Sunset Yellow protects against oxidative damage and exhibits chemoprevention in chemically induced skin cancer model.

Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural products and repurposed compounds hold promise as novel therapeutic and preventive agents. Strengthening the skin's antioxidant defense mechanisms is pivotal in neutralizing reactive oxygen species (ROS) and mitigating oxidative stress. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. This study aimed to investigate the antioxidant and anti-genotoxic properties of SY using in-silico, in vitro, and physiochemical test systems, and to further explore its potential role in 7,12-dimethylbenz(a) anthracene (DMBA)/ 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis. In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). This increase was accompanied by reduced ROS levels, restoration of mitochondrial membrane potential, and notable reduction in DNA damage in (SY + tBHP) treated cells. Mechanistic investigations using DPPH chemical antioxidant activity test and potentiometric titrations confirmed SY's antioxidant properties, with a standard reduction potential ( E o ) of 0.211 V. Remarkably, evaluating the effect of topical application of SY in DMBA/TPA-induced two-step skin carcinogenesis model revealed dose-dependent decreases in tumor latency, incidence, yield, and burden over 21-weeks. Furthermore, computational analysis and experimental validations identified GSK3ß, KEAP1 and EGFR as putative molecular targets of SY. Collectively, our findings reveal that SY enhances cellular antioxidant defenses, exhibits anti-genotoxic effects, and functions as a promising chemopreventive agent.

In Vitro Effects of Zirconia Nanoparticles: Uptake, Genotoxicity, and Mutagenicity in V-79 cells.

Zirconia nanoparticles are used in various industrial and biomedical applications such as dental implants, thermal barrier sprays, and fuel cells. The interaction of nanoparticles with the environment and humans is inevitable. Despite the enormous application potential of these nanoparticles, there are still some gaps in the literature regarding potential toxicological mechanisms and the genotoxicity of zirconia nanoparticles. The lung is one of the main exposure routes to nanomaterials; therefore, the present study was designed to determine the genotoxic and mutagenic effect of zirconia NPs in V-79 lung cells. Zirconia nanoparticles showed significant internalization in cells at 100 µg/mL and 150 µg/mL concentrations. Zirconia nanoparticles showed low cytotoxicity and were found to generate ROS in V-79 cells. In alkaline comet assay, zirconia nanoparticles (10 µg/mL, 50 µg/mL, and 100 µg/mL) exposed cells exhibited significant DNA strand breaks, while the neutral comet assay, which was used for double-strand break assessment, only revealed significant damage at 100 µg/mL. Chromosomal aberration induced by zirconia nanoparticles mainly resulted in the generation of gaps, few fragments, and breaks which signifies the low clastogenic activity of these nanoparticles in the V-79 cell line. In MN assay, zirconia nanoparticles resulted in no significant micronuclei induction at any given concentration. In the HPRT mutation assay, the particle shows a dose-dependent increase in the mutant frequency. It is evident from the result that zirconia nanoparticles cause dose-dependent cytotoxicity and genotoxicity, but still, more studies are needed to evaluate the clastogenic potential and the possible mechanism involved.

Physicochemical characterization and oxidative potential of size fractionated Particulate Matter: Uptake, genotoxicity and mutagenicity in V-79 cells.

For many years, the impact of Particulate Matter (PM) in the ambient air has been one of the major concerns for the environment and human health. The consideration of the heterogeneity and complexity of different size fractions is notably important for the assessment of PM toxicological effects. The aim of the study was to present a comprehensive size-composition-morphology characterization and to assess the oxidative potential, genotoxicity, and mutagenicity of the atmospheric PM fractions, collected by using MOUDI near a busy roadside in Lucknow, India. Physicochemical characterization of ambient coarse particles (1.8-10 µm), fine particles (0.32-1.8 µm), quasi-ultrafine (0.1-0.32 µm) and ultrafine particles (≤0.1 µm) along with SRM 1649b was done using TEM, SEM, DLS, NTA, ICP-MS, and IC in parallel with the estimation of exogenous Reactive Oxygen Species (ROS) by acellular assays. In this study, two different acellular assays, dithiothreitol (DTT) and the CM-H2DCFDA assay, indicated stronger mass-normalized bioactivity for different size ranges. Enrichment factor analysis indicated that the different size fractions were highly enriched with elements of anthropogenic origin as compared to elements of crustal origin. The endotoxin concentration in different size fractions was also estimated. Cellular studies demonstrated significant uptake, cytotoxicity, ultrastructural changes, cellular ROS generation, and changes in the different phases of the cell cycle (Sub G1, G1, S, G2/M) exposed to different size fractions. The Comet assay and the Micronucleus assay were used to estimate genotoxicity. Mutagenic potential was revealed by the HGPRT gene forward mutation assay in V-97 cells. Conclusively, our results clearly indicate that the genotoxic and mutagenic potential of the coarse PM was greater than the other fractions, and interestingly, the ultrafine PM has higher bioactivity as compared to quasi-ultrafine PM.