Efecto protector de la silimarina y la mitoquinona (MitoQ) contra la hepatotoxicidad de las nanopartículas de puntos cuánticos de telururo de cadmio (CdTe QDs) en ratones

• Seda Şimşek Selcuk University, School of Medicine, Department of Histology and Embryology. Konya, Türkiye
• Merve Solmaz Selcuk University, School of Medicine, Department of Histology and Embryology. Konya, Türkiye
• İsmail Hakkı Nur Erciyes University, School of Veterinary, Department of Anatomy. Kayseri, Türkiye
• Muslu Kazım Körez Selcuk University, School of Medicine, Department of Biostatistics. Konya, Türkiye
• Nejat Ünlükal Selcuk University, School of Medicine, Department of Histology and Embryology. Konya, Türkiye
• Ender Erdoğan Selcuk University, School of Medicine, Department of Histology and Embryology. Konya, Türkiye

DOI: https://doi.org/10.52973/rcfcv-e34481

Palabras clave: Antioxidante, punto cuántico, mitoquinona, estrés oxidativo, silimarina

Resumen

Como consecuencia del creciente uso de puntos cuánticos (QD) y de la mayor exposición de los seres humanos a los mismos, el estudio de la toxicidad de las partículas se ha convertido en una cuestión importante. En este estudio se investigó la actividad protectora de la silimarina y la mitoquinona (MitoQ), conocidas por sus propiedades antioxidantes, sobre los cambios histopatológicos y bioquímicos observados en el hígado de ratones tratados con CdTe QDs. Se dividieron aleatoriamente 26 ratones suizos macho en cuatro grupos: Control (G1), CdTe QDs (G2), silimarina + CdTe QDs (G3), mitoquinona + CdTe QDs (G4) grupos de aplicación. Los animales fueron sacrificados 24 horas (h) después de las inyecciones y se obtuvieron imágenes de microscopía hiperespectral. Según los resultados de ICP–MS, los CdTe QDs inyectados a través de la vena de la cola se acumularon en el hígado al cabo de 24 h y causaron daños tisulares según el examen de hematoxilina y eosina, y se observó una mejor conservación con el pretratamiento antioxidante. Los resultados de la inmunofluorescencia mostraron un aumento de la inflamación y la apoptosis en el grupo de QDs. Se observó que la silimarina y la mitoquinona disminuyeron los niveles de anti–MMP–9, anti–IL–10, anti–IL–1b, anti–TNF–α y anti–caspasa–9, la proporción de células TUNEL positivas y los niveles de MDA hepáticos. No hubo diferencias significativas en los niveles séricos de TAS (P=0.509), TOS (P=0.588), pero los antioxidantes también aumentaron los niveles tisulares de SOD y CAT. Los antioxidantes no tuvieron un efecto significativo en los niveles de anti–MT–MMP2 y anti–caspasa–8 (P<0.001). En conclusión, se demostró que el pretratamiento de ratones tratados con CdTe QD con silimarina y mitoquinona, que tienen fuertes propiedades antioxidantes, puede reducir el estrés oxidativo en el tejido hepático y puede tener un efecto protector gracias a la reducción de la apoptosis y la inflamación.

Citas

Yong KT, Law WC, Hu R, Ye L, Liu L, Swihart MT, Prasad PN. Nanotoxicity assessment of quantum dots: from cellular to primate studies. Chem. Soc. Rev. [Internet]. 2013; 42(3):1236–1250. doi: https://doi.org/gs9p5s

Pandit A, Sachdeva T, Bafna P. Drug–induced hepatotoxicity: a review. J. Appl. Pharm. Sci. [Internet]. 2012; 2(5):233–243.doi: https://doi.org/g8tnf6

Chen S, Chen Y, Chen Y, Yao Z. InP·ZnS–1 quantum dots cause inflammatory response in macrophages through endoplasmic reticulum stress and oxidative stress. Int. J. Nanomedicine. [Internet]. 2019; 14:9577–9586. doi: https://doi.org/g8tnf7

