University of Nis

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant subtypes of breast malignancies, defined by the absence of hormone receptors and HER2 amplification. This study introduces an integrated computer-aided drug design (CADD) framework that combines Monte Carlo-optimized QSAR modeling, molecular docking, and in silico pharmacokinetic assessment to identify dual c-Met/β-tubulin inhibitors with potential anti-TNBC activity. Robust conformation-independent QSAR models were developed using SMILES- and graph-based descriptors, achieving high internal consistency (R² > 0.84) and strong external predictivity (Q²ext > 0.77). Statistical validation and the CORAL-based "defect-of-correlation" approach confirmed reliability within the defined applicability domain. Fragment-level interpretation revealed molecular motifs associated with enhanced cytotoxicity, which were subsequently used in the CADD design of new multitarget analogs, enabling rational structure-activity relationship (SAR) refinement. Molecular docking against both c-Met and β-tubulin demonstrated complementary binding orientations and stable non-covalent interactions, supporting the proposed multitarget mechanism. In silico pharmacokinetic analysis indicated favorable drug-likeness, high gastrointestinal absorption, absence of major metabolic liabilities, and low predicted toxicity, suggesting a well-balanced safety-efficacy profile. Collectively, this study establishes a CADD-based multitarget modeling platform that integrates predictive, mechanistic, and pharmacokinetic insights, providing a rational foundation for the development of next-generation personalized therapeutics for TNBC.

Balkan endemic nephropathy (BEN) is a chronic kidney disease associated with the consumption of aristolochic acids (AAs) through contaminated food sources. AAs are known to form DNA adducts that are implicated in tumorigenesis and kidney fibrosis. Given the sensitivity of DNA adduct formation to dietary factors, this study aimed to investigate the impact of various dietary practices on AA-DNA adduct formation, thereby assessing the risk of developing BEN. We quantified AA-DNA adducts in DNA extracted from the kidneys and livers of mice subjected to high-fat, high-protein, high-sucrose, and high-salt diets, utilizing a highly sensitive liquid chromatography-tandem mass spectrometry method combined with stable isotope dilution. Our results demonstrated that unbalanced diets significantly elevated the formation of DNA adducts from AAs. Notably, mice fed high-fat diets exhibited increases in adduct levels of 71 and 114% for diets containing 17 and 25% fat, respectively. Mice on a 20% sucrose diet showed an 80% increase in adduct levels compared to those on a standard diet. Further investigations using gut sacs from the small intestines of these mice revealed that the increased level of DNA adduct formation was primarily attributed to enhanced intestinal absorption. Additionally, we observed that drinking alkaline water reduced adduct levels by 30% compared to tap water, likely by decreasing AA absorption. In contrast, commonly used dietary supplements, such as vitamin C and cysteine, significantly increased AA-DNA adduct levels by enhancing the activity of enzymes involved in the metabolic activation of AAs. These findings highlight the critical role of a balanced diet in mitigating the risk of BEN and suggest that alkaline water consumption may serve as a protective strategy for individuals living in AA-contaminated regions.

This study investigates the performance of zero-valent iron (ZVI) impregnated apricot stone-derived biochar (ZVI/ASB) for the removal of atenolol (ATL), a widely detected pharmaceutical pollutant, from contaminated water. The biochar was synthesized at pyrolysis temperatures of 800, 900, and 1000 °C, with ZVI/ASB-800 exhibiting the highest sorption capacity due to its superior textural properties, including a Brunauer-Emmett-Teller (BET) surface area of 1162 m²/g and a well-developed porous structure. Characterization techniques such as X-Ray diffraction (XRD) analysis, Fourier Transform Infrared Spectroscopy (FTIR), and Scanning electron microscopy (SEM) confirmed the successful incorporation of ZVI and the material's enhanced physicochemical properties. Batch sorption experiments evaluated the effects of pH, sorbent dosage, stirring speed, and initial ATL concentration, with optimal conditions identified at pH 9, a dosage of 0.75 g/L, and a stirring speed of 250 rpm. The sorption process followed the Langmuir isotherm model and pseudo-second-order kinetics. The maximum experimental sorption capacity reached 129 mg/g, demonstrating competitive performance compared to commercial sorbents. Reusability tests showed a retention of 73.2 % removal efficiency after five cycles, highlighting the material's considerable stability. These findings underscore the potential of ZVI/ASB-800 as a cost-effective and sustainable sorbent for pharmaceutical pollutant removal, leveraging agricultural waste for environmental remediation.