Deleterious reproductive effects of nilotinib in mouse model.

Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) that is widely used to treat patients with Philadelphia chromosome-positive chronic myeloid leukaemia (CML). TKIs provided a significant improvement in terms of survival rates and disease-free period in CML; however, there is insufficient knowledge about their side effects, including reproductive toxicity. Since nearly half of the CML patients are in their reproductive age, and newly announced indications cover the treatment of the paediatric age groups, concerns arise about the effects of these drugs on the reproductive system, as there are no controlled preclinical studies. We investigated acute and long-term gonadotoxic and teratogenic effects of nilotinib, utilising a mouse model that simulates various clinical scenarios. We observed significant testicular damage in mice receiving nilotinib according to Johnsen's score analysis. Alterations were observed in female mice's number of follicles, as the primordial follicle numbers significantly decreased. Proliferating cell number in both genders' gonads decreased and apoptosis rate increased significantly. The nilotinib-received female and male mice's pregnancy rates were low compared to controls. A significant decrease in the thickness of the spongiotrophoblast and decidual layers of the placenta was detected in pregnancies consisting of male and/or female mice treated with nilotinib. The results of this study establish a critical point of view for clinical translation and indicate the importance of consulting patients for directing them to fertility preservation and contraception options for both genders before nilotinib treatment.

FoxO1 is a cell-specific core transcription factor for endometrial remodeling and homeostasis during menstrual cycle and early pregnancy.

BACKGROUND: Endometrium is a vital multicellular tissue for progression of pregnancy. Forkhead box O1 (FoxO1) transcription factor plays an important role in the endometrium as it regulates various cellular processes with its unique expression in different cell types. OBJECTIVE AND RATIONALE: This review focuses on the role of FoxO1 in endometrium with a particular emphasis on FoxO1 signaling in individual endometrial cell types during the menstrual cycle and early pregnancy. SEARCH METHODS: A literature search was conducted in PubMed, Web of Science and Scopus to select studies reporting the role of FoxO1 in endometrium using the keywords: FoxO1, endometrium, menstrual cycle, early pregnancy, endometrial receptivity, implantation, decidualization, angiogenesis and neoplasia. Papers published before October 2020 were selected. Drawing on advances in laboratory science and preclinical studies, we performed a narrative review of the scientific literature to provide a timely update on the roles of FoxO1 during the menstrual cycle and early pregnancy. OUTCOMES: FoxO1 is considered to be a decidualization marker in endometrial stromal cells, mainly because it regulates the transcription of decidual prolactin and insulin-like growth factor-binding protein 1 genes. Importantly, 507 of 3405 genes that are specifically regulated during decidualization of human endometrial stromal cells are expressed abnormally as a result of FOXO1 reduction. Epithelial FoxO1 is currently accepted as a novel endometrial receptivity marker for humans and mice owing to its timely and specific expression at the window of implantation. On the other hand, FOXO1 is essential in endometrial epithelial cell proliferation and differentiation to achieve endometrial homeostasis since loss of function of FOXO1 causes endometrial neoplasia. Last but not least, FoxO1 seems to act like a navigator molecule for embryo homing owing to its notably decreased nuclear expression in endometrial luminal epithelial cells, specifically at the blastocyst attachment region, which results in differentiation, entosis and apoptosis of endometrial epithelial cells during the peri-implantation period. In endothelium, FoxO1 expression coincides with the timing of increased vascular permeabilization during early pregnancy. There are limited data regarding the importance of FoxO1 upregulation in endometrial endothelial cells, therefore, it is time to investigate the role of endothelial FoxO1, which is the missing piece in the puzzle of the enigmatic endometrium. Another missing piece in the puzzle for the role of FoxO1 is on embryo development. WIDER IMPLICATIONS: FoxO1 is a cell-specific core transcription factor involved in efficient endometrial remodeling during the menstrual cycle and early pregnancy. A better understanding of the role of FoxO1 as a decidualization marker, as an emerging marker of endometrial receptivity, and as a therapeutic target to prevent endometrial neoplasia could help us to make sense of endometrial biology and thus to improve the outcomes of ART in the clinic.

Correction to: FoxO transcription factors regulate mouse preimplantation embryo development.

The original article unfortunately contained a mistake. There is a misplaced "1" in the article title and the correct title is shown above.

FoxO transcription factors 1 regulate mouse preimplantation embryo development.

