Thioredoxin Reductase Activity Research Articles

Modulation of the Nrf-2 and HO-1 signalling axis is associated with Betaine's abatement of fluoride-induced hepatorenal toxicities in rats.

Sodium fluoride (NaF) ingestion has several detrimental effects in humans and rodents. NaF mechanisms of toxicity include perturbation of intracellular redox homeostasis and apoptosis. Betaine (BET) is a modified amino acid with anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigates BET's effect on NaF-induced hepatorenal toxicities in rats. Experimental rats (n=30) were randomly assigned to groups (n=6) and treated by gavage for 28 days. Group I (2 mL of distilled water), Group II (NaF: 9 mg/kg) alone, Group III: (BET: 100 mg/kg), Group IV: (NaF: 9 mg/kg and BET 1: 50 mg/kg), and Group V: (NaF: 9 mg/kg and BET 2: 100 mg/kg). Our findings revealed significantly (p<0.05) increased hepatic transaminase activities alongside creatinine and urea levels following NaF-alone treatment in addition to increased oxidative status, lipid peroxidation, reactive oxygen and nitrogen species, decreased superoxide dismutase, catalase, glutathione-s-transferase, glutathione peroxidase, glutathione, and total sulfhydryl groups. The reduced levels of nuclear factor erythroid 2-related factor-2 and the activities of heme oxygenase-1, thioredoxin, and thioredoxin reductase in NaF-alone treated rats equally compromised cellular molecular responses to oxidative stress. Also, NaF increased (p<0.05) hepatorenal inflammatory biomarkers-nitric oxide, interleukin-10, myeloperoxidase, and xanthine oxidase. Furthermore, caspase-3 and caspase-9 were increased (p<0.05) in rats treated with NaF alone. Contrastingly, BET was observed to alleviate the harmful effects of NaF. Treatment with BET mitigated NaF-induced oxido-inflammatory responses and apoptosis in the experimental rat's hepatorenal system. The study demonstrates the potential of BET to abate NaF-induced hepatorenal toxicity.

Synthesis, characterization and anti-ovarian cancer activities of novel biphenyl-NHC-gold(I) complexes

Fifteen novel biphenyl-N-heterocyclic carbene (NHC)-gold(I) complexes were designed and synthesized to treat ovarian cancer (OC). Among these, complex Au-1 showed significant antiproliferative activity against A2780 cells and A2780/CDDP cells. Notably, Au-1 exhibited low toxicity to normal ovarian epithelial IOSE-80 cells. Further studies revealed that Au-1 strongly inhibited thioredoxin reductase (TrxR) activity. Collectively, our results demonstrated that Au-1 could be a promising candidate for the treatment of OC.

The selenoprotein from selenium-rich glutinous rice improves spleen immune protection by inhibiting the NF-κB pathway

Moderate amounts of selenium supplementation have a positive effect on the immune response. Selenium deficiency status can lead to reduced immunity, but the benefits of a natural selenium-rich diet for selenium deficiency are unknown. In this experiment, low selenium feed (0.02 mg Se/kg diet) was given to the mice for 5 weeks and selenium supplementation with selenoprotein (SeP) for 4 weeks, and the selenium-deficient mouse model was successfully established. SeP supplementation had significant protective effects, including increased antioxidant capacity and alleviation of inflammatory damage. SeP markedly elevated the activities of thioredoxin reductase (TrxR) and glutathione peroxidase (GSH-Px) in the serum, kidney, liver, and spleen of selenium-deficient mice. SeP can restore the condition of damaged spleen tissue, raise the spleen index in mice, and encourage an increase in immunoglobulin (IgA, IgG, and IgM) content. The levels of catalase (CAT), total antioxidant capacity (T-AOC), GSH-Px, and cytokines (IL-1β, IL-6, and TNF-α) were all significantly elevated by SeP. SeP showed superior immunomodulatory effects over inorganic selenium (Na2SeO3). Together, these results suggest that SeP may be a potential dietary selenium supplement that can reduce symptoms of spleen damage caused by selenium deficiency.

Melatonin antagonizes oxidative stress-induced apoptosis in retinal ganglion cells through activating the thioredoxin-1 pathway.

