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Inflammopharmacology

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Open Access 20-06-2023 | Cytostatic Therapy | Original Article

Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study

Authors: Prasad Kisan Tambe, H. S. Qsee, Sanjay Bharati

Published in: Inflammopharmacology | Issue 4/2023

Abstract

Background

Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity.

Methods

Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress.

Results

5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO.

Conclusion

Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy.

Al-Asmari AK, Khan AQ, Al-Qasim AM, Al-Yousef Y (2015) Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators. Toxicol Rep 2:908–916PubMedPubMedCentral

Ambrož M, Lněničková K, Matoušková P, Skálová L, Boušová I (2019) Antiproliferative effects of hop-derived prenylflavonoids and their influence on the efficacy of oxaliplatin, 5-fluorouracil and irinotecan in human colorectalC cells. Nutrients https://doi.org/10.3390/nu11040879

Atiq A, Shal B, Naveed M, Khan A, Ali J, Zeeshan S, Khan S (2019) Diadzein ameliorates 5-fluorouracil-induced intestinal mucositis by suppressing oxidative stress and inflammatory mediators in rodents. Eur J Pharmacol 843:292–306PubMed

Avila TV, Menezes-Garcia Z, do Nascimento Arifa RD, Soriani FM, Machado ADMV, Teixeira MM, Souza DG (2022) Mitochondrial DNA as a possible ligand for TLR9 in irinotecan-induced Small Intestinal Mucositis. Immunol Investig 51(6):1756–1771

Babu D, Leclercq G, Goossens V, Berghe TV, Van Hamme E, Vandenabeele P, Lefebvre RA (2015) Mitochondria and NADPH oxidases are the major sources of TNF-α/cycloheximide-induced oxidative stress in murine intestinal epithelial MODE-K cells. Cell Signal 27(6):1141–1158PubMed

Bharati S, Shetty S (2020) Mitochondria-Targeted antioxidants and cancer. Handbook of Oxidative Stress in Cancer: Mechanistic Aspects, 1–22

Bhardwaj P, Goswami N, Narula P, Jain CK, Mathur A (2018) Zinc oxide nanoparticles (ZnO NP) mediated regulation of bacosides biosynthesis and transcriptional correlation of HMG-CoA reductase gene in suspension culture of Bacopa monnieri. Plant Physiol Biochem 130:148–156. https://doi.org/10.1016/j.plaphy.2018.07.001CrossRefPubMed

Bindhumol V, Chitra KC, Mathur PP (2003) Bisphenol a induces reactive oxygen species generation in the liver of male rats. Toxicology 188(2–3):117–124. https://doi.org/10.1016/S0300-483X(03)00056-8CrossRefPubMed

Boeing T, Gois MB, de Souza P, Somensi LB, Sant´ Ana DDMG, da Silva LM (2021) Irinotecan-induced intestinal mucositis in mice: a histopathological study. Cancer chemother Pharmacol 87: 327–336PubMed

Bowen JM, Stringer AM, Gibson RJ, Yeoh AS, Hannam S, Keefe DM (2007) VSL# 3 probiotic treatment reduces chemotherapy-induced diarrhoea and weight loss. Cancer Biol Ther 6(9):1445–1450

Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Investig Dermatol 78(3):206–209PubMed

Chami B, Martin NJ, Dennis JM, Witting PK (2018) Myeloperoxidase in the inflamed colon: A novel target for treating inflammatory bowel disease. Arch Biochem Biophys 645:61–71PubMed

Chamseddine AN, Ducreux M, Armand JP, Paoletti X, Satar T, Paci A, Mir O (2019) Intestinal bacterial β-glucuronidase as a possible predictive biomarker of irinotecan-induced diarrhea severity. Pharmacol Ther 199:1–15PubMed

Chen KJ, Huang YL, Kuo LM, Chen YT, Hung CF, Hsieh PW (2022) Protective role of casuarinin from Melastoma malabathricum against a mouse model of 5-fluorouracil–induced intestinal mucositis: Impact on inflammation and gut microbiota dysbiosis. Phytomedicine 101:154092PubMed