Sharma V, Anderson D, Dhawan A. Zinc oxide nanoparticles induce oxidative DNA damage and ROS–triggered mitochondria mediated apoptosis in human liver cells (HepG2). Apoptosis [Internet]. 2012;17(8):852–870. doi: https://doi.org/f32tfs

Vargas–Mendoza N, Madrigal–Santillán E, Morales–González A, Esquivel–Soto J, Esquivel–Chirino C, García–Luna YG–RM, Gayosso–de–Lucio JA, Morales–González JA. Hepatoprotective effect of silymarin. World J. Hepatol. [Internet]. 2014; 6(3):144–149. doi: https://doi.org/ggj6rw

Chen IS, Chen YC, Chou CH, Chuang RF, Sheen LY, Chiu CH. Hepatoprotection of silymarin against thioacetamide–induced chronic liver fibrosis. J. Sci. Food. Agric. [Internet]. 2012; 92(7):1441–1447. doi: https://doi.org/ https://doi.org/c4s25b

Zholobenko A, Modriansky M. Silymarin and its constituents in cardiac preconditioning. Fitoterapia [Internet]. 2014; 97(1):122–132. doi: https://doi.org/f6pzgb

Smith RA, Porteous CM, Gane AM, Murphy MP. Delivery of bioactive molecules to mitochondria in vivo. Proc. Natl. Acad. Sci. USA. [Internet]. 2003; 100(9):5407–5412. doi: https://doi.org/c8rqxg

Murphy MP, Smith RA. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol. [Internet]. 2007; 47:629–656. doi: https://doi.org/d342dn

Yan M, Zhang Y, Xu K, Fu T, Qin H, Zheng X. An in vitro study of vascular endothelial toxicity of CdTe quantum dots. Toxicology [Internet]. 2011; 282(3):94–103. doi: https://doi.org/cnxkz7

Li X, Zhang H, Sun F. CdSe·ZnS–1 quantum dots exhibited nephrotoxicity through mediating oxidative damage and inflammatory response. Aging [Internet]. 2020; 13(8):12194–12206. doi: https://doi.org/g8tnf8

Liu Q, Wu D, Ma Y, Cao Y, Pang Y, Tang M, Pu Y, Zhang T. Intracellular reactive oxygen species trigger mitochondrial dysfunction and apoptosis in cadmium telluride quantum dots–induced liver damage. NanoImpact [Internet]. 2022; 25:100392. doi: https://doi.org/gwkr79

Julshamn K, Maage A, Norli HS, Grobecker KH, Jorhem L, Fecher P. Determination of arsenic, cadmium, mercury, and lead by inductively coupled plasma/mass spectrometry in foods after pressure digestion: NMKL interlaboratory study. J. AOAC Int. [Internet]. 2007; 90(3):844–856. doi: https://doi.org/g8tnf9

Bancroft JD, Gamble M. Theory and practice of histological techniques. 6th ed. London: Churchill Livingstone; 2008. 725 p.

Arnao MB, Casas JL, del Río JA, Acosta M, García–Cánovas F. An enzymatic colorimetric method for measuring naringin using 2,2’–azino–bis–(3–ethylbenzthiazoline–6–sulfonic acid) (ABTS) in the presence of peroxidase. Anal. Biochem. [Internet]. 1990; 185(2):335–338. doi: https://doi.org/dmtpgv

Erel O. A new automated colorimetric method for measuring total oxidant status. Clin. Biochem. [Internet]. 2005; 38(12):1103–1111. doi: https://doi.org/dzjwc5

Du Y, Zhong Y, Dong J, Qian C, Sun S, Gao L, Yan D. The effect of PEG functionalization on the in vivo behavior and toxicity of CdTe quantum dots. RSC Adv. [Internet]. 2019; 9(22):12218–12225. doi: https://doi.org/g8tngc