This study aimed to explore the role of melatonin in oxidative stress-induced injury on retinal ganglion cells and the underlying mechanisms. The immortalized RGC-5 cells were treated with H2O2 to induce oxidative injury. Cell viability was measured by Cell Counting Kit-8, and apoptosis was determined by flow cytometry and western blot assays. Reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels were examined to evaluate oxidative stress levels. In addition, Thioredoxin-1 (Trx1) was silenced in RGC-5 cells using small interfering RNA followed by signaling pathway examination to explore the underlying mechanisms of melatonin in alleviating oxidative injury. Melatonin pre-treatment significantly alleviated H2O2-induced apoptosis in RGC-5 cells. Melatonin also markedly reversed the upregulation of cleaved-caspase 3, cleaved-caspase 9, and Bax expression and downregulation of Bcl-2 expression induced by H2O2. Further analyses presented that melatonin significantly attenuated the increase of ROS, LDH, and MDA levels in RGC-5 cells after H2O2 treatment. Melatonin also abolished the downregulated expression of Superoxide dismutase type 1, Trx1, and Thioredoxin reductase 1, and the reduced activity of thioredoxin reductase in RGC-5 cells after H2O2 treatment. Notably, Trx1 knockdown significantly mitigated the protective effect of melatonin in alleviating H2O2-induced apoptosis and oxidative stress, while administration of compound C, a common inhibitor of c-Jun N-terminal kinase (JNK) signaling, partially reversed the effect of Trx1 silencing, thereby ameliorating the apoptosis and oxidative injury induced by H2O2 in RGC-5 cells. Melatonin could significantly alleviate oxidative stress-induced injury of retinal ganglion cells via modulating Trx1-mediated JNK signaling pathway.

The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection

In the cytosol of human cells under low oxidative loads, hydrogen peroxide is confined to microdomains around its supply sites, due to its fast consumption by peroxiredoxins. So are the sulfenic and disulfide forms of the 2-Cys peroxiredoxins, according to a previous theoretical analysis [Travasso et al., Redox Biology 15 (2017) 297]. Here, an extended reaction-diffusion model that for the first time considers the differential properties of human peroxiredoxins 1 and 2 and the thioredoxin redox cycle predicts important new aspects of the dynamics of redox microdomains. The peroxiredoxin 1 sulfenates and disulfides are more localized than the corresponding peroxiredoxin 2 forms, due to the former peroxiredoxin's faster resolution step. The thioredoxin disulfides are also localized. As the H2O2 supply rate (vsup) approaches and then surpasses the maximal rate of the thioredoxin/thioredoxin reductase system (V), these concentration gradients become shallower, and then vanish. At low vsup the peroxiredoxin concentration determines the H2O2 concentrations and gradient length scale, but as vsup approaches V, the thioredoxin reductase activity gains influence. A differential mobility of peroxiredoxin disulfide dimers vs. reduced decamers enhances the redox polarity of the cytosol: as vsup approaches V, reduced decamers are preferentially retained far from H2O2 sources, attenuating the local H2O2 buildup. Substantial total protein concentration gradients of both peroxiredoxins emerge under these conditions, and the concentration of reduced peroxiredoxin 1 far from the H2O2 sources even increases with vsup. Altogether, the properties of 2-Cys peroxiredoxins and thioredoxin are such that localized H2O2 supply induces a redox and functional polarization between source-proximal regions (redox microdomains) that facilitate peroxiredoxin-mediated signaling and distal regions that maximize antioxidant protection.

Optimum Doses and Forms of Selenium Maintaining Reproductive Health via Regulating Homeostasis of Gut Microbiota and Testicular Redox, Inflammation, Cell Proliferation, and Apoptosis in Roosters