Diba M, Seghatoleslam A, Namavari M, Sh A, Babaei Z, Akmali M (2021) Potential protective role of cyrtopodion scabrum in antioxidant parameters in serum and liver of rats with 5-FU-induced oxidative damage. Arch Razi Inst 76(1):95PubMedPubMedCentral

El-Beshbishy HA, Aly HAA, El-Shafey M (2013) Lipoic acid mitigates bisphenol A-induced testicular mitochondrial toxicity in rats. Toxicol Ind Health 29(10):875–887. https://doi.org/10.1177/0748233712446728CrossRefPubMed

Ellman GL (1959) Tissue Su~yd~l Groups. Arch Biochem Biophys 82:70–77

Fujimoto S, Miyazaki M, Kitsukawa Y, Okui K, Hosaka T, Karaki SI, Kawanomoto S (1983) Clinical evaluation of prolonged chemotherapy combined with induction of hepatic drug-metabolizing enzymes as an adjuvant for treating patients with gastric cancer. Jpn J Surg 13:486–492PubMed

Gawish SAAE, Omar N, Sarhan N (2013) Histological and ultrastructural study of 5-fluorouracil induced small intestinal mucosal damage in rats. Asian J Cell Biol 8(1):1–21

Gui MX, Huang B, Peng J, Chen X, Muthu R, Gao Y, Lin JM, Babao Dan (2022) (八宝丹) Alleviates 5-Fluorouracil-Induced Intestinal Damage via Wnt/β-Catenin Pathway. Chinese J Integ Med 1–7

Hu Q, Ren H, Ren J, Liu Q, Wu J, Wu X, Li G, Wang G, Gu G, Guo K et al (2018) Released mitochondrial DNA following intestinal ischemia reperfusion induces the inflammatory response and gut barrier dysfunction. Sci Rep 8:7350PubMedPubMedCentral

Hudita A, Radu IC, Galateanu B, Ginghina O, Herman H, Balta C, Hermenean A (2021) Bioinspired silk fibroin nano-delivery systems protect against 5-FU induced gastrointestinal mucositis in a mouse model and display antitumor effects on HT-29 colorectal cancer cells in vitro. Nanotoxicology 15(7):973–994PubMed

Ishibashi M, Ishii M, Yamamoto S, Mori Y, Shimizu S (2021) Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice. Eur J Pharmacol 891:173671PubMed

Jardi F, Kelly C, Teague C, Fowler-Williams H, Sevin DC, Rodrigues D, Pritchard DM (2022) Mouse organoids as an in vitro tool to study the in vivo intestinal response to cytotoxicants. Arch Toxicol 90:235–254

Ji Y, Zhou W, Tan W, Chen Z, Lu H, You Y, Zhao X (2022) Protective effect of polysaccharides isolated from the seeds of Cuscuta chinensis Lam on 5-fluorouracil-induced intestinal mucositis in mice. Acta Cirúrgica Brasileira. https://doi.org/10.1590/acb370204CrossRefPubMedPubMedCentral

Jiang Q, Yin J, Chen J, Ma X, Wu M, Liu G, Yin Y (2020) Mitochondria-targeted antioxidants: a step towards disease treatment. Oxidat Med Cellular Longev. https://doi.org/10.1155/2020/8837893CrossRef

Keshtzar E, Khodayar MJ, Javadipour M, Ghaffari MA, Bolduc DL, Rezaei M (2016) Ellagic acid protects against arsenic toxicity in isolated rat mitochondria possibly through the maintaining of complex II. Hum Exp Toxicol 35(10):1060–1072. https://doi.org/10.1177/0960327115618247CrossRefPubMed

Koli VK, Natarajan K, Isaac B, Selvakumar D, Abraham P (2014) Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. Hum Exp Toxicol 33(10):1051–1065

Lee CS, Ryan EJ, Doherty GA (2014) Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation. World J Gastroenterol: WJG 20(14):3751PubMedPubMedCentral

Legha SS, Wang YM, Mackay B, Ewer M, Hortobagyi GN, Benjamin RS, Ali MK (1982) Clinical and pharmacologic investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann N Y Acad Sci 393:411–418PubMed

