The non-random selection of medicinal plants theory, which states that phylogeny affects the selection of medicinal plants, was proposed by Daniel Moerman to indirectly prove that traditional medicinal systems are rational and based in part by the therapeutic efficacy of plants. The logic of this theory is that because members of a taxonomical group share similar characteristics, some groups will be more medicinal and will be over-used in pharmacopoeias, while other groups bereft of secondary metabolites and therapeutic potential will be under-used medicinally. To test this theory, Moerman linearly regressed the total number of medicinal plants per family against the total number of plants per family present in an area and examined residual values to find over-used and under-used medicinal plant families. The method has been praised for its simplicity. Nonetheless, shortcomings have been noted and criticized, inspiring researchers to propose new procedures to test for phylogenetic biases in pharmacopoeias. Negative Binomial regression and examination of studentized residuals, the method used in this investigation, ameliorates the original one with a few corrections, conserving the simplicity and solving for all the criticized flaws. Also, this study incorporated different sociodemographic factors to determine if the intracultural homogeneity of traditional knowledge affects the results of the non-random selection of medicinal plants theory analysis. By testing Moerman’s theory, which is one of Ethnobotany’s major theories, this investigation is in agreement with the call to have more hypothesis-driven research within a theoretical framework to continue to advance the Ethnobotany field. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Objective: To evaluate the antibacterial and cytotoxic effect of Myrciaria dubia (Camu camu) (M. dubia) methanol extract, against Streptococcus mutans (ATCC 25175) (S. mutans) and Streptococcus sanguinis (ATCC 10556) (S. sanguinis). Methods: Two methanol extracts of M. dubia were prepared in vitro, from the seeds and pulp. Ten independent tests were prepared for each type of extract, using 0.12% chlorhexidine solution as positive control. Agar diffusion test was used by preparing wells with the experimental solutions cultivated in anaerobic conditions for 48 h at 37 °C. Meanwhile, the minimum inhibitory concentration and the cytotoxic effect over MDCK cell line was found. Results: A higher antibacterial effect was observed with the methanol seed extract with an inhibitory halo of (21.36 ± 6.35) mm and (19.21 ± 5.18) mm against S. mutans and S. sanguinis, respectively. The methanol extract of the pulp had an effect of (16.20 ± 2.08) mm and (19.34 ± 2.90) mm, respectively. The minimum inhibitory concentration of the pulp extract was 62.5 µg/mL for both strains, whereas for the seed antibacterial activity was observed even at low concentrations. The CC50 of the seeds extract was at a higher concentration than 800 µg/mL and 524.37 µg/mL for the pulp extract. / This study was supported by Universidad Peruana de Ciencias Aplicadas (UPC) Lima-Peru with Grant No. MANUSCRIPT ACCEPTED ACCEPTED MANUSCRIPT UPC-501-2015

by Chan Po Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 110-117). / Table of Contents --- p.i / Abbreviations --- p.iv / Abstract --- p.v / List of Figures --- p.vii / List of Tables --- p.xi / Chapter Chapter One: --- Introduction / Chapter 1.1 --- Objective and scope of the project --- p.1 / Chapter 1.2 --- Literature review --- p.3 / Chapter 1.2.1 --- Balkan endemic nephropathy --- p.3 / Chapter 1.2.2 --- Chinese herbs nephropathy --- p.4 / Chapter 1.2.3 --- Aristolochic acid --- p.6 / Chapter 1.2.4 --- Guan-mu-tong --- p.9 / Chapter 1.2.4.1 --- Plant --- p.9 / Chapter 1.2.4.2 --- Traditional uses --- p.10 / Chapter 1.2.4.3 --- Chemical constituents --- p.11 / Chapter 1.2.4.4 --- Pharmacological study --- p.11 / Chapter 1.2.4.5 --- Reported adverse cases --- p.12 / Chapter 1.2.5 --- Ma-dou-ling --- p.12 / Chapter 1.2.5.1 --- Plant --- p.12 / Chapter 1.2.5.2 --- Traditional uses --- p.13 / Chapter 1.2.5.3 --- Chemical constituents --- p.14 / Chapter 1.2.5.4 --- Clinical and pharmacological studies --- p.14 / Chapter 1.2.5.5 --- Reported adverse cases --- p.15 / Chapter 1.3 --- Chemical analysis --- p.16 / Chapter 1.3.1 --- Thin layer chromatography --- p.16 / Chapter 1.3.2 --- High performance liquid chromatography --- p.17 / Chapter 1.4 --- Toxicology --- p.18 / Chapter 1.4.1 --- Acute toxicity --- p.18 / Chapter 1.4.2 --- Subchronic toxicity --- p.19 / Chapter 1.4.3 --- Reproductive toxicity --- p.23 / Chapter Chapter Two: --- Materials & Methods / Chapter 2.1 --- Materials --- p.24 / Chapter 2.2 --- Methods --- p.27 / Chapter 2.2.1 --- "Aqueous extraction of Guan-mu-tong and Ma-dou-ling for acute, subchronic and reproductive toxicity tests" --- p.27 / Chapter 