these substances, especially for their antitumoral potential. Based on the research of alternative ways for studying the metabolism of new drugs, especially from natural products, the goal of this study was to investigate the oxidative profile of piperine and piplartine through different metalloporhyrins, which biomimic the metabolism of cytochrome P450. For doing this research, piperine and piplartine were exposed to oxidation in homogeneous media, using iodosilbenzene (PhIO) as oxygen donor and synthetic metalloporphyrins of first and second generations as catalysts for the reaction, that were [Fe(TPP)]Cl, [Mn(TPP)]Cl, [Fe(TFPP)]Cl and [Mn(TFPP)]Cl. The solvents used for the reaction media were 1, 2- dichloroetane and acetonitrile. The standards and reaction media containing the oxidation products were analysed by gas chromatography coupled to mass spectrometry (GC-MS) with electron ionization (EI), and by mass spectrometry and mass spectrometry tandem with electrospray ionization (ESI-EM and ESI-EM/EM), in positive mode. Through the analysis of spectra obtained by GC-MS and ESI-MS, it was possible to observe the presence of the oxidation products, formed with all the metalloporphyrins tested, especially the fluoreted ones from the second generation. Despite having been detected small formation of oxidized product on piperine, this was practically insignificant. Piplartine shown to be a more reactive substrate in front of the catalysts tested. In piperine, it was possible to verify the presence of the hydroxylated product. In piplartine, the oxidized products observed were the demetoxilated, monohydroxilated and dihydroxilated, the last two being verified only through the technique of electrospray. The structures were proposed based on their fragment patterns presented on spectra of EI-MS (low resolution) an ESI-MS with high resolution in positive mode. The results of this work are promising to obtain oxidized derivatives of piperine and piplartine through synthetic metalloporphyrins.

Made available in DSpace on 2016-04-28T20:17:25Z (GMT). No. of bitstreams: 1 2007-Veronica da Silva Cardoso.pdf: 1668808 bytes, checksum: 8c509f980dcd2dcbfda2f388e9cd9a42 (MD5) Previous issue date: 2007-03-05 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The aim of the present study was to analyze the interference of the administration of piperine in broiler chickens with prolonged aflatoxins intoxication. The experiment was accomplished in two phases: (i) the chickens were separate in four groups test (n=15 broilers / I group), that received different piperine concentrations (1.12, 2.25 and 4.5mg/kg orally/14 days), and a control group, that was only inoculated with the vehicle; (ii) chickens were separate in 3 groups (n=15 broilers/group), a group that received only piperine (2.25 mg/kg), a group that received aflatoxins only (2.0 mg/kg) and another group that received an association of piperine (2.25 mg/kg) and aflatoxins (2.0 mg/kg), all orally / 14 days. At the end of the experiment, the chickens were slaughted and productivity indexes, hematological parameters and histopathological parameters of every digesting tract were evaluated. The results obtained in the first phase showed that the piperine, in the employed doses, didn't interfere in the productivity indexes nor in the result of the values of hematocrit, hemoglobin concentration, fibrinogen and erythrocyte counts, except for the highest doses of piperine, which were capable to promote an increase in the total counting of the white blood cells. The dose of 2.25 piperine mg/kg was not toxic or had and the histopathological lesions observed were dose-dependent. In the second phase of the experiment, it was observed that the productivity indexes in the group that received the association piperine and aflatoxins obtained better performing comparatively with those that just received aflatoxins. The piperine in the concentration of 2.25 mg/kg reduced in a significant way the immunosuppresor activity and the histopathological lesions caused by the aflatoxins. It can be suggested that piperine interferes in a positive way, reducing