Liu T, Zhang L, Joo D, Sun SC (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2(1):1–9

Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338PubMed

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT. J Biol Chem. https://doi.org/10.1016/S0021-9258(19)52451-6CrossRefPubMed

Macnicol PK, Jacobsen JV (1992) Endosperm acidification and related metabolic changes in the developing barley grain. Plant Physiol. https://doi.org/10.1104/pp.98.3.1098CrossRefPubMedPubMedCentral

Mcfarland VA, Inouye LS, Lutz CH, Jarvis AS, Clarke JU, Mccant DD (1999) Biomarkers of oxidative stress and genotoxicity in livers of field-collected brown bullhead. Ameiurus nebulosus. Environ. Contam. Toxicol 37:236–241

Minakami S, Ringler RL, Singer TP (1962) Studies on the respiratory chain-linked dihydrodiphosphopyridine nucleotide dehydrogenase I Assay of the enzyme in particulate and in soluble preparations*. J Biol Chem 237:569–576PubMed

Natarajan K, Abraham P, Isaac B (2016) Effect of methotrexate treatment on iNOS gene expression, protein tyrosine nitration protein cysteine nitrosylation, and the activities of mitochondrial enzymes in the small. Asian J PharmacolToxicol 1

Natarajan K, Abraham P, Kota R (2017) Activation of the mitochondrial apoptotic pathway contributes to methotrexate-induced small intestinal injury in rats. Cell Biochem Funct 35(7):378–391PubMed

Ndrepepa G (2019) Myeloperoxidase–A bridge linking inflammation and oxidative stress with cardiovascular disease. Clin Chim Acta 493:36–51PubMed

Pearl W, Cascarano J, Zweifach BW (1962) M ICRODetermination of cytochrome oxidase in rat tissues by the oxidation of n-phenyl-p-phenylenediamine or ascorbic acid. J Histochem Cytochem. https://doi.org/10.1177/11.1.102CrossRef

Peltzer N, Walczak H (2019) Cell death and inflammation–a vital but dangerous liaison. Trends Immunol 40(5):387–402PubMed

Qsee HS, Tambe PK, De S, Bharati S (2022) MitoQ demonstrates connexin- and p53-mediated cancer chemoprevention in N-nitrosodiethylamine-induced hepatocarcinogenesis rodent model. Toxicol Appl Pharmacol. https://doi.org/10.1016/j.taap.2022.116211CrossRefPubMed

Raffa RB, Tallarida RJ (2011) Chemo fog: cancer chemotherapy-related cognitive impairment. Vol. 678. Springer Science & Business Media

Rapa SF, Magliocca G, Pepe G, Amodio G, Campiglia P, Marzocco S (2021) Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes. Antioxidants 10:203PubMedPubMedCentral

Redza-Dutordoir M, Averill-Bates DA (2021) Interactions between reactive oxygen species and autophagy: special issue: death mechanisms in cellular homeostasis. Biochimica et Biophysica Acta (BBA)-Molecular Cell Res 1868(8): 119041

Ribeiro RA, Wanderley CW, Wong DV, Mota JMS, Leite CA, Souza MH, Lima-Junior RC (2016) Irinotecan-and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol 78:881–893PubMed

Rocha VCJ, França LSDA, de Araújo CF, Ng AM, de Andrade CM, Andrade AC, Pontes-de-Carvalho LC (2016) Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice. Cancer Chemother Pharmacol 77:659–662PubMed

Rodrigues D, de Souza T, Coyle L, Di Piazza M, Herpers B, Ferreira S, de Kok TM (2021) New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol 95:2691–2718PubMedPubMedCentral

Sacks B, Onal H, Martorana R, Sehgal A, Harvey A, Wastella C, Chen Q (2021) Mitochondrial targeted antioxidants, mitoquinone and SKQ1, not vitamin C, mitigate doxorubicin-induced damage in H9c2 myoblast: pretreatment vs. co-treatment. BMC Pharmacol Toxicol 22:1–16

Santandreu FM, Valle A, Oliver J, Roca P (2011) Resveratrol potentiates the cytotoxic oxidative stress induced by chemotherapy in human colon cancer cells. Cell Physiol Biochem 28(2):219–228PubMed