BackgroundThere is a U-shaped relationship between dietary selenium (Se) ingestion and optimal sperm quality. ObjectivesThis study aimed to investigate the optimal dietary dose and forms of Se for sperm quality of breeder roosters and the relevant mechanisms. MethodsIn experiment 1, 18-wk-old Jingbai laying breeder roosters were fed a Se-deficient base diet (BD, 0.06 mg Se/kg), or the BD + 0.1, 0.2, 0.3, 0.4, 0.5, or 1.0 mg Se/kg for 9 wk. In experiment 2, the roosters were fed the BD or the BD + sodium selenite (SeNa), seleno-yeast (SeY), or Se-nanoparticles (SeNPs) at 0.2 mg Se/kg for 9 wk. ResultsIn experiment 1, added dietary 0.2 and 0.3 mg Se/kg led to higher sperm motility and lower sperm mortality than the other groups at weeks 5, 7, and/or 9. Furthermore, added dietary 0.2–0.4 mg Se/kg produced better testicular histology and/or lower testicular 8-hydroxy-deoxyguanosine than the other groups. Moreover, integrated testicular transcriptomic and cecal microbiomic analysis revealed that inflammation, cell proliferation, and apoptosis-related genes and bacteria were dysregulated by Se deficiency or excess. In experiment 2, compared with SeNa, SeNPs slightly increased sperm motility throughout the experiment, whereas SeNPs slightly reduced sperm mortality compared with SeY at week 9. Both SeY and SeNPs decreased malondialdehyde in the serum than those of SeNa, and SeNPs led to higher glutathione peroxidase (GPX) and thioredoxin reductase activities and GPX1 and B-cell lymphoma 2 protein concentrations in the testis compared with SeY and SeNa. ConclusionsThe optimal dietary Se dose for reproductive health of breeder roosters is 0.25–0.35 mg Se/kg, and SeNPs displayed better effects on reproductive health than SeNa and SeY in laying breeder roosters. The optimal doses and forms of Se maintain reproductive health of roosters associated with regulation intestinal microbiota homeostasis and/or testicular redox balance, inflammation, cell proliferation, and apoptosis.

The Antioxidant and anti-inflammatory Activity of Selenium and Lecithin Combination Against ethanol-induced Gastric Ulcer in mice via Modulating IGF-1/PTEN/Akt/FoxO3a Signaling.

Gastric ulcers are one of the most prevalent gastrointestinal disorders. The current study investigated the antioxidant and anti-inflammatory effects of selenium (Se) and lecithin (Lec) alone and in combination against ethanol-induced gastric ulcers in mice, and their ability to modulate insulin-like growth factor-1 (IGF-1)/ Phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/ Protein kinase B (Akt)/ Forkhead box O3a (FoxO3a) signaling. The mice were divided into normal, ethanol, Se + ethanol, Lec + ethanol, Se + Lec + ethanol, and omeprazole + ethanol groups. Treatment with the selected doses was continued for 14 days before a single dose of absolute ethanol (5 ml/kg body weight) was administered to induce gastric ulcers in mice. The results showed that pretreatment with Se and Lec combination effectively decreased both the macro- and microscopic gastric lesions and increased the protection index compared to the ethanol group. Remarkably, the Se and Lec combination decreased the levels of reactive oxygen species, malondialdehyde, and cytochrome c and increased glutathione, glutathione peroxidase, and thioredoxin reductase activities in gastric tissues. The Se and Lec combination increased prostaglandin E2 and interleukin-10 levels but decreased tumor necrosis factor-α, interleukin-6 and interleukin-1β levels compared to either treatment alone. Interestingly, this combination decreased the expression of IGF-1, p-Akt, and FoxO3a proteins and increased PTEN expression in gastric tissues. The gastric tissues examination by hematoxylin and eosin staining confirmed these results. Therefore, the Se and Lec combination showed superior protective effects against ethanol-induced gastric ulcers in mice, compared to either treatment alone, through antioxidant, and anti-inflammatory activities, in addition to modulating IGF-1/PTEN/Akt/FoxO3a pathway signaling.

Haloxyfop-P-methyl induces immunotoxicity and glucose metabolism disorders and affects the Nrf2/ARE pathway mediated antioxidant system in Chiromantes dehaani

