Background: Thalidomide (THD) and its analogues were recently reported as a promising treatment for different types of solid tumors due to their antiangiogenic effect. Methods: In this work, we synthesized a novel THD analogue (TA), and its chemistry was confirmed with different techniques such as IR, mass spectroscopy, elemental analysis as well as ¹H and ¹³C NMR. To increase solubility and anticancer efficacy, a new oil in water (O/W) nanoemulsion (NE) was used in the formulation of the analogue. The novel formula’s surface charge, size, stability, FTIR, FE-TEM, in vitro drug release and physical characteristics were investigated. Furthermore, molecular docking studies were conducted to predict the possible binding modes and molecular interactions behind the inhibitory activities of the THD and TA. Results: TA showed a significant cytotoxic activity with IC₅₀ ranging from 0.326 to 43.26 μmol/mL when evaluated against cancerous cells such as MCF-7, HepG2, Caco-2, LNCaP and RKO cell lines. The loaded analogue showed more potential cytotoxicity against MDA-MB-231 and MCF-7-ADR cell lines with IC₅₀ values of 0.0293 and 0.0208 nmol/mL, respectively. Moreover, flow cytometry of cell cycle analysis and apoptosis were performed showing a suppression in the expression levels of TGF-β, MCL-1, VEGF, TNF-α, STAT3 and IL-6 in the MDA-MB-231 cell line. Conclusion: The novel NE formula dramatically reduced the anticancer dosage of TA from micromolar efficiency to nanomolar efficiency. This indicates that the synthesized analogue exhibited high potency in the NE formulation and proved its efficacy against triple-negative breast cancer cell line. Graphical Abstract:

Aquatic pollution has increased significantly in recent decades due to increased waste from various sources. Pollutants like bisphenol A (BPA) are endocrine disruptors that interfere with natural hormones, impacting development, fertility, and homeostasis. This study assessed the impact of BPA on the freshwater fish Oreochromis niloticus , focusing on genotoxicity, reproductive toxicity, and endocrine disruption. It also explored the protective effects of dietary grape seed extract (GREX ^® ) against BPA toxicity. One hundred eighty mixed-sex fish, averaging 15.04 ± 0.13 g, were randomly divided into four groups (three replicates each). The first group served as the control (0 mg GREX ^® /kg), the second group received 200 mg GREX ^® /kg, the third group was exposed to 3 mg BPA/L in water, and the fourth group received 3 mg BPA/L and 200 mg GREX ^® /kg. Treatments lasted for 60 days. Body weight, gonadosomatic index (GSI), hepatosomatic index (HSI), cholesterol, triglycerides (TG), estradiol (E2), testosterone (T), cortisol, gonadal malondialdehyde (MDA), and superoxide dismutase (SOD) were measured. A histopathological examination of the liver, testes, and ovaries was conducted. BPA exposure induced significant pathophysiological alterations, including a significant decrease in GSI, HSI, E2, T, and gonadal antioxidant enzymes, while increasing cortisol, cholesterol, triglycerides (TG), and gonadal MDA. It also resulted in detrimental gonadal histology and downregulation of vitellogenin (VTG) mRNA levels. However, GREX ^® significantly improved these BPA-induced effects and restored the VTG mRNA levels. GREX ^® likely ameliorates BPA reproductive toxicity via antioxidant and stress-relieving mechanisms that improve gonadal sex hormones and pathology.