With numerous new chemicals introduced into the environment everyday, identification of their potential hazards to the environment and human health is a considerable challenge. Developing adverse outcome pathway (AOP) framework is promising in helping to achieve this goal as it can bring In Vitro testing into toxicity measurement and understanding. To explore the toxic mechanism underlying environmental chemicals via the AOP approach, an integration of adequate experimental data with systems biology understanding is preferred. Here, we describe a novel method to develop reliable and sensible AOPs that relies on chemical-gene interactions, toxicity pathways, molecular regulations, phenotypes, and outcomes information obtained from comparative toxicogenomics database (CTD) and Ingenuity Pathway Analysis (IPA). Using Benzo(a)pyrene (BaP), a highly studied chemical as a stressor, we identified the pivotal IPA toxicity pathways, the molecular initiating event (MIE), and candidate key events (KEs) to structure AOPs in the liver and lung, respectively. Further, we used the corresponding CTD information of multiple typical AHR-ligands, including 2,3,7,8-tetrachlorodibenzoparadioxin (TCDD), valproic acid, quercetin, and particulate matter, to validate our AOP networks. Our approach is likely to speed up AOP development as providing a time- and cost-efficient way to collect all fragmented bioinformation in published studies. It also facilitates a better understanding of the toxic mechanism of environmental chemicals, and potentially brings new insights into the screening of critical paths in the AOP network.

An emerging stress of pesticides in plant and soil is closely watched as it affects crop antioxidant systems, nutritional quality, and flavor. Although selenium (Se) can enhance the resistance of plants, the protective mechanism of nanoselenium is still not known under the long-term pesticide stress in tea trees. In this study, we investigated the potential effects of foliar application of nanoselenium for a two-year field experiment on tea plants under pesticide-induced oxidative stress. Compared to control, nano-Se (10 mg/L) markedly enhanced the protein, soluble sugar, carotenoid, tea polyphenols, and catechins contents. High levels of theanine, glutamic acid, proline, and arginine were found to be induced most likely by adjusting the GS-GOGAT cycle. Se-supplementation may promote tea leaves’ secondary metabolism, thus increasing the accumulation of total phenols and flavonoids (apigenin, kaempferol, quercetin, myricetin, and rutin). It also minimized the accumulation of malondialdehyde, hydrogen peroxide, and superoxide anion by activating the antioxidants enzymes including in the AsA-GSH cycle. Selenium-rich tea also showed better fragrance and flavor. In summary, nano-Se can ameliorate the nutrients quality and abiotic stresses resistance of crops.

Imidacloprid (IMI) is widely used in agriculture, and is toxic to non-target aquatic species. Quercetin (Que) is a flavonoid abundant in fruits and vegetables that exhibits anti-oxidant activity. In the present study, we treated grass carp hepatocytes (L8824) with 0.1 μM Que and/or 1 mM IMI for 24 h to explore the effect of Que on IMI-induced mitochondrial apoptosis. We found that IMI exposure enhanced reactive oxygen species (ROS) generation, inhibiting the activities of SOD, CAT and T-AOC, exacerbating the accumulation of MDA, aggravating the expression of mitochondrial apoptosis pathway (Cyt-C, BAX, Caspase9 and Caspase3) related genes and decreased the expression of anti-apoptosis gene B-cell lymphoma-2 (Bcl-2). In addition, Que and IMI co-treatment significantly restored the activity of anti-oxidant enzymes, downregulated ROS level and apoptosis rate, thereby alleviating the depletion of mitochondrial membrane potential (ΔΨm) and the expression of cytochrome c (Cyt-C), Bcl-2-associated X (BAX), and cysteinyl aspartate specific proteinases (Caspase9 and 3), increasing the Bcl-2 level. Furthermore, we elucidated that Que could inhibit the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), thus activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway to attenuate IMI-induced apoptosis. Molecular docking provides assertive evidence for the interaction between Que ligand and PTEN receptor. Consequently, these results indicate that Que effectively antagonizes IMI-induced mitochondrial apoptosis in grass carp hepatocytes via regulating the PTEN/PI3K/AKT pathway.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and several other environment/food-borne toxic compounds induce their toxicity via the aryl hydrocarbon receptor (AhR). AhR is also modulated by various endogenous ligands e.g. highly potent tryptophan (Trp)-derivative FICZ (6-formylindolo[3,2-b]carbazole) and natural ligands abundant in the human diet e.g. polyphenols. Therefore, evaluating AhR species-specific responses is crucial for understanding AhR physiological functions, establishing risk assessments, and exploring the applicability of AhR mediators in drug and food industry towards human-based usages. We studied AhR transactivation of FICZ/TCDD in vitro in a time-dependent and species-specific manner using dioxin responsive luciferase reporter gene assays derived from rat (DR-H4IIE) and human (DR-HepG2) hepatoma cells. We observed for the first time that FICZ potency was similar in both cell lines and was 40 times higher than TCDD in DR-HepG2 cells. Depleting Trp-derivative endogenously produced ligands by using culture medium without Trp, resulted in 3-fold higher AhR activation upon adding FICZ in DR-H4IIE cells, in contrast to DR-HepG2 cells which revealed a fast degradation of FICZ induction from 10 h post-exposure to complete disappearance after 24 h. Seven polyphenols and a mixture thereof, chosen based on commercially recommended doses and adjusted to human realistic exposure, caused rat and human species-specific AhR responses. Two isoflavones (daidzein and genistein) induced rat AhR synergistic effects with FICZ and/or TCDD, while quercetin, chrysin, curcumin, resveratrol, and the mixture exerted a strong inhibitory effect on the human AhR. Strikingly, resveratrol and quercetin at their realistic nanomolar concentrations acted additively in the mixture to abolish human AhR activation induced by various TCDD concentrations. Taken together, these results illustrate the species-specific complexity of AhR transcriptional activities modulated by various ligands and highlight the need for studies of human-based approaches.