Haloxyfop-P-methyl is used extensively in agricultural production, and its metabolites in soil have potentially toxic effects on aquatic ecosystems. In this study, we explored the toxicity of haloxyfop-P-methyl on Chiromantes dehaani. The results of the 21-day toxicity test showed that haloxyfop-P-methyl decreased the weight gain (WG), specific growth rate (SGR) and hepatosomatic index (HSI). In glucose metabolism, haloxyfop-P-methyl reduced pyruvate, lactate, lactate dehydrogenase and succinate dehydrogenase, but enhanced glucose-6-phosphate dehydrogenase and hexokinase. Furthermore, expression of glucose metabolism-related genes was upregulated. We cloned the full-length CdG6PDH gene, which contains a 1587 bp ORF that encoded a 528 amino acid polypeptide. In antioxidant system, haloxyfop-P-methyl increased glutathione, thioredoxin reductase and thioredoxin peroxidase activities and activated the Nrf2/ARE pathway through upregulation of ERK, JNK, PKC and Nrf2. In immunity, low concentrations haloxyfop-P-methyl, or short-term exposure, upregulated the expression of immune-related genes and enhanced immune-related enzymes activity, while high concentrations or long-term exposure inhibited immune function. In summary, haloxyfop-P-methyl inhibited the growth performance, disrupted glucose metabolism, activated the antioxidant system, and led to immunotoxicity. The results deepen our understanding of the toxicity mechanism of haloxyfop-P-methyl and provide basic biological data for the comprehensive assessment of the risk of haloxyfop-P-methyl to the environment and humans.

Hydrogen Sulfide Gas Amplified ROS Cascade: FeS@GOx Hybrid Nanozyme Designed for Boosting Tumor Chemodynamic Immunotherapy.

Chemodynamic immunotherapy that utilizes catalysts to produce reactive oxygen species (ROS) for killing tumor cells and arousing antitumor immunity, has received considerable attention. However, it is still restricted by low ROS production efficiency and insufficient immune activation, due to intricate redox homeostasis in tumor microenvironment (TME). Herein, a metalloprotein-like hybrid nanozyme (FeS@GOx) is designed by in situ growth of nanozyme (ferrous sulfide, FeS) in natural enzyme (glucose oxidase, GOx) to amplify ROS cascade for boosting chemodynamic immunotherapy. In FeS@GOx, GOx allows the conversion of endogenous glucose to gluconic acid and hydrogen peroxide, which provides favorable increasing hydrogen peroxide for subsequent Fenton reaction of FeS nanozymes, thus reinforcing the ROS production. Notably, H2 S release is activated by the gluconic acid generation-related pH decrease, which can suppress the activity of endogenous thioredoxin reductase and catalase to further inhibit the ROS elimination. Thus, FeS@GOx can sustainably amplify ROS accumulation and perturb intracellular redox homeostasis to improve chemodynamic therapy and trigger robust immunogenic cell death for effective immunotherapy combined with immune checkpoint blockade. This work proposes a feasible H2 S amplified ROS cascade strategy employing a bioinspired hybrid nanozyme, providing a novel pathway to multi-enzyme-mediated TME modulation for precise and efficient chemodynamic immunotherapy. This article is protected by copyright. All rights reserved.

Thioredoxin Is a New Target for the Phytotoxicity of Small Lactone Mycotoxins, Patulin and Penicillic Acid on Maize Seedlings

The phytotoxic mechanisms of patulin (PAT) and penicillic acid (PA) have not been identified unambiguously. This study aims to clarify their effects on thioredoxins (Trxs). Aflatoxin B1 (AFB1), PAT and PA were isolated by solvent extraction and chromatographic techniques from the cultures of Aspergillus flavus Z2 (LC171449), Penicillium vulpinum CM1 and Aspergillus ochraceus EMCC516, respectively. The three mycotoxins showed phytotoxicity to the germination of maize seeds, which was manifested by inhibiting radicle and coleoptile emergence, in addition to their toxic effects on fresh weights and root and shoot lengths. The phytotoxicity of AFB1 and PAT was greater than that of PA. Due to the central roles exhibited by plant Trxs in cellular metabolic activities, they were tested as target proteins for PAT and PA using AFB1 as positive control. In vivo studies showed that the mycotoxins significantly reduced Trx activity measured in the roots and shoots of maize seedlings. PAT showed greater Trx-inhibiting activity than PA and AFB1. In vitro studies of the mycotoxins on Trx y1 (from Arabidopsis thaliana) and thioredoxin reductase (Tr, from rat liver) activities confirm the results of in vivo studies. The inactivation of Trx with PAT and PA was reduced in the presence of glutathione (GSH). Data obtained suggest that lactone mycotoxins are more highly reactive with simple low-molecular-weight thiols (like GSH) than with complex ones (like Trx).

N-Acetyl Cysteine Restores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings.

