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Acute lymphoblastic leukemia (ALL) encompasses a spectrum of lymphoid progenitors that have undergone malignant transformation and clonal proliferation at various stages of differentiation. Some cases of ALL have been documented to have prenatal origins and in particular neonatal exposure to various environmental pollutants is associated with increased disease risk, including childhood lymphoma and leukemia. Dibenzo[def,p]chrysene (DBC) is a polycyclic aromatic hydrocarbon (PAH) and in our laboratory has been established as a transplacental carcinogen in mice, producing aggressive T-cell lymphoblastic lymphomas, lung, liver, uterine, ovarian, and testicular lesions, depending on timing and dose of exposure. Investigation of the transplacental and translactational transfer of DBC was warranted following a cross-foster experiment demonstrating the greatest tumorigenic response occurred in offspring both gestating in and nursed by an exposed female. [¹⁴C]-DBC (GD17) dosing was utilized to examine time-dependent alterations of [¹⁴C] in maternal and fetal tissues, excreta, and residual levels at weaning. Fetal tissue levels of [¹⁴C]-DBC equivalents were 10-fold lower than maternal tissue, and after weaning the residual body burden was roughly equivalent in offspring exposed only in utero or only via lactation. Certain bioactive food components, including indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), and sulforaphane (SFN) from cruciferous vegetables have been shown to target cellular pathways regulating carcinogenesis. In the above mentioned DBC initiated model of carcinogenesis, I3C is an effective transplacental chemopreventive agent. We sought to extend our chemoprevention studies in mice to a human neoplasm in cell culture, analogous to the observed murine T-cell lymphomas. Treatment of the human T-ALL cell line CCRF-CEM (CEM) with I3C reduced cell proliferation and viability only at supraphysiologic concentrations whereas DIM, the primary acid condensation product of I3C, had a marked effect at low micromolar concentrations in vitro and reduced growth of CEM xenografts in vivo. Additional T-ALL lines, selected to represent the heterogeneity of the disease, (CCRF-HSB2, Jurkat, and SUP-T1) responded similarly in vitro, demonstrating a potential therapeutic value of DIM in T-ALL. Given that epigenetic reprograming is especially active during fetal development and that DNA hypermethylation contributes to the etiology of T-ALL we examined genome-wide DNA methylation in CEM. Differential methylation analysis revealed that DIM and I3C alter CpG methylation in unique, yet overlapping, gene targets. DIM treated cells exhibited a dose-dependent decrease in hypermethylation, an observation consistent with an epigenetic mechanism of cancer suppression. Pyroseqencing and RTPCR technologies were utilized to validate changes in DNA methylation and to compare these patterns with a transcriptional response in both novel targets and candidate genes selected from the literature. Collectively, these studies merited returning to the murine transplacental model for further investigation of genetic and epigenetic changes upon maternal dietary intervention with I3C. More importantly we incorporated whole cruciferous vegetable diets (10% broccoli sprouts or 10% Brussels sprouts), SFN diet, or the combination of SFN and I3C, in order to examine matrix and mixture effects. Preliminary analysis suggests a worse prognosis for those animals exposed in utero to SFN or the whole foods, especially males. As this is the first study to administer SFN or whole cruciferous vegetables in a transplacental model of carcinogenesis, our results warrant further study on the concentration dependent influence of these potent phytochemicals during the perinatal window. / Graduation date: 2012

Chemotherapy, employing single-molecule or multidrug concoctions inspired by the diverse repository of plant chemicals, has been the mainstay of cancer treatment for years. However, isolating single molecules has proven to be expensive along with limited therapeutic window and toxicity. On the other hand, whole foods, while preserving the natural complex balance between their constituent phytochemicals and being non-toxic, have proven to impart better disease-fighting efficacies, thus leading to an increased focus on dietary interventions to both treat and prevent cancer. Owing to the complex interactions between their constituent phytochemicals, several dietary agents have been investigated for their therapeutic and preventive efficacies. However, due to lack of emphasis on confounding factors like bioavailability, absorption, metabolism, and excretion, essentially driven by phytocomplexity, incorporation of whole foods in therapeutic regimen has not been successful. This thesis exemplifies the need to investigate factors associated with the limitations in the current approach with respect to dietary agents. Bioactivity-guided fractionation of sweet potato greens extract (SPGE) led to the identification of ~100-fold more potent fraction in vitro. However, this efficacy could not be translated in vivo. We also studied whole ginger extract (GE) for its in vitro and in vivo prostate tumor growth-inhibitory and apoptosis-inducing effects. In addition, GE proved to be more efficacious as compared to its individual most-active constituents owing to the differences in their pharmacokinetic (PK) and bioavailability measurements. Hence, these studies emphasize the crucial role of synergistic/additive interactions among the constituents of whole foods in successful translation of their therapeutic benefits. Another factor that seeks further attention is the unique cellular mechanisms engaged by these phytochemicals to confer their remarkable effects. Phenolic compounds, the most-abundant of all phytochemicals, are well known for their antioxidant properties and act via reactive oxygen species (ROS)-mediated mechanisms. We however assert the underappreciated xenohormetic prooxidant role of phenolics, where cancer cell death is caused by induction of intolerable levels of ROS. We demonstrated that a Piper betel constituent, hydroxychavicol (HC), mediates cytotoxicity via ROS-induced DNA-damage. This thesis thus provides compelling grounds for future preclinical studies to validate their potential usefulness for cancer management.

This study investigated potential apoptotic and anti-proliferative effects of the phytochemicals, genistein and anthocyanin extract, as single and combined treatments in MCF-7 human breast cancer cells. Cells were exposed to single and combined treatments with the phytochemiclas for 48 and 72 hours. Cell viability was assessed using the MTT bioassay. Apoptosis induction was assessed using acridine orange ethidium bromide and rhodamine 123 ethidium bromide fluorescence assays. Both singe and combination treatments induced dose- and time-dependent apoptotic cell death in MCF-7 cells. The percentage of apoptosis was higher in combination treatments than single treatments with either phytochemical, although the difference was not statistically significant. The combination of genistein and anthocyanin extract peaked in efficacy at 48 hours of treatment, to exhibit significantly greater (P<. O5) dose- and time-dependent cell cytotoxicity than single treatments. This study reveals potential chemopreventive implications for the complementary effects of genistein and anthocyanin extract. / by Corine M. Stinson. / Thesis (M.S.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Prostate cancer is the most common form of non-skin cancer and the second leading cause of cancer deaths within the United States. The five year survival rate has increased from 69% to 99% over the last 25 years for the local and regional disease, but has remained fairly low (approximately 34%) for the advanced disease. Therefore, current research is aimed at finding complementary or alternative treatments that will specifically target components of the signal transduction, cell-cycle and apoptosis pathways to induce cell death, with little or no toxic side effects to the patient. In this study we investigated the effect of genistein on expression levels of genes involved in these pathways. Genistein is a (4 , 5 , 7-trihydroxyisoflavone) is a major isoflavone constituent of soy that has been shown to inhibit growth proliferation and induce apoptosis in cancer cells. The mechanism of genistein-induced cell death and potential molecular targets for genistein in LNCaP prostate cancer c ells was investigated using several techniques. The chemosensitivity of genistein towards the prostate cancer cells was investigated using the ATP and MTS assays and apoptosis induction was determined using apoptosis and caspase assays. Several molecular targets were also identified using cDNA microarray and RT-PCR analysis. Our results revealed that genistein induces cell death in a time and dose-dependent manner and regulates expression levels of several genes involved in carcinogenesis and immunogenicity. Several cell cycle genes were down-regulated, including the mitotic kinesins, cyclins and cyclin dependent kinases, indicating that genistein is able to halt cell cycle progression through the regulation of genes involved in this process. / Several members of the Bcl-2 family which are involved in apoptosis were also affected and a number of genes involved in immunogenicity were up-regulated including the DefB1 and HLA membrane receptors. The results of this study provide evidence of genistein's ability to inhibit growth proliferation and induce apoptosis and indicates its potential as an adjuvant in chemotherapy and immunotherapy. / by Kendra Merchant. / Thesis (Ph.D.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.

