Environmental Chemical-Induced Reactive Oxygen Species Generation and Immunotoxicity: A Comprehensive Review.

Significance: Reactive oxygen species (ROS), the reactive oxygen-carrying chemicals moieties, act as pleiotropic signal transducers to maintain various biological processes/functions, including immune response. Increased ROS production leads to oxidative stress, which is implicated in xenobiotic-induced adverse effects. Understanding the immunoregulatory mechanisms and immunotoxicity is of interest to developing therapeutics against xenobiotic insults. Recent Advances: While developmental studies have established the essential roles of ROS in the establishment and proper functioning of the immune system, toxicological studies have demonstrated high ROS generation as one of the potential mechanisms of immunotoxicity induced by environmental chemicals, including heavy metals, pesticides, aromatic hydrocarbons (benzene and derivatives), plastics, and nanoparticles. Mitochondrial electron transport and various signaling components, including NADH oxidase, toll-like receptors (TLRs), NF-κB, JNK, NRF2, p53, and STAT3, are involved in xenobiotic-induced ROS generation and immunotoxicity. Critical Issues: With many studies demonstrating the role of ROS and oxidative stress in xenobiotic-induced immunotoxicity, rigorous and orthogonal approaches are needed to achieve in-depth and precise understanding. The association of xenobiotic-induced immunotoxicity with disease susceptibility and progression needs more data acquisition. Furthermore, the general methodology needs to be possibly replaced with high-throughput precise techniques. Future Directions: The progression of xenobiotic-induced immunotoxicity into disease manifestation is not well documented. Immunotoxicological studies about the combination of xenobiotics, age-related sensitivity, and their involvement in human disease incidence and pathogenesis are warranted. Antioxid. Redox Signal. 40, 691-714.

Therapeutic potential of low dose ionizing radiation against cancer, dementia, and diabetes: evidences from epidemiological, clinical, and preclinical studies.

The growing use of ionizing radiation (IR)-based diagnostic and treatment methods has been linked to increasing chronic diseases among patients and healthcare professionals. However, multiple factors such as IR dose, dose-rate, and duration of exposure influence the IR-induced chronic effects. The predicted links between low-dose ionizing radiation (LDIR) and health risks are controversial due to the non-availability of direct human studies. The studies pertaining to LDIR effects have importance in public health as exposure to background LDIR is routine. It has been anticipated that data from epidemiological and clinical reports and results of preclinical studies can resolve this controversy and help to clarify the notion of LDIR-associated health risks. Accumulating scientific literature shows reduced cancer risk, cancer-related deaths, curtailed neuro-impairments, improved neural functions, and reduced diabetes-related complications after LDIR exposure. In addition, it was found to alter evolutionarily conserved stress response pathways. However, the picture of molecular signaling pathways in LDIR responses is unclear. Besides, there is limited/no information on biomarkers of epidemiological LDIR exposure. Therefore, the present review discusses epidemiological, clinical, and preclinical studies on LDIR-induced positive effects in three chronic diseases (cancer, dementia, and diabetes) and their associated molecular mechanisms. The knowledge of LDIR response mechanisms may help to devise LDIR-based therapeutic modalities to stop disease progression. Modulation of these pathways may be helpful in developing radiation resistance among humans. However, more clinical evidence with additional biochemical, cellular, and molecular data and exploring the side effects of LDIR are the major areas of future research.

Novel hybrids of thiazolidinedione-1,3,4-oxadiazole derivatives: synthesis, molecular docking, MD simulations, ADMET study, in vitro, and in vivo anti-diabetic assessment.