SARS-CoV-2 infects type II pneumocytes and disrupts redox homeostasis by overproducing reactive oxygen species (ROS). N-acetyl cysteine (NAC) is a precursor of the synthesis of glutathione (GSH) and it restores the loss of redox homeostasis associated to viral infections. The aim of the study is to evaluate the effect of the treatment with NAC on the enzymatic antioxidant system in serum from patients infected by SARS-CoV-2. We evaluated the enzymatic activities of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), -S-transferase (GST), and reductase (GR) by spectrophotometry and the concentrations of the glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2-), and lipid peroxidation (LPO) in serum. The activity of the extracellular super oxide dismutase (ecSOD) was determined by native polyacrylamide gels, and 3-nitrotyrosine (3-NT) was measured by ELISA. A decrease in the activities of the ecSOD, TrxR, GPx, GST GR, (p = 0 ≤ 0.1), and the GSH, TAC, thiols, and NO2- (p ≤ 0.001) concentrations and an increase in LPO and 3-NT (p = 0.001) concentrations were found in COVID-19 patients vs. healthy subjects. The treatment with NAC as an adjuvant therapy may contribute to a reduction in the OS associated to the infection by SARS-CoV-2 through the generation of GSH. GSH promotes the metabolic pathways that depend on it, thus contributing to an increase in TAC and to restore redox homeostasis.

Abstract 5034: Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas

Abstract Introduction/Background: Atypical lung carcinoids and lung neuroendocrine carcinomas (NECs) are currently incurable. Most of these cancers express the C-X-C chemokine receptor 4 (CXCR4), making CXCR4 an attractive target for cancer diagnosis and treatment using radioligand therapy (RLT) with nuclides such as alpha emitter Pb212 conjugated to Pentixather (Pent). Alpha particles produce dense ionization tracks and damage cytosolic structures such as mitochondria, leading to the generation of reactive oxygen species such as superoxide (O2 ●−) and hydroperoxides (H2O2 and ROOH) in targeted cancer cells. The FDA approved thioredoxin reductase inhibitor, auranofin (Aur), inhibits peroxiredoxin-mediated hydroperoxide metabolism increasing cell killing in targeted cancer cells. Hypothesis: Inhibition of hydroperoxide metabolism using Aur can enhance therapeutic efficacy of alpha particle emitting 212Pb-Pent in preclinical models of lung carcinoids and NECs. Results: Clinically, IHC revealed greater than 75% of atypical carcinoids and NECs tested had moderate to high CXCR4. qRT-PCR, flow cytometry and immunohistochemistry performed on different lung carcinoid and NEC lung cell lines, determined that the majority moderately or highly express CXCR4. The minimal non-toxic dose of Aur that inhibits 50-70% of thioredoxin reductase activity was 4 mg/kg (intraperitoneal once a day) in DMS273 (small cell lung cancer) xenografts 212Pb-Pent given IV (1 and 3 µCu/g) was effective at increasing the survival of mice with DMS273 xenografts. Mice were then treated with 1.5, 3 or 6 µCu/g 212Pb-Pent w/wo Aur 4 mg/kg/day. A trend test showed that both increasing dose of 212Pb-Pent and the addition of Aur, caused a significant (p&amp;lt;0.01) delay in tumor growth. There were no significant changes in body weights, complete blood counts, and serum alanine aminotransferase indicating the combination treatments were well tolerated. Radiation dosimetry estimates using quantitative SPECT/CT imaging with Pb203-Pent demonstrated average absorbed doses of 0.133 Gy/µCi (liver), 0.098 Gy/µCi (kidneys), 0.013 Gy/µCi (H292 xenografts), 0.028 Gy/µCi (DMS53 xenografts), 0.057 Gy/µCi (DMS273 xenografts), and 0.096 Gy/µCi (H69AR xenografts). Xenograft absorbed dose levels were positively correlated with CXCR4 expression. Conclusion: The use of 212Pb-Pent therapy to target CXCR4 on NECs showed pre-clinical efficacy in a dose dependent manner that was enhanced by Aur without significant normal tissue toxicity supporting the hypothesis that CXCR4 can be successfully targeted with the radionuclide theragnostic pair, Pb212/Pb203-pentixather. Citation Format: Melissa A. Fath, Dijie Liu, Claudia Robles-Planells, Jordan T. Ewald, Keegan A. Christensen, Spenser S. Johnson, Stephen A. Graves, Douglas R. Spitz, Yusuf Menda, M. Sue O’Dorisio. Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5034.