the toxic effects of the aflatoxins intoxication in broiler chickens. / Este trabalho teve como objetivo analisar a interfer?ncia da administra??o da piperina em frangos de corte com intoxica??o prolongada por aflatoxinas. O experimento foi realizado em duas fases: (i) os frangos foram separados em quatro grupos teste (n=15 aves/ grupo), que receberam diferentes concentra??es de piperina (1,12; 2,25 e 4,5mg/kg por via oral/14 dias), e um grupo controle, que foi inoculado apenas com o ve?culo; (ii) os frangos foram separados em 3 grupos (n=15 aves/grupo), um grupo que recebeu apenas piperina (2,25 mg/kg), um grupo que recebeu apenas aflatoxinas (2,0 mg/kg) e outro grupo recebeu piperina (2,25 mg/kg) em associa??o com aflatoxinas (2,0 mg/kg), todos por via oral/ 14 dias. Ao final do experimento, os frangos foram abatidos e avaliados quanto aos ?ndices de produtividade, par?metros hematol?gicos e par?metros histopatol?gicos de todo trato digest?rio. Os resultados obtidos na primeira fase mostraram que a piperina, nas doses empregadas, n?o interferiu nos ?ndices de produtividade ou nos valores de hemat?crito, hemoglobina, fibrinog?nio e n?mero de hem?cias, com exce??o das doses mais elevadas de piperina, as quais foram capazes de promover um aumento na contagem total de leuc?citos. A dose de 2,25 mg/kg de piperina n?o foi t?xica ou imunossupressora e as les?es histopatol?gicas observadas foram dose dependente. Na segunda fase do experimento, observou-se que de acordo com os ?ndices de produtividade, o grupo que recebeu piperina em associa??o com aflatoxinas obteve melhor desempenho comparativamente com aqueles que receberam apenas aflatoxinas. A piperina na concentra??o de 2,25 mg/kg reduziu de forma significativa ? imunossupress?o e as les?es histopatol?gicas causada pelas aflatoxinas. Desta forma, pode-se sugerir que a piperina interfere de forma positiva na intoxica??o de frangos de corte por aflatoxinas, diminuindo seus efeitos t?xicos.

Made available in DSpace on 2016-04-28T20:17:25Z (GMT). No. of bitstreams: 1 2007- Thalita Gagini Braga.pdf: 8852629 bytes, checksum: e6a948ca864bea46a3f48309716903c7 (MD5) Previous issue date: 2007-03-05 / Made available in DSpace on 2016-04-28T20:17:25Z (GMT). No. of bitstreams: 1 2007- Thalita Gagini Braga.pdf: 8852629 bytes, checksum: e6a948ca864bea46a3f48309716903c7 (MD5) Previous issue date: 2007-03-05 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Piperine (1- piperoyl piperidine) main black pepper (Pipper nigrum Linn.) and long pepper (Piper longum Linn.) alkaloid presents several pharmacological and biochemical effects as enzymes inhibition from hepatic metabolism interfering on xenobiotics and pro-carcinogenic substances biotransformation activated by P-450 cytochromo cycle. According to the scientific bibliography reports, piperine has been able in vitro for decreasing cytotoxicity as well as aflatoxin B1 genotoxicity on mice cells through the competition by P-450 cytochromo. Due to the importance of grains contamination by aflatoxinas, this survey had as proposal to verify piperine ability for decreasing in vivo some damages caused by these toxins. On first, at different piperine doses (1,12; 2,25 and 4,50 mg/Kg) Lou-M strain rats groups were inoculated by oral administrated to evaluated this amide toxicity on animal pattern. Parameters as: weight grain, anatomopathological and histopathological analyses beyond changes on hematological values have been researched. Piperine doses (1,12 mg/Kg) has showed to be appropriate as well as safe on biological assays and it has been used on rats experimental intoxication assays by aflatoxins. Three rats groups were inoculated with piperine (1,12 mg/Kg), aflatoxins (72 μg/ 100 g) as well as piperine + aflatoxins according to the same parameters above described. Piperine has been able for interfering in vivo on aflatoxins toxicity, conspicuously decreasing histopathological injuries on intoxicated animals and significantly returning immunosupression mediated by aflatoxins. / A piperina (1-piperoil piperidina), principal amida constituinte da pimenta preta (Piper nigrum Linn.) e da pimenta longa (P. longum Linn.), apresenta diversos efeitos farmacol?gicos e bioqu?micos, como a inibi??o de enzimas do metabolismo hep?tico, interferindo na biotransforma??o de xenobi?ticos e subst?ncias pr?