Complex Interplay between Autophagy and Oxidative Stress in the Development of Endometriosis
Ramona D’Amico,
Daniela Impellizzeri,
Marika Cordaro,
Rosalba Siracusa,
Livia Interdonato,
Ylenia Marino,
Rosalia Crupi,
Enrico Gugliandolo,
Francesco Macrì,
Davide Di Paola,
Alessio Filippo Peritore,
Roberta Fusco,
Salvatore Cuzzocrea,
Rosanna Di Paola
Affiliations
Ramona D’Amico
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Daniela Impellizzeri
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Marika Cordaro
Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
Rosalba Siracusa
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Livia Interdonato
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Ylenia Marino
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Rosalia Crupi
Department of Veterinary Sciences, University of Messina, Viale Annunzita, 98168 Messina, Italy
Enrico Gugliandolo
Department of Veterinary Sciences, University of Messina, Viale Annunzita, 98168 Messina, Italy
Francesco Macrì
Department of Veterinary Sciences, University of Messina, Viale Annunzita, 98168 Messina, Italy
Davide Di Paola
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Alessio Filippo Peritore
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Roberta Fusco
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Salvatore Cuzzocrea
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, n 31, 98166 Messina, Italy
Rosanna Di Paola
Department of Veterinary Sciences, University of Messina, Viale Annunzita, 98168 Messina, Italy
Endometriosis (Endo) is a chronic gynecological disease. This paper aimed to evaluate the modulation of autophagy, oxidative stress and apoptosis with Açai Berries in a rat model of endometriosis. Endometriosis was induced with an intraperitoneal injection of minced uterus tissue from a donor rat into a recipient one. The abdominal high-frequency ultrasound (hfUS) analysis was performed at 7 and 14 days from the endometriosis induction to evaluate the growth of the lesion during the experiment. Seven days from the induction, once the lesions were implanted, an Açai Berry was administered daily by gavage for the next seven days. At the end of the experiment, the hfUS analysis showed a reduced lesion diameter in animals given the Açai Berry. A macroscopical and histological analysis confirmed this result. From the molecular point of view, Western blot analyses were conducted to evaluate the autophagy induction. Samples collected from the Endo group showed impaired autophagy, while the Açai Berry administration inhibited PI3K and AKT and ERK1/2 phosphorylation and promoted autophagy by inactivating mTOR. Additionally, Açai Berry administration dephosphorylated ATG1, promoting the activity of the ATG1/ULK1 complex that recruited Ambra1/Beclin1 and Atg9 to promote autophagosome nucleation and LC3II expression. Açai Berry administration also restored mitophagy, which increased Parkin cytosolic expression. The Açai Berry increased the expression of NRF2 in the nucleus and the expression of its downstream antioxidant proteins as NQO-1 and HO-1, thereby restoring the oxidative imbalance. It also restored the impaired apoptotic pathway by reducing BCL-2 and increasing BAX expression. This result was also confirmed by the TUNEL assay. Overall, our results displayed that Açai Berry administration was able to modulate autophagy, oxidative stress and apoptosis during endometriosis.
