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Article

Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis

by
Tiziana Genovese
1,†,
Rosalba Siracusa
1,†,
Ramona D’Amico
1,†,
Marika Cordaro
2,
Alessio Filippo Peritore
1,
Enrico Gugliandolo
3,
Rosalia Crupi
3,
Angela Trovato Salinaro
4,
Emanuela Raffone
5,
Daniela Impellizzeri
1,*,
Salvatore Cuzzocrea
1,*,
Roberta Fusco
1,‡ and
Rosanna Di Paola
1,‡
1
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy
2
Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy
3
Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy
4
Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy
5
Multi-Specialist Institute Rizzo, Torregrotta, 98043 Messina, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors shared senior authorship.
Int. J. Mol. Sci. 2021, 22(11), 5998; https://doi.org/10.3390/ijms22115998
Submission received: 14 May 2021 / Revised: 28 May 2021 / Accepted: 30 May 2021 / Published: 1 June 2021
(This article belongs to the Special Issue Inflammation and Resolution in Endometriosis: From Science to Clinic)
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Abstract

Endometriosis is a common disease. Its pathogenesis still remains uncertain, but it is clear that cell proliferation, apoptosis and chronic inflammation play an important role in its development. This paper aimed to investigate the anti-proliferative and anti-inflammatory effects of a combined therapy with fotemustine and dexamethasone. Endometriosis was induced by intraperitoneal injections of uterine fragments from donor animals to recipient animals. Next, the pathology was allowed to develop for 7 days. On the seventh day, fotemustine was administered once and dexamethasone was administered daily for the next 7 days. On Day 14, the animals were sacrificed, and peritoneal fluids and lesions were explanted. In order to evaluate the gastrointestinal side effects of the drugs, stomachs were harvested as well. The combined therapy of fotemustine and dexamethasone reduced the proinflammatory mediator levels in the peritoneal fluid and reduced the lesions’ area and diameter. In particular, fotemustine and dexamethasone administration reduced the heterogeneous development of endometrial stroma and glands (histological analysis of lesions) and hyperproliferation of endometriotic cells (immunohistochemical analysis of Ki67 and Western blot analysis of PCNA) through the mitogen-activated protein kinase (MAPK) signaling pathway. Combined fotemustine and dexamethasone therapy showed anti-inflammatory effects by inducing the synthesis of anti-inflammatory mediators at the transcriptional and post-transcriptional levels (Western blot analysis of NFκB, COX-2 and PGE2 expression). Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.
Keywords: endometriosis; inflammation; pathways endometriosis; inflammation; pathways

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MDPI and ACS Style

Genovese, T.; Siracusa, R.; D’Amico, R.; Cordaro, M.; Peritore, A.F.; Gugliandolo, E.; Crupi, R.; Trovato Salinaro, A.; Raffone, E.; Impellizzeri, D.; et al. Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis. Int. J. Mol. Sci. 2021, 22, 5998. https://doi.org/10.3390/ijms22115998

AMA Style

Genovese T, Siracusa R, D’Amico R, Cordaro M, Peritore AF, Gugliandolo E, Crupi R, Trovato Salinaro A, Raffone E, Impellizzeri D, et al. Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis. International Journal of Molecular Sciences. 2021; 22(11):5998. https://doi.org/10.3390/ijms22115998

Chicago/Turabian Style

Genovese, Tiziana, Rosalba Siracusa, Ramona D’Amico, Marika Cordaro, Alessio Filippo Peritore, Enrico Gugliandolo, Rosalia Crupi, Angela Trovato Salinaro, Emanuela Raffone, Daniela Impellizzeri, and et al. 2021. "Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis" International Journal of Molecular Sciences 22, no. 11: 5998. https://doi.org/10.3390/ijms22115998

APA Style

Genovese, T., Siracusa, R., D’Amico, R., Cordaro, M., Peritore, A. F., Gugliandolo, E., Crupi, R., Trovato Salinaro, A., Raffone, E., Impellizzeri, D., Cuzzocrea, S., Fusco, R., & Di Paola, R. (2021). Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis. International Journal of Molecular Sciences, 22(11), 5998. https://doi.org/10.3390/ijms22115998

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