Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway

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aut.relation.endpage5967
aut.relation.issue11en_NZ
aut.relation.journalInternational Journal of Molecular Sciencesen_NZ
aut.relation.startpage5967
aut.relation.volume23en_NZ
aut.researcherHassouna, Amira
dc.contributor.authorEbrahim, Nen_NZ
dc.contributor.authorAl Saihati, HAen_NZ
dc.contributor.authorMostafa, Oen_NZ
dc.contributor.authorHassouna, Aen_NZ
dc.contributor.authorAbdulsamea, Sen_NZ
dc.contributor.authorAbd El Aziz M. El Gebaly, Een_NZ
dc.contributor.authorAbo-Rayah, NHen_NZ
dc.contributor.authorSabry, Den_NZ
dc.contributor.authorEl-Sherbiny, Men_NZ
dc.contributor.authorMadboly, AGen_NZ
dc.contributor.authorHussien, NIen_NZ
dc.contributor.authorSaadani, REHen_NZ
dc.contributor.authorEbrahim, HAen_NZ
dc.contributor.authorBadr, OAMen_NZ
dc.contributor.authorElsherbiny, NMen_NZ
dc.contributor.authorSalim, RFen_NZ
dc.date.accessioned2022-08-03T01:48:51Z
dc.date.available2022-08-03T01:48:51Z
dc.description.abstractTrastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca2+ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects.en_NZ
dc.identifier.citationInternational Journal of Molecular Sciences, 23(11), 5967. https://doi.org/10.3390/ijms23115967
dc.identifier.doi10.3390/ijms23115967en_NZ
dc.identifier.issn1422-0067en_NZ
dc.identifier.urihttps://hdl.handle.net/10292/15336
dc.languageenen_NZ
dc.publisherMDPI AGen_NZ
dc.relation.urihttps://www.mdpi.com/1422-0067/23/11/5967
dc.rights© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
dc.rights.accessrightsOpenAccessen_NZ
dc.subjectTrastuzumab; Doxorubicin; Stem cells; Exosomes; Cardiac toxicity; NRG-1; MAPK; AKT
dc.titleProphylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathwayen_NZ
dc.typeJournal Article
pubs.elements-id457519
pubs.organisational-data/AUT
pubs.organisational-data/AUT/Faculty of Health & Environmental Science
pubs.organisational-data/AUT/Faculty of Health & Environmental Science/School of Public Health & Interdisciplinary Studies
pubs.organisational-data/AUT/Faculty of Health & Environmental Science/School of Public Health & Interdisciplinary Studies/Biosciences Department
pubs.organisational-data/AUT/PBRF
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences/HI Interprofessional 2018 PBRF
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