-carcin?genas ativadas pela via do citocromo P450. A literatura descreve a piperina como sendo capaz, in vitro, de diminuir a citotoxidez e a genotoxidez da aflatoxina B1 em c?lulas de ratos, atrav?s da competi??o pelo citocromo P450. Devido ? import?ncia da contamina??o de gr?os por aflatoxinas, este trabalho teve como objetivo verificar a capacidade da piperina em diminuir, in vivo, os danos causados por essas toxinas. Inicialmente, grupos de ratos da linhagem LOUM foram inoculados, via oral, com diferentes doses de piperina (1,12; 2,25 e 4,50 mg/kg de peso corporal), visando avaliar a toxidez dessa amida no modelo animal empregado. Par?metros como: ganho de peso, an?lises anatomopatol?gica e histopatol?gica, al?m das altera??es nos valores hematol?gicos foram investigados. A dose de 1,12 mg/kg de peso corporal de piperina demonstrou ser segura nos ensaios biol?gicos e foi empregada nos ensaios de intoxica??o experimental de ratos com aflatoxinas. Tr?s grupos de ratos foram inoculados com piperina (1,12 mg/kg de peso corporal), aflatoxinas (72 μg/100g de peso corporal) e, piperina + aflatoxinas, sendo avaliados os mesmos par?metros acima descritos. A piperina foi capaz de interferir na toxidez das aflatoxinas, in vivo, diminuindo de forma acentuada as les?es histopatol?gicas evidenciadas nos animais intoxicados e, revertendo de forma significativa a imunossupress?o mediada pelas aflatoxinas.

Submitted by Celso Magalhaes (celsomagalhaes@ufrrj.br) on 2017-11-08T15:16:23Z No. of bitstreams: 1 2016 - Poliana de Araujo Oliveira.pdf: 1134800 bytes, checksum: 79b02bbcfb332c5fbb799d7840ccc773 (MD5) / Made available in DSpace on 2017-11-08T15:16:23Z (GMT). No. of bitstreams: 1 2016 - Poliana de Araujo Oliveira.pdf: 1134800 bytes, checksum: 79b02bbcfb332c5fbb799d7840ccc773 (MD5) Previous issue date: 2016-07-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Drugs currently used in pain and inflammation are responsible for a large number of adverse effects, due to chronic use, producing in the patients a decrease of symptoms, but not an overall improvement in quality of life, therefore it is of extreme importance to search for new drugs. Piperine is the main active compound of black pepper (Piper nigrum), known in Brazil as black pepper, popularly used by several beneficial effects. Studies in vitro and in vivo show that piperine has functional involvement in antidepressant, hepatoprotective, anti-metastatic antiparasitic, antithyroid, immunomodulatory, anti-inflammatory and analgesic effects. To improve the selectivity and potency, molecular changes were made in the piperine, obtaining the piperic acid. The objective of this study was to evaluate, through of models of acute and chronic pain, and inflammation; a potential nociceptive and anti-inflammatory compound. In the model of writhing induced by acetic acid was observed a percentage inhibition of writhes of 77,9% compared to the control, in the highest dose tested (10mg / kg). In the formalin test, the compound inhibited both phases of the test, wich the dose of 10mg/kg The inhibitory effect was 30% in stage 1 and stage 2 at 67%. The increase in the latency time in tail flick test had an earlier action compared to morphine and the piperic acid increased the latency time in 58% in 80min time in relation to baseline. We investigated the possible pathways involved in the mechanism of action of the compound by prior administration of antagonists in the tail flick test. We found that the muscarinic antagonist, atropine, was able to completely inhibit the effect of the compound, demonstrating the involvement of the cholinergic pathway in the mechanism of action. The opioid and nitrergic pathways and the potassium channel ATPdependent are not involved in the mechanism of action, since these antagonists do not inhibit the effect of the compound. The compound was able to inhibit capsaicin-induced nociception, capsaicina is agonist