Complex Interplay between Autophagy and Oxidative Stress in the Development of Endometriosis

Abstract

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.

Regulated Cell Death in Endometriosis

“…Baicalein is a potential anti-ferroptosis compound that increases GPX4 expression, significantly inhibits ferroptosis, and restores phagocytosis in THP-1 cells (a human leukemia monocytic cell line) in vitro [113]. Açai Berry administration was able to modulate autophagy, oxidative stress, and apoptosis in mouse endometriosis models [114]. Alpinumisoflavone is an isoflavonoid extracted from fruit that inhibits cell migration and proliferation and leads to cell apoptosis in endometriosis cell lines [115].…”

Açaí (Euterpe oleracea Mart.) in Health and Disease: A Critical Review

“…Moreover, açaí increased the lifespan of females subjected to oxidative stress, suggesting that açaí improves survival [ 159 ]. Açaí may be an effective antagonist of the deleterious effects of high-fat diets and oxidative stress, which accelerate the aging process [ 87 , 115 , 116 , 117 , 158 , 159 ].…”

Modulation of the Proliferative Pathway, Neuroinflammation and Pain in Endometriosis

“…Abdominal B-mode was performed with a high-frequency linear array (4-15 MHz) transducer. Longitudinal and transverse scanning planes were employed for the evaluation of different abdominal structures [46]. All analyses were performed double-blind.…”

“…An ultrasonographic examination was conducted on anesthetized rats (2% isoflurane) placed in dorsal recumbency, using the Esaote MYLAB OMEGA VET. A B-mode ultrasound of the abdomen was carried out using a high-frequency linear array transducer (4-15 MHz) [46]. Both longitudinal and transverse scanning planes were utilized to examine various abdominal structures.…”