PURPOSE: The aim of the present study is to investigate role of FoxO transcription factors in preimplantation embryo development by knocking down FoxO1, FoxO3, and FoxO4 genes and also to assess cell cycle arrest related proteins, p53 and p21, and apoptosis-related proteins, fas ligand (FASL), and cleaved caspase 3. METHODS: Knockdown of FoxOs using siRNA was confirmed utilizing RT-PCR and qRT-PCR in gene level and using immunofluorescence in protein level. Following knockdown of FoxO1, FoxO3, and FoxO4 in two-cell mouse embryos with or without resveratrol treatment; developmental competence of embryos and expression patterns of SIRT1, p53, p21, FASL, and CLEAVED CASPASE 3 proteins in embryos by immunofluorescence were assessed after 48 h. ROS levels were measured in knockdown embryos. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to determine resveratrol dose. RESULTS: Successful knockdown of FoxO genes in mouse embryos utilizing a non-invasive siRNA method was achieved. Significantly, knockdown of FoxO genes impaired preimplantation embryo development which cannot be prevented by resveratrol treatment. Immunofluorescence results showed that resveratrol could protect embryos from cell cycle arrest and apoptosis. FOXO proteins regulate apoptosis and cell cycle related proteins in mouse preimplantation embryos. Moreover, there might be an autofeedback mechanism where FOXO1, FOXO3, and FOXO4 regulate SIRT1 protein expression. CONCLUSIONS: These results suggest that FOXO transcription factors could contribute to mouse preimplantation embryo development, and it remains to investigate whether they have crucial roles in human preimplantation embryo and infertility.

Spatiotemporal expression and regulation of FoxO1 in mouse uterus during peri-implantation period.

Recent studies indicate that FoxO1 has roles in female reproductive system, especially in maternal endometrium. Although various cellular aspects and molecular pathways have been identified, the exact molecular characteristics of embryo implantation are still not completely understood. In this study, we aimed to investigate uterine expression and regulation of FoxO1 during peri-implantation period in mice. Experimental mouse models including, normal pregnancy, pseudopregnancy, artificial decidualization, and delayed implantation and activation were performed. Our results showed that FoxO1 expression was spatiotemporal in mouse endometrial tissue throughout peri-implantation period and its expression was significantly upregulated in luminal and glandular epithelium at the time of implantation. Moreover, on day 5 morning (09:00 AM) of pregnancy, expression of FoxO1 was cytoplasmic in endometrial luminal epithelial cells where embryo homing takes place. With progressing time on day 5 evening (19:00 PM) of pregnancy FoxO1 expression was nuclear in luminal epithelium at implantation site. Pseudopregnancy and artificial decidualization models indicated that FoxO1 expression was regulated by pregnancy hormones. Delayed implantation and activation model indicated that FoxO1 expression at the time of implantation is dependent upon activation status of blastocyst due to E2 induction and uterine sensitivity to implantation. In conclusion, our findings highlight a perspective for FoxO1 expression and regulation in mouse uterus during peri-implantation period indicating that its expression is regulated by implanting embryo and pregnancy hormones.

Cardioprotective effect of nesfatin-1 against isoproterenol-induced myocardial infarction in rats: Role of the Akt/GSK-3ß pathway.

The present study was designed to evaluate the cardioprotective effects of nesfatin-1, a novel peptide with anorexigenic properties, in rats with isoproterenol (ISO)-induced myocardial infarction (MI), and to further investigate the role of Akt/GSK-3ß signaling pathway in the protective effect of nesfatin-1. To induce MI, ISO was subcutaneously injected into the rats for two consecutive days at a dosage of 85mg/kg/day. ISO-induced myocardial damage was indicated by elevated levels of cardiac specific troponin-T, enhanced myocardial expression of proinflammatory cytokines (interleukin-1ß, interleukin-6 and tumor necrosis factor-α), and increased number of cells with apoptotic and necrotic appearance in the myocardial tissue. Levels of p-Akt/Akt and p-GSK-3ß/GSK-3ß significantly decreased in heart tissue after ISO-induced MI. However, intraperitoneal administration of nesfatin-1 (10µg/kg/day) elicited a significant cardioprotective activity by lowering the levels of cardiac troponin-T and proinflammatory cytokines, indicating the protective effect of nesfatin-1 against ISO-induced MI. The biochemical findings were further confirmed by histopathological examination, which was demonstrated by reduced number of apoptotic and necrotic cells. Moreover, expressions of p-Akt/Akt and p-GSK-3ß/GSK-3ß in the myocardium of MI group rats were significantly increased by nesfatin-1 administration, suggesting that nesfatin-1, which appears to possess anti-apoptotic and anti-inflammatory properties, may confer protection against ISO-induced MI via an Akt/GSK-3ß-dependent mechanism.