Thesis (MTech (Horticulture))--Cape Peninsula University of Technology, 2018. / Ticks and tick-borne diseases are important limiting factors to the attainment of sustainable animal and human health, affecting livelihood of resource poor farming communities in developing countries. Rhipicephalus appendiculatus and Amblyomma variegatum (Ixodidae) are among the most troubling tick species in Africa. While ticks can be controlled by applying chemical acaricides, these chemicals are quite expensive, especially, for small-scale famers in developing countries. Hence, the quest for alternative tick control over the years have revealed that entomopathogenic fungi (EPF) and plant extracts have huge prospects as sustainable alternatives for tick control. Beauveria bassiana (Hypocreales) is a fungal entomopathogen with the ability to colonize plants endophytically and induce secondary metabolite production in plants, and it has been found to be a potential biological control agent against a wide range of arthropods. Several plant species including plant species belonging to the family Alliaceae possess anti-tick activities (repellent and toxic); therefore, integrating the two strategies by inoculating Tulbaghia violacea with B. bassiana could enhance secondary metabolite contents in extracts obtained from the plant and increase medicinal materials. The primary purpose of the present study was to evaluate the effect of indigenous endophytic entomopathogens inoculation of T. violacea on the plant growth, tissue nutrient contents and secondary metabolites, and anti-tick activities of extracts of T. violacea. The specific objectives were: (i) to carry out a study on the effects of inoculating T. violacea with fungal strains of B. bassiana and Clonostachys rosea on plant growth and tissue nutrient contents in extracts of T. violacea with the view of selecting one of the two fungi for further investigation (ii) to compare secondary metabolite profiles of extracts obtained from plants exposed to fungus (EPF) inoculum and control treatment during cultivation, and (iii) to determine whether exposure of T. violacea to an endophytic fungus (B. bassiana) during cultivation affects the repellent and acaricidal activities of extracts of T. violacea on A. variegatum and R. appendiculatus. The study had two experiments, presented in chapters two and three. In the first experiment, eight weeks old potted seedlings of T. violacea were inoculated separately with B. bassiana (strain SM3) and C. rosea (strain SM8) conidia suspended at concentrations of 1 x 106 conidia mL-1. Plant growth parameters, such as number of leaves, plant height (aerial part), fresh weights of aerial parts, and tissue nutrient contents were assessed. Results indicated that B. bassiana induced higher growth of plants than C. rosea. Inoculation with B. bassiana did not significantly (P ˃ 0.05) influence most of the growth parameters, number of leaves, fresht weight of roots and of fresh weight aerial parts (leaves) of T. violacea assessed in the current study. However, mean plant heights and root lengths were significantly (P < 0.05) higher in favour of B. bassiana treated plants compared to those in C. rosea. Fe contents in the roots (1416.3 ± 305.10 mg/kg) were found to be positively influenced (P < 0.05) by the fungal inoculation. There was a significant difference in roots (P < 0.05) on the uptake of Mn in C. rosea treated plants (243 ± 19 mg/kg) compared to the control group (169 ± 16.37 mg/kg) and B. bassiana treated roots (161.3 ± 14.44 mg/kg). Macro nutrients up take did not differ significantly among treatments on both leaves and roots (P > 0.05).