Different Effects and Mechanisms of Selenium Compounds in Improving Pathology in Alzheimer’s Disease

Owing to the strong antioxidant capacity of selenium (Se) in vivo, a variety of Se compounds have been shown to have great potential for improving the main pathologies and cognitive impairment in Alzheimer's disease (AD) models. However, the differences in the anti-AD effects and mechanisms of different Se compounds are still unclear. Theoretically, the absorption and metabolism of different forms of Se in the body vary, which directly determines the diversification of downstream regulatory pathways. In this study, low doses of Se-methylselenocysteine (SMC), selenomethionine (SeM), or sodium selenate (SeNa) were administered to triple transgenic AD (3× Tg-AD) mice for short time periods. AD pathology, activities of selenoenzymes, and metabolic profiles in the brain were studied to explore the similarities and differences in the anti-AD effects and mechanisms of the three Se compounds. We found that all of these Se compounds significantly increased Se levels and antioxidant capacity, regulated amino acid metabolism, and ameliorated synaptic deficits, thus improving the cognitive capacity of AD mice. Importantly, SMC preferentially increased the expression and activity of thioredoxin reductase and reduced tau phosphorylation by inhibiting glycogen synthase kinase-3 beta (GSK-3β) activity. Glutathione peroxidase 1 (GPx1), the selenoenzyme most affected by SeM, decreased amyloid beta production and improved mitochondrial function. SeNa improved methionine sulfoxide reductase B1 (MsrB1) expression, reflected in AD pathology as promoting the expression of synaptic proteins and restoring synaptic deficits. Herein, we reveal the differences and mechanisms by which different Se compounds improve multiple pathologies of AD and provide novel insights into the targeted administration of Se-containing drugs in the treatment of AD.

In vitro evaluation of dioscin and protodioscin against ER-positive and triple-negative breast cancer.

Women's breast cancer is one of the most significant healthcare issues for the human race that demands a proactive strategy for a cure. In this study, the cytotoxic activity (MTT assay) of two natural steroidal compounds, protodioscin and dioscin, against two major subtypes of human breast cancer estrogen receptor-positive (ER-positive)/MCF-7 and triple-negative breast cancer (TNBC)/MDA-MB-468), was assessed. The clonogenic capacity was evaluated using the clonogenic assay. Oxidative stress was determined by measuring the formation of malondialdehyde and H2O2 and the assessment of total antioxidant enzyme activities (SOD, GPx, GR, and TrxR). Protodioscin and dioscin were highly cytotoxic against the tested cell lines (1.53 μM <IC50< 6 μM) with low cytotoxicity on normal cells (PBMC; IC50 ≥ 50 μM). Interestingly, these compounds were responsible for a substantial decrease in the clonogenic capacity of both cell lines. Moreover, dioscin was able to reduce the cell motility of the invasive breast cancer cells (MDA-MB-468). At the molecular level, the two treatments resulted in an increase of reactive oxygen species. Notably, both compounds were responsible for decreasing the enzymatic activities of glutathione reductase and thioredoxin reductase. On the basis of such considerations, protodioscin and dioscin may serve as promising natural compounds to treat TNBC and ER-positive breast cancer through the induction of oxidative stress.

A Novel Organic Selenium Compound Exerts Unique Regulation of Selenium Speciation, Selenogenome, and Selenoproteins in Broiler Chicks