As compared to standard medicinal compounds, hybrid molecules that contain multiple biologically active functional groups have greater affinity and efficiency. Hence based on this concept, we predicted that a combination of thiazolidinediones and 1,3,4-oxadiazoles may enhance α-amylase and α-glucosidase inhibition activity. A series of novel 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)thiazolidine-2,5-dione derivatives (5a-5j) were synthesized and characterized using different spectroscopic techniques i.e., FTIR, 1H-NMR, 13C-NMR and MS. To evaluate in silico, molecular docking, MMGBSA, and MD simulations were carried out which were further evaluated via in vitro inhibition of α-amylase and α-glycosidase enzyme inhibition assays. In addition, the in vivo study was performed on a genetic model of Drosophila melanogaster to assess the antihyperglycemic effects. The compounds (5a-5j) demonstrated α-amylase and α-glucosidase inhibitory activity in the range of IC50 values 18.42 ± 0.21-55.43 ± 0.66 µM and 17.21 ± 0.22-51.28 ± 0.88 µM respectively when compared to standard acarbose. Based on the in vitro studies, compounds 5a, 5b, and 5j were found to be potent against both enzymes. In vivo studies have shown that compounds 5a, 5b, and 5j lower glucose levels in Drosophila. These compounds could be further developed in the future to produce a new class of antidiabetic agents.

Dextran sodium sulfate alters antioxidant status in the gut affecting the survival of Drosophila melanogaster.

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic inflammation in the intestine. Several studies confirmed that oxidative stress induced by an enormous amount of reactive free radicals triggers the onset of IBD. Currently, there is an increasing trend in the global incidence of IBD and it is coupled with a lack of adequate long-term therapeutic options. At the same time, progress in research to understand the pathogenesis of IBD has been hampered due to the absence of adequate animal models. Currently, the toxic chemical Dextran Sulfate Sodium (DSS) induced gut inflammation in rodents is widely perceived as a good model of experimental colitis or IBD. Drosophila melanogaster, a genetic animal model, shares ~ 75% sequence similarity to genes causing different diseases in humans and also has conserved digestion and absorption features. Therefore, in the current study, we used Drosophila as a model system to induce and investigate DSS-induced colitis. Anatomical, biochemical, and molecular analyses were performed to measure the levels of inflammation and cellular disturbances in the gastrointestinal (GI) tract of Drosophila. Our study shows that DSS-induced inflammation lowers the levels of antioxidant molecules, affects the life span, reduces physiological activity and induces cellular damage in the GI tract mimicking pathophysiological features of IBD in Drosophila. Such a DSS-induced Drosophila colitis model can be further used for understanding the molecular pathology of IBD and screening novel drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03349-2.

Systematic toxicity assessment of CdTe quantum dots in Drosophila melanogaster.

The risk assessment of cadmium (Cd)-based quantum dots (QDs) used for biomedical nanotechnology applications has stern toxicity concerns. Despite cytotoxicity studies of cadmium telluride (CdTe) QDs, the systematic in vivo study focusing on its organismal effects are more relevant to public health. Therefore, the present study aims to investigate the effect of chemically synthesized 3-mercapto propionic acid-functionalized CdTe QDs on organisms' survival, development, reproduction, and behaviour using Drosophila melanogaster as a model. The sub-cellular impact on the larval gut was also evaluated. First/third instar larvae or the adult Drosophila were exposed orally to green fluorescence emitting CdTe QDs (0.2-100 µM), and organisms' longevity, emergence, reproductive performance, locomotion, and reactive oxygen species (ROS), and cell death were assessed. Uptake of semiconductor CdTe QDs was observed as green fluorescence in the gut. A significant decline in percentage survivability up to 80% was evident at high CdTe QDs concentrations (25 and 100 µM). The developmental toxicity was marked by delayed and reduced fly emergence after CdTe exposure. The teratogenic effect was evident with significant wing deformities at 25 and 100 µM concentrations. However, at the reproductive level, adult flies' fecundity, fertility, and hatchability were highly affected even at low concentrations (1 µM). Surprisingly, the climbing ability of Drosophila was unaffected at any of the used CdTe QDs concentrations. In addition to organismal toxicity, the ROS level and cell death were elevated in gut cells, confirming the sub-cellular toxicity of CdTe QDs. Furthermore, we observed a significant rescue in CdTe QDs-associated developmental, reproductive, and survival adversities when organisms were co-exposed with N-acetyl-cysteine (NAC, an antioxidant) and CdTe QDs. Overall, our findings indicate that the environmental release of aqueously dispersible CdTe QDs raises a long-lasting health concern on the development, reproduction, and survivability of an organism.