International audience | The neurological damages resulted by endosulfan poisoning is not completely elucidated, especially in cellular organelles such as mitochondria. In the present study, the pro-oxidant effect of endosulfan on brain mitochondria was first investigated. Gavages of endosulfan into rats at the dose of 2 mg/kg induced oxidative stress in this organelle since it provokes a significant reduction of catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) level. In addition, a significant increase in mitochondria swelling and malondialdehyde (MDA) levels were observed in neuronal mitochondria, indicating clearly an intense peroxidation within mitochondria. Second, the protective effect of quercetin (QE) (10 mg/kg) against endosulfan-induced oxidative stress in mitochondria was also assessed. Indeed, the pretreatment of rats with QE protects brain mitochondria from oxidative stress, lipid peroxidation, and mitochondria swelling induced by endosulfan. The activities of antioxidant enzymes and the mitochondrial content of GSH and MDA were returned to control values. Thus, although endosulfan can have neurotoxic effects in brain rats, this toxicity can be prevented by quercetin.

Type 2 diabetes mellitus is a complicated metabolic disorder with no definite treatment. Cyperus iria (Cyperaceae) possess several traditional therapeutic uses. According to the folklore tales, the whole plant of Cyperus iria possesses antihyperglycemic activity. The present study was undertaken to investigate whether aqueous-ethanol extract of Cyperus iria can ameliorate the altered activities of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats along with appraisal of inflammatory and stress markers involved in endocrine dysfunction. Presence of biophenolics and flavonoids might be responsible for the antidiabetic potential. STZ-induced diabetic rats were treated orally with Cyperus iria extract (125, 250, and 500 mg/kg) for 15 days. Blood samples were collected. Metformin was used as positive control. Significantly higher quantities of phenolic (82.79±0.003 mg/g GAE) and flavonoid (13.61±0.002 mg/g QE) contents were present. Inhibitory concentration (IC50) exhibited an excellent potential for both antioxidant (IC50= 3.22 μg/mL) and alpha amylase (IC50=36.29 μg/mL) inhibitory assays. High-performance liquid chromatography (HPLC) confirmed the existence of myercetin, quercetin, kaempferol, and ferulic acid. Cyperus iria aqueous-ethanol extract exhibits good tolerance against glucose at 90 min in normal rats. Streptozotocin-induced hyperglycemia declined significantly at day 9 (265 mg/dL) along with improvement in inflammatory (TNF-α=15.6± 0.2 g/l, COX-2=357±0.396 U/l, IL-6= 572±0.99 pg/l) and oxidative stress markers (SOD= 163±0.616 and GSH-ST= 95.8±0.44 U/mL) along with biochemical parameters in a dose-dependent manner. Present study suggests that Cyperus iria aqueous-ethanol extract possesses hypoglycemic potential which might be attributed to the decrease in oxidative stress and inflammatory markers.