BackgroundA new organic selenium compound, 2-hydroxy-4-methylselenobutanoic acid (SeO), displayed a greater bioavailability than sodium selenite (SeNa) or seleno-yeast (SeY) in several species. ObjectiveThis study sought to determine the regulation of the speciation of selenium, expression of selenogenome and selenocysteine biosynthesis and degradation-related genes, and production of selenoproteins by the 3 forms of selenium in the tissues of broiler chicks. MethodsDay-old male chicks (n = 6 cages/diet, 6 chicks/cage) were fed a selenium-deficient, corn and soy–based diet [base diet (BD), 0.05 mg Se/kg] or the BD + SeNa, SeY, or SeO at 0.2 mg Se/kg for 6 wk. Plasma, livers, and pectoral and thigh muscles were collected at weeks 3 and 6 to assay for total selenium, selenomethionine, selenocysteine, redox status, and selected genes, proteins, and enzymes. ResultsAlthough both SeY and SeO produced greater concentrations (P < 0.05) of total selenium (20–172%) and of selenomethionine (≤15-fold) in the liver, pectoral muscle, and thigh than those of SeNa, SeO further raised (P < 0.05) these concentrations by 13–37% and 43–87%, respectively, compared with SeY. Compared with the BD, only SeO enhanced (P < 0.05) the mRNA of selenoprotein (Seleno) s and methionine sulfoxide reductase B1 (Msrb1) in the liver and thigh (62–98%) and thioredoxin reductase (TXRND) activity in the pectoral and thigh muscles (20–37%) at week 3. Furthermore, SeO increased (P < 0.05) the expression of glutathione peroxidase (Gpx) 3, GPX4, SELENOP, and SELENOU relative to the SeNa group by 26–207%, and the expression of Selenop, O-phosphoseryl-transfer RNA (tRNA):selenocysteinyl-tRNA synthase, GPX4, and SELENOP relative to the SeY group by 23–55% in various tissues. ConclusionsCompared with SeNa or SeY, SeO demonstrated a unique ability to enrich selenomethionine and total selenium depositions, to induce the early expression of Selenos and Mrsb1 mRNA and TXRND activity, and to enhance the protein production of GPX4, SELENOP, and SELENOU in the tissues of chicks.

T-2 toxin-induced intestinal damage with dysregulation of metabolism, redox homeostasis, inflammation, and apoptosis in chicks.

T-2 toxin is a worldwide problem for feed and food safety, leading to livestock and human health risks. The objective of this study was to explore the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating the advanced microbiomic, metabolomic and transcriptomic technologies. Four groups of 1-day-old male broilers (n = 4 cages/group, 6 birds/cage) were fed a control diet and control diet supplemented with T-2 toxin at 1.0, 3.0, and 6.0mg/kg, respectively, for 2weeks. Compared with the control, dietary T-2 toxin reduced feed intake, body weight gain, feed conversion ratio, and the apparent metabolic rates and induced histopathological lesions in the small intestine to varying degrees by different doses. Furthermore, the T-2 toxin decreased the activities of glutathione peroxidase, thioredoxin reductase and total antioxidant capacity but increased the concentrations of protein carbonyl and malondialdehyde in the duodenum in a dose-dependent manner. Moreover, the integrated microbiomic, metabolomic and transcriptomic analysis results revealed that the microbes, metabolites, and transcripts were primarily involved in the regulation of nucleotide and glycerophospholipid metabolism, redox homeostasis, inflammation, and apoptosis were related to the T-2 toxin-induced intestinal damage. In summary, the present study systematically elucidated the intestinal toxic mechanisms of T-2 toxin, which provides novel ideas to develop a detoxification strategy for T-2 toxin in animals.

Advances in the Mechanistic Understanding of Iron Oxide Nanoparticles' Radiosensitizing Properties.

Among the plethora of nanosystems used in the field of theranostics, iron oxide nanoparticles (IONPs) occupy a central place because of their biocompatibility and magnetic properties. In this study, we highlight the radiosensitizing effect of two IONPs formulations (namely 7 nm carboxylated IONPs and PEG5000-IONPs) on A549 lung carcinoma cells when exposed to 225 kV X-rays after 6 h, 24 h and 48 h incubation. The hypothesis that nanoparticles exhibit their radiosensitizing effect by weakening cells through the inhibition of detoxification enzymes was evidenced by thioredoxin reductase activity monitoring. In particular, a good correlation between the amplification effect at 2 Gy and the residual activity of thioredoxin reductase was observed, which is consistent with previous observations made for gold nanoparticles (NPs). This emphasizes that NP-induced radiosensitization does not result solely from physical phenomena but also results from biological events.

