Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2004. / "A dissertation in pharmaceutical science and chemistry." Advisor: Ashim K. Mitra. Typescript. Vita. Description based on contents viewed Feb. 27, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 175-199). Online version of the print edition.

Made available in DSpace on 2015-03-03T11:52:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-07-25Bitstream added on 2015-03-03T12:06:59Z : No. of bitstreams: 1 000810985_20160725.pdf: 68863 bytes, checksum: e31a70f7392e0a8fa06a27c80bc87a8c (MD5) Bitstreams deleted on 2016-07-25T13:17:40Z: 000810985_20160725.pdf,. Added 1 bitstream(s) on 2016-07-25T13:18:47Z : No. of bitstreams: 1 000810985.pdf: 519868 bytes, checksum: 4fb63307e7d938ba410aa29f6f3812fb (MD5) / Sabe-se que dentro dos diferentes ecossistemas e em culturas de origem antrópica as plantas podem exercer interferência sobre outros vegetais ou microorganismos. Diferentes autores classificam esse evento como atividade alelopática, e esta ocorre principalmente pela liberação de biomoléculas (aleloquímicos), que podem variar sua constituição e classe química dependendo da espécie produtora. Estudos recentes têm demonstrado que os aleloquímicos constituem-se em importantes candidatos com potencial para serem utilizados como praguicidas e herbicidas naturais, transformando-se em aliados para o manejo agroecológico. Assim, o objetivo deste trabalho foi avaliar o potencial fitotóxico e antioxidante dos diferentes extratos das folhas de Tridax procumbens L., espécie ivasora e daninha, e Ouratea spectabilis (Mart. ex Engl.) Engl., nativa do cerrado brasileiro, por meio dos bioensaios laboratoriais de pré e pós- emergência em sementes de Lactuca sativa L. Além de avaliar o índice mitótico, aberrações cromossômicas e freqüência de micronúcleo em células de raiz de Allium cepa L. Adicionalmente, buscou-se determinar a atividade antioxidante e também elucidar fitoquimicamente os componentes fitotóxicos presentes nos extratos destas espécies. No bioensaio de pré-emergência as diferentes concentrações dos diferentes extratos reduziram os índices de germinação tanto para T. procumbens quanto para O. spectabilis quando comparados com o controle, alterando ainda o tempo médio, velocidade média e sincronismo da germinação. Semelhantemente ao encontrado nos bioensaios de pós- emergência, onde alterações no desenvolvimento de plântulas de alface (radícula e hipocótilo) foram observadas, apresentando inibição do crescimento da raíz principal e do hipocótilo quando comparados com o controle. Quanto ao índice mitótico, foi possível observar que os diferentes extratos... / It is known that within the different ecosystems and cultures of anthropogenic origin the plants can exercise interference on other plants or microorganisms. Different authors classify this event as allelopathic activity this occurs mainly by the release of biomolecules (allelochemicals) that can vary its constitution and chemical class depending on the producing species. Recent researches have shown that allelochemicals are important candidates with potential to be used as natural pesticides and herbicides, becoming an ally to agroecological management. Thus the aim of this study was to evaluate the phytotoxic and antioxidant potential of different extracts of leaves of Tridax procumbens L. ivasive and weed species and Ouratea spectabilis (Mart. ex Engl.) Engl. native to the Brazilian Cerrado through laboratory bioassays pre-and post-emergence in seeds of Lactuca sativa L. Besides assessing the mitotic index, chromosomal aberrations and frequency of micronuclei in root cells of Allium cepa L. We also determine the antioxidant activity and the chemical profile of phytotoxic compounds present in the extract of these species. In bioassay of pre-emergence the different concentrations of different extracts reduced the germination rates for both T. procumbens how O. spectabilis as compared with the control, even changing the average time, average speed and timing of germination. Similarly to that found in bioassays post-emergence, where changes in the development of lettuce seedlings (radicle and hypocotyl) were observed, with inhibition of root growth and hypocotyl compared with the control. Regarding the mitotic index was observed that the different extracts of the two species tested reduced when they were compared to the negative control. Introducing yet changes to the treatments with T. procumbens in rates of death and mutagenicity and O. spectabilis in the death rate, chromosomal alterations...

