PMID- 34064310 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210615 IS - 2076-3921 (Print) IS - 2076-3921 (Electronic) IS - 2076-3921 (Linking) VI - 10 IP - 5 DP - 2021 May 4 TI - Hidrox((R)) and Endometriosis: Biochemical Evaluation of Oxidative Stress and Pain. LID - 10.3390/antiox10050720 [doi] LID - 720 AB - Endometriosis is a gynecological and painful condition affecting women of reproductive age. It is characterized by dysfunctional endometrium-like implants outside of the uterine cavity. The purpose of this study was to evaluate the effects of Hidrox((R)), an aqueous extract of olive pulp containing hydroxytyrosol, on endometriotic lesions associated with pro-oxidative alterations and pain-like behaviors. Endometriosis was induced by intraperitoneal injection of uterine fragments, and Hidrox((R)) was administered daily. At the end of the 14-day treatment, behavioral alterations were assessed and hippocampal tissues were collected. Laparotomy was performed, and the endometrial implants were harvested for histological and biochemical analysis. Hidrox((R)) treatment reduced endometriotic implant area, diameter and volumes. Vehicle-treated rats showed lesional fibrosis, epithelial-mesenchymal transition and fibroblast-myofibroblast transdifferentiation, angiogenesis and pro-oxidative alterations in the peritoneal cavity. Hidrox((R)) treatment reduced the aniline blue-stained area, alpha-smooth muscle actin (alpha-sma) and CD34 positive expressions. Moreover, it reduced mast cell recruitment into the lesions, myeloperoxidase activity and lipid peroxidation and increased superoxide dismutase (SOD) activity and glutathione levels in the endometrial explants. In the peritoneal fluid, Hidrox((R)) treatment reduced interleukin (IL)-1beta, IL2, IL6, tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial grow factor (VEGF) levels increased by the disease. Hidrox((R)) administration also reduced peripheral and visceral sensibility as shown by the behavioral tests (open field test, hot plate test, elevated plus maze test and acetic-acid-induced abdominal contractions). Animals treated with Hidrox((R)) also showed reduced blood-brain barrier permeability and mast cell infiltration in the hippocampus, as well as astrocyte and microglia activation and brain oxidative status restoring brain-derived neurotrophic factor (BDNF) protein expression and increasing Nuclear factor erythroid 2-related factor 2 (Nfr2) nuclear translocation. In conclusion, Hidrox((R)) displayed potential ameliorative effects on endometriotic implants and related pain-induced behaviors due to its potent antioxidative properties. FAU - Cordaro, Marika AU - Cordaro M AUID- ORCID: 0000-0002-3980-0043 AD - Department of Biomedical, Dental and Morphological and Functional Imaging University of Messina, Via Consolare Valeria, 98125 Messina, Italy. FAU - Trovato Salinaro, Angela AU - Trovato Salinaro A AUID- ORCID: 0000-0003-2377-858X AD - Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy. FAU - Siracusa, Rosalba AU - Siracusa R AUID- ORCID: 0000-0001-7868-2505 AD - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy. FAU - D'Amico, Ramona AU - D'Amico R AUID- ORCID: 0000-0003-0389-3871 AD - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy. FAU - Impellizzeri, Daniela AU - Impellizzeri D AUID- ORCID: 0000-0001-9492-3161 AD - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy. FAU - Scuto, Maria AU - Scuto M AUID- ORCID: 0000-0003-1019-5158 AD - Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy. FAU - Ontario, Maria Laura AU - Ontario ML AD - Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy. FAU - Interdonato, Livia AU - Interdonato L AD - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy. FAU - Crea, Roberto AU - Crea R AD - Oliphenol LLC., 26225 Eden Landing Road, Unit C, Hayward, CA 94545, USA. FAU - Fusco, Roberta AU - Fusco R AUID- ORCID: 0000-0003-0223-1403 AD - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy. FAU - Cuzzocrea, Salvatore AU - Cuzzocrea S AUID- ORCID: 0000-0001-6131-3690 AD - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy. FAU - Di Paola, Rosanna AU - Di Paola R AUID- ORCID: 0000-0001-6725-8581 AD - Department of Biomedical, Dental and Morphological and Functional Imaging University of Messina, Via Consolare Valeria, 98125 Messina, Italy. FAU - Calabrese, Vittorio AU - Calabrese V AUID- ORCID: 0000-0002-0478-985X AD - Department of Biomedical, Dental and Morphological and Functional Imaging University of Messina, Via Consolare Valeria, 98125 Messina, Italy. LA - eng PT - Journal Article DEP - 20210504 PL - Switzerland TA - Antioxidants (Basel) JT - Antioxidants (Basel, Switzerland) JID - 101668981 PMC - PMC8147870 OTO - NOTNLM OT - endometriosis OT - oxidative stress OT - pain COIS- Roberto Crea is the president of Oliphenol LLC and owns a patent for the Hidrox compound. The other authors declare no conflict of interest. EDAT- 2021/06/03 06:00 MHDA- 2021/06/03 06:01 PMCR- 2021/05/04 CRDT- 2021/06/02 01:09 PHST- 2021/03/25 00:00 [received] PHST- 2021/04/26 00:00 [revised] PHST- 2021/04/30 00:00 [accepted] PHST- 2021/06/02 01:09 [entrez] PHST- 2021/06/03 06:00 [pubmed] PHST- 2021/06/03 06:01 [medline] PHST- 2021/05/04 00:00 [pmc-release] AID - antiox10050720 [pii] AID - antioxidants-10-00720 [pii] AID - 10.3390/antiox10050720 [doi] PST - epublish SO - Antioxidants (Basel). 2021 May 4;10(5):720. doi: 10.3390/antiox10050720.