Zhang T, Hu Y, Tang M, Kong L, Ying J, Wu T, Xue Y, Pu Y. Liver toxicity of cadmium telluride quantum dots (CdTe QDs) due to oxidative stress in vitro and in vivo. Int. J. Mol. Sci. [Internet]. 2015; 16(10):23279–23299. doi: https://doi.org/f7x28r

Lin CH, Yang MH, Chang LW, Yang CS, Chang H, Chang WH, Tsai MH, Wang CJ, Lin P. Cd/Se/Te–based quantum dot 705 modulated redox homeostasis with hepatotoxicity in mice. Nanotoxicology [Internet]. 2011; 5(4):650–663. doi: https://doi.org/c3cbgm

Su Y, Peng F, Jiang Z, Zhong Y, Lu Y, Jiang X, Huang Q, Fan C, Lee ST, He Y. In vivo distribution, pharmacokinetics, and toxicity of aqueous synthesized cadmium–containing quantum dots. Biomaterials [Internet]. 2011; 32(25):5855–5862. doi: https://doi.org/cdsnr7

Liu J, Erogbogbo F, Yong KT, Ye L, Liu J, Hu R, Chen H, Hu Y, Yang Y, Yang J, Roy I, Karker NA, Swihart MT, Prasad PN. Assessing clinical prospects of silicon quantum dots: studies in mice and monkeys. ACS Nano [Internet]. 2013; 7(8):7303–7310. doi: https://doi.org/f48p2q

Nurunnabi M, Khatun Z, Huh KM, Park SY, Lee DY, Cho KJ, Lee YK. In vivo biodistribution and toxicology of carboxylated graphene quantum dots. ACS Nano [Internet]. 2013;7(8):6858–6867. doi: https://doi.org/f48mz8

Yaghini E, Turner H, Pilling A, Naasani I, MacRobert AJ. In vivo biodistribution and toxicology studies of cadmium–free indium–based quantum dot nanoparticles in a rat model. Nanomedicine [Internet]. 2018; 14(8):2644–2655. doi: https://doi.org/gjqrpm

Figueira E, Branco D, Antunes SC, Gonçalves F, Freitas R. Are metallothioneins equally good biomarkers of metal and oxidative stress? Ecotoxicol. Environ. Saf. [Internet]. 2012; 84:185–190. doi: https://doi.org/f364ht

Lin CH, Chang LW, Chang H, Yang MH, Yang CS, Lai WH, Chang WH, Lin P. The chemical fate of the Cd/Se/Te–based quantum dot 705 in the biological system: toxicity implications. Nanotechnology [Internet]. 2009; 20(21):215101. doi: https://doi.org/d43skd

Sulaimon L, Afolab LO, Adisa RA, Ayankojo AG, Afolabi MO, Adewolu AM, Wan X. (2022). Pharmacological significance of MitoQ in ameliorating mitochondria–related diseases. Adv. Redox Res. [Internet]. 2022; 5:100037. doi: https://doi.org/g8tngd

Surai PF. Silymarin as a natural antioxidant: An overview of the current evidence and perspectives. Antioxidants [Internet]. 2015; 4(1):204–247. doi: https://doi.org/gddh4t

Parks WC, Wilson CL, López–Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. [Internet]. 2004; 4(8):617–629. doi: https://doi.org/bdzhqv

Hamada T, Fondevila C, Busuttil RW, Coito AJ. Metalloproteinase–9 deficiency protects against hepatic ischemia/reperfusion injury. Hepatology [Internet]. 2008; 47(1):186–198. doi: https://doi.org/fsmj2h

Serban AI, Stanca L, Sima C, Staicu AC, Zarnescu O, Dinischiotu A. Complex responses to Si quantum dots accumulation in carp liver tissue: Beyond oxidative stress. Chem. Biol. Interact. [Internet]. 2015; 239:56–66. doi: https://doi.org/f7rqmn

Chen L, Miao Y, Chen L, Jin P, Zha Y, Chai Y, Zheng F, Zhang Y, Zhou W, Zhang J, Wen L, Wang M. The role of elevated autophagy on the synaptic plasticity impairment caused by CdSe·ZnS–1 quantum dots. Biomaterials [Internet]. 2013; 34(38):10172–10181. doi: https://doi.org/f5j53v

Dai T, Li N, Liu L, Liu Q, Zhang Y. AMP–Conjugated Quantum Dots: Low Immunotoxicity Both In vitro and In vivo. Nanoscale Res. Lett. [Internet]. 2015;10(1):434. doi: https://doi.org/f78n5d

Chen T, Li L, Lin X, Yang Z, Zou W, Chen Y, Xu J, Liu D, Wang X, Lin G. In vitro and In vivo immunotoxicity of PEGylated Cd–free CuInS2/ZnS quantum dots. Nanotoxicology [Internet]. 2020;14(3):372–387. doi: https://doi.org/gs9p5t

Kara E, Coşkun T, Kaya Y, Yumuş O, Vatansever S, Var A. Effects of silymarin and pentoxifylline on matrix metalloproteinase–1 and –2 expression and apoptosis in experimental hepatic fibrosis. Curr. Ther. Res. Clin. Exp. [Internet]. 2008; 69(6):488–502. doi: https://doi.org/cwwn92

Ramakrishnan G, Jagan S, Kamaraj S, Anandakumar P, Devaki T. Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases–2 and 9 in rat liver carcinogenesis. Invest. New Drugs [Internet]. 2009;27(3):233–240. doi: https://doi.org/fgv7ts

Kanawati GM, Al–Khateeb IH, Kandil YI. Arctigenin attenuates CCl4–induced hepatotoxicity through suppressing matrix metalloproteinase–2 and oxidative stress. Egyptian Liver J. [Internet]. 2021; 11(1):1–7. doi: https://doi.org/g58728

Wang J, Sun H, Meng P, Wang M, Tian M, Xiong Y, Zhang X, Huang P. Dose and time effect of CdTe quantum dots on antioxidant capacities of the liver and kidneys in mice. Int. J. Nanomed. [Internet]. 2017; 2017(12):6425–6435. doi: https://doi.org/gbv8fg

Negahdary M, Ezhgi M, Ajdary M. Effects of Silymarin on oxidative stress markers in rats treated with magnesium oxide nanoparticles. Annu. Res. Rev. Biol. [Internet]. 2014; 5(3):254–261. doi: https://doi.org/g8tngf

Zhou J, Wang H, Shen R, Fang J, Yang Y, Dai W, Zhu Y, Zhou M. Mitochondrial–targeted antioxidant MitoQ provides neuroprotection and reduces neuronal apoptosis in experimental traumatic brain injury possibly via the Nrf2–ARE pathway. Am. J. Transl. Res. [Internet]. 2018 [cited 24 May. 2024]; 10(6):1887–1889. Available in: https://goo.su/PK4SWh

Tabet M, El–Kurdi M, Haidar MA, Nasrallah L, Reslan MA, Shear D, Shear D, Pandya JD, El–Yazbi AF, Sabra M, Mondello S, Mechref Y, Shaito A, Wang KK, El–Khoury R, Kobeissy F. Mitoquinone supplementation alleviates oxidative stress and pathologic outcomes following repetitive mild traumatic brain injury at a chronic time point. Exp. Neurol. [Internet]. 2022; 351:113987. doi: https://doi.org/gn9pbw

Turkseven S, Bolognesi M, Brocca A, Pesce P, Angeli P, Di Pascoli M. Mitochondria–targeted antioxidant mitoquinone attenuates liver inflammation and fibrosis in cirrhotic rats. Am. J. Physiol. Gastrointest. Liver. Physiol. [Internet]. 2020; 318(2):G298–G304. doi: https://doi.org/g664sp