Shetty S, Kumar R, Bharati S (2019) Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine-induced hepatocarcinogenesis in mice. Free Radical Biol Med 136:76–86. https://doi.org/10.1016/j.freeradbiomed.2019.03.037CrossRef

Shetty S, Anushree U, Kumar R, Bharati S (2021) Mitochondria-targeted antioxidant, mito-TEMPO mitigates initiation phase of N-Nitrosodiethylamine-induced hepatocarcinogenesis. Mitochondrion 58:123–130PubMed

Stanbury DM (2022) The principle of detailed balancing, the iron-catalyzed disproportionation of hydrogen peroxide, and the Fenton reaction. Dalton Trans 51(6):2135–2157PubMed

Stringer AM, Al-Dasooqi N, Bowen JM, Tan TH, Radzuan M, Logan RM, Gibson RJ (2013) Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases. Support Care Cancer 21:1843–1852PubMed

Sun L, Shen W, Liu Z, Guan S, Liu J, Ding S (2010) Endurance exercise causes mitochondrial and oxidative stress in rat liver: effects of a combination of mitochondrial targeting nutrients. Life Sci 86(1–2):39–44. https://doi.org/10.1016/j.lfs.2009.11.003CrossRefPubMed

Tabassum H, Parvez S, Pasha ST, Banerjee BD, Raisuddin S (2010) Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria. Food Chem Toxicol 48(7):1973–1979. https://doi.org/10.1016/j.fct.2010.04.047CrossRefPubMed

Toyama S, Shimoyama N, Szeto HH, Schiller PW, Shimoyama M (2018) Protective effect of a mitochondria-targeted peptide against the development of chemotherapy-induced peripheral neuropathy in mice. ACS Chem Neurosci 9(7):1566–1571PubMed

Valavanidis A, Vlachogianni T, Fiotakis C (2009) 8-hydroxy-2′-deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C 27(2):120–139

Wei L, Wang J, Yan L, Shui S, Wang L, Zheng W, Zheng L (2020) Sulforaphane attenuates 5-fluorouracil induced intestinal injury in mice. Journal of Functional Foods 69:103965

Xia J, Chen J, Vashisth MK, Ge Y, Dai Q, He S, Wang XB (2022) Metformin ameliorates 5-fluorouracil-induced intestinal injury by inhibiting cellular senescence, inflammation, and oxidative stress. Int Immunopharmacol 113:109342PubMed

Xu X, Muller JG, Ye Y, Burrows CJ (2008) DNA− protein cross-links between guanine and lysine depend on the mechanism of oxidation for formation of C5 vs C8 guanosine adducts. J Am Chem Soc 130(2):703–709PubMed

Yanez JA, Teng XW, Roupe KA, Fariss MW, Davies NM (2003) Chemotherapy induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and cyclooxygenase-2. J Pharm Pharm Sci 6(3):308–314PubMed

Yim SK, Kim KM, Lee CH, Song EK, Lee SO, Kim SW, Lee ST (2021) The superoxide dismutase mimetic M40403, improves 5-fluorouracil-induced small intestinal mucositis in a mouse model. In Vivo 35(3):1485–1497PubMedPubMedCentral

Yu QQ, Zhang H, Guo Y, Han B, Jiang P (2022) The intestinal redox system and its significance in chemotherapy-induced intestinal mucositis. Oxidat Med Cell Longev

Zhao G, Williams J, Washington MK, Yang Y, Long J, Townsend SD, Yan F (2022) 2’-Fucosyllactose ameliorates chemotherapy-induced intestinal mucositis by protecting intestinal epithelial cells against apoptosis. Cell Mol Gastroenterol Hepatol 13(2):441–457PubMed

Title: Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study
Authors: Prasad Kisan Tambe
H. S. Qsee
Sanjay Bharati
Publication date: 20-06-2023
Publisher: Springer International Publishing
Keyword: Cytostatic Therapy
Published in: Inflammopharmacology / Issue 4/2023
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-023-01261-6

At a glance: The STEP trials

Springer Medicine

Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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