A fitoterapia e o uso de plantas medicinais fazem parte da prática da medicina popular, que diminuiu frente ao processo de industrialização nas décadas de 1940 e 1950, aumentando a busca, pela população, por terapias menos agressivas destinadas ao atendimento primário à saúde. Essa complementa o tratamento usualmente empregado para a população de menor renda. O objetivo deste trabalho foi analisar o conhecimento dos gestores e profissionais de saúde que atuam na atenção primária, sobre fitoterapia e uso de plantas medicinais, nos municípios de Cascavel e Foz do Iguaçu - Paraná. Para tanto, no período de fevereiro a julho de 2009, foi realizado estudo exploratório, descritivo, qualitativo, empregando como instrumentos de pesquisa entrevistas semiestruturadas e um questionário estruturado, auto aplicado, com perguntas fechadas, a fim de contemplar os seguintes aspectos: perfil dos profissionais; aceitabilidade quanto à implantação da fitoterapia na atenção básica; confiança nos tratamentos com fitoterápicos; capacitação e formação profissional relacionadas à fitoterapia, entre outros itens. Um dos gestores considerou recente o programa de fitoterapia. Indicadores de satisfação da população quanto ao uso dos fitoterápicos ou plantas medicinais ainda não existem. O gestor do município de Cascavel relatou interesse na implantação do programa. Os demais profissionais entrevistados, de maneira geral, relataram não haver recebido formação sobre o tema durante a graduação, nem mesmo dentro das UBS onde trabalham. Entre os profissionais entrevistados seis (60%) relataram o acesso às informações sobre fitoterapia através do conhecimento popular, uma (10%) formação na UBS, dois (20%) através de periódicos, quatro (40%) através de meio de comunicação, sendo que quatro citaram mais que uma das opções. Em Foz do Iguaçu, nas UBS onde a terapêutica está implantada, os profissionais relataram não terem sido consultados antes de sua implantação, e a avaliação das plantas utilizadas pelos pacientes atendidos ocorre somente através de avaliação objetiva e subjetiva do tratamento Para implantação da fitoterapia nas UBS desses dois municípios, é necessário capacitar os profissionais quanto ao tema, desde o cultivo até a prescrição, melhorando o uso racional desses medicamentos. / The phytoterapy and the use of medicinal plants are part of practice of the popular medicine, that decreased with industrialization, in the 1940 and 1950s, increasing the search, of population, of therapies less aggressive, in the primary health care. This practice is complementary to the usual treatment used for the poor population. The purpose of this work was analyze the knowledge of the managers and health professionals, which works in the primary attention, about phytoterapy and use of medicinal plants, in the cities of Cascavel and Foz do Iguaçu - Paraná. For this, in the period of February to July of 2009, was done an exploratory, descriptive, and qualitative study, using as research instruments halfstructuralized interviews and a structuralized, auto-applied questionnaire, with closed questions, in order to contemplate the following aspects: profile of the professionals; acceptability of the introduction of the phytoterapy in the basic attention; the trust in the treatments with phytoterapy; related qualification and professional formation to the phytoterapy, among others itens. One of the health managers judged the program of phytoterapy recent. Pointers of satisfaction of the population about the use of the phytoterapy or medicinal plants dont exist. The health manager of Cascavel related interest in the introduction of the program. The other professionals interviewed, related that didnt have received formation about the subject during the graduation, not even inside of the health basic unit where they work. Six (60%) related the access to the information on phytoterapy through the popular knowledge, one (10%) formation in the health basic unit , two (20%) through periodic, four (40%) through media, four (40%) had cited more than one of the options. At Foz do Iguaçu, in the health basic unit where the therapy is implanted the professionals had told that they arent consulted previously its implantation.The evaluation of the plants used for the patients in this city only occurs through an objective and subjective evaluation of the treatment. For implantation of the phytotherapy in the UBS of these two cities, is necessary qualification of the professionals about the subject, about the cultivation and prescription of the plants, improving the rational use of these medicines.

