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The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) represents the master regulator of the cellular antioxidant response and plays a critical role in tumorigenesis. This includes a preventive effect of Nrf2 on cell death through ferroptosis, which represents an essential mechanism of therapy resistance in malignant tumors, such as pancreatic ductal adenocarcinoma (PDAC) as one of the most aggressive and still incurable tumors. Addressing this issue, we provide an overview on Nrf2 mediated antioxidant response with particular emphasis on its effect on mitochondria as the organelle responsible for the execution of ferroptosis. We further outline how deregulated Nrf2 adds to the progression and therapy resistance of PDAC, especially with respect to the role of ferroptosis in anti-cancer drug mediated cell killing and how this is impaired by Nrf2 as an essential mechanism of drug resistance. Our review further discusses recent approaches for Nrf2 inhibition by natural and synthetic compounds to overcome drug resistance based on enhanced ferroptosis. Finally, we provide an outlook on therapeutic strategies based on Nrf2 inhibition combined with ferroptosis inducing drugs.

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BACKGROUND: Genetic background of healthy or pathological styles of aging and human lifespan is determined by joint gene interactions. Lucky combinations of antioxidant gene polymorphisms can result in a highly adaptive phenotype, providing a successful way to interact with external triggers. Our purpose was to identify the polygenic markers of survival and longevity in the antioxidant genes among elderly people with physiological and pathological aging. METHODS: In a 20-year follow-up study of 2350 individuals aged 18-114 years residing in the Volga-Ural region of Russia, sex-adjusted association analyses of MTHFR rs1801133, MSRA rs10098474, PON1 rs662, PON2 rs7493, SOD1 rs2070424, NQO1 rs1131341 and CAT rs1001179 polymorphic loci with longevity were carried out. Survival analysis was subsequently performed using the established single genes and gene-gene combinations as cofactors. RESULTS: The PON1 rs662*G allele was defined as the main longevity marker in women (OR = 1.44, p = 3E-04 in the log-additive model; HR = 0.77, p = 1.9E-04 in the Cox-survival model). The polymorphisms in the MTHFR, MSRA, PON2, SOD1, and CAT genes had an additive effect on longevity. A strong protective effect of combined MTHFR rs1801133*C, MSRA rs10098474*T, PON1 rs662*G, and PON2 rs7493*C alleles against mortality was obtained in women (HR = 0.81, p = 5E-03). The PON1 rs662*A allele had a meaningful impact on mortality for both long-lived men with cerebrovascular accidents (HR = 1.76, p = 0.027 for the PON1 rs662*AG genotype) and women with cardiovascular diseases (HR = 1.43, p = 0.002 for PON1 rs662*AA genotype). The MTHFR rs1801133*TT (HR = 1.91, p = 0.036), CAT rs1001179*TT (HR = 2.83, p = 0.031) and SOD1 rs2070424*AG (HR = 1.58, p = 0.018) genotypes were associated with the cancer mortality. CONCLUSION: In our longitudinal 20-year study, we found the combinations of functional polymorphisms in antioxidant genes involved in longevity and survival in certain clinical phenotypes in the advanced age.

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Semen possesses a variety of antioxidant defense mechanisms which protect sperm DNA from the damaging effects of oxidative stress. Correlation between antioxidant genes variants and sperm DNA fragmentation (SDF) level is not sufficiently studied. Therefore, we investigated the association between several single nucleotide polymorphisms (SNPs): CYP1A1 (rs1048943A > G), CYP4F2 (rs2108622G > A), NRF2 (rs6721961C > A), PON1 (rs662A > G), NOS3 (rs1799983G > T), GSTM1 (null), CAT (rs1001179C > T), SOD2 (rs4880A > G), GSTP1 (rs1695A > G), PON2 (rs7493G > C), EPHX2 (rs1042064T > C), and AHR (rs2066853G > A) and elevated SDF. The study employed a case-control design where, the allele and genotype frequencies of the selected SNPs were compared between 75 semen samples with abnormal SDF (the cases) and 75 samples with normal SDF (the controls). DNA was extracted from the semen samples and allele-specific PCR (AS-PCR) was used for genotyping the SNPs. Relevant data were collected from the patients' records et al.-Basma Fertility Center. Suitable statistical tests and multifactorial dimensionality reduction (MDR) test were used to anticipate SNP-SNP interactions. Comparison of semen parameters revealed significant differences between cases and controls in terms of liquefaction time, sperm total motility, and normal form. Genotype frequencies of NOS3 G > T (GT), SOD2 A > G (AA and AG), EPHX2 T > C (CC and CT), and AHR G > A (GA and GG) were significantly different between cases and controls. Allele frequencies of SOD2 (G-allele), and EPHX2 (T-allele) also significantly varied between cases and controls. MDR analysis revealed that the NOS3, SOD2, and EPHX2 SNPs combination has the highest impact on SDF. The study findings suggest that genetic variations in genes involved antioxidant defenses contribute to abnormal SDF.