TRPV1, in 45,34% demonstrating the involvement of TRPV1. The von Frey test evaluate allodynia after chronic constriction of the sciatic nerve. In this test, the compound did not show antinociceptive activity with the doses tested. The open field test was used to determine the influence of the compound on the animal's mobility, and we observe that the action of the compound did not interfere on animal's motor performance. The antiinflammatory activity was evaluated in models of inflammation induced by carrageenan. In the paw oedema test, the compound significantly reduced the oedema at doses of 5 and 10 mg/kg. In the air pouch test, we found that the leukocyte migration was reduced, as well as the production of TNF-? and IL-1?. The piperic acid was shown to be selective for COX-1 in the assessment of enzymatic activity of COX-1 and COX-2. We suggest that the effects of piperine can be mediated primarily through the portion of the molecule related to piperic acid / Os f?rmacos atualmente utilizados em dor e inflama??o s?o respons?veis por um grande n?mero de efeitos adversos, e devido ao uso cr?nico, fazem com que o paciente tenha uma diminui??o dos sintomas, mas n?o uma total melhoria da qualidade de vida, sendo assim ? de extrema import?ncia a busca por novos f?rmacos. A piperina ? o principal composto ativo da pimenta preta (Piper nigrum), mais conhecida no Brasil como pimenta do reino, popularmente utilizada por diversos efeitos ben?ficos. Estudos in vitro e in vivo demonstram que a piperina tem envolvimento funcional como antidepressivo, hepatoprotetor, antiparasit?rio antimetast?tico, antitiroidiano, imunomodulador, anti-inflamat?rio e analg?sico. A fim de produzir melhora em sua seletividade e pot?ncia, altera??es moleculares foram realizadas na piperina, obtendo-se ent?o o ?cido pip?rico. O objetivo deste trabalho foi avaliar, atrav?s da execu??o de modelos experimentais de dor aguda, cr?nica e inflama??o, o potencial farmacol?gico antinociceptivo e anti-inflamat?rio do composto. No modelo de contor??es abdominais induzidas por ?cido ac?tico foi verificada um percentual de inibi??o das contor??es de 77,9% comparado ao controle, na maior dose testada (10mg/kg). No modelo da formalina o composto inibiu ambas as fases do modelo, com a dose de 10mg/kg o efeito inibit?rio chegou a 30% na 1? fase e 67% na 2? fase. O aumento do tempo de lat?ncia no modelo de retirada de cauda com o composto foi alcan?ado mais precocemente do que a morfina, o ACP aumentou o tempo de lat?ncia em 58% no tempo de 80 min comparado a linha de base na maior dose testada. Investigamos as poss?veis vias envolvidas no mecanismo de a??o do composto atrav?s da administra??o pr?via de antagonistas, no modelo de retirada de cauda. Verificamos que o antagonista de receptores muscar?nicos, atropina, foi capaz de inibir completamente o efeito do composto, demonstrando a participa??o da via colin?rgica no mecanismo de a??o. As vias opioide, nitr?rgica e o canal de pot?ssio dependente de ATP parecem n?o estar envolvidas no mecanismo de a??o, visto que os antagonistas destas vias n?o inibiram o efeito do composto. O composto inibiu a nocicep??o induzida pela capsaicina, que ? agonista de receptores TRPV1 em 45,34%, demonstrando envolvimento de TRPV1. No modelo de Von Frey avaliamos a alodinia ap?s a constri??o cr?nica do nervo ci?tico. Neste modelo, o composto n?o demonstrou atividade antinociceptiva nas doses testadas. O modelo de campo aberto foi usado para verificar a influ?ncia do composto sobre a mobilidade do animal, e observamos que o mesmo n?o interfere no desempenho motor do animal. A atividade anti-inflamat?ria foi avaliada em modelos de inflama??o induzido por carragenina. No modelo de edema de pata, o composto reduziu o edema em 75% na dose de 10mg/kg. No modelo da bolsa de ar subcut?nea verificamos que a migra??o leucocit?ria foi reduzida assim como a produ??o de TNF-? e IL-1?. O ?cido pip?rico demonstrou ser seletivo para COX-1, na avalia??o da atividade enzim?tica de COX-1 e COX-2. Podemos sugerir que os efeitos da piperina podem ser mediados atrav?s da por??o da mol?cula referente ao ?cido pip?rico.