Environmental toxicants, oxidative stress and health adversities: interventions of phytochemicals.

OBJECTIVES: Oxidative stress is the most common factor mediating environmental chemical-induced health adversities. Recently, an exponential rise in the use of phytochemicals as an alternative therapeutics against oxidative stress-mediated diseases has been documented. Due to their free radical quenching property, plant-derived natural products have gained substantial attention as a therapeutic agent in environmental toxicology. The present review aimed to describe the therapeutic role of phytochemicals in mitigating environmental toxicant-mediated sub-cellular and organ toxicities via controlling cellular antioxidant response. METHODS: The present review has covered the recently related studies, mainly focussing on the free radical scavenging role of phytochemicals in environmental toxicology. KEY FINDINGS: In vitro and in vivo studies have reported that supplementation of antioxidant-rich compounds can ameliorate the toxicant-induced oxidative stress, thereby improving the health conditions. Improving the cellular antioxidant pool has been considered as a mode of action of phytochemicals. However, the other cellular targets of phytochemicals remain uncertain. CONCLUSIONS: Knowing the therapeutic value of phytochemicals to mitigate the chemical-induced toxicity is an initial stage; mechanistic understanding needs to decipher for development as therapeutics. Moreover, examining the efficacy of phytochemicals against mixer toxicity and identifying the bioactive molecule are major challenges in the field.

Insight into the evolutionary profile of radio-resistance among insects having intrinsically evolved defence against radiation toxicity.

Ionizing radiation (IR) has wide-ranging applications in various fields. In agriculture, pest control is one of the important applications, because insect pests have become a threat to the global agriculture industry. IR are used routinely to prevent crop loss and to protect stored food commodities. Radio-sterilization and disinfestation treatments are commonly used procedures for insect pest control. From various studies on insect radio-sterilization and disinfestation, it has been established that compared to vertebrates' insects have high levels of radiation resistance. Therefore, to achieve adequate radio-sterilization/disinfestation; exposure to high doses of IR is necessary. However, studies over decades made a presumption that radiation resistance is general among insects. Recent studies have shown that some insect orders are having high IR resistance and some insect orders are sensitive to IR. These studies have clarified that radiation resistance is not uniform throughout insect class. The present review is an attempt to insight at the evolutionary profile of insect species studied for radio-sterilization and disinfestation treatment and are having the trait of radio-resistance. From various studies on insect radiation resistance and after phylogenetic analysis of insect species it appears that the evolutionary near species have drastically different levels of radio-resistance and trait of radiation resistance appears to be independent of insect evolution.

Heavy metal associated health hazards: An interplay of oxidative stress and signal transduction.

Heavy metal-induced cellular and organismal toxicity have become a major health concern in biomedical science. Indiscriminate use of heavy metals in different sectors, such as, industrial-, agricultural-, healthcare-, cosmetics-, and domestic-sectors has contaminated environment matrices and poses a severe health concern. Xenobiotics mediated effect is a ubiquitous cellular response. Oxidative stress is one such prime cellular response, which is the result of an imbalance in the redox system. Further, oxidative stress is associated with macromolecular damages and activation of several cell survival and cell death pathways. Epidemiological as well as laboratory data suggest that oxidative stress-induced cellular response following heavy metal exposure is linked with an increased risk of neoplasm, neurological disorders, diabetes, infertility, developmental disorders, renal failure, and cardiovascular disease. During the recent past, a relation among heavy metal exposure, oxidative stress, and signaling pathways have been explored to understand the heavy metal-induced toxicity. Heavy metal-induced oxidative stress and its connection with different signaling pathways are complicated; therefore, the systemic summary is essential. Herein, an effort has been made to decipher the interplay among heavy metals/metalloids (Arsenic, Chromium, Cadmium, and Lead) exposures, oxidative stress, and signal transduction, which are essential to mount the cellular and organismal response. The signaling pathways involved in this interplay include NF-κB, NRF2, JAK-STAT, JNK, FOXO, and HIF.

