In Vitro and In Vivo Preventive Effects of Thymoquinone against Breast Cancer: Role of DNMT1.

Breast cancer (BC) is one of the most common cancers in women and is a major cause of female cancer-related deaths. BC is a multifactorial disease caused by the dysregulation of many genes, raising the need to find novel drugs that function by targeting several signaling pathways. The antitumoral drug thymoquinone (TQ), found in black seed oil, has multitargeting properties against several signaling pathways. This study evaluated the inhibitory effects of TQ on the MCF7 and T47D human breast cancer cell lines and its antitumor activity against BC induced by a single oral dose (65 mg/kg) of 7,12-dimethylbenzanthracene (DMBA) in female rats. The therapeutic activity was evaluated in DMBA-treated rats who received oral TQ (50 mg/kg) three times weekly. TQ-treated MCF7 and T47D cells showed concentration-dependent inhibition of cell proliferation and induction of apoptosis. TQ also decreased the expression of DNA methyltransferase 1 (DNMT1) in both cancer cell types. In DMBA-treated animals, TQ inhibited the number of liver and kidney metastases. These effects were associated with a reduction in DNMT1 mRNA expression. These results indicate that TQ has protective effects against breast carcinogens through epigenetic mechanisms involving DNMT1 inhibition.

Mannosylated PAMAM G2 dendrimers mediated rate programmed delivery of efavirenz target HIV viral latency at reservoirs.

In this current research, we conceptualized a novel nanotechnology-enabled synthesis approach of targeting HIV-harboring tissues via second-generation (G2) polyamidoamine (PAMAM) mannosylated (MPG2) dendrimers for programmed delivery of anti-HIV drugs efavirenz (EFV) and ritonavir (RTV). Briefly, here mannose served purpose of ligand in this EFV and RTV-loaded PAMAM G2 dendrimers, synthesized by divergent techniques, denoted as MPG2ER. The developed nanocarriers were characterized by different analytical tools FTIR, NMR, zeta potential, particle size, and surface morphology. The results of confocal microscopy showed substantial alterations in the morphology of H9 cells, favored by relatively higher drug uptake through the MPG2ER. Interestingly, the drug uptake study and cytotoxicity assay of MPG2ER demonstrated that it showed no significant toxicity up to 12.5 µM. A typical flow cytometry histogram also revealed that MPG2ER efficiently internalized both drugs, with an increase in drug uptake of up to 81.2 %. It also enhanced the plasma pharmacokinetics of EFV, with Cmax7.68 µg/ml, AUC of 149.19 (µg/ml) * hr, and MRT of 26.87 hrs. Subsequently, tissue pharmacokinetics further evidence that MPG2ER accumulated more in distant Human immunodeficiency virus (HIV) reservoir tissues, such as the lymph nodes and spleen, but without exhibiting significant toxicity. Abovementioned compelling evidences strongly favored translational roles of MPG2 as a potential therapeutic strategy in the clinical eradication of HIV from viral reservoir tissue.