L’objectif de cette thèse était d’acquérir des connaissances nouvelles sur les caractéristiques des poivres sauvages malgaches (Tsiperifery) et réunionnais (Piper borbonense) et d’étudier l’impact des procédés de transformation sur leur qualité, évaluée à travers le piquant, l’arôme et la couleur. L’enjeu étant, grâce aux résultats obtenus, de pouvoir proposer un ou plusieurs procédés de transformation revisités permettant de valoriser la qualité de ces poivres. Ce travail de thèse a consisté dans un premier temps à étudier les procédés traditionnels de transformation du poivre sauvage mis en œuvre à Madagascar. Deux procédés de transformation distincts ont été identifiés: une « voie sèche » consistant en un simple séchage et une « voie humide » incluant blanchiment et étuvage avant séchage. Ensuite, des expérimentations ont été menées en conditions maîtrisées à la Réunion sur du poivre Piper borbonense. Ainsi, la morphologie, l’anatomie et la composition biochimique du poivre sauvage réunionnais ont été caractérisées. Enfin, dans la mesure où c’est la couleur, rouge, du poivre sauvage, qui est la plus affectée, les mécanismes impliqués dans l’altération de la couleur ont été analysés. Le Piper borbonense de la Réunion se distingue du Piper nigrum par sa très faible teneur en pipérine (0,2 % bs), sa forte teneur en huile essentielle (9,8 % bs), la présence d’un pédicelle solidaire du grain ainsi que par sa forme ovoïde. Il se différentie aussi des poivres sauvages malgaches, notamment par sa teneur en pipérine deux fois plus faible. Les composés d’arômes principaux mesurés sont le limonène, l’α-phellandrène et l’asaricin qui représentent à eux trois 50 % du total de l’huile essentielle. C’est à pleine maturité, lorsque le Piper borbonense est de couleur rouge vif, qu’il est préférable de le récolter pour maximiser le rendement massique. Le blanchiment, l’étuvage et le séchage ont peu d’impact sur le piquant et l’arôme mais dégradent significativement la couleur du poivre. Les oxydations chimiques des polyphénols qui semblent prépondérantes dans le brunissement du poivre s’avèrent délicates à contrôler. Le blanchiment présente de nombreux avantages : il nettoie et décontamine le poivre, augmente la vitesse du séchage et limite le brunissement enzymatique. L’étuvage est à bannir car il dégrade la couleur et augmente les risques microbiens. Le séchage par entrainement bien qu’il impacte négativement la couleur reste indispensable pour stabiliser le poivre. Plutôt qu’un procédé universel, une « voie sèche » (séchage direct) et une « voie humide » (intégrant blanchiment et séchage) sont proposées. Le choix d’en appliquer l’une ou l’autre est à raisonner par rapport à la qualité de la matière première d’une part et en fonction du contexte, c’est-à-dire selon des critères économiques, environnementaux voire même sociaux d’autre part. / The objective of this thesis work was to acquire new knowledge on the characteristics of Malagasy (Tsiperifey) and Réunion (Piper borbonense) wild peppers. The impact of transformation processes on their quality was evaluated by measuring pungency, aroma and color. The challenge was to propose, according to the data obtained, one or more revisited transformation processes to valorize the quality of the peppers. This PhD work initially consisted of studying the traditional transformation processes of the wild peppers implemented in Madagascar. Two distinct transformation processes have been identified: a "dry process" consisting of simple drying step and a "wet process" including blanching and steaming steps before drying. Then, experiments were carried out under controlled conditions in Reunion Island on Piper borbonense. Thus, the morphology, anatomy and biochemical composition of Reunion wild pepper were characterized. Finally, since the red color of