Effect of melatonin on male offspring testis and sperm parameters in BALB/c mice after exposing their mother to METHamphetamine during pregnancy and lactation.

Objectives: Methamphetamine (METH) is a psychostimulant that has harmful effects on all organs, the nervous system, cardiovascular system, and reproductive system. Since many METH consumers are young people of reproductive age, it poses a risk to the next generation of METH consumers. METH can pass through the placenta and is also secreted into breast milk. Melatonin (MLT) is the primary hormone of the pineal gland that regulates the circadian cycle, and it is also an antioxidant that can mitigate the effects of toxic substances. This study aims to investigate the protective effect of melatonin against the detrimental effects that METH has on the reproductive system of male newborns, whose mothers consumed METH during pregnancy and lactation. Materials and Methods: In the current study, 30 female adult balb/c mice were divided into three groups: control group, vehicle group that received normal saline, and the experimental group that received 5 mg/kg METH intraperitoneally during gestation and lactation. After lactation, the male offspring of each group were randomly divided into two subgroups, one of which received 10 mg/kg melatonin intragastrically for 21 days (corresponding to the lactation period of the mice) (METH-MLT) and the other did not (METH -D.W). After treatment, the mice were sacrificed and testicular tissue and epididymis were obtained for the following tests. Results: The diameter of seminiferous tubules, SOD activity, total Thiol groups concentration, catalase activity, sperm count, and PCNA and CCND gene expression were significantly increased in the METH-MLT group compared with the METH-DW. Apoptotic cells and MDA level ameliorated in the METH-MLT group compared with METH-D.W, and testicular weight had no notable change. Conclusion: The current study represents that consumption of METH during pregnancy and lactation can have adverse effects on the histological and biochemical factors of testis and sperm parameters of male newborns, which can be mitigated by taking melatonin after the end of the breastfeeding period.

Tamoxifen resistance induction results in the upregulation of ABCG2 expression and mitoxantrone resistance in MCF-7 breast cancer cells.

Cancer endocrine therapy can promote evolutionary dynamics and lead to changes in the gene expression profile of tumor cells. We aimed to assess the effect of tamoxifen (TAM)-resistance induction on ABCG2 pump mRNA, protein, and activity in ER + MCF-7 breast cancer cells. We also evaluated if the resistance to TAM leads to the cross-resistance toward mitoxantrone (MX), a well-known substrate of the ABCG2 pump. The ABCG2 mRNA and protein expression were compared in MCF-7 and its TAM-resistant derivative MCF-7/TAMR cells using RT-qPCR and western blot methods, respectively. Cross-resistance of MCF-7/TAMR cells toward MX was evaluated by the MTT method. Flow cytometry was applied to compare ABCG2 function between cell lines using MX accumulation assay. ABCG2 mRNA expression was also analyzed in tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) breast tumor tissues. The levels of ABCG2 mRNA, protein, and activity were significantly higher in MCF-7/TAMR cells compared to TAM-sensitive MCF-7 cells. MX was also less toxic in MCF-7/TAMR compared to MCF-7 cells. ABCG2 was also upregulated in tissue samples obtained from TAM-R cancer patients compared to TAM-S patients. Prolonged exposure of ER + breast cancer cells to the active form of TAM and clonal evolution imposed by the selective pressure of the drug can lead to higher expression of the ABCG2 pump in the emerged TAM-resistant cells. Therefore, in choosing a sequential therapy for a patient who develops resistance to TAM, the possibility of the cross-resistance of the evolved tumor to chemotherapy drugs that are ABCG2 substrates should be considered. Prolonged exposure of MCF-7 breast cancer cells to tamoxifen can cause resistance to it and an increase in the expression of the ABCG2 mRNA and protein levels in the cells. Tamoxifen resistance can lead to cross-resistance to mitoxantrone.

Expression analysis elucidates the roles of Nicastrin, Notch4, and Hes1 in prognosis and endocrine-therapy resistance in ER-positive breast cancer patients.

Background and purpose: Although some proposed mechanisms responsible for tamoxifen resistance have already been present, further study is needed to determine the mechanisms underlying tamoxifen resistance more clearly. The critical role of Notch signaling has been described in promoting resistance in therapeutics, but there is little information about its role in tamoxifen resistance progression. Experimental approach: In the present study, the expression of Notch pathway genes, including Notch4, nicastrin and the Notch downstream target Hes1 was evaluated using quantitative RT-PCR in 36 tamoxifen-resistant (TAM-R) and 36 tamoxifen-sensitive (TAM-S) patients. Expression data were correlated with the clinical outcome and survival of patients. Findings/Results: mRNA levels of Notch4 (fold change = 2.7), nicastrin (fold change = 6.71), and Hes1 (fold change= 7.07) were significantly higher in TAM-R breast carcinoma patients compared to sensitive cases. We confirmed all these genes were co-expressed. Hence, it seems that Notch signaling is involved in tamoxifen resistance in our TAM-R patients. Obtained results showed that Hes1, nicastrin, and Notch4 mRNA upregulation was correlated with the N stage. The extracapsular nodal extension was associated with nicastrin and Notch4 overexpression. Moreover, nicastrin overexpression was correlated with perineural invasion. Hes1 upregulation was also associated with nipple involvement. Finally, the Cox regression proportional hazard test revealed that overexpression of nicastrin was an independent worse survival factor. Conclusion and implications: Presumably, upregulation of the Notch pathway may be involved in tamoxifen resistance in breast cancer patients.