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Overdoses of pesticides lead to a decrease in the yield and quality of plants, such as beans. The unconscious use of deltamethrin, one of the synthetic insecticides, increases the amount of reactive oxygen species (ROS) by causing oxidative stress in plants. In this case, plants tolerate stress by activating the antioxidant defense mechanism and many genes. 5-Aminolevulinic acid (ALA) improves tolerance to stress by acting exogenously in low doses. There are many gene families that are effective in the regulation of this mechanism. In addition, one of the response mechanisms at the molecular level against environmental stressors in plants is retrotransposon movement. In this study, the expression levels of superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR), and stress-associated protein (SAP) genes were determined by Q-PCR in deltamethrin (0.5 ppm) and various doses (20, 40, and 80 mg/l) of ALA-treated bean seedlings. In addition, one of the response mechanisms at the molecular level against environmental stressors in plants is retrotransposon movement. It was determined that deltamethrin increased the expression of SOD (1.8-fold), GPX (1.4-fold), CAT (2.7-fold), and SAP (2.5-fold) genes, while 20 and 40 mg/l ALA gradually increased the expression of these genes at levels close to control, but 80 mg/l ALA increased the expression of these genes almost to the same level as deltamethrin (2.1-fold, 1.4-fold, 2.6-fold, and 2.6-fold in SOD, GPX, CAT, and SAP genes, respectively). In addition, retrotransposon-microsatellite amplified polymorphism (REMAP) was performed to determine the polymorphism caused by retrotransposon movements. While deltamethrin treatment has caused a decrease in genomic template stability (GTS) (27%), ALA treatments have prevented this decline. At doses of 20, 40, and 80 mg/L of ALA treatments, the GTS ratios were determined to be 96.8%, 74.6%, and 58.7%, respectively. Collectively, these findings demonstrated that ALA has the utility of alleviating pesticide stress effects on beans.

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Exposure to water-pipe smoking, whether flavored or unflavored, has been shown to instigate inflammation and oxidative stress in BALB/c mice. This consequently results in alterations in the expression of inflammatory markers and antioxidant genes. This study aimed to scrutinize the impact of Epigallocatechin gallate (EGCG)-a key active component of green tea-on inflammation and oxidative stress in BALB/c mice exposed to water-pipe smoke. The experimental setup included a control group, a flavored water-pipe smoke (FWP) group, an unflavored water-pipe smoke (UFWP) group, and EGCG-treated flavored and unflavored groups (FWP + EGCG and UFWP + EGCG). Expression levels of IL-6, IL1B, TNF-α, CAT, GPXI, MT-I, MT-II, SOD-I, SOD-II, and SOD-III were evaluated in lung, liver, and kidney tissues. Histopathological changes were also assessed. The findings revealed that the EGCG-treated groups manifested a significant decline in the expression of inflammatory markers and antioxidant genes compared to the FWP and UFWP groups. This insinuates that EGCG holds the capacity to alleviate the damaging effects of water-pipe smoke-induced inflammation and oxidative stress. Moreover, enhancements in histopathological features were observed in the EGCG-treated groups, signifying a protective effect against tissue damage induced by water-pipe smoking. These results underscore the potential of EGCG as a protective agent against the adverse effects of water-pipe smoking. By curbing inflammation and oxidative stress, EGCG may aid in the prevention or mitigation of smoking-associated diseases.

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The leading cause of mortality from SARS-CoV-2 is an exaggerated host immune response, triggering cytokine storms, multiple organ failure and death. Current drug- and vaccine-based therapies are of limited efficacy against novel viral variants. Infrared therapy is a non-invasive and safe method that has proven effective against inflammatory conditions for over 100 years. However, its mechanism of action is poorly understood and has not received widespread acceptance. We herein investigate whether near-infrared (NIR) light exposure in human primary alveolar and macrophage cells could downregulate inflammatory cytokines triggered by the SARS-CoV-2 spike (S) protein or lipopolysaccharide (LPS), and via what underlying mechanism. Our results showed a dramatic reduction in pro-inflammatory cytokines within days of NIR light treatment, while anti-inflammatory cytokines were upregulated. Mechanistically, NIR light stimulated mitochondrial metabolism, induced transient bursts in reactive oxygen species (ROS) and activated antioxidant gene transcription. These, in turn, downregulated ROS and inflammatory cytokines. A causal relationship was shown between the induction of cellular ROS by NIR light exposure and the downregulation of inflammatory cytokines triggered by SARS-CoV-2 S. If confirmed by clinical trials, this method would provide an immediate defense against novel SARS-CoV-2 variants and other inflammatory infectious diseases.

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Short tandem repeats (STRs) have orders of magnitude higher mutation rates than single nucleotide variants (SNVs) and have been proposed to accelerate evolution in many organisms