Functional constipation (FC) is a major gastrointestional (GI) disorder which affects about 14% population worldwide. However, due to efficacy and safety concerns, more than 50% FC patients are not completely satisfied with current conventional therapies, thus alternative therapies are needed. A substantial part of FC patients have symptom of slow colonic motility, while therapy targeting a single pathway cannot benefit all of them. In this thesis, we searched for novel FC therapeutics from two distinct sources, both of which can improve colonic motility significantly: (1) MaZiRenWan (MZRW), an herb formula from Traditional Chinese Medicine (TCM); and (2) Spexin (SPX), a newly identified neuropeptide that is deregulated in FC. On the basis of efficacy validation for MZRW by randomized, placebo-controlled clinical studies, we investigated the bioactive compounds and pharmacological actions of MZRW. Firstly, a machine-learning based method, namely MOST, was developed to relate bioactive compounds with their mechanism-of-action targets. MOST demonstrated good performance in 7-fold cross-validation (over 87% accuracy) and temporal validation (over 76% accuracy). In the case laxative effect, MOST predicted that acetylcholinesterase (ACHE) was the mechanism-of-action target of aloe-emodin; in vivo studies validated this prediction. Secondly, we analyzed the bioactive compounds and mechanism-of-actions of MZRW with combination of UPLC-QTOF-MS/MS, clustering analysis, organ bath, and MOST approaches. 97 compounds were identified in MZRW extract, and 35 of them can be found in plasma and feces samples of rats with oral administration of MZRW. Chemical space analysis suggested that these compounds can be classified into component groups, while the corresponding pharmacology can be studied with representative compounds. Emodin, amygdalin, albiflorin, honokiol, and naringin were shown to induce spontaneous contractions of rat colonic smooth muscle in vitro. Biological targets in ACh-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and component groups. Pharmacological actions of MZRW are mixture of five classic paradigms. Thirdly, the latest results of three-armed, randomized and controlled clinical study showed that MZRW demonstrated comparable efficacy with the first line drug Senna, the first line drug for constipation in HK, during treatment period, both were better than placebo; and the efficacy was more sustainable in follow-up period when comparing that of Senna and placebo. These data suggested the unique pharmacological profile of MZRW for FC. With pharmacometabolomic analysis, we found that change of oleamide is negatively correlated (pearson r = -0.59, p<0.001) with improvement of Complete Spontaneous Bowel Movement (CSBM) in MZRW group, but not in Senna or placebo group. Oleamide is up-regulated in FC patients compared with healthy controls, and MZRW can significantly reduce oleamide in FC patients (n=30), healthy human volunteers (n=23), and in normal mice (n=12) serum, ileum, and colon. The regulation of oleamide by MZRW is possibly via augmenting FAAH-mediated degradation. Lastly, we investigated the possibility to use SPX, the newly identified, FC-associated neuropeptide to change GI motility. The deregulation of SPX has been found in several disorders including FC, however, the metabolic instability of SPX prevent it to be directly used in clinical practices. Our investigation through combination of molecular dynamics (MD) simulations and NMR analysis suggested a β-turn-helix-β-turn (βαβ) conformation for human spexin (hSPX) adopts in solution. Consistent with this conformation, cyclic analogues of hSPX with a disulfide bond between residue 1 and 13, LH101 (CWTPQAMLYLKGCQ-NH2), activated both GalR2 (EC50=1.19 μM) and GalR3 (EC50=1.56 μM) with potency comparable to wild type, and that the acetylation at the N-terminal, LH101(Ac) raises the potency EC50=0.38 μM on GalR2 and EC50=0.39 μM on GalR3. The serum half lives of LH101 (t1/2=355.7 min) and LH101(Ac) (t1/2=1973.7 min) were significantly longer than the wild type (t1/2=66.5 min), and LH101(Ac) induces the contractions of mice intestinal segment in vitro and attenuates the oleamide-induced slow GI motility in vivo. Collectively, our studies in MZRW suggested that estrogen and oleamide signaling pathways are potential new targets to develop novel therapeutics for FC, while lead compounds targeting these pathways could be found from MZRW. The final study suggested CSAs have potential to be developed as new FC therapy by targeting the galanin receptor associated pathway.

The aim of this Thesis was find out if adult population has experience with the use of medicinal plants, if people prefer local herbs to exotic plants, what is their knowledge in the preparation of herbal products and if they ever know what the herbs are and what is the meaning of the term Phytotherapy. Another aim was the creation of electronic manual of the most used herbs, which would include information on sellected medicinal plants and their effects on human body. In this thesis there are comprehensively summarized the theroetical and practical knowledge, which should be beneficial for general population. Research survey in the form of a questionnaire was focused on experience and utilization of herbal therapy in adult population. That was realized in South Bohemian and Pilsen Regions. Results of this work point out, that respondents still consider herbal medicine as an important supplement to classical medical treatment. On the basis of the research there were conclusion written and made the recommendation for practise.

Understanding the importance and the possible use of clover in permanent grassland is very important. Their irreplaceable role in nitrogen fixation and enrich the soil of this essential element is very important. The significance of herbs in grassland is also significant, even though its importance is often overlooked. Herbs not only serve as indicators of habitat conditions, but also can improve the quality and palatability of forage. If we know the herbs and legumes and their habitat requirements will help us select the most suitable way of management and the effective use of the potential of the habitat. The aim of the thesis was to observe conditions of use and the occurrence of selected legumes and herbs in TTP. Research can therefore conclude that the biggest influence on the composition of the grassland have ecological conditions. Way management can to some extent affect the crop themselves, but the biggest factor remains what we can not influence and that is the weather. The results also shows that the richer pastures.

The diploma thesis concentrates on medicinal plants, their use and effects in the treatment of diseases. The thesis summarizes some effects of medicinal substances contained in plants and herbs. They are suitable for use in selected diseases. The research part of diploma thesis deals with the mapping of methods of treatment and production of herbal products among university students. The thesis also examines whether students are inclined to use more herbal therapy over conventional pharmaceutical drugs. It investigated whether information on herbs in schools sufficient. KEY WORDS medicinal plants, plant's medicinal substances, herbs, products, phytotherapy

Cell metabolism disorder is considered as both direct and indirect consequence of oncogenic mutations for tumoigenesis. Autophagy is a metabolic stress response and a mechanism of natural cellular degradation. It is believed that autophagy, as well as metabolism, is a crucial process for the adaptation of cancer cells to changes in nutrient availability. Understanding the relationship between metabolism and autophagy and targeting on the key steps are regarded as a promising strategy to treat cancer. Halofuginone (HF), a semisynthetic quinazolinone alkaloid originally derived from the plant Dichroa febrifuga Lour., has gained attention for its potential therapeutic effects in a variety of cancers. We hypothesize that HF may inhibit cancer cell proliferation by inducing changes in glucose metabolism and modulating related autophagy. A series of studies, from in vitro to in vivo, were designed to approve this concept in colorectal cancer (CRC);Firstly, we found that HF inhibited human CRC cell proliferation and induced the generation of reactive oxygen species (ROS) and apoptosis. As expected, a reduced level of NADPH was also observed, at least in part due to inactivation of glucose-6-phosphate dehydrogenase (G6PD) in pentose phosphate pathway (PPP) upon HF treatment. Given these findings, we further investigated metabolic regulation of HF through Akt/mTORC1-mediated aerobic glycolysis and found that HF downregulated the Akt/mTORC1 signaling pathway. Moreover, metabolomics found slower rates in both glycolytic flux and glucose-derived tricarboxylic acid cycle flux. Meanwhile, both