Radioprotective role of uric acid: evidence from studies in Drosophila and human dermal fibroblast cells.

Exposure to ionizing radiation (IR) is a common phenomenon during medical diagnosis and treatment. IRs are deleterious because cellular exposure to IR can cause a series of molecular events that may lead to oxidative stress and macromolecular damage. Radiation protection is therefore essential and significant for improving safety during these procedures. Over decades several antioxidant molecules have been screened to explore their potential as radio-protectors with little success. Therefore, the current study was carried out to confirm the role of uric acid (UA)-a putative antioxidant molecule in radioprotection using radio-resistant insect Drosophila and human dermal fibroblast (HDF) cells. Here, we demonstrate the depleted levels of UA in the mutant flies of Drosophila melanogaster-rosy and by targeting xanthine oxidase (XO an enzyme involved in UA metabolism), through maintaining flies on an allopurinol mixed diet. Allopurinol is a drug that reduces UA levels by inhibiting XO; it reduces the survival percentage in D. melanogaster compared to wild type flies following gamma irradiation at a dose of 1000 Gy. Enzymatic antioxidants such as superoxide dismutase (SOD), catalase, D. melanogaster glutathione peroxidase (DmGPx) and levels of non-enzymatic antioxidants were measured to evaluate the importance of UA. The results indicate that lack of UA reduces the total antioxidant capacity. The activity of SOD was lowered in male flies. Furthermore, we show that supplementation of UA to HDFs cells in media improved their survival rate following gamma irradiation (2 Gy). From the present study we conclude that UA is a potent antioxidant molecule present in high levels among insects. Also, it appears that UA contributes to the radiation resistance of Drosophila flies. Hence, UA emerges as a promising molecule for mitigating radiation-induced oxidative damage in higher organisms.

Levels and fluxes in enzymatic antioxidants following gamma irradiation are inadequate to confer radiation resistance in Drosophila melanogaster.

Ionizing radiation (IR) causes biological effects either by directly damaging the molecules or by generating free radicals. Antioxidant mechanisms are believed to be involved in neutralising free radicals. Levels of antioxidants therefore assume significance in determining the extent of radiation damage. The fruit fly Drosophila melanogaster (D. melanogaster) exhibits remarkable IR tolerance compared to mammals. Present study addresses the questions (1) Whether levels of antioxidants are high in radio-tolerant fruit fly D. melanogaster compared to mammals? (2) Does the antioxidant activity enhance adequately enough post-irradiation? We analysed enzymatic antioxidant profiles and their fluxes prior to and 60 min post-irradiation (50 Gy). Enzymatic antioxidants were analysed in all the developmental stages of D. melanogaster as the fruit fly shows dramatic changes in radiation resistance during development. Activity of superoxide dismutase (SOD) in Drosophila (pre-irradiation) was comparable to that of mammals. Catalase activity was lower than mammals while glutathione peroxidise (DmGPx) activity was significantly higher. Following irradiation SOD showed changes ranging from 1.40 to 1.62 folds only in larval stages. Catalase activity showed positive change of 1.25 folds only in adults. Activity of DmGPx was largely unaffected. Early pupae showed increased (3.67 fold) glutathione S-transferase activity post-irradiation. Non-enzymatic antioxidants such as total antioxidant capacity showed significant whereas reduced glutathione showed insignificant flux. In conclusion, the levels of enzymatic antioxidants in Drosophila compared to IR sensitive mammals and post-irradiation fluxes in antioxidant enzyme levels appear inadequate to explicate the dramatic radiation resistance observed in Drosophila. The observations are in agreement with the recent findings refuting the role of enzymatic antioxidants in radiation resistance.