wild pepper appear to be the most affected by the process, the mechanisms involved in color alteration were investigated. The Piper borbonense of Réunion Island can be distinguished from Piper nigrum according to its very low content of piperine (0.2% bs), its high content of essential oil (9.8% bs), the presence of a pedicel and only its ovoid shape. Piper borbonense can also be differentiated from Malagasy wild peppers, notably by its lower piperine content. The main volatile compounds found are limonene, α-phellandrene and asaricin, which together account for 50% of the total essential oil composition. Piper borbonense should be harvested at full maturity stage, bright red-colored, as this allows optimum mass yield. Blanching, sweating and drying steps have little impact on pungency and aroma but significantly degrade the color of the pepper. The chemical oxidation of polyphenols, which seems to be preponderant in the browning of the pepper, is difficult to control. Blanching has many advantages: it helps cleaning and decontaminating pepper, reduces drying time and limits enzymatic browning. The sweating step has to be banned because it degrades the color and increases the microbial risk. Drying, although negatively impacting the color, is essential to stabilize the pepper. As opposed to a universal process, a "dry way" (direct drying) and a "wet way" (integrating blanching and drying) are proposed. The choice to apply one or the other could be made according to the quality of the raw material on the one hand and to the context of production (economic, environmental and even social criteria) on the other hand.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-09-08T13:25:55Z No. of bitstreams: 1 arquivototal.pdf: 2508821 bytes, checksum: 881e48cd3cb91d680602af2fa3e62a64 (MD5) / Made available in DSpace on 2017-09-08T13:25:55Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2508821 bytes, checksum: 881e48cd3cb91d680602af2fa3e62a64 (MD5) Previous issue date: 2015-02-27 / Cancer is characterized by uncontrolled proliferation of abnormal cells. The high mortality rate associated with the disease, coupled to severe side effects caused by conventional treatments and the increasing development of resistance, has conducted to the demand for effective therapies with less toxicity. In this context, it is of great relevance the synthesis of synthetic products with structures based on natural products, which continue to be the main source of new medicines. In order to increase the effect and minimize the toxicity of piperine, an amide alkaloid with antitumor activity, it was obtained novel synthetic analogues, among them the 2-oxo-2-(4-ethylamine)-piperinoato acetate (HE-03). This study aimed to investigate the antitumor activity and toxicity of HE-03. The data demonstrate that HE-03 induced a small percentage of hemolysis to the highest concentration tested (1250 mg/mL), which suggests low toxicity to erythrocytes. In the preclinical acute toxicity study, the treatment with doses of 300 mg/kg and 2000 mg/kg of HE-03 in mice caused no deaths, and the changes observed in the CNS and ASN level were transient (30 min.). The LD50 value was estimated to be about 5000 mg/kg. HE-03 (6.25, 12.5 and 25 mg/kg) showed significant antitumor activity in vivo in ascites Ehrlich carcinoma model, especially considering the viability parameters and total cell. Its effect in doses of 12.5 and 25 mg/kg was similar to the one observed for the anticancer drug 5-fluorouracil (25 mg/kg). Cell cycle profile analysis showed that treatment with HE-03 (12.5 mg/kg) induced the appearance of sub-G1 peak, which was accompanied by a reduction in the number of cells in G0/G1 and S phases, suggesting induction of cell death by apoptosis. The treatment with HE-03 (12.5 mg/kg) significantly reduced peritumoral