The therapeutic effect of melatonin on female offspring ovarian reserve and quality in BALB/c mice after exposing their mother to methamphetamine during pregnancy and lactation.

Objectives: Nowadays, methamphetamine (METH) abuse as a psychotropic drug is increasing. There is insufficient information about its adverse effects on the ovarian reserve of the next generation. Herein, we tried to investigate the effect of METH abuse during pregnancy and lactation and, subsequently, the therapeutic effect of melatonin on ovarian reserve in offspring. Materials and Methods: In the present study, BALB/c pregnant female mice were divided into 3 groups: Control, Saline, and METH (5mg/Kg). METH was injected during pregnancy and lactation, and the female offspring of each group was divided into 2 subgroups: A) treated with 10 mg/kg Melatonin daily until puberty (6 weeks old) and B) received distilled water. The animals were sacrificed at 6 weeks of age, and blood samples were collected for hormonal assessments; the right ovaries were removed and fixed for TUNEL and Hematoxylin & Eosin staining, and the left ovaries were removed and stored for gene expression and oxidative stress evaluation. Results: In the MTEH group, two indicators of ovarian reserve (including anti-Müllerian hormone (AMH) and primordial follicle, and Cyclin D1 (CCND-1) and proliferating cell nuclear antigen (PCNA) genes expression significantly decreased, and the oxidative stress and apoptosis significantly increased in comparison with other groups. After lactation in the MTEH group, melatonin treatment significantly improved the ovarian reserve and gene expression and declined apoptosis and oxidative stress. Conclusion: METH abuse during pregnancy and lactation decreased ovarian reserve in offspring. The administration of melatonin as an anti-oxidant agent after lactation can counteract the adverse effects of METH on offspring ovaries.

The Potential for Natural Products to Overcome Cancer Drug Resistance by Modulation of Epithelial-Mesenchymal Transition.

The acquisition of resistance and ultimately disease relapse after initial response to chemotherapy put obstacles in the way of cancer therapy. Epithelial-mesenchymal transition (EMT) is a biologic process that epithelial cells alter to mesenchymal cells and acquire fibroblast-like properties. EMT plays a significant role in cancer metastasis, motility, and survival. Recently, emerging evidence suggested that EMT pathways are very important in making drug-resistant involved in cancer. Natural products are gradually emerging as a valuable source of safe and effective anticancer compounds. Natural products could interfere with the different processes implicated in cancer drug resistance by reversing the EMT process. In this review, we illustrate the molecular mechanisms of EMT in the emergence of cancer metastasis. We then present the role of natural compounds in the suppression of EMT pathways in different cancers to overcome cancer cell drug resistance and improve tumor chemotherapy. HighlightsDrug-resistance is one of the obstacles to cancer treatment.EMT signaling pathways have been correlated to tumor invasion, metastasis, and drug-resistance.Various studies on the relationship between EMT and resistance to chemotherapy agents were reviewed.Different anticancer natural products with EMT inhibitory properties and drug resistance reversal effects were compared.

Role of SALL4 and Nodal in the prognosis and tamoxifen resistance of estrogen receptor-positive breast cancer.

Despite the discovery of a number of different mechanisms underlying tamoxifen resistance, its molecular pathway is not completely clear. The upregulation of SALL4 and Nodal has been reported in breast cancer. Nevertheless, their role in tamoxifen resistance has not been investigated. In the present study, we compared Nodal and SALL4 expression in 72 tamoxifen sensitive (TAMS) and tamoxifen-resistant (TAMR) patients. Afterward, the correlation of expression data with clinicopathological features and survival of patients was studied. Results showed that both SALL4 and Nodal were significantly upregulated in TAMR compared to TAMS patients. Besides, there was a positive association between Nodal and SALL4 expression. Furthermore, we evaluated their correlation with the expression of Oct4, Nanog and Sox2 stemness markers. The results demonstrated that in most tissue samples there was a positive correlation between Nodal and SALL4 expression with these stemness markers. Besides, the overexpression of SALL4 and Nodal significantly correlated with the N stage. Moreover, the overexpression of SALL4 was associated with extracapsular invasion and lymphatic invasion. High level expressions of SALL4 and Nodal had a significant association with worse disease-free survival (DFS) rates. In addition, increased level of Nodal expression provides a superior predictor factor for DFS. The multivariate Cox regression analysis also revealed that for DFS, perineural invasion (PNI) was independently an unfavorable prognostic value. These findings suggest that the high expression of SALL4 and Nodal could contribute to tamoxifen resistance and worse survival rates in tamoxifen-treated ER+ breast cancer patients.