Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy

Ilustraciones

Autores:: Muñoz Gil, Susana

Tipo de recurso:

Fecha de publicación:: 2023

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: eng

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network_acronym_str	UNACIONAL2
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repository_id_str
dc.title.eng.fl_str_mv	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
dc.title.translated.spa.fl_str_mv	Neurotoxicidad de los deoxyesfingolipidos en un modelo in vitro de neuropatía periférica inducida por taxanos
title	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
spellingShingle	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy 660 - Ingeniería química::666 - Cerámica y tecnologías afines 1-deoxysphingolipids (deoxySL) 1-deoxysphingosine 1-deoxysphinganine 1-deoxyceramide taxane-induced peripheral neuropathy (TIPN) sphingosine-1-phosphate (S1P) sphingosine-1-phosphate receptors (S1PRs) FTY720 1-deoxiesfingolípidos 1-deoxiesfingosina 1- deoxiesfinganine 1-deoxiceramida Neuropatía periférica inducida por taxanos (TIPN) Receptores de esfingosina 1-fosfato (S1PR) Neurotoxicidad Neuroblastoma
title_short	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
title_full	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
title_fullStr	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
title_full_unstemmed	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
title_sort	Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy
dc.creator.fl_str_mv	Muñoz Gil, Susana
dc.contributor.advisor.none.fl_str_mv	Spassieva, Stefanka Vásquez Araque, Neil Aldrin
dc.contributor.author.none.fl_str_mv	Muñoz Gil, Susana
dc.contributor.orcid.spa.fl_str_mv	Muñoz Gil, Susana [0000000254305323]
dc.subject.ddc.spa.fl_str_mv	660 - Ingeniería química::666 - Cerámica y tecnologías afines
topic	660 - Ingeniería química::666 - Cerámica y tecnologías afines 1-deoxysphingolipids (deoxySL) 1-deoxysphingosine 1-deoxysphinganine 1-deoxyceramide taxane-induced peripheral neuropathy (TIPN) sphingosine-1-phosphate (S1P) sphingosine-1-phosphate receptors (S1PRs) FTY720 1-deoxiesfingolípidos 1-deoxiesfingosina 1- deoxiesfinganine 1-deoxiceramida Neuropatía periférica inducida por taxanos (TIPN) Receptores de esfingosina 1-fosfato (S1PR) Neurotoxicidad Neuroblastoma
dc.subject.proposal.eng.fl_str_mv	1-deoxysphingolipids (deoxySL) 1-deoxysphingosine 1-deoxysphinganine 1-deoxyceramide taxane-induced peripheral neuropathy (TIPN) sphingosine-1-phosphate (S1P) sphingosine-1-phosphate receptors (S1PRs) FTY720
dc.subject.proposal.spa.fl_str_mv	1-deoxiesfingolípidos 1-deoxiesfingosina 1- deoxiesfinganine 1-deoxiceramida Neuropatía periférica inducida por taxanos (TIPN) Receptores de esfingosina 1-fosfato (S1PR)
dc.subject.wikidata.none.fl_str_mv	Neurotoxicidad Neuroblastoma
description	Ilustraciones
publishDate	2023
dc.date.issued.none.fl_str_mv	2023
dc.date.accessioned.none.fl_str_mv	2024-05-28T18:35:18Z
dc.date.available.none.fl_str_mv	2024-05-28T18:35:18Z
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TM
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/86170
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/86170 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	eng
language	eng
dc.relation.indexed.spa.fl_str_mv	LaReferencia
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spelling	Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Spassieva, Stefanka2c9f7ee8a3d942a7699c481d7e5addd5Vásquez Araque, Neil Aldrinb738c93743b300229ba7dce362dc8bc0Muñoz Gil, Susanab4597bbf07f4d06d34228bbb95d25d25Muñoz Gil, Susana [0000000254305323]2024-05-28T18:35:18Z2024-05-28T18:35:18Z2023https://repositorio.unal.edu.co/handle/unal/86170Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/IlustracionesThe use of chemotherapeutic agents such as taxanes, paclitaxel, and docetaxel, can cause neurotoxicity leading to Taxane-Induced Peripheral Neuropathy (TIPN) side effect. Previous research showed