This current study seeks to examine the pre-protective function of Quercetin in Cadmium (Cd)-induced liver damage, along with its modulation of the PI3K/Akt/NF-kappaB signaling pathway. A total of 60 male C57BL/6J mice were randomly assigned to four groups: control (C), quercetin (Q, 100 mg/kg/day), Cd (Cd, 2.5 mg/kg/day), and quercetin and Cd (Q+Cd). Before receiving Cd treatment, quercetin was administered intragastrically for 4 weeks. In the present study, liver markers, oxidative stress parameters, pro-inflammatory cytokines, liver histopathology, apoptotic markers and PI3K/Akt/NF-kappaB signaling molecules were examined. We observed that the body weight of the Cd-treated mice dramatically rise after 4 weeks of quercetin pre-administration, and the Cd concentration was significantly decreased. Liver function markers like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were significantly reduced in quercetin treatment in Cd-induced mice. Additionally, we observed that quercetin reduced Cd-mediated liver injury in mice by assessing the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) concentrations and the histological alterations. By monitoring tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), quercetin successfully reduced the inflammatory cytokines that the Cd metal caused in the liver. Additionally, in the liver tissues of Cd-mediated, quercetin could enhance the expression of Bcl-2 and decrease the expression of p-Akt, p-PI3K, Bax, Caspase-9, Caspase-3, NF-kappaB. In conclusion, quercetin protects against Cd induced liver injury via several pathways, including oxidative stress, inflammation and apoptosis, and its protective effect correlates with antioxidant activity.

• MeSH
• Antioxidants * pharmacology   MeSH
• Phosphatidylinositol 3-Kinases * metabolism   MeSH
• Liver drug effects   pathology   metabolism   MeSH
• Cadmium * toxicity   MeSH
• Chemical and Drug Induced Liver Injury * prevention & control   metabolism   pathology   MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• NF-kappa B * metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Proto-Oncogene Proteins c-akt * metabolism   MeSH
• Quercetin * pharmacology   therapeutic use   MeSH
• Signal Transduction * drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized for playing a dual role, since they can be either deleterious or beneficial to biological systems. An imbalance between ROS production and elimination is termed oxidative stress, a critical factor and common denominator of many chronic diseases such as cancer, cardiovascular diseases, metabolic diseases, neurological disorders (Alzheimer's and Parkinson's diseases), and other disorders. To counteract the harmful effects of ROS, organisms have evolved a complex, three-line antioxidant defense system. The first-line defense mechanism is the most efficient and involves antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). This line of defense plays an irreplaceable role in the dismutation of superoxide radicals (O2•-) and hydrogen peroxide (H2O2). The removal of superoxide radicals by SOD prevents the formation of the much more damaging peroxynitrite ONOO- (O2•- + NO• → ONOO-) and maintains the physiologically relevant level of nitric oxide (NO•), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., β-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion.

• MeSH
• Anthocyanins metabolism   pharmacology   MeSH
• Antioxidants * pharmacology   metabolism   MeSH
• Chronic Disease MeSH
• Peroxynitrous Acid pharmacology   MeSH
• Humans MeSH
• Neoplasms * MeSH
• Nitric Oxide MeSH
• Oxidative Stress MeSH
• Hydrogen Peroxide MeSH
• Reactive Oxygen Species metabolism   MeSH
• Superoxide Dismutase metabolism   MeSH
• Superoxides MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Carotenoids are the most abundant lipid-soluble phytochemicals and are used as dietary supplements to protect against diseases caused by oxidative stress. Astaxanthin, a xanthophyll carotenoid, is a very potent antioxidant with numerous beneficial effects on cellular functions and signaling pathways. In this study, using spleen cells from healthy Balb/c mice, we report the bio-functional effects of an astaxanthin-rich extract (EXT) prepared from the microalga Haematococcus pluvialis and its astaxanthin monoesters-rich fraction (ME) and astaxanthin diesters-rich fraction (DE) obtained by fractionation of EXT using countercurrent chromatography (CCC). After incubation under standard culture conditions (humidity, 37 °C, 5% CO2, atmospheric oxygen), the viability of untreated splenocytes, as determined by the trypan blue exclusion assay, the MTT assay, and the neutral red assay, decreases to approximately 75% after 24 h compared with naïve splenocytes. This effect correlated with the decrease in mitochondrial membrane potential and the transition of ~59% of cells to the early stage of apoptosis, as well as with the decreased ROS production, indicating that hyperoxia in cell-culture deteriorates cell functions. They are restored or stimulated by co-cultivation with EXT, ME, and DE up to 10 μg/mL in the order EXT > DE > ME, suggesting that esterification increases bioavailability to cells in vitro. ROS and H2O2 concentrations reflect mRNA transcriptional activity of Nrf2, superoxide dismutase 1 (SOD1), catalase, and glutathione peroxidase 1, as well as SOD-mediated ROS conversion, whereas they inversely correlate with iNOS-mediated NO production. The highest-tested concentration of EXT, ME, and DE (40 μg/mL) is detrimental to cells, probably because of the overwhelming scavenging activity of astaxanthin and its esters for the reactive oxygen/nitrogen species required for cellular functions and signal transduction at low physiological concentrations. In this study, we demonstrate that differential activities of ME and DE contribute to the final antioxidant and cytoprotective effects of astaxanthin extract, which is beneficial in preventing a wide range of ROS-induced adverse effects, with DE being more effective. In addition, the selection of physioxia-like conditions for pharmacological research is highlighted.