Concomitant changes in radiation resistance and trehalose levels during life stages of Drosophila melanogaster suggest radio-protective function of trehalose.

PURPOSE: During development, various life stages of Drosophila melanogaster (D. melanogaster) show different levels of resistance to gamma irradiation, with the early pupal stage being the most radiation sensitive. This provides us an opportunity to explore the biochemical basis of such variations. The present study was carried out to understand the mechanisms underlying radiation resistance during life stages of D. melanogaster. MATERIALS AND METHODS: Homogenates from all the life stages of D. melanogaster were prepared at stipulated age. These homogenates were used for the determination of (1) enzymatic antioxidants: superoxide dismutase (SOD), catalase, D. melanogaster glutathione peroxidase (DmGPx), and glutathione S-transferase (GST); (2) reducing non-enzymatic antioxidants: total antioxidant capacity (TAC), reduced glutathione (GSH) and non-reducing non-enzymatic antioxidant trehalose; and (3) levels of protein carbonyl (PC) content. Age-dependent changes in radiation resistance and associated biochemical changes were also studied in young (2 d) and old (20 and 30 d) flies. RESULTS: TAC and GSH were found high in the early pupal stage, whereas catalase and DmGPx were found to increase in the early pupal stage. The non-feeding third instar (NFTI) larvae were found to have high levels of SOD and GST, besides NFTI larvae showed high levels of trehalose. A remarkable decrease was observed in radiation resistance and trehalose levels during the early pupal stage. The PC level was the highest during early pupal stage and was the lowest in NFTI larvae. Older flies showed high level of PC compared with young flies. CONCLUSION: In vitro increments in trehalose concentration correspond to reduced formation of PCs, suggesting a protective role of trehalose against free radicals. A strong correlation between levels of trehalose and PC formation suggests amelioration of proteome damage due to ionizing radiation (IR). Stages with high trehalose levels showed protected proteome and high radiation resistance, suggesting a significant role for this disaccharide in radiation resistance.

Gamma radiation tolerance in different life stages of the fruit fly Drosophila melanogaster.

PURPOSE: Insects are known to have higher levels of radiation tolerance than mammals. The fruit fly Drosophila provides opportunities for genetic analysis of radiation tolerance in insects. A knowledge of stage-specific sensitivity is required to understand the mechanisms and test the existing hypothesis of insect radiation tolerance. MATERIALS AND METHODS: Drosophila melanogaster were irradiated using gamma rays at different life stages. Irradiation doses were chosen to start from 100-2200 Gy with increments of 100 Gy, with a dose rate of 12.5 and 25 Gy/min. The threshold of mortality, LD50 and LD100 1 h post-irradiation was recorded for larvae and adults and 24 h post-irradiation for eggs and after 2-3 days for early and late pupae. Total antioxidant capacity for all the life stages was measured using the phosphomolybdenum method. RESULTS: Twenty-four hours post-irradiation, 100% mortality was recorded for eggs at 1000 Gy. One hour post irradiation 100% mortality was recorded at 1300 Gy for first instar larvae, 1700 Gy for second instar larvae, 1900 Gy for feeding third instar larvae and 2200 Gy for non-feeding third instar larvae. Post-irradiation complete failure of emergence (100% mortality) was observed at 130 Gy for early pupae and 1500 Gy for late pupae; 100% mortality was observed at 1500 Gy for adults. The values of LD50 were recorded as 452 Gy for eggs, 1049 Gy for first instar larvae, 1350 Gy for second instar larvae, 1265 Gy for feeding third instar larvae, 1590 Gy for non-feeding third instar larvae, 50 Gy for early pupae, 969 Gy for late pupae, 1228 Gy for adult males and 1250 Gy for adult females. CONCLUSIONS: Early pupae were found to be prone to radiation, whereas the non-feeding third instar larvae were most resistant among all stages. The chromosome number being constant and total antioxidant capacity being nearly constant in all stages, we suggest that high rate of cell division during early pupae makes this stage sensitive to radiation.