Publication: Betalaínas con actividad frente a Alzheimer y cáncer : bioprospección, diversificación estructural y caracterización funcional
Authors
Martínez Rodríguez, Pedro
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Escuela Internacional de Doctorado
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Gandía Herrero, Fernando ; Guerrero Rubio, Alejandra
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
La presente Tesis Doctoral abordó de manera integral el estudio de las betalaínas, superando las limitaciones impuestas por el uso habitual de extractos complejos de fuentes convencionales como Beta vulgaris y Opuntia ficus-indica. La investigación exploró desde el origen y la presencia de pigmentos hasta ahora no considerados en la naturaleza hasta su potencial terapéutico en enfermedades de alto impacto como el Alzheimer y el cáncer. Así, la Tesis se estructuró en tres ejes principales: la bioprospección de betalaínas singulares, la modificación estructural del ácido betalámico para la obtención de nuevas familias de pigmentos a partir de sustratos no convencionales, y la caracterización funcional de la bioactividad de moléculas individuales tanto in vitro como in vivo utilizando el modelo animal Caenorhabditis elegans.
La investigación comenzó expandiendo las fronteras conocidas de estos pigmentos, documentando por primera vez la amplia distribución (29 compuestos identificados) de betalaínas descarboxiladas, derivadas de la dopamina, en especies de la familia Amaranthaceae, especialmente en la quinoa (Chenopodium quinoa), consolidándolas como una familia de fitoquímicos relevante para la fisiología de estas plantas. Asimismo, se exploró la biosíntesis de betalaínas en el hongo "fósil viviente" Neolecta irregularis. Mediante la caracterización de su enzima 4,5-DOPA-extradiol-dioxigenasa (NiDODA), se demostró la capacidad formadora de betalaínas en este ascomiceto basal, expandiendo así la distribución filogenética de esta ruta biosintética fuera del reino vegetal.
Por otro lado, se llevó a cabo la modificación química de la unidad estructural y funcional de las betalaínas: el ácido betalámico. En este ámbito, se describió la síntesis y caracterización de una nueva familia de betalaínas metiladas mediante la incorporación de un grupo metilo para formar el ácido 6-metil-betalámico. Además, se sintetizaron betalaínas hidroxiladas utilizando como molécula precursora la noradrenalina, resultando en pigmentos con mayor polaridad. Así, la investigación llevada a cabo representa el inicio de la era de la química del núcleo central de las betalaínas, abriendo una vía para el diseño de nuevos pigmentos bioactivos hechos a medida.
Asimismo, se evaluó la actividad biológica de estos pigmentos utilizando el modelo animal Caenorhabditis elegans. Respecto a la enfermedad de Alzheimer, se demostró que las betalaínas poseen propiedades anti-amiloidogénicas; 22 moléculas redujeron la agregación del péptido amiloide in vitro, y los ensayos in vivo confirmaron una mejora significativa en el comportamiento quimiotáctico en estirpes de C. elegans que son modelo de Alzheimer, respaldada además por estudios de docking molecular. En cuanto a la actividad antitumoral, las betalaínas metiladas mostraron una potente capacidad para reducir la proliferación de células tumorales en C. elegans. Entre ellas, la prolina-6-metil-betaxantina destacó como el pigmento más efectivo, logrando reducir el tamaño tumoral en un 48,4 %.
Como estrategia para trasladar estos hallazgos a una aplicación real, se desarrollaron liposomas cargados con betalaínas que garantizan su biodisponibilidad. Estos sistemas no solo preservaron las propiedades antioxidantes de los pigmentos, sino que liposomas cargados con betalaínas aumentaron la vida media de C. elegans hasta en un 21,8 %, demostrando ser un sistema eficaz de administración. En conjunto, esta Tesis posiciona a las betalaínas, tanto tradicionales como modificadas estructuralmente, como candidatas prometedoras para el desarrollo de nutracéuticos y agentes farmacológicos. Los resultados obtenidos proporcionan una base sólida que va desde la caracterización más básica hasta la evidencia preclínica, destacando el papel de las betalaínas como potenciales moléculas de interés en la lucha contra enfermedades neurodegenerativas y oncológicas.