Date was considered a high nutritional value fruit due to its high content of active ingredients. Frequent exposure to cosmetic radiations including UVC caused deleterious effects and tissue damage and organ affection. This study investigated the efficacy of Ajwa date extract (ADE) in protection against UVC-induced kidney injury in rats. Five groups of rats were included in this study. Group I: Rats were exposed to UVC radiation at a dose 5 kJ (1 h/day) for 28 days. Group II: Rats were pretreated orally with ADE (10 mg/kg/day) 1 h before exposure to UVC radiation with dose 5 kJ. Group III: Rats were pretreated with ADE (15 mg/kg) 1 h before exposure to UVC radiation. Group IV: Rats were exposed to UVC radiation then treated with ADE (10 mg/kg). Group V: Rats exposed to UV radiation then treated with ADE (15 mg/kg) after 1 h from exposure. Analyzing the active constituents of ADE by GC/MS showed that, quercetin, myricetin kaempferol, thymine, and catechol are the most active ingredients. Biochemical markers obtained showed that, serum 8-oxoguanine as marker for DNA damage was increased, and total antioxidant activity and glutathione reduced were decreased (p < 0.01), while neutrophil (p < 0.001), conjugated diene (p < 0.05), and interferon-γ (p < 0.01) were increased after exposure to UVC. However, all the parameters changed were reversed by ADE-treated rats compared with untreated; the higher dose was more effective and protective effect was better than treated effect. Kidney total proteins and reduced glutathione and procollagen levels were decreased while malondialdehyde was increased after exposure to UVC (p < 0.01). These abnormalities were normalized by ADE treatment and protected. It was concluded that, flavonoids from Ajwa extract protected against deleterious effects of UVC by enhancing antioxidant activities and reducing infiltration of neutrophils that caused kidney injury.

In this study, we investigated the possible role of pesticide exposure in contributing to neurological diseases such as depression. Here, we evaluated whether a subchronic low dose of a glyphosate-based herbicide (GBH) could induce alterations in the central nervous system, using the flavonoid quercetin as a therapeutic strategy. Forty mice were divided into four treatment groups: control, GBH, quercetin, and GBH+Quer groups and received 50 mg/kg of GBH solution, 30 mg/kg of quercetin, and/or vehicles for 30 days via gavage. After performing behavioral tests, such as the open field (OF), elevated plus maze (EPM), forced swim test (FST), and sucrose preference test (SPT), the mice were euthanized and their hippocampal tissues were collected to measure the levels of oxidative stress markers such as reactive species (RS), total antioxidant capacity (FRAP), reduced glutathione (GSH), and acetylcholinesterase activity (AChE), as well as for histological evaluation. The GBH group showed anxious and depressive-like behavior in the EPM and FST tests, as well as increased levels of RS and decreased GSH levels in the hippocampus. Quercetin treatment in the GBH+Quer group allowed partial or total improvement in behavioral tests (EPM and FST) and in the levels of oxidative stress markers (RS and GSH). However, the quercetin group showed similar behavior to the GBH group after treatment. The results revealed that oral exposure to a subchronic low dose of GBH was capable of promoting effects on behavior and oxidative stress in the hippocampus of mice. In addition, despite quercetin having a neuroprotective role, caution is needed when considering the possible per se effects of its continuous supplementation.

After the early advent of the Coronavirus Disease 2019 (COVID-19) pandemic, myriads of FDA-approved drugs have been massively repurposed for COVID-19 treatment based on molecular docking against selected protein targets that play fundamental roles in the replication cycle of the novel coronavirus. Honeybee products are well known of their nutritional values and medicinal effects. Bee products contain bioactive compounds in the form of a collection of phenolic acids, flavonoids, and terpenes of natural origin that display wide spectrum antiviral effects. We revealed by molecular docking the profound binding affinity of 14 selected phenolics and terpenes present in honey and propolis (bees glue) against the main protease (Mᵖʳᵒ) and RNA-dependent RNA polymerase (RdRp) enzymes of the novel SARS-CoV-2 virus (the causative agent of COVID-19) using AutoDock Vina software. Of these compounds, p-coumaric acid, ellagic acid, kaempferol, and quercetin have the strongest interaction with the SARS-CoV-2 target enzymes, and it may be considered an effective COVID-19 inhibitor.

The present study focused on the full valorization of the tomato by-product, also known as tomato pomace consisting mainly of tomato peels and tomato seeds, by recovering natural antioxidants and edible oil, and subsequently reutilizing the leftover solid residues for the production of low-cost biosorbent. The tomato peel extract recovered using ethanol as food-grade solvent contained high phenol and flavonoid contents (199.35 ± 0.35-mg gallic acid equivalents (GAE)/g and 102.10 ± 0.03-mg quercetin equivalent (QE)/g, respectively). Even its lower content of lycopene (3.67 ± 0.04 mg/100 g), tomato peel extract showed potent antioxidant activity and can be therefore used as natural antioxidants either for food or cosmetic applications. High nutritional quality edible oil (17.15%) was extracted from tomato seeds and showed richness in unsaturated fatty acids (74.62%), with linoleic acid being the most abundant polyunsaturated fatty acid (49.70%). After recovery of these valuable compounds, the extraction solid leftovers were used to produce low-cost biosorbent tested for dye removal. Results showed that the highest biosorption yields were increasingly attributed to the acidic, direct, anthraquinone, then reactive dyes. Overall, the obtained results strongly support the complete utilization of tomato pomace for the recovery of valuable compounds and the sequential production of low-cost biosorbent.