2.2.2 --- Chemical analysis --- p.28 / Chapter 2.2.2.1 --- Thin layer chromatography --- p.28 / Chapter 2.2.2.2 --- High performance liquid chromatography --- p.28 / Chapter 2.2.3 --- Assays for the toxicity --- p.30 / Chapter 2.2.3.1 --- Acute toxicity --- p.30 / Chapter 2.2.3.2 --- Subchronic toxicity --- p.31 / Chapter 2.2.3.3 --- Reproductive toxicity --- p.32 / Chapter 2.2.4 --- Statistical analysis --- p.33 / Chapter Chapter Three: --- Results / Chapter 3.1 --- Chemical Analysis --- p.34 / Chapter 3.1.1 --- Thin layer chromatography --- p.34 / Chapter 3.1.2 --- High performance liquid chromatography --- p.34 / Chapter 3.2 --- Toxicity of Guan-mu-tong --- p.42 / Chapter 3.2.1 --- Acute toxicity --- p.42 / Chapter 3.2.2 --- Subchronic toxicity --- p.44 / Chapter 3.2.3 --- Reproductive toxicity --- p.54 / Chapter 3.3 --- Toxicity of Ma-dou-ling --- p.56 / Chapter 3.3.1 --- Acute toxicity --- p.56 / Chapter 3.3.2 --- Subchronic toxicity --- p.66 / Chapter 3.3.3 --- Reproductive toxicity --- p.89 / Chapter Chapter Four: --- Discussion / Chapter 4.1 --- Chemical Analysis --- p.91 / Chapter 4.1.1 --- Thin layer chromatography --- p.91 / Chapter 4.1.2 --- High performance liquid chromatography --- p.91 / Chapter 4.2 --- Toxicity of Guan-mu-tong --- p.93 / Chapter 4.2.1 --- Acute toxicity --- p.93 / Chapter 4.2.2 --- Subchronic toxicity --- p.93 / Chapter 4.2.3 --- Reproductive toxicity --- p.94 / Chapter 4.3 --- Toxicity of Ma-dou-ling --- p.95 / Chapter 4.3.1 --- Acute toxicity --- p.95 / Chapter 4.3.2 --- Subchronic toxicity --- p.97 / Chapter 4.3.3 --- Reproductive toxicity --- p.105 / Chapter Chapter Five: --- Conclusion --- p.107 / Bibliography --- p.110 / Appendix A: Procedure on determining the total urinary protein --- p.119 / Appendix B: Procedure on determining the total urinary glucose using Sigma diagnostic kits --- p.121 / Appendix C: Procedure on determining the activity of aspartate aminotransferase --- p.123 / Appendix D: Procedure on determining the activity of alanine aminotransferase --- p.124 / Appendix E: Procedure for preparing a calibration curve for the measurement of aspartate aminotransferase and alanine aminotransferase activities --- p.125 / Appendix F: Procedure on tissue preparation for light microscopic study --- p.128

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Mestrado em Controlo de Qualidade / MSc in Quality Control

Mestrado em Controlo de Qualidade / MSc in Quality Control / A 3,4-metilenodioximetanfetamina (MDMA; ecstasy ), tal como outras anfetaminas, tem sido considerada por muitos como sendo uma droga segura . No entanto estão descritas na literatura muitas respostas de toxicidade, reacções adversas e mortes relacionadas com a sua ingestão recreativa. Um dos seus efeitos adversos, potencialmente fatal, é a hiponatrémia. Este efeito foi relacionado com alterações na secreção da hormona antidiurética (ADH, AVP ou arginina-vasopressina) desencadeadas pela MDMA. A hiponatrémia foi apontada como causa possível para numerosas intoxicações severas e por vezes fatais decorrentes da ingestão desta droga. Estudos recentes in vivo, em humanos saudáveis do sexo masculino, e in vitro, em hipotálamo isolado de rato, demonstraram que a bioactivação metabólica da MDMA, nomeadamente a desmetilenação seguida pela O-metilação do catecol resultante, é crucial para a libertação da AVP quer in vivo quer in vitro. Para a avaliação da contribuição desta via metabólica para a expressão in vivo do efeito de hiponatrémia causado pela ingestão da MDMA, é crucial quantificar estes metabolitos e relacionar o perfil metabólico com a magnitude do efeito hiponatrémico. Com este objectivo, foi desenvolvido e validado um método de GC-MS/MS para a quantificação da MDMA e dos seus principais metabolitos, metilenodioxianfetamina (MDA), 4-hidroxi-3-metoxianfetamina (HMA) e 4-hidroxi-3-metoximetanfetamina (HMMA), no plasma e na urina. Para melhor compreender a influência da MDMA e da sua bioactivação na secreção da AVP foram realizados estudos in vivo em ratos Wistar machos e fêmeas, aos quais foi administrada MDMA na dose 20 mg/kg. Nos estudos realizados 1 hora após a administração de MDMA foram avaliados os níveis plasmáticos de AVP e as concentrações plasmáticas da MDMA e dos metabolitos MDA, HMA e HMMA. Com estas quantificações foi possível observar, nos ratos de ambos os géneros, o aumento estatisticamente significativo dos níveis de AVP em relação aos animais controlo, ao mesmo tempo que não se detectaram correlações estatisticamente significativas entre os níveis de AVP a MDMA e os metabolitos MDA, HMA e HMMA. Nos estudos realizados 24 horas após a administração de MDMA foram avaliados os níveis plasmáticos e urinários de AVP e as concentrações urinárias de MDMA, MDA, HMA e HMMA. Os resultados destas determinações demonstraram que apesar de não se detectarem diferenças significativas nas concentrações plasmáticas de AVP entre os animais tratados e os animais controlo, existem diferenças estatisticamente significativas para as concentrações urinárias de AVP, verificando-se que os animais tratados com MDMA apresentam concentrações urinárias de AVP superiores. Além disso verificou-se também que os animais tratados excretaram menos urina relativamente à água ingerida, mostrando o efeito anti-diurético desencadeado pela AVP. Neste estudo foram também estabelecidas correlações positivas e estatisticamente significativas entre os níveis de AVP e as concentrações de MDMA, MDA, HMA e HMMA. A correlação com maior significado estatístico foi estabelecida com o metabolito HMMA. Estes resultados permitiram pela primeira vez demonstrar a secreção da AVP em ratos após a administração da MDMA. Com estes estudos foi possível observar, in vivo, não só as alterações da secreção da AVP induzidas pela MDMA mas também as consequências dessas alterações nomeadamente na resposta antidiurética e o envolvimento desta resposta no efeito de hiponatrémia. Finalmente foi possível observar a contribuição da bioactivação metabólica para a secreção de AVP. Estes resultados permitem assim compreender melhor o envolvimento da MDMA e do seu metabolismo na resposta hiponatrémica. / Although considered as safe drugs by many, exaggerated responses and deaths have been reported due to 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) abuse. One of the adverse effects associated with ecstasy intoxications is hyponatremia that has been related with a disruption on the release of the antidiuretic hormone (ADH or arginine-vasopressin) and pointed out as the possible cause of numerous severe and fatal intoxications after intake of this drug. Recent in vivo studies with human healthy volunteers and also in vitro studies performed with rat isolated hypothalamus have shown that the metabolic bioactivation of MDMA, namely its demethylenation followed by O-methylation of the resulting cathecol metabolite are crucial for the release of ADH both in vivo and in vitro. For the evaluation of the contribution of this metabolic pathway to the in vivo expression of the hyponatremic effect of MDMA it is crucial to quantify these metabolites, and to relate the metabolic profile with the magnitude of the hyponatremic effect. For this purpose, a GC-MS/MS method was developed to quantify MDMA and its main metabolites: methylenedioxyamphetamine (MDA), 4-hydroxy-3- methoxyamphetamine (HMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in plasma and urine. To better understand the influence of MDMA and its metabolic bioactivation in the secretion of AVP in vivo studies were performed with male and female Wistar rats, the MDMA dose tested was 20 mg/kg. In the studies preformed 1 hour after the MDMA administration the plasmatic levels of AVP and the plasmatic concentrations of MDMA, MDA, HMA and HMMA were evaluated. The plasmatic concentrations of AVP obtained with the treated animals were compared with the concentrations obtained with the controls showing a statistically significant increase of AVP levels in the animals treated with MDMA. Correlations between the MDMA, MDA, HMA and HMMA and the AVP plasmatic levels were also preformed. No significant correletions were obtained. In the studies preformed 24 hours after the administration of MDMA the urinary and plasmatic levels of AVP were evaluated. The concentration of MDMA, MDA, HMA and HMMA were determined in plasma and urine. It was also established the ratio between the volume of ingested water and the volume of excreted urine. The plasmatic and urinary AVP concentrations obtained in the treated animals were compared with the concentrations obtained from the controls. This compairison showed significant increases of the urinary AVP levels in the treated animals. The evaluation of the correlations between the urinary concentrations of AVP and the urinary concentrations of MDMA, MDA, HMA and HMMA showed significant correlations between AVP and MDMA, MDA, HMA and HMMA. The evaluation of the ratio between the volume of ingested water and the volume of excreted urine showed that the treated animals excreted less urine in comparison with the ingested water. The studies performed with urines collected 24 hours after MDMA administration have shown significant positive correlations between AVP and the concentrations of MDMA, MDA, HMA and HMMA. The strongest correlation was established between the concentrations of HMMA and AVP. With this study it was possible to confirm the in vivo changes in the AVP secretion profile and relate those changes with the levels of MDMA, MDA, HMA and HMMA. It was also shown for the first time the induction of the secretion of AVP in male and female rats, one hour after the administration of MDMA. The consequent antidiuretic effect can be related with the hiponatremic effect.

Mestrado em Controlo de Qualidade / MSc in Quality Control

Mestrado em Controlo de Qualidade / MSc in Quality Control / Aiming for new compounds with antitumor activity, the synthesis of prenylated xanthones and prenylated and geranylated flavones was recently achieved on CEQOFFUP. In this work the potential antitumor activity of these compounds in three tumor cell lines, namely MCF-7 (human breast cancer cells expressing estrogen receptors (ER+)), MDA-MB-231 (human breast cancer cells non expressing estrogen receptors (ER-)) and NCI-H460 (non-small cell lung cancer) was evaluated. Structure-activity relationships were established highlighting the influence of prenylation and geranylation. Concerning xanthones, prenylation of 3,4-dihydroxyxanthone (XXIX) furnished more potent and selective derivates for MCF-7 (ER+) cells than the original oxygenated xanthone. Xanthone derivate XP13 showed the strongest inhibitory effect on the growth of breast adenocarcinoma cell line ER+, MCF-7 (GI50 = 5,3 M). Thus, potential estrogenic/antiestrogenic properties were investigated for this compound. No proliferative effect at low concentrations was observed for XP13 in experiments performed in steroid-free medium (RPMI-SFM). However, when high concentrations of XP13 were used, this prenylated xanthone inhibit cancer cell growth in a dose-dependent manner, being more active on MCF-7 (ER+) cell line than on MDA-MB-231 (ER -) cell line. This antiproliferative effect was not influenced by the culture medium (steroid (RPMI) or steroid-free medium (RPMI-SFM)). From these results it can be inferred that XP13 does not directly act on the estrogen receptor, suggesting that it could interfere with other signaling pathways. Moreover, XP13 enhanced the growth inhibitory action of 4-hydroxytamoxifen (4-OHT, XIV), a partial antiestrogen in estrogen sensitive breast cancer cells. Concerning flavone derivates, none of the six flavones investigated, that were resulted from prenylation and geranylation of baicalein (BAIC, XIX), presented a higher cytotoxic effect on all tumor cellular lines (MCF-7 (ER+), MDA-MB-231 (ER -) and NCI-H460) when compared to the original oxygenated flavone BAIC (XIX). However, monoprenylation in C(7) conduced to a flavone (FP2) with a selective inhibitory effect on the growth of MCF-7 (ER+) cells. Possible estrogenic/antiestrogenic properties were investigated for this compound. It was verified that in steroid-free medium (RPMI-SFM) experiments, FP2 presented a biphasic effect in vitro growth on the ER-positive MCF-7 cell line. Although at low concentrations this flavone has stimulated cell growth, at high concentrations a cell growth inhibition was observed. Then, the effect of FP2 in combination with E2 was examinated. Results showed that FP2 suppressed at low concentrations, the mitogenic effect enhanced by estrogenic stimulation, suggesting a competition for ERs. Also, the FP2 cancer cell growth inhibitory effect on MCF-7 (ER+) cells was stronger when assed in steroid free medium, i.e., in the absence of estrogenic stimulation. These results suggest a direct involvement of estrogen receptor in the proliferative/antiproliferative effect of flavone FP2. Moreover, FP2 enhanced the growth inhibitory action of partial (4-OHT, XIV) and pure (ICI 182,780, XII) antiestrogens in estrogen sensitive breast cancer cells. These results were consistent with previous reports of prenylated flavones and disclose for prenylated xanthones effects compatible with antiestrogenic activity. Thus, the present work represents a promising contribution for the prevention and treatment of hormone-dependent breast cancer.

University of Macau / Institute of Chinese Medical Sciences