Made available in DSpace on 2017-07-21T18:53:02Z (GMT). No. of bitstreams: 1 VIVIAN ITO.pdf: 2690679 bytes, checksum: 986e658b539e22ec97b7923bb505ed9a (MD5) Previous issue date: 2015-02-13 / The apple is a very popular fruit because of its aroma, flavor and attractive look, its consumption is related to several benefits to human health. With industrialization, a residue of juice extraction is generated, the apple pomace, with similar characteristics of nutrients and bioactive compounds that fruit. This apple pomace after stabilization becomes a by-product with excellent biotechnological applications. The positive effects of irradiation in food has been exploration, especially in increasing the useful life of the product. This study aimed to evaluate the effects of gamma radiation on the physicochemical characteristics, thermogravimetric, microstructural and microbiological, phenolic compounds and antioxidant potential of apple cake meal, for nine months of storage, with the help of multivariate techniques such as analysis Principal Components (PCA) and Hierarchical Cluster Analysis (HCA). Gamma radiation and the storage period did not influence the parameters of lipid, sucrose, fructose and ashes. Reducing sugars were not affected by the irradiation and the dose of 1 kGy remained stable during the storage period. The glucose was stable from the third month, and the highest levels were found at a dose of 2 kGy. The mineral calcium levels were higher in the irradiated samples. The dietary fiber content of the irradiated samples resulted in lower values compared to the control sample, but remained within the contents found in the literature. The irradiated samples were stable during storage for protein, lipid, dietary fiber, total reducing sugar, minerals K, Zn, Fe and Mn. The Phlorizin was the phenolic compound that remained constant levels during the search. Chlorogenic acid and its class hydroxycinnamic acids increased proportionally with time in the irradiated samples. The chemometric approach is effective to facilitate the visualization of samples of apple cake meal, the physical-chemical parameters and by HCA, the phenolic compounds were separated into three groups, the first characterized in that only samples without irradiation, the Then, samples with 2 kGy and third represent characterized by a dose of 1 kGy. Thermogravimetry curves with four major mass loss in consecutive reactions. In the hotomicrographs, there was an organic material composition and heterogeneous, with agglomerates of particles which have irregular shapes and sizes. From a microbiological point of view the dose of 2 kGy was lethal to the inhibition of yeasts and molds to the end of the study. This raw material is a great source of fiber and can be applied to products with high added value, aiming economy and reducing the environmental impact. / A maçã é uma fruta muito popular devido ao seu aroma, sabor e visual atrativo, seu consumo está relacionado a vários benefícios a saúde humana. Com a industrialização, é gerado um resíduo da extração do suco, o bagaço de maçã, com características similares de nutrientes e compostos bioativos que a fruta. Esse bagaço quando estabilizado se torna um subproduto com excelentes aplicações biotecnológicas. Os efeitos positivos da irradiação em alimentos tem sido exploratório, principalmente no aumento do tempo de vida útil do produto. Este trabalho teve por objetivo avaliar os efeitos da radiação gama nas características físico-químicas, termogravimétricas, microestruturais e microbiológicas, compostos fenólicos e potencial antioxidante da farinha de bagaço de maçã, durante nove meses de armazenamento, com auxílio de técnicas multivariadas, como a Análise de Componentes Principais (PCA) e a Análise Hierárquica de Agrupamentos (HCA). A radiação gama e o período de armazenamento não influenciaram nos parâmetros de lipídeos, sacarose, frutose e cinzas. Os açúcares redutores não foram influenciados pela irradiação e com a dose de 1 kGy se manteve estável durante o período de armazenamento. A glucose se manteve estável a partir do terceiro mês, e os maiores teores foram encontrados com a dose de 2 kGy. O mineral cálcio apresentou maiores teores nas amostras irradiadas. Os teores de fibra alimentar nas amostras irradiadas resultam em menores valores comparadas a amostra controle, mas continuaram dentro dos índices encontrados na literatura. As amostras irradiadas durante o armazenamento foram estáveis para os teores de proteína, lipídeos, fibra alimentar, açúcar redutor total, os minerais K, Zn, Fe e Mn. A floredizina foi o composto fenólico que manteve teores constantes durante a pesquisa. O ácido clorogênico e a sua classe de ácidos hidroxicinâmicos aumentaram proporcionamente com o tempo nas amostras irradiadas. A abordagem quimiométrica se mostrou eficaz ao facilitar a visualização das amostras da farinha de bagaço de maçã, nos parâmetros físicoquímicos e através da HCA, os compostos fenólicos foram separados em 3 grupos, o primeiro caracterizado por apresentar apenas as amostras sem irradiação, o segundo, amostras com 2 kGy e o terceiro caracterizou-se por representar a dose de 1 kGy. As curvas de termogravimetria apresentam quatro perdas principais de massa, em reações consecutivas. Com as fotomicrografias, observou-se um material de composição orgânica, bem heterogêneo, com aglomerados de partículas que apresentam formas e tamanhos irregulares. Do ponto de vista microbiológico a dose de 2 kGy foi letal para a inibição de bolores e leveduras ao término da pesquisa. Essa matéria prima é uma ótima fonte de fibras e pode ser aplicada em produtos com alto valor agregado, visando economia e reduzindo o impacto ambiental.