RÉSUMÉ
Despite progress in diagnosis and treatment strategies, breast cancer remains a primary risk to female health as indicated by second most cancer-deaths globally caused by this cancer. High risk mutation is linked to prognosis of breast cancer. Due to high resistance of breast cancer against current therapies, there is necessity of novel treatment strategies. Sirtuins are signaling proteins belonging to histone deacetylase class III family, known to control several cellular processes. Therefore, targeting sirtuins could be one of the approaches to treat breast cancer. Several plants synthesize phytoestrogens which exhibit structural and physiological similarities to estrogens and have been recognized to possess anticancer activity. In our study, we investigated several phytoestrogens for sirtuin inhibition by conducting molecular docking studies, and in-vitro studies against breast cancer cell lines. In molecular docking studies, we identified coumestrol possessing high binding energy with sirtuin proteins 1-3 as compared to other phytoestrogens. The molecular dynamic studies showed stable interaction of ligand and protein with higher affinity at sirtuin proteins 1-3 binding sites. In cell proliferation assay and colony formation assay using breast cancer cell lines (MCF-7 and MDAMB-231) coumestrol caused significant reduction in cell proliferation and number of colonies formed. Further, the flow cytometric analysis showed that coumestrol induces intracellular reactive oxygen species and the western blot analysis revealed reduction in the level of SIRT-1 expression in breast cancer cell lines. In conclusion, in-silico data and in-vitro studies suggest that the phytoestrogen coumestrol has sirtuin inhibitory activity against breast cancer.
RÉSUMÉ
AIM: To determine the role of geminin as a tool for differentiating various types of cervical intraepithelial neoplasia (CIN) and cervical carcinoma (CC). METHODS: Seventy women newly diagnosed with CIN or CC undergoing cervical biopsy were included; their clinical profile, human papilloma virus (HPV) positivity, and colposcopy findings were noted, and biopsy tissue was analyzed for geminin content. RESULTS: On geminin immunohistochemistry, 100% of women with CIN3 and 96.29% of women with CC had geminin two plus or more. When analyzed as ordinal variables, there was a significant correlation (spearman's rho 0.35, p 0.01) between geminin and biopsy results (CIN1, CIN2, CIN3, and CC). CONCLUSIONS: Screening tests for cervical cancer, like conventional pap smears, liquid-based pap smears, and triaging with HPV, have limitations. It is important to be able to differentiate between high-grade lesions, invasive cancer, and low-grade lesions. The detection of geminin in these cells may aid in the confirmation of the diagnosis and ensure adequate treatment. Cervical intraepithelial lesions and carcinoma cervix demonstrated a correlation between increased geminin expression in CIN1 vs. CC and CIN2 vs. CC. Geminin may be a potential surrogate marker for higher-grade cervical lesions, and further research is needed to corroborate evidence in this direction.
RÉSUMÉ
Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aß and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood-brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aß1-42 aggregation. Observing the neuroprotection ability of 12o against H2O2-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.