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Phthalates have been used in a wide variety of consumer goods. Their versatility as plasticizers has translated into worldwide use in a vast array of consumer products. These compounds can leach into matrices, such as food and liquids that can be routed for human exposure. One of the most used phthalates is Diethylhexyl phthalate (DEHP). Diethylhexyl phthalate and its metabolite 2-ethyl-1-hexanol (2-EH) have demonstrated biological effects which merit further evaluation. In this work, we expand on our previous work with DEHP and screen the 2-EH metabolite for different cell death endpoints such as growth inhibition, apoptosis, autophagy, caspase activation, DNA fragmentation, and cell cycle arrest using fluorophores and the NC3000 instrument. Significant results (p < 0.05) revealed higher toxicity for the 2-EH metabolite when compared to DEHP. Also, 2-EH presented apoptosis induction with characteristic hallmarks, such as loss of mitochondrial membrane potential, caspase activation, DNA fragmentation and cell cycle arrest at the S phase. In addition, the presence of autophagosome was detected through L3CB protein staining. We conclude that 2-EH presents differences in cell death endpoints that interestingly differ from the DEHP parent compound. Further studies are needed to establish the molecular pathways responsible for the observed effects.

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Pese a la urbanización de los últimos 20 años, en Sayausí aún se mantienen costumbres ancestrales andinas como el uso de plantas medicinales, recurso preventivo y terapéutico en salud. Objetivo:Conocer los principios de la cosmovisión andina y relacionarlos al manejo de las plantas medicinales en Sayausí. Material y métodos:Estudio descriptivo cualitativo de tipo narrativo con enfoque intercultural. Se investigó el uso de plantas medicinales bajo los postulados de la cosmovisión andina. Se entrevistó a cinco sabios de la medicina ancestral de la parroquia Sayausí durante los meses de julio y agosto de 2015. Fundamento teórico para el análisis de los datos: el diseño narrativo, generando conceptos e interpretaciones a partir de la información obtenida de los hombres y mujeres de sabiduría. Técnicas utilizadas: entrevistas. Instrumentos: formularios con preguntas abiertas, grabaciones y fotografías. Las entrevistas se redactaron utilizando citas, códigos y memos, procesadas con el programa Atlas ti versión 7. Las categorías principales fueron agrupadas según taxonomías; la información fue complementada con tablas y figuras.Resultados: Los sabios andinos explicaron con sus propias palabras los principios: relacionalidad, reciprocidad, correspondencia, complementariedad. En su racionalidad todo funcionaba como un proceso holístico, involucraba a todos los componentes del Universo. El sanar con montes se constituye en un verdadero ritual que aplica paradigmas y principios; las plantas armonizan el cuerpo-espíritu en unidad. Las plantas tuvieron tres funciones principales: sanación, alimentación y elemento sagrado. Las formas para clasificar las plantas fueron: género, forma, color, y estado térmico. La recolección de las plantas, su preparación y la administración fueron los tres momentos del proceso de curación.

Despite the urbanization of the last 20 years, Sayausí still maintains ancestral Andean customs such as the use of medicinal plants, a preventive and therapeutic resource in health.Objetive:To determinate the principles of the Andean worldview and relate them to the management of medicinal plants in Sayausí.Method:It is a qualitative descriptive study of a narrative type with an intercultural approach. The use of medical plants was investigated under the postulates of the Andean worldwide. Five wise men of the ancestral medicine of the Sayausí parish were interviewed during the months of July and August in 2015. The theoretical basis for the analysis of the data: the narrative design, generating concepts and interpretations from the information obtained from the wise men. The techniques used were interviews. The Instruments were forms with open questions, recordings and photographs. The interviews were written using citations, codes and memos, which were processed with the Atlas program. The main categories were grouped according to taxonomies; the information was complemented with tables and figures.Results: The Andean sages explained in their own words the principles: relationality, reciprocity, correspondence, and complementarity. In its rationality, everything worked as a holistic process, involving all the components of the universe. To heal with plants was a true ritual, including principles, plants, body and spirit. The plants had three main functions: healing, feeding and a sacred element. The ways to classify the plants were: gender, shape, color, and thermal state. The herb harvest, preparation and administration were the three stages of the healing processConclusions:The Andean sages from Sayausí parish applied the principles of the Andean worldview both in practicing healing with medicinal plants and activities of their daily lives.

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OBJECTIVES: The present study evaluates novel cationic quinoline derivatives known as benzimidazo[3,2-a]quinolinium salts (BQS) named NBQ-48 and ABQ-48 that have structural similarities to known anti-cancer substances such as ellipticine and berberine. METHODS: Toledo human lymphoma (ATCC CRL2631) cells were treated for 24 to 48 hours. Apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, RNS and ROS generation and the activity of several apoptosis related proteins such as caspases and apoptosis inducing factor (AIF) were studied using fluorescence staining and western blot respectively. RESULTS: Results indicated a higher toxicity from the amino substituted ABQ-48 versus the NBQ-48 (GI50's of 50uM versus 100uM respectively). Both compounds induced cell death through various apoptosis related endpoints including a decrease in mitochondrial membrane potential with an increase in ROS and activation of the effector caspase 3. Interestingly, AIF release was observed on cells treated with the amino substituted ABQ-48 but not on the nitro substituted NBQ-48 samples suggesting a caspase independent mechanism for ABQ-48. CONCLUSIONS: The results obtained presents the toxic effects of two novel benzimidazo[3,2-a]quinolinium salts in human lymphoma tumor cells. The identified mechanism of action includes multiple apoptosis related effects. Furthermore the data presents a clear variation in caspase dependent or independent mechanism for each compound.

