ABSTRACT
BACKGROUND AND AIM: Cyclophosphamide (CP) chemotherapy is a significant iatrogenic component of premature ovarian failure (POF). The aim of this work was to evaluate the potential protective effects of donepezil, a centrally acting acetylcholinesterase (AChE) inhibitor, on CP-induced POF in mice. METHODS: 40 female Swiss albino mice were split into 5 equal groups: group 1 (control), group 2 (CP-POF); induced by intraperitoneal injection of CP on 8th day of the experiment, and group (3-5); mice received oral donepezil daily (1, 2, or 4 mg/kg, respectively) 8 days before CP injection. Mice were euthanized after 24 h of CP injection, and blood samples were collected to assay serum anti-Mullerian hormone (AMH) levels. Ovarian tissues were dissected, and the right ovary was processed for further assays of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interlukin-6 (IL-6), nucleotide-binding domain-like receptor family, the Pyrin domain-containing 3 (NLRP3) inflammasome, and Toll-like receptor 4 (TLR-4), while the left one was processed for histopathological and immunohistochemical examination of nuclear factor-Kappa beta (NF-κB) and caspase-3. RESULTS: Donepezil, in a dose-dependent manner particularly (4 mg/kg), has an inhibitory action on NO (40 ± 2.85 vs. 28.20 ± 2.23, P < 0.001), proinflammatory cytokines (P < 0.001), the TLR-4/ NF-κB / NLRP3 inflammasome pathway (P < 0.001), and apoptosis (P < 0.001), with a significant elevation in the AMH levels (4.57 ± 1.08 vs. 8.57 ± 0.97, P < 0.001) versus CP-POF group. CONCLUSION: Donepezil may be a potential protective agent against CP-induced POF in mice, but further research is needed to fully understand its therapeutic function experimentally and clinically.
Subject(s)
Cholinesterase Inhibitors , Cyclophosphamide , Cytokines , Donepezil , NF-kappa B , NLR Family, Pyrin Domain-Containing 3 Protein , Primary Ovarian Insufficiency , Toll-Like Receptor 4 , Animals , Female , Donepezil/pharmacology , Mice , Toll-Like Receptor 4/metabolism , Cyclophosphamide/toxicity , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Cytokines/metabolism , Primary Ovarian Insufficiency/chemically induced , Primary Ovarian Insufficiency/prevention & control , Primary Ovarian Insufficiency/pathology , Cholinesterase Inhibitors/pharmacology , Ovary/drug effects , Ovary/metabolism , Ovary/pathology , Signal Transduction/drug effectsABSTRACT
Special AT-rich sequence-binding protein 2 (SATB2) is a new marker that could identify the colonic origin, but whether its expression is preserved in metastatic colorectal carcinomas (CRCs) remains unclear. This study was designed to investigate SATB2 validity in the identification of CRC either alone or in combination with caudal-type homeobox 2 (CDX2) and/or cytokeratin 20 (CK20). Moreover, we examined the concordance of SATB2 expression in primary CRC and paired metastatic specimen. Immunohistochemical expression of SATB2, CDX2 and CK20 was evaluated in primary CRC, 50 paired metastatic CRC and 80 non-CRC specimens. This study demonstrated that the ideal SATB2 cut-off value for recognising colonic from non-colonic origin was 10%. SATB2 was more sensitive and specific than CK20. However, it was more specific but less sensitive than CDX2. Analysing the combined markers expression, SATB2 and CDX2 combination revealed better sensitivity, specificity and larger area under curve compared to SATB2 alone, CDX2 alone and combined CDX2 and CK20. Moreover, SATB2 was able to retain its expression at the metastatic sites. SATB2 was totally concordant between primary CRC and their paired metastatic sites (concordance rate = 100%) with perfect level of agreement. SATB2 could be considered as an accurate diagnostic marker of primary and metastatic CRC. SATB2 and CDX2 is the best combination serving the highest sensitivity and specificity in detection of CRC.
