Growing evidence has highlighted that mitochondrial dysfunction contributes to drug-induced toxicities and leads to drug attrition and post-market withdrawals. The acetylation or deacetylation of mitochondrial proteins can affect mitochondrial functions as the cells adapt to various cellular stresses and other metabolic challenges. SIRTs act as critical deacetylases in modulating mitochondrial function in response to drug toxicity, oxidative stress, reactive oxygen species (ROS), and energy metabolism. We previously showed that a recently characterised SIRT inhibitor (BZD9L1) is non-toxic in rodents in a short-term toxicity evaluation. However, the impact of BZD9L1 on mitochondrial function is unknown. This work aims to determine the effects of BZD9L1 on mitochondrial function in human normal liver and kidney-derived cell lines using the Agilent Seahorse Cell Mito Stress Test to complement our short-term toxicity evaluations in vivo. The Mito Stress assay revealed that BZD9L1 could potentially trigger oxidative stress by inducing ROS, which promotes proton leak and reduces coupling efficiency in liver-derived THLE cells. However, the same was not observed in human kidney-derived HEK293 cells. Interestingly, BZD9L1 had no impact on SIRT3 protein expression in both cell lines but affected SOD2 and its acetylated form at 72 h in THLE cells, indicating that BZD9L1 exerted its effect through SIRT3 activity rather than protein expression. In contrast, BZD9L1 reduced SIRT1 protein expression and impacted the p53 protein differently in both cell lines. Although BZD9L1 did not affect the spare respiratory capacity in vitro, these findings call for further validation of mitochondrial function through assessment of other mitochondrial parameters to evaluate the safety of BZD9L1.
The journey of chemotherapeutic drugs from the site of administration to the site of action is confronted by several factors including low bioavailability, uneven distribution in major organs, limited accessibility of drug molecules to the distant tumor tissues, and lower therapeutic indexes. These unavoidable features of classical chemotherapeutics necessitate an additional high, repetitive dose of drugs to obtain maximum therapeutic responses with the result of unintended adverse side effects. An erratic tumor microenvironment, notable drawbacks of conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells warrant precisely designed therapeutics for the treatment of cancers. In recent decades, nanoparticles have been deployed for the delivery of standard anticancer drugs to maximize the therapeutic potency while minimizing the adverse effects to increase the quality and span of life. Several organic and inorganic nanoplatforms that have been designed exploiting the distinctive features of the tumor microenvironment and tumor cells offer favorable physicochemical properties and pharmacokinetic profiles of a parent drug, with delivery of higher amounts of the drug to the pathological site and its controlled release, thereby improving the balance between its efficacy and toxicity. Advances to this front have included design and construction of targeted nanoparticles by conjugating homing devices like peptide, ligand, and Fab on the surface of nanomaterials to navigate nanoparticledrug complexes towards the target tumor cell with minimal destruction of healthy cells. Furthermore, actively targeting nanoparticles can facilitate the delivery and cellular uptake of nanoparticle-loaded drug constructs via binding with specific receptors expressed aberrantly on the surface of a tumor cell. Herein, we present an overview of the principle of targeted delivery approaches, exploiting drug-nanoparticle conjugates with multiple targeting moieties to target specific receptors of breast cancer cells and highlighting therapeutic evaluation in preclinical studies. We conclude that an understanding of the translational gap and challenges would show the possible future directions to foster the development of novel targeted nanotherapeutics.
BPA is identified as an endocrine-disrupting chemical that deteriorates the physiological function of the hormones of the male reproductive system. Bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF) are actively explored as substitutes for BPA and are known as BPA analogues in most manufacturing industries. These analogues may demonstrate the same adverse effects as BPA on the male reproductive system; however, toxicological data explaining the male reproductive hormones' physiological functions are still limited. Hence, this mini-review discusses the effects of BPA and its analogues on the physiological functions of hormones in the male reproductive system, focusing on the hypothalamus-pituitary-gonad (HPG) axis, steroidogenesis, and spermatogenesis outcomes. The BPA analogues mainly show a similar negative effect on the hormones' physiological functions, proven by alterations in the HPG axis and steroidogenesis via activation of the aromatase activity and reduction of spermatogenesis outcomes when compared to BPA in in vitro and in vivo studies. Human biomonitoring studies also provide significant adverse effects on the physiological functions of hormones in the male reproductive system. In conclusion, BPA and its analogues deteriorate the physiological functions of hormones in the male reproductive system as per in vitro, in vivo, and human biomonitoring studies.