microvessels, which suggests anti-angiogenic activity. The toxicological analyzes indicate that the nine days of treatment with HE-03 at all doses, induced a significant increase in serum aspartate aminotransferase (AST) and urea. However, histopathology of the liver and kidneys showed that HE-03 does not induce changes of clinical importance. Leukopenia, accompanied by neutropenia, observed in animals treated with 25 mg/kg of HE-03 is one of the major side effects associated with cancer therapy. Futhermore, HE-03 did not induce an increase in the number of micronucleated erythrocytes in the micronucleus assay in peripheral blood, which indicates lack of genotoxicity in the evaluated conditions. Therefore, it is possible to infer that the synthetic analogue of studied piperine has potent antitumor activity in vivo, with mechanism that possibly involves the induction of apoptosis and antiangiogenic effects, as well as low toxicity. / O câncer caracteriza-se pela proliferação descontrolada de células. A elevada taxa de mortalidade associada à doença, aliada aos graves efeitos indesejáveis causados pelos tratamentos convencionais e ao crescente desenvolvimento de resistência, tem impulsionado a procura por terapias mais eficazes com menor toxicidade. Nesse contexto, é de grande relevância a síntese de produtos sintéticos com estruturas baseadas em produtos naturais, que continuam a ser a principal fonte de novos medicamentos. Com o intuito de potencializar o efeito e minimizar a toxicidade da piperina, um alcaloide amida com atividade antitumoral, foram obtidos análogos sintéticos inéditos, dentre estes o 2-oxo-2-(4-etilamina)-piperinoato de etila (HE-03). Esse trabalho objetivou investigar a atividade antitumoral, bem como a toxicidade do HE-03. Os dados demonstram que HE-03 induziu pequeno percentual de hemólise até a maior concentração testada (1250 μg/mL), o que sugere baixa toxicidade nos eritrócitos. No ensaio de toxicidade pré-clínica aguda, o tratamento com as doses de 300 mg/kg e 2000 mg/kg do HE-03 não provocou mortes nos camundongos, e as alterações observadas em nível de SNC e SNA foram e de curta duração (30 min.) e sem significância no tempo observado. O valor da DL50 foi estimado em torno de 5000 mg/kg. HE-03 (6,25; 12,5 e 25 mg/kg) mostrou significante atividade antitumoral in vivo em modelo de carcinoma ascítico de Ehrlich, considerando especialmente os parâmetros viabilidade e total celular. Seu efeito nas doses de 12,5 e 25 mg/kg foi semelhante ao observado para o antineoplásico 5-fluorouracil (25 mg/kg). Na análise do perfil do ciclo celular, foi observado que o tratamento com HE-03 (12,5 mg/kg) induziu o aparecimento do pico sub-G1, que foi acompanhado por uma redução na quantidade de células nas fases G0/G1 e S, o que sugere indução de morte celular por apoptose. O tratamento com HE-03 (12,5 mg/kg) reduziu significativamente a microdensidade vascular peritumoral, o que sugere atividade antiangiogênica. As análises toxicológicas indicam que o tratamento de nove dias com HE-03, em todas as doses, induziu aumento significativo de aspartato aminotransferase (AST) e de ureia. Todavia, a histopatologia do fígado e dos rins mostrou que HE-03 não induz alterações de importância clínica. A leucopenia, acompanhada de neutropenia, observadas nos animais tratados com 25 mg/kg de HE-03 é um dos principais efeitos indesejáveis associados a terapia do câncer. Ainda, HE-03 não induziu aumento no número de eritrócitos micronucleados, no ensaio do micronúcleo em sangue periférico, o que indica ausência de genotoxicidade, nas condições avaliadas. Portanto, é possível inferir que o análogo sintético da piperina estudado apresenta potente atividade antitumoral in vivo, com mecanismo que envolve possivelmente a indução de apoptose e efeitos antiangiogênicos, bem como, baixa toxicidade.