Selenium-decorated biocompatible honeycomb films with redox-switchable surface for controlling cell adhesion/detachment

Hypothesis.Selenium (Se)-containing compound is sensitive to redox stimulation, showing hydrophobic-hydrophilic reversible transition. Introduction of such compound into honeycomb film could confer on it redox-switchable surface wettability, which is expected to control cell adhesion/detachment behavior.Experiments.Didodecyl selenide was designed and mixed with polystyrene to prepare honeycomb films using “breath figure” method. The film microstructures were characterized by scanning electron microscope and atomic force microscopy, and the arrangement of Se atoms in honeycomb film was determined by X-ray photoelectron spectroscopy and energy dispersive spectrometry. The variation of film wettability upon the alternating stimulation of H2O2 and Vc was examined. Then the cell adhesion, proliferation, and controlled detachment on honeycomb films were conducted.Findings.The introduction of didodecyl selenide helps to form ordered honeycomb film, and Se atoms were found to located on the bottom, pore walls, and top surface of the film. The presence of didodecyl selenide not only greatly improves film biocompatibility by enhancing cell thioredoxin reductase activity, but also imparts the film with H2O2–/vitamin C-regulated tunable wettability that controls cell adhesion and detachment. H2O2 treatment produces a hydrophilic surface for cell adhesion and proliferation, whereas the addition of vitamin C generates hydrophobic surfaces and allows cells to detach while remaining alive with high activity.

Inhibition of thioredoxin reductase activity reduces the antioxidant defense capacity of human pluripotent stem cells under conditions of mild but not severe oxidative stress

Pro-oxidative shift in redox balance, usually termed as “oxidative stress”, can lead to different cell responses depending on its intensity. Excessive accumulation of reactive oxygen species (“oxidative distress”) can cause DNA, lipid and protein damage. Physiological oxidative stimulus (“oxidative eustress”), in turn, can favor cell proliferation and differentiation – the processes of paramount importance primarily for stem cells. Functions of antioxidant enzymes in cells is currently a focus of intense research, however the role of different antioxidant pathways in pluripotent cell responses to oxidative distress/eustress is still under investigation. In this study, we assessed the contribution of the thioredoxin reductase (TrxR)-dependent pathways to maintaining the redox homeostasis in human induced pluripotent stem cells and their differentiated progeny cells under basal conditions and under conditions of oxidative stress of varying intensity. Employing the genetically encoded H2O2 biosensor cyto-HyPer and two inhibitors of thioredoxin reductase (auranofin and Tri-1), we show that the reduced activity of TrxR-dependent enzymatic systems leads to the non-cytotoxic disruption of thiol-disulfide metabolism in the cytoplasm of both pluripotent and differentiated cells under basal conditions. Quantifying the cytoplasmic concentrations of peroxide establishing in H2O2-stressed cells, we demonstrate that TrxR-dependent pathways contribute to the antioxidant activity in the cell cytoplasm under conditions of mild but not severe oxidative stress in both cell lines tested. The observed effects may testify about a conservative role of the TrxR-controlled enzymatic systems manifested as a response to physiological redox stimuli rather than a protection against the severe oxidative stress.

Reduction of plasma homocysteine and 8-iso-prostaglandin F2α concentrations in hypercholesterolemic rats treated with clove essential oil

Cardiovascular diseases are associated with a chronic state of oxidative stress that is induced by fat accumulation. The current study aims to investigate the potential effects of oral consumption of clove essential oil on the lipid profile, oxidative stress markers and antioxidant enzyme activity, in hypercholesterolemic rats. Two groups of Wistar rats were fed a cholesterol-enriched diet supplemented (CEO) or not (HC) with 4 mg/kg b.w of clove essential oil, for six weeks. A control group (C) was fed a standard diet during the experiment. After six weeks, in clove essential oil treated as compared to untreated hypercholesterolemic rats, daily supplementation with essential oil attenuated serum levels of total cholesterol (-57%), LDL-cholesterol (-28%), triacyglycerols (-26%), total homocysteine (-17%) and 8-Iso-prostaglandin F2α (-39%). Furthermore, TBARS values were decreased in LDL (-37%), liver (-45%) and adipose tissue (-34%). Interestingly, clove essential oil increased respectively thioredoxin reductase activity in liver and adipose tissue by +67% and +66%, respectively. These results demonstrate the therapeutic potential of clove essential oil to reduce dyslipidemia, oxidative stress by increasing the thioredoxin reductase activity.