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Neuroprotective properties of exosomes and chitosan nanoparticles of Tomafran, a bioengineered tomato enriched in crocins |
| Mikel Etxebeste-Mitxeltorena1, Enrique Niza2,3, Cristián Martinez Fajardo2, Carmen Gil1, Lourdes Gómez-Gómez2,3, Ana Martinez1,4, Oussama Ahrazem2,5 |
1. Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, C/Ramiro de Maeztu, 9, 28040, Madrid, Spain;
2. Instituto Botánico, Universidad de Castilla-La Mancha, Campus Universitario s/n, 02071, Albacete, Spain;
3. Facultad de Farmacia, Departamento de Ciencia y Tecnología Agroforestal y Genética, Universidad de Castilla-La Mancha, Campus Universitario s/n, 02071, Albacete, Spain;
4. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031, Madrid, Spain;
5. Escuela Técnica Superior de Ingeniería Agronómica y de Montes y Biotecnología. Departamento de Ciencia y Tecnología Agroforestal y Genética, Universidad de Castilla-La Mancha, Albacete, Spain |
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Abstract Saffron has many pharmacological properties in addition to being a frequently used food seasoning. Crocin and picrocrocin which accumulate in saffron stigma, are responsible for these pharmacological properties. These natural products have health‐promoting effects for the prevention and treatment of numerous diseases, including age‐related cognitive and memory disfunction. Currently, crocin and picrocrocin are obtained from saffron, considered as the spice with the highest price in the market. To develop an efficient and low‐cost approach to producing these compounds with high bioactivity, biosynthetic genes isolated from saffron can be exploited in the metabolic engineering of heterologous hosts and the production of crocins in productive crop plants. Recently, we engineered tomato fruit producing crocins (Tomafran). In this study, we demonstrated that crocin-rich extract, encapsulated in chitosan or in exosomes may function as a neuroprotective strategy. Crocins contained in the Tomafran extracts and much lower doses in chitosan nanoparticles or exosomes were enough to rescue the neuroblastoma cell line SH-SY5Y after damage caused by okadaic acid. Our results confirm the neuroprotective effect of Tomafran and its exosomes that may be useful for the delay or prevention of neurodegenerative disorders such as Alzheimer’s disease.
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| Keywords
Alzheimer’s disease
Saffron
Tomato
Crocins
Tomafran
Neuroprotection
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| Fund:This work was supported by grants BIO2016-77000-R, PIB2020-114761RB-I00 and FJC2021-046632-I (to M.E.) from the Ministerio de Ciencia e Innovación (MCIN), SBPLY/17/180501/000234, and SBPLY/21/180501/000012 from the Junta de Comunidades de Castilla-La Mancha (co-financed European Union FEDER funds) to LGG and OA. |
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Corresponding Authors:
Ana Martinez,E-mail:Ana.martinez@cib.csic.es;Oussama Ahrazem,E-mail:Oussama.ahrazem@uclm.es
E-mail: Ana.martinez@cib.csic.es;Oussama.ahrazem@uclm.es
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Issue Date: 19 February 2024
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[1] Lamptey RN, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J. A review of the common neurodegenerative disorders: current therapeutic approaches and the potential role of nanotherapeutics. Int J Mol Sci. 2022;23(3):1851.
[2] Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer’s disease. The Lancet. 2021;397(10284):1577–90.
[3] Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, Bohr VA. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019;15(10):565–81.
[4] de la Fuente AG, Pelucchi S, Mertens J, Di Luca M, Mauceri D, Marcello E. Novel therapeutic approaches to target neurodegeneration. Br J Pharmacol. 2023;180(13):1651–73.
[5] Gregory J, Vengalasetti YV, Bredesen DE, Rao RV. Neuroprotective herbs for the management of Alzheimer’s disease. Biomolecules. 2021;11(4):543.
[6] Rodriguez-Concepcion M, Avalos J, Bonet ML, Boronat A, Gomez-Gomez L, Hornero-Mendez D, Limon MC, Melendez-Martinez AJ, Olmedilla-Alonso B, Palou A, Ribot J, Rodrigo MJ, Zacarias L, Zhu C. A global perspective on carotenoids: metabolism, biotechnology, and benefits for nutrition and health. Prog Lipid Res. 2018;70:62–93. https://doi.org/10.1016/j.plipres.2018.04.004I.