that sphingolipid (SL) metabolism was deregulated in TIPN. Specifically, the research showed an overproduction of atypical SL called 1-deoxysphingolipids (deoxySL) as a result of taxane treatment. The deoxySL have a slower degradation compared to the canonical SL, and when produced in excess, tend to accumulate, leading to neurotoxicity. The first goal of this research aimed at evaluating the neurotoxicity of individual deoxySL. We tested the toxicity of the individual deoxySL, in two neuroblastoma cell model, KCNR and Neuro2a by LDH cytotoxicity assay and by measuring morphological changes such as neurite swellings and cell rounding. Our results showed that 1-deoxysphinganine was the most cytotoxic of the 1-deoxysphingoid bases for both neuroblastoma cell lines, KCNR and N2a. DeoxySL treatment showed morphological changes. In differentiated N2a cells, the individual deoxySL induced neurite swellings at different time points or concentrations, suggesting that neurite swellings are likely a transient neurotoxic effect of deoxySL treatment. In KCNR neuroblastoma cells, the neurotoxic effects of deoxySL manifested in rounding of the cells’ bodies. Differences in cytotoxicity and neurite swellings were evidenced in the neurotoxic effects of the 1-deoxysphingoid bases and the 1-deoxyceramides, also in the double bond isomers 4E and 14Z 1-deoxysphingosines and 1-deoxyceramides. In addition, to test if the neurotoxic effects of deoxySL include effects on actin organization we used immunocytochemistry and live cell fluorescent imaging to visualize cellular actin architecture. Our results showed that in KCRN cells, deoxySL caused actin stress fibers disruption and re-organization to cell cortex. In primary dorsal root ganglia (DRG) neurons, neurite swellings were also evidenced, and neurite actin distribution. Additionally, we addressed the question if deoxySLs’ neurotoxicity is mediated by the sphingosine-1-phosphate receptors (S1PRs) We utilized a broader functional antagonist of S1PRs, FTY720, in combination with deoxySL to identify if there is attenuation of neuritic damage caused by deoxySL. Results for the FTY720 treatment did not show attenuation of neuritic damage due to deoxySL, suggesting that other mechanisms than S1P signaling, might interact or modulate deoxySL toxicity. In conclusion, neurotoxicity of deoxySL resulted in cytotoxicity, and morphological changes such as neurite swellings and rounding cells, in neuroblastoma cell lines, including actin re-organization in KCNR cells and DRG neurons. S1P signaling and other mechanisms that might be implicated in deoxySL neurotoxicity must continue to be studied.El uso de agentes quimioterapéuticos como taxanos, paclitaxel y docetaxel, puede causar neurotoxicidad que conlleva a un efecto secundario de neuropatía periférica inducida por taxanos (TIPN). Investigaciones anteriores mostraron que el metabolismo de los esfingolípidos (SL) estaba desregulado en la TIPN. Esta investigación mostró una sobreproducción de SL atípico llamado 1-deoxiesfingolípidos (deoxySL) como resultado del tratamiento con taxanos. Los deoxySL tienen una degradación más lenta en comparación con los SL canónicos y, cuando se producen en exceso, tienden a acumularse, lo que lleva a la neurotoxicidad. El primer objetivo de esta investigación consistía en evaluar la neurotoxicidad de los deoxySL individuales. Probamos la toxicidad de los deoxySL individuales, en dos modelos de células de neuroblastoma, KCNR y Neuro2a mediante el ensayo de citotoxicidad LDH y midiendo los cambios morfológicos, como las hinchazones de neuritas y el redondeo celular. Nuestros resultados mostraron que la 1-deoxiesfinganina fue la más citotóxica de las bases 1-deoxiesfingoide para ambas líneas celulares de neuroblastoma, KCNR y N2a. El tratamiento con DeoxySL mostró cambios morfológicos. En células N2a diferenciadas, los deoxySL individuales indujeron a hinchazones de neuritas en diferentes momentos o concentraciones, lo