A piperina e a piplartina são alcalóides isolados de espécies do gênero Piper. A escolha destas moléculas para este estudo foi baseada em suas atividades biológicas, em especial pelo seu potencial antitumoral. Tendo em vista a procura de meios alternativos para o estudo do metabolismo de novos fármacos, especialmente aqueles provenientes de produtos naturais, este trabalho teve como objetivo avaliar o perfil oxidativo da piperina e da piplartina através de diferentes metaloporfirinas, que biomimetizam o metabolismo do citocromo P450. Para a realização deste trabalho, a piperina e a piplartina foram expostas à oxidação em meio homogêneo, utilizando o iodosilbenzeno (PhIO) como doador de oxigênio e metaloporfirinas sintéticas de primeira e segunda geração como catalisadores da reação, que foram [Fe(TPP)]Cl, [Mn(TPP)]Cl, [Fe(TFPP)]Cl e [Mn(TFPP)]Cl. Como solvente para os meios reacionais foram utilizados 1,2-dicloroetano e acetonitrila. Os padrões e os meios reacionais contendo os produtos de oxidação foram analisados por cromatografia gasosa acoplada à espectrometria de massas (CG-EM) com ionização por elétrons (IE), e por espectrometria de massas tandem com ionização por electrospray em modo positivo. Através das análises dos espectros obtidos por CG-EM e IES-EM, foi possível observar a presença de produtos de oxidação, formados com todas as metaloporfirinas testadas, especialmente as fluoradas. Apesar de ter sido detectada pequena formação de produto oxidado na piperina, este foi praticamente insignificante. A piplartina mostrou-se um substrato mais reativo frente aos catalisadores testados. Na piperina foi verificada a presença do produto hidroxilado. Na piplartina os produtos de oxidação observados foram as substâncias desmetoxilada, monohidroxilada e dihidroxiladada, sendo os dois últimos observados apenas através da técnica de electrospray. As estruturas foram propostas baseadas nas vias de fragmentação apresentadas nos espectros de IE-EM de baixa resolução, e também através de IES-EM/EM de alta resolução em modo positivo. Os resultados deste trabalho são promissores para a obtenção de derivados oxidados de piperina e piplartina através das metaloporfirinas. / Piperine and piplartine are alkaloids isolated from species of Piper genus. The choice of these molecules for this study was based on the promising biological activities presented by these substances, especially for their antitumoral potential. Based on the research of alternative ways for studying the metabolism of new drugs, especially from natural products, the goal of this study was to investigate the oxidative profile of piperine and piplartine through different metalloporhyrins, which biomimic the metabolism of cytochrome P450. For doing this research, piperine and piplartine were exposed to oxidation in homogeneous media, using iodosilbenzene (PhIO) as oxygen donor and synthetic metalloporphyrins of first and second generations as catalysts for the reaction, that were [Fe(TPP)]Cl, [Mn(TPP)]Cl, [Fe(TFPP)]Cl and [Mn(TFPP)]Cl. The solvents used for the reaction media were 1, 2- dichloroetane and acetonitrile. The standards and reaction media containing the oxidation products were analysed by gas chromatography coupled to mass spectrometry (GC-MS) with electron ionization (EI), and by mass spectrometry and mass spectrometry tandem with electrospray ionization (ESI-EM and ESI-EM/EM), in positive mode. Through the analysis of spectra obtained by GC-MS and ESI-MS, it was possible to observe the presence of the oxidation products, formed with all the metalloporphyrins tested, especially the fluoreted ones from the second generation. Despite having been detected small formation of oxidized product on piperine, this was practically insignificant. Piplartine shown to be a more reactive substrate in front of the catalysts tested. In piperine, it was possible to verify the presence of the hydroxylated product. In piplartine, the oxidized products observed were the demetoxilated, monohydroxilated and dihydroxilated, the last two being verified only through the technique of electrospray. The structures were proposed based on their fragment patterns presented on spectra of EI-MS (low resolution) an ESI-MS with high resolution in positive mode. The results of this work are promising to obtain oxidized derivatives of piperine and piplartine through synthetic metalloporphyrins.