[7] Beltran JCM, Stange C. Apocarotenoids: a new carotenoid-derived pathway. Carotenoids Nat Biosynth Regul Funct. 2016;79:239–72.
[8] Xi L, Qian Z. Pharmacological properties of crocetin and crocin (digentiobiosyl ester of crocetin) from saffron. Nat Prod Commun. 2006. https://doi.org/10.1177/1934578X0600100.
[9] Ahrazem O, Diretto G, Rambla JL, Rubio-Moraga A, Lobato M, Frusciante S, Argandoña J, Presa S, Granell A, Gómez LGM. Engineering high levels of saffron apocarotenoids in tomato. Horticult Res. 2022;9:uhac074.
[10] Gomez Gomez L, Morote L, Frusciante S, Rambla JL, Diretto G, Niza E, Lopez-Jimenez AJ, Mondejar M, Rubio-Moraga A, Argandona J, Presa S, Martin-Belmonte A, Lujan R, Granell A, Ahrazem O. Fortification and bioaccessibility of saffron apocarotenoids in potato tubers. Front Nutr. 2022;9:1045979. https://doi.org/10.3389/fnut.2022.1045979I.
[11] Morote L, Lobato-Gómez M, Ahrazem O, Argandoña J, Olmedilla-Alonso B, López-Jiménez AJ, Diretto G, Cuciniello R, Bergamo P, Frusciante S. Crocins-rich tomato extracts showed enhanced protective effects in vitro. J Funct Foods. 2023;101: 105432.
[12] Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, Sinakos Z. Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies. J Agric Food Chem. 2012;60(24):6131–8.
[13] D’Onofrio G, Nabavi SM, Sancarlo D, Greco A, Pieretti S. Crocus sativus L. (Saffron) in Alzheimer’s disease treatment: bioactive effects on cognitive impairment. Curr Neuropharmacol. 2021;19(9):1606.
[14] Naqvi S, Panghal A, Flora S. Nanotechnology: a promising approach for delivery of neuroprotective drugs. Front Neurosci. 2020;14:494.
[15] Caprifico AE, Foot PJ, Polycarpou E, Calabrese G. Overcoming the blood-brain barrier: Functionalised chitosan nanocarriers. Pharmaceutics. 2020;12(11):1013.
[16] Cai Q, He B, Wang S, Fletcher S, Niu D, Mitter N, Birch PR, Jin H. Message in a bubble: shuttling small RNAs and proteins between cells and interacting organisms using extracellular vesicles. Annu Rev Plant Biol. 2021;72:497–524.
[17] Nemati M, Singh B, Mir RA, Nemati M, Babaei A, Ahmadi M, Rasmi Y, Golezani AG, Rezaie J. Plant-derived extracellular vesicles: a novel nanomedicine approach with advantages and challenges. Cell Commun Signal. 2022;20(1):69.
[18] Boban M, Leko MB, Miškić T, Hof PR, Šimić G. Human neuroblastoma SH-SY5Y cells treated with okadaic acid express phosphorylated high molecular weight tau-immunoreactive protein species. J Neurosci Methods. 2019;319:60–8.
[19] Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood–brain barrier. Eur J Med Chem. 2003;38(3):223–32.
[20] Crivori P, Cruciani G, Carrupt P-A, Testa B. Predicting blood- brain barrier permeation from three-dimensional molecular structure. J Med Chem. 2000;43(11):2204–16.
[21] Lautenschläger M, Sendker J, Hüwel S, Galla H, Brandt S, Düfer M, Riehemann K, Hensel A. Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier. Phytomedicine. 2015;22(1):36–44.
[22] Lechtenberg M, Schepmann D, Niehues M, Hellenbrand N, Wünsch B, Hensel A. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and σ1 (sigma-1) receptors. Planta Med. 2008;74(07):764–72.
[23] Trapani A, De Giglio E, Cafagna D, Denora N, Agrimi G, Cassano T, Gaetani S, Cuomo V, Trapani G. Characterization and evaluation of chitosan nanoparticles for dopamine brain delivery. Int J Pharm. 2011;419(1–2):296–307.
[24] Cortés H, Alcalá-Alcalá S, Caballero-Florán IH, Bernal-Chávez SA, Ávalos-Fuentes A, González-Torres M, González-Del Carmen M, Figueroa-González G, Reyes-Hernández OD, Floran B. A reevaluation of chitosan-decorated nanoparticles to cross the blood-brain barrier. Membranes. 2020;10(9):212.