This Doctoral Thesis comprehensively addressed the study of betalains, overcoming the limitations imposed by the traditional use of complex extracts from conventional sources such as Beta vulgaris and Opuntia ficus-indica. The research explored different aspects covering from the origin and presence of new pigments in nature to their therapeutic potential in high-impact diseases such as Alzheimer's and cancer. Thus, the Thesis was structured into three main axes: the bioprospecting of unique betalains, the structural diversification of betalamic acid to obtain new families of pigments from unconventional substrates, and the functional characterization of the bioactivity of individual molecules using the Caenorhabditis elegans animal model. The research began by expanding the known frontiers of these pigments, documenting for the first time the wide distribution (29 compounds identified) of decarboxylated betalains, derived from dopamine, in species of the Amaranthaceae family, especially in quinoa (Chenopodium quinoa), consolidating them as a family of phytochemicals relevant to the physiology of these plants. Likewise, the biosynthesis of betalains was explored in the "living fossil" fungus Neolecta irregularis. Through characterization of its 4,5-DOPA-extradiol-dioxygenase enzyme (NiDODA), the betalain-forming capacity of this basal ascomycete was demonstrated, thereby expanding the phylogenetic distribution of this biosynthetic pathway beyond the Plant Kingdom. On the other hand, the chemical modification of the structural and functional unit of betalains, betalamic acid, was carried out. In this field, the synthesis and characterization of a new family of methylated betalains through the incorporation of a methyl group to form 6-methyl-betalamic acid was described. Furthermore, hydroxylated betalains were synthesized using noradrenaline as a precursor molecule, resulting in pigments with higher polarity. Thus, the research carried out represents the beginning of the era of betalain core chemistry, opening a path for the design of new custom-made bioactive pigments. Likewise, the biological activity of these pigments was evaluated using the C. elegans animal model. In Alzheimer's disease, it was demonstrated that betalains possess anti-amyloidogenic properties; 22 molecules reduced the aggregation of the amyloid peptide in vitro, and in vivo assays confirmed a significant improvement in chemotactic behavior in C. elegans strains that are models of Alzheimer's, further supported by molecular docking studies. As for antitumor activity, methylated betalains showed a potent ability to reduce the proliferation of tumor cells in C. elegans. Among them, proline-6-methyl-betaxanthin stood out as the most effective pigment, reducing tumor size by up to 48.4 %. As a strategy to translate these findings into a real-world application, betalain-loaded liposomes were developed to guarantee their bioavailability. These systems not only preserved the antioxidant properties of the pigments but also increased the lifespan of C. elegans by up to 21.8 %, proving to be an effective delivery system. Taken together, this Thesis positions betalains, both traditional and structurally modified, as promising candidates for the development of nutraceuticals and pharmacological agents. The results obtained provide a solid foundation ranging from basic science to preclinical evidence, highlighting the role of betalains as potential lead molecules in the fight against neurodegenerative and oncological diseases.
This Doctoral Thesis comprehensively addressed the study of betalains, overcoming the limitations imposed by the traditional use of complex extracts from conventional sources such as Beta vulgaris and Opuntia ficus-indica. The research explored different aspects covering from the origin and presence of new pigments in nature to their therapeutic potential in high-impact diseases such as Alzheimer's and cancer. Thus, the Thesis was structured into three main axes: the bioprospecting of unique betalains, the structural diversification of betalamic acid to obtain new families of pigments from unconventional substrates, and the functional characterization of the bioactivity of individual molecules using the Caenorhabditis elegans animal model. The research began by expanding the known frontiers of these pigments, documenting for the first time the wide distribution (29 compounds identified) of decarboxylated betalains, derived from dopamine, in species of the Amaranthaceae family, especially in quinoa (Chenopodium quinoa), consolidating them as a family of phytochemicals relevant to the physiology of these plants. Likewise, the biosynthesis of betalains was explored in the "living fossil" fungus Neolecta irregularis. Through characterization of its 4,5-DOPA-extradiol-dioxygenase enzyme (NiDODA), the betalain-forming capacity of this basal ascomycete was demonstrated, thereby expanding the phylogenetic distribution of this biosynthetic pathway beyond the Plant Kingdom. On the other hand, the chemical modification of the structural and functional unit of betalains, betalamic acid, was carried out. In this field, the synthesis and characterization of a new family of methylated betalains through the incorporation of a methyl group to form 6-methyl-betalamic acid was described. Furthermore, hydroxylated betalains were synthesized using noradrenaline as a precursor molecule, resulting in pigments with higher polarity. Thus, the research carried out represents the beginning of the era of betalain core chemistry, opening a path for the design of new custom-made bioactive pigments. Likewise, the biological activity of these pigments was evaluated using the C. elegans animal model. In Alzheimer's disease, it was demonstrated that betalains possess anti-amyloidogenic properties; 22 molecules reduced the aggregation of the amyloid peptide in vitro, and in vivo assays confirmed a significant improvement in chemotactic behavior in C. elegans strains that are models of Alzheimer's, further supported by molecular docking studies. As for antitumor activity, methylated betalains showed a potent ability to reduce the proliferation of tumor cells in C. elegans. Among them, proline-6-methyl-betaxanthin stood out as the most effective pigment, reducing tumor size by up to 48.4 %. As a strategy to translate these findings into a real-world application, betalain-loaded liposomes were developed to guarantee their bioavailability. These systems not only preserved the antioxidant properties of the pigments but also increased the lifespan of C. elegans by up to 21.8 %, proving to be an effective delivery system. Taken together, this Thesis positions betalains, both traditional and structurally modified, as promising candidates for the development of nutraceuticals and pharmacological agents. The results obtained provide a solid foundation ranging from basic science to preclinical evidence, highlighting the role of betalains as potential lead molecules in the fight against neurodegenerative and oncological diseases.
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25-abr-2027
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