glucose transporter GLUT1 and hexokinase-2 in glycolysis were suppressed in CRC cells by HF. These findings support our notion that HF regulates the Akt/mTORC1 signaling pathway to dampen glucose uptake and glycolysis in CRC cells. Furthermore, HF retarded tumor growth in nude mice inoculated with HCT116 cells and reduced the viability of primary cells from the tissues of CRC patients. This finding further confirmed our hypothesis that HF inhibits CRC cell growth through metabolic regulation of Akt/mTORC1. Because mTORC1 can inhibit autophagy through phosphorylation and inactivation of the initiating kinase ULK1 in cancer cells, we further studied the HF effects on CRC in different nutritional conditions. The results showed that HF in nutrient-rich conditions could reduce SQSTM1/p62 through mTORC1-mediated phosphorylation at Ser757 of ULK1. More interestingly, HF elevated SQSTM1 protein level in low nutrient condition through AMPK-mediated phosphorylation at Ser317/777 of ULK1. It showed that HF could regulate nutrient-sensing mTORC1-ULK1 or AMPK-ULK1 to dually modulate autophagy in CRC cells. Further study by using a variety of methods, including mRFP-GFP-LC3 puncta formation, transmission electron microscope (TEM) analysis and monodansylcadaverine (MDC) staining, found that HF could induce autophagosome formation and inhibit autophagosome membrane elongation, depending on nutrient-sensing pathways. Furthermore, we found HF pronouncedly enhanced expression level of Atg7 under nutrient-rich conditions while it decreased Atg7 in CRC cells under nutrient-poor conditions. These two findings imply that Atg7 is required in dual regulation of autophagic flux depending on nutrient conditions. This conclusion was then validated by comparing with autophagy-related proteins in Atg7 knockout (KO) MEFs and Wild-type (WT) MEFs upon HF treatment. Importantly, through analysis of metabolome and metabolic enzymes, we found that HF inhibited glycolysis under nutrient-rich conditions while it inhibited gluconeogenesis under nutrient-poor conditions in an Atg7-dependent manner. In subsequent studies, we found that caloric restriction (CR) in a xenograft mouse model, which mimics low nutrition in vitro, enhanced the anticancer activity of HF. Further analysis of the expression of TQTSM1 and LC3 in tumor tissues demonstrated that HF is an autophagic inducer in xenograft-bearing nude mice with ad libitum feeding, whereas it is an autophagic inhibitor when using CR.;In summary, this study explains how HF controls CRC cell growth through its influences on glucose metabolism and autophagy regulation. HF not only dually regulates autophagy in vitro and in vivo to inhibit cancer cell growth and proliferation through nutrient-sensing pathways under different conditions, but also modulates glycolysis/gluconeogenesis through an autophagic pathway. These results suggest that HF could turn out to be a potent therapeutic drug for treating CRC.

Rheumatoid arthritis (RA), the most common autoimmune disease, affects billions of people worldwide. Conventional therapeutics do not provide satisfactory efficacy and even cause severe adverse reactions. Researchers are seeking new approaches for RA management. Toll-like receptor 4 (TLR4) signalling plays a pivotal role in the pathogenesis of RA, and has been proposed as a potential therapeutic target for RA. Chinese medicines are believed to be alternative options for conventional RA therapeutics. A herbal formula RL, consisting of Rosae Multiflorae Fructus and Lonicerae Japonicae Flos, has traditionally been used in treating various inflammatory disorders including RA. In this study we assessed the anti-arthritic efficacy of RL in animals, and investigated the involvement of TLR4 signalling in RL's effects in vivo and in vitro. In vivo anti-arthritic efficacy of RL was evaluated using CIA (collagen-induced arthritis) rats, a model that is well established for studying human RA. Articular disease manifestations were investigated grossly, radiographically, and histologically. Isolated splenocytes were used to determine the effects of RL on immune responses. Molecular events in the TLR4 pathways upon RL treatment were examined in sera and joint tissues of CIA rats as well as in cultured lipopolysaccharide (LPS)-stimulated murine RAW264.7 and human THP-1 cells.