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ABQ-48 (3-amino-7-benzylbenzimidazo[3,2-a]quinolinium chloride) and NBQ-48 (3-nitro-7-benzylbenzimidaw[3,2-a] quinolinium chloride) are un-natural alkaloids containing a planar heteroaromatic systems characterized by quaternized nitrogen fused to benzothiazole nucleus. Both compounds are structurally related to naturally occurring substances such as elliptine (from Ochrosia), and berberine (from Berberis). Previous in vitro studies have shown these agents to control tumor-cell proliferation indicating that both BQS are active but especially ABQ-48 at a 1 OuM dose with over 80% control of the proliferation of multiple cancer cell lines from various etiologies including colon, melanoma, CNS and ovarian cells. Mechanism of action studies have also been conducted however this is the first approach to evaluate immune modulatory activity of these novel BQS. Immune-based therapy is an increasing field in which scientists identify how the immunomodulatory activity of known and newly discovered compounds elicits an immune response that could be used against diseases. In this study, our main objective was to apply an in vitro model to show the immunomodulatory effects of ABQ-48 and NBQ-48 by analyzing the cytokine profile resulting after extracted murine spleen cells were treated with both BQS using a fluorescence-based multiplex ELISA approach. Screened cytokines included: G-CSF, GM-CSF, IL-1a, IL-2, IL-3, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-21, IL-23, IFN-γ, and TNF-α. Our study results show ABQ 48 and NBQ-48 to stimulate the release of G-CSF, IL-2, IL-6, and, IFN-γ when mouse splenocytes are incubated with serial dilutions of these agents. Our finding opens new possibilities of potentially using ABQ-48 and NBQ-48 as immunomodulatory agents; with intend to activate the immune system such as the production of neutrophils against cancer or reducing chemotherapy side effects.

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This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ's are unnatural alkaloids possessing a positive charge that could facilitate interaction with cell organelles. The anticancer activities of these compounds were evaluated through the National Cancer Institute (NCI) 60 cell line screening which represents diverse histologies. The screening was performed at 10 µM on all cell lines. Results from the NCI screening indicated cytotoxicity activity on six cell lines. In order to explore a possible mechanism of action, a detailed biological activity study of NBQ 95 and NBQ 38 was performed on A431 human epidermoid carcinoma cells to determine an apoptotic pathway involving, cell cycle changes, DNA fragmentation, mutations, mitochondrial membrane permeabilization and caspases activation. DNA fragmentation, cell cycle effects, mutagenesis, mitochondrial permeabilization and activation of caspases were determined by fluorimetry and differential imaging. Our data showed that A431 growth was inhibited with an average IC50 of 30 µM. In terms of the mechanism, these compounds interacted with DNA causing fragmentation and cell cycle arrest at sub G0/G1 stage. Mutagenesis was higher for NBQ 38 and moderate for NBQ 95 Mitochon-drial permeabilization was observed with NBQ 38 and slightly for NBQ 95. Both compounds caused activation of Caspases 3 and 7 suggesting an apoptotic cell death pathway through an intrinsic mechanism. This study reports evidence of the toxicity of these novel compounds with overlapping structural and mechanistic similarities to ellipticine, a known anti-tumor compound.

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Phthalates are ubiquitous compounds used in the manufacturing industry. Some are known endocrine disruptors, acting as xenoestrogens, others induce reproductive toxicity and damage to DNA among other effects. Studies on apoptosis induction and mitochondrial damage capacity of phthalates on the immune system are limited. This study aims to determine cell viability inhibition and apoptosis induction of diethylhexyl phthalate (DEHP) and monoethylhexyl phthalate (MEHP) on the human TK6 lymphoblast cell line at concentrations found in the environment. Key hallmark events, such as mitochondrial membrane permeability, generation of reactive oxygen species (ROS) and activation of caspase 3 and 7 were measured. Concentrations that inhibit viability of 50% (IC50) of the cells were determined at 24, 48 and 72 h with doses ranging from 10 to 500 µM. Changes in mitochondrial membrane permeability, ROS generation and activation of caspases 3 and 7, were measured as part of the cell death mechanism. The IC50 at 24 h was approximately 250 µM for both phthalates; at 48 h were 234 and 196 µM for DEHP and MEHP, respectively and at 72 h IC50s were 100 and 80 µM for DEHP and MEHP, respectively. Overall the longer the time of exposure the lower the IC50's for both compounds. Both compounds affected mitochondrial membrane potential, promoted ROS generation and activated caspases 3 and 7. MEHP is more toxic, promotes higher level of ROS production and caspases activation. Our findings suggest that DEHP and MEHP have the capacity to induce apoptosis in cells of the immune system at concentrations found in the environment.

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