[25] Mondéjar-López M, López-Jimenez AJ, Martínez JCG, Ahrazem O, Gómez-Gómez L, Niza E. Comparative evaluation of carvacrol and eugenol chitosan nanoparticles as eco-friendly preservative agents in cosmetics. Int J Biol Macromol. 2022;206:288–97.
[26] Hogan DE, Tian F, Malm SW, Kegel LL, Szabó LZ, Hunjan AS, Pemberton JE, Klimecki WT, Polt R, Maier RM. Biodegradability and toxicity of cellobiosides and melibiosides. J Surfactants Deterg. 2020;23(4):715–24.
[27] Ismail AF, Matsuura T. Progress in transport theory and characterization method of Reverse Osmosis (RO) membrane in past fifty years. Desalination. 2018;434:2–11.
[28] Mondéjar-López M, Rubio-Moraga A, López-Jimenez AJ, Martínez JCG, Ahrazem O, Gómez-Gómez L, Niza E. Chitosan nanoparticles loaded with garlic essential oil: a new alternative to tebuconazole as seed dressing agent. Carbohyd Polym. 2022;277: 118815.
[29] Lee B, Yoon S, Lee JW, Kim Y, Chang J, Yun J, Ro JC, Lee J-S, Lee JH. Statistical characterization of the morphologies of nanoparticles through machine learning based electron microscopy image analysis. ACS Nano. 2020;14(12):17125–33.
[30] Souza TG, Ciminelli VS, Mohallem NDS, editors. A comparison of TEM and DLS methods to characterize size distribution of ceramic nanoparticles. Journal of physics: conference series. IOP Publishing; 2016.
[31] Nowak A, Kojder K, Zielonka-Brzezicka J, Wróbel J, Bosiacki M, Fabiańska M, Wróbel M, Sołek-Pastuszka J, Klimowicz A. The use of Ginkgo biloba L. as a neuroprotective agent in the Alzheimer’s disease. Front Pharmacol. 2021;12: 775034.
[32] Chen Y-X, Cai Q. Plant exosome-like nanovesicles and their role in the innovative delivery of RNA therapeutics. Biomedicines. 2023;11(7):1806.
[33] Soo CY, Song Y, Zheng Y, Campbell EC, Riches AC, Gunn-Moore F, Powis SJ. Nanoparticle tracking analysis monitors microvesicle and exosome secretion from immune cells. Immunology. 2012;136(2):192–7.
[34] Kilasoniya A, Garaeva L, Shtam T, Spitsyna A, Putevich E, Moreno-Chamba B, Salazar-Bermeo J, Komarova E, Malek A, Valero M. Potential of plant exosome vesicles from grapefruit (Citrus×paradisi) and Tomato (Solanum lycopersicum) juices as functional ingredients and targeted drug delivery vehicles. Antioxidants. 2023;12(4):943.
[35] Yıldırım M, Ünsal N, Kabataş B, Eren O, Şahin F. Effect of Solanum lycopersicum and citrus limon–derived exosome-like vesicles on chondrogenic differentiation of adipose-derived stem cells. Appl Biochem Biotechnol. 2023. https://doi.org/10.1007/s12010-023-04491-0.
[36] Tieman D, Zhu G, Resende MF Jr, Lin T, Nguyen C, Bies D, Rambla JL, Beltran KS, Taylor M, Zhang B, Ikeda H, Liu Z, Fisher J, Zemach I, Monforte A, Zamir D, Granell A, Kirst M, Huang S, Klee H. A chemical genetic roadmap to improved tomato flavor. Science. 2017;355(6323):391–4. https://doi.org/10.1126/science.aal1556355/6323/391[pii]I.
[37] Morgan DM. Tetrazolium (MTT) assay for cellular viability and activity. Polyamine protocols. Humana Press; 1998. p. 179–84.
[38] Keawchaoon L, Yoksan R. Preparation, characterization and in vitro release study of carvacrol-loaded chitosan nanoparticles. Colloids Surf, B. 2011;84(1):163–71.
[39] Ahrazem O, Rubio-Moraga A, Berman J, Capell T, Christou P, Zhu C, Gomez-Gomez L. The carotenoid cleavage dioxygenase CCD2 catalysing the synthesis of crocetin in spring crocuses and saffron is a plastidial enzyme. N Phytol. 2016;209(2):650–63. https://doi.org/10.1111/nph.13609I. |
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