que sugiere que las hinchazones de neuritas son probablemente un efecto neurotóxico transitorio del tratamiento con deoxySL. En las células de neuroblastoma KCNR, los efectos neurotóxicos de deoxySL se manifestaron en el redondeo de los cuerpos de las células. Las diferencias en la citotoxicidad y la hinchazón de las neuritas se evidenciaron en los efectos neurotóxicos de las bases 1-deoxiesfingoide y las 1-deoxiceramidas, también en los isómeros de doble enlace 4E y 14Z 1-deoxiesfingosinas y 1-deoxiceramidas. Además, para probar si los efectos neurotóxicos de deoxySL incluyen efectos sobre la organización de actina, utilizamos inmunocitoquímica e imágenes fluorescentes de células vivas para visualizar la arquitectura de actina celular. Nuestros resultados mostraron que en las células KCRN, deoxySL provocó la disrupción y reorganización de las fibras de estrés de actina en la corteza celular. En las neuronas DRG por sus siglas en inglés (Dorsal Root Ganglia), también se evidenciaron hinchazones de neuritas y distribución de actina de neuritas. Además, abordamos la cuestión de si la neurotoxicidad de deoxySL está mediada por los receptores de esfingosina-1-fosfato (S1PR). Utilizamos un antagonista funcional más amplio de S1PR, FTY720, en combinación con los deoxySL para identificar si hay atenuación del daño neurítico causado por los deoxySL. Los resultados del tratamiento con FTY720 no mostraron atenuación del daño neurítico causado por los deoxySL, lo que sugiere que otros mecanismos, además de la señalización de S1P podrían interactuar o modular la toxicidad de los deoxySL. En conclusión, la neurotoxicidad de los deoxySL resultó en citotoxicidad y cambios morfológicos tales como hinchazones de neuritas y células redondeadas en líneas celulares de neuroblastoma, incluida la reorganización de actina en células KCNR y neuronas DRG. La señalización de S1P y otros mecanismos que podrían estar implicados en la neurotoxicidad de los deoxySL deben continuar estudiándose.MaestríaMagister en Ciencias- BiotecnologíaÁrea curricular Biotecnología75 páginasengUniversidad Nacional de ColombiaMedellín - Ciencias - Maestría en Ciencias - BiotecnologíaFacultad de CienciasMedellín, ColombiaUniversidad Nacional de Colombia - Sede Medellín660 - Ingeniería química::666 - Cerámica y tecnologías afines1-deoxysphingolipids (deoxySL)1-deoxysphingosine1-deoxysphinganine1-deoxyceramidetaxane-induced peripheral neuropathy (TIPN)sphingosine-1-phosphate (S1P)sphingosine-1-phosphate receptors (S1PRs)FTY7201-deoxiesfingolípidos1-deoxiesfingosina1- deoxiesfinganine1-deoxiceramidaNeuropatía periférica inducida por taxanos (TIPN)Receptores de esfingosina1-fosfato (S1PR)NeurotoxicidadNeuroblastomaNeurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathyNeurotoxicidad de los deoxyesfingolipidos en un modelo in vitro de neuropatía periférica inducida por taxanosTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMLaReferenciaAcevedo, J. 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Diabetes, 63(4), 1326–1339. https://doi.org/10.2337/DB13-1042Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathyInvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/86170/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1037652261.20241.pdf1037652261.20241.pdfTesis de Maestría en Ciencias - Biotecnologíaapplication/pdf1439149https://repositorio.unal.edu.co/bitstream/unal/86170/2/1037652261.20241.pdf7f48fb462ebc93acc5ea49dcbc3f95c1MD52THUMBNAIL1037652261.20241.pdf.jpg1037652261.20241.pdf.jpgGenerated Thumbnailimage/jpeg4760https://repositorio.unal.edu.co/bitstream/unal/86170/3/1037652261.20241.pdf.jpg326f637b38c24ffe6b8f2e52518fc56cMD53unal/86170oai:repositorio.unal.edu.co:unal/861702024-08-23 23:11:33.786Repositorio Institucional Universidad Nacional de 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

Neurotoxicity of deoxysphingolipids in an in vitro model of taxane induced peripheral neuropathy

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