A fitoterapia e o uso de plantas medicinais fazem parte da prática da medicina popular, que diminuiu frente ao processo de industrialização nas décadas de 1940 e 1950, aumentando a busca, pela população, por terapias menos agressivas destinadas ao atendimento primário à saúde. Essa complementa o tratamento usualmente empregado para a população de menor renda. O objetivo deste trabalho foi analisar o conhecimento dos gestores e profissionais de saúde que atuam na atenção primária, sobre fitoterapia e uso de plantas medicinais, nos municípios de Cascavel e Foz do Iguaçu - Paraná. Para tanto, no período de fevereiro a julho de 2009, foi realizado estudo exploratório, descritivo, qualitativo, empregando como instrumentos de pesquisa entrevistas semiestruturadas e um questionário estruturado, auto aplicado, com perguntas fechadas, a fim de contemplar os seguintes aspectos: perfil dos profissionais; aceitabilidade quanto à implantação da fitoterapia na atenção básica; confiança nos tratamentos com fitoterápicos; capacitação e formação profissional relacionadas à fitoterapia, entre outros itens. Um dos gestores considerou recente o programa de fitoterapia. Indicadores de satisfação da população quanto ao uso dos fitoterápicos ou plantas medicinais ainda não existem. O gestor do município de Cascavel relatou interesse na implantação do programa. Os demais profissionais entrevistados, de maneira geral, relataram não haver recebido formação sobre o tema durante a graduação, nem mesmo dentro das UBS onde trabalham. Entre os profissionais entrevistados seis (60%) relataram o acesso às informações sobre fitoterapia através do conhecimento popular, uma (10%) formação na UBS, dois (20%) através de periódicos, quatro (40%) através de meio de comunicação, sendo que quatro citaram mais que uma das opções. Em Foz do Iguaçu, nas UBS onde a terapêutica está implantada, os profissionais relataram não terem sido consultados antes de sua implantação, e a avaliação das plantas utilizadas pelos pacientes atendidos ocorre somente através de avaliação objetiva e subjetiva do tratamento Para implantação da fitoterapia nas UBS desses dois municípios, é necessário capacitar os profissionais quanto ao tema, desde o cultivo até a prescrição, melhorando o uso racional desses medicamentos. / The phytoterapy and the use of medicinal plants are part of practice of the popular medicine, that decreased with industrialization, in the 1940 and 1950s, increasing the search, of population, of therapies less aggressive, in the primary health care. This practice is complementary to the usual treatment used for the poor population. The purpose of this work was analyze the knowledge of the managers and health professionals, which works in the primary attention, about phytoterapy and use of medicinal plants, in the cities of Cascavel and Foz do Iguaçu - Paraná. For this, in the period of February to July of 2009, was done an exploratory, descriptive, and qualitative study, using as research instruments halfstructuralized interviews and a structuralized, auto-applied questionnaire, with closed questions, in order to contemplate the following aspects: profile of the professionals; acceptability of the introduction of the phytoterapy in the basic attention; the trust in the treatments with phytoterapy; related qualification and professional formation to the phytoterapy, among others itens. One of the health managers judged the program of phytoterapy recent. Pointers of satisfaction of the population about the use of the phytoterapy or medicinal plants dont exist. The health manager of Cascavel related interest in the introduction of the program. The other professionals interviewed, related that didnt have received formation about the subject during the graduation, not even inside of the health basic unit where they work. Six (60%) related the access to the information on phytoterapy through the popular knowledge, one (10%) formation in the health basic unit , two (20%) through periodic, four (40%) through media, four (40%) had cited more than one of the options. At Foz do Iguaçu, in the health basic unit where the therapy is implanted the professionals had told that they arent consulted previously its implantation.The evaluation of the plants used for the patients in this city only occurs through an objective and subjective evaluation of the treatment. For implantation of the phytotherapy in the UBS of these two cities, is necessary qualification of the professionals about the subject, about the cultivation and prescription of the plants, improving the rational use of these medicines.