• Publication type
• Journal Article MeSH

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.

• MeSH
• Zebrafish MeSH
• Lymphoma, Large B-Cell, Diffuse drug therapy   genetics   metabolism   pathology   MeSH
• Dimethyl Fumarate pharmacology   MeSH
• Ferroptosis drug effects   MeSH
• Humans MeSH
• Mice MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• NF-kappa B genetics   metabolism   MeSH
• Lipid Peroxidation drug effects   genetics   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   genetics   MeSH
• STAT3 Transcription Factor genetics   metabolism   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Halogenated phenols, such as 2,4-dichlorophenol (2,4-DCP) and 4-bromophenol (4-BP) are pollutants generated by a various industrial sectors like chemical, dye, paper bleaching, pharmaceuticals or in an agriculture as pesticides. The use of Horseradish peroxidase (HRP) in the halogenated phenols treatment has already been mentioned, but it is not well understood how the different phenolic substrates can bind in the peroxidase active site nor how these specific interactions can influence in the bioremediation potential. In this work, different removal efficiencies were obtained for phenolic compounds investigated using HRP as catalyst (93.87 and 59.19% to 4BP and 2,4 DCP, respectively). Thus, to rationalize this result based on the interactions of phenols with active center of HRP, we combine computational and experimental methodologies. The theoretical approaches utilized include density functional theory (DFT) calculations, docking simulation and quantum mechanics/molecular mechanics (QM/MM) technique. Michaelis Menten constant (Km) obtained through experimental methodologies were 2.3 and 0.95 mM to 2,4-DCP and 4-BP, respectively, while the specificity constant (Kcat/Km) found was 1.44 mM-1 s-1 and 0.62 mM-1 s-1 for 4-BP and 2,4-DCP, respectively. The experimental parameters appointed to the highest affinity of HRP to 4-BP. According to the molecular docking calculations, both ligands have shown stabilizing intermolecular interaction energies within the HRP active site, however, the 4-BP showed more stabilizing interaction energy (-53.00 kcal mol-1) than 2,4-dichlorophenol (-49.23 kcal mol-1). Besides that, oxidative mechanism of 4-BP and 2,4-DCP was investigated by the hybrid QM/MM approach. This study showed that the lowest activation energy values for transition states investigated were obtained for 4-BP. Therefore, by theoretical approach, the compound 4-BP showed the more stabilizing interaction and activation energy values related to the interaction within the enzyme and the oxidative reaction mechanism, respectively, which corroborates with experimental parameters obtained. The combination between experimental and theoretical approaches was essential to understand how the degradation potential of the HRP enzyme depends on the interactions between substrate and the active center cavity of the enzyme.

• MeSH
• Biodegradation, Environmental * MeSH
• Phenols metabolism   MeSH
• Catalysis MeSH
• Kinetics MeSH
• Horseradish Peroxidase chemistry   MeSH
• Environmental Pollutants MeSH
• Oxidation-Reduction MeSH
• Peroxidases metabolism   MeSH
• Molecular Docking Simulation MeSH
• Publication type
• Journal Article MeSH

The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.

• MeSH
• Antioxidant Response Elements drug effects   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Hep G2 Cells MeSH
• NF-E2-Related Factor 2 genetics   MeSH
• Humans MeSH
• Lipid Peroxidation drug effects   MeSH
• Pyocyanine chemistry   MeSH
• Stilbenes chemistry   pharmacology   MeSH
• Thiobarbiturates chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Neutrophils impact on processes preceding the formation of bradykinin, a major swelling mediator in hereditary angioedema (HAE), yet their potential role in HAE pathogenesis has not been sufficiently studied. We assessed the relative mRNA expression of 10 genes related to neutrophil activation using RNA extracted from the peripheral blood neutrophils of 23 HAE patients in a symptom-free period and 39 healthy donors. Increased relative mRNA expression levels of CD274, IL1B, IL1RN, IL8, MMP9, and TLR4, together with a lack in their mutual correlations detected in HAE patients compared to healthy controls, suggested a preactivated state and dysregulation of patients' neutrophils. Patients' neutrophil-alerted state was further supported by increased CD11b, decreased CD16 plasma membrane deposition, and increased relative CD274+ and CD87+ neutrophil counts, but not by increased neutrophil elastase or myeloperoxidase plasma levels. As CD274 mediates inhibitory signals to different immune cells, neutrophils were cocultured with T-cells/PBMC. The decrease in CD25+ and IFN-γ+ T-cell/PBMC ratio in patients indicated the patients' neutrophil suppressive functions. In summary, the results showed neutrophils' alerted state and dysregulation at the transcript level in patients with HAE types I and II even in a symptom-free period, which might make them more susceptible to edema formation. Neutrophils' T-cell suppressive capacity in HAE patients needs to be further investigated.

• MeSH
• Interleukin 1 Receptor Antagonist Protein metabolism   MeSH
• CD11b Antigen metabolism   MeSH
• B7-H1 Antigen metabolism   MeSH
• Child MeSH
• Adult MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Hereditary Angioedema Types I and II metabolism   MeSH
• Interleukin-1beta metabolism   MeSH
• Interleukin-8 metabolism   MeSH
• Cells, Cultured MeSH
• Leukocytes, Mononuclear metabolism   MeSH
• Humans MeSH
• Matrix Metalloproteinase 9 metabolism   MeSH
• RNA, Messenger MeSH
• Adolescent MeSH
• Young Adult MeSH
• Neutrophils metabolism   MeSH
• Pancreatic Elastase blood   MeSH
• Peroxidase blood   MeSH
• Flow Cytometry MeSH
• Receptors, IgG metabolism   MeSH
• Receptors, Urokinase Plasminogen Activator metabolism   MeSH
• Toll-Like Receptor 4 metabolism   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH

The potential contamination of the food chain is the most important aspect of arsenic (As) pollution, since it is highly toxic to all organisms. Thus, the search for As hyperaccumulators suitable to remove As from contaminated soils appears to be a vital task. Horseradish (Armoracia rusticana), a crop plant with a high potential to accumulate heavy metals, can also serve to study the physiological processes that accompany arsenic stress. The significant adverse effect caused by arsenic exposure is an oxidative stress. Plants have developed a highly organized system to quench free radicals, which includes the action of both enzymatic and non-enzymatic quenching. Saccharides are proposed to possess outstanding antioxidant activity in vitro, and thus, they are likely to effectively quench free radicals also in plant tissues. In this study, root cultures (hairy root type) of horseradish were grown in vitro on media with different concentrations of arsenic (5-60 µg l-1). Arsenic slowed down the growth, nevertheless up to three-fold biomass increase was achieved at the highest dose. Moreover, root tissues were able to remove as much as 75% of arsenic from the cultivation medium within 7 days. We also evaluated diverse oxidative-stress-related features: contents of reactive oxygen species, the activities of key antioxidant enzymes, and the contents of important antioxidant molecules, such as glutathione, proline, phenolic compounds and non-structural carbohydrates. At all arsenic treatments, we observed a significant proline content increase and enhanced antioxidant enzymes (peroxidase, catalase and glutathione-S-transpherase) activities peaking, however, at different doses. Soluble carbohydrates contents also significantly increased after 7-day treatment a then decreased nearly to the original levels. This study points to efficient antioxidant system of horseradish hairy roots enabling good growth and substantial As accumulation even under high As exposure. Providing that horseradish shares these important features with this model system, we could propose that horseradish is a promising candidate to exploit in arsenic phytoremediation.

• MeSH
• Antioxidants metabolism   MeSH
• Armoracia growth & development   metabolism   MeSH
• Arsenic metabolism   toxicity   MeSH
• Biodegradation, Environmental MeSH
• Plant Roots growth & development   metabolism   MeSH
• Soil Pollutants metabolism   toxicity   MeSH
• Oxidative Stress drug effects   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Models, Theoretical MeSH
• Publication type
• Journal Article MeSH

Although humic acids (HA) are involved in many biological processes in soils and thus their ecological importance has received much attention, the degradative pathways and corresponding catalytic genes underlying the HA degradation by bacteria remain unclear. To unveil those uncertainties, we analyzed transcriptomes extracted from Pseudomonas sp. PAMC 26793 cells time-dependently induced in the presence of HA in a lab flask. Out of 6288 genes, 299 (microarray) and 585 (RNA-seq) were up-regulated by > 2.0-fold in HA-induced cells, compared with controls. A significant portion (9.7% in microarray and 24.1% in RNA-seq) of these genes are predicted to function in the transport and metabolism of small molecule compounds, which could result from microbial HA degradation. To further identify lignin (a surrogate for HA)-degradative genes, 6288 protein sequences were analyzed against carbohydrate-active enzyme database and a self-curated list of putative lignin degradative genes. Out of 19 genes predicted to function in lignin degradation, several genes encoding laccase, dye-decolorizing peroxidase, vanillate O-demethylase oxygenase and reductase, and biphenyl 2,3-dioxygenase were up-regulated > 2.0-fold in RNA-seq. This induction was further confirmed by qRT-PCR, validating the likely involvement of these genes in the degradation of HA.

• MeSH
• Genes, Bacterial MeSH
• Biodegradation, Environmental MeSH
• Databases, Protein MeSH
• Humic Substances microbiology   MeSH
• Lignin metabolism   MeSH
• Metabolic Networks and Pathways * MeSH
• Pseudomonas genetics   metabolism   MeSH
• Soil Microbiology * MeSH
• Gene Expression Regulation, Bacterial MeSH
• Gene Expression Profiling * MeSH
• Tundra * MeSH
• Publication type
• Journal Article MeSH

Here we present the preparation of 14 pairs of cis- and trans-diammine monochlorido platinum(II) complexes, coordinated to heterocycles (i.e., imidazole, 2-methylimidazole and pyrazole) and linked to various acylhydrazones, which were designed as potential inhibitors of the selenium-dependent enzymes glutathione peroxidase 1 (GPx-1) and thioredoxin reductase 1 (TrxR-1). However, no inhibition of bovine GPx-1 and only weak inhibition of murine TrxR-1 was observed in in vitro assays. Nonetheless, the cis configured diammine monochlorido Pt(II) complexes exhibited cytotoxic and apoptotic properties on various human cancer cell lines, whereas the trans configured complexes generally showed weaker potency with a few exceptions. On the other hand, the trans complexes were generally more likely to lack cross-resistance to cisplatin than the cis analogues. Platinum was found bound to the nuclear DNA of cancer cells treated with representative Pt complexes, suggesting that DNA might be a possible target. Thus, detailed in vitro binding experiments with DNA were conducted. Interactions of the compounds with calf thymus DNA were investigated, including Pt binding kinetics, circular dichroism (CD) spectral changes, changes in DNA melting temperatures, unwinding of supercoiled plasmids and ethidium bromide displacement in DNA. The CD results indicate that the most active cis configured pyrazole-derived complex causes unique structural changes in the DNA compared to the other complexes as well as to those caused by cisplatin, suggesting a denaturation of the DNA structure. This may be important for the antiproliferative activity of this compound in the cancer cells.

• MeSH
• Enzyme Activation drug effects   MeSH
• Chondroitin analogs & derivatives   chemistry   pharmacology   MeSH
• DNA chemistry   drug effects   MeSH
• Enzymes metabolism   MeSH
• Glutathione Peroxidase antagonists & inhibitors   MeSH
• Inhibitory Concentration 50 MeSH
• Aspartic Acid analogs & derivatives   chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Oxidation-Reduction MeSH
• Platinum chemistry   pharmacology   toxicity   MeSH
• Cell Proliferation drug effects   MeSH
• Selenium chemistry   pharmacology   toxicity   MeSH
• Cattle MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH