arad boustan

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. 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. 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. 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.

The development of multidrug resistance (MDR) is a major barrier to achieving effective chemotherapy in cancer. Studies have shown that epithelial ovarian cancer initially responds to platinum-based therapy, however, the recurrent type is often resistant to treatment and is associated with high mortality. Fucoxanthin, a natural component found in marine algae, possesses various pharmacologic properties. This study evaluated the cytotoxicity and resistance reversal activity of fucoxanthin on multidrug resistance-associated protein 2 (MRP2)- overexpressing, cisplatin-resistant ovarian cancer cells (A2780RCIS) and their parental cells (A2780).

Cell viability was evaluated in the presence of different concentrations of fucoxanthin or cisplatin or fucoxanthin/cisplatin combination using the MTT assay. Propidium iodide staining and subG1 analysis were used to evaluate fucoxanthin potential for cell cycle modification and apoptosis induction in cancer cell lines.

The results showed that fucoxanthin was able to cause similar toxicity in both cell lines via apoptosis induction. Co-treatment of cells with cisplatin (3.125 to 100 µM) and nontoxic concentrations of fucoxanthin (1 and 2.5 µM) did not reverse resistance to cisplatin in A2780RCIS cells.

Although fucoxanthin was not able to modify cisplatin resistance in ovarian cancer cells, it was equally effective in inducing apoptosis and death in both A2780 and A2780RCIS cells, indicating it is not an MRP2 substrate.

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.

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.

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.

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.

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.

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.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) caused an outbreak in Wuhan, China in December 2019, and right after that SARS-COV-2 spreads around the world infecting millions of people worldwide. This virus belongs to wide range virus family and cause moderate to severe signs in patients, the Sars-COV-2, can spread faster than others between humans and leads to severe outbreak. Recently researchers succeed to develop various vaccines including inactivated or attenuated viral vaccines as well as subunit vaccines to prevent SARS-COV-2 infection. Nanotechnology is advantageous for the design of vaccines since nano scale materials could benefit the delivery of antigens, and could be used as adjuvants to potentiate the response to the vaccines. Indeed, among various vaccines entered clinical trials, there are mRNA-based vaccine designed based on lipid nanoparticles. Herein, we summarized SARS-COV-2 structure, pathogenesis, therapeutic approaches and some COVID-19 vaccine candidates and highlighted the role of nanotechnology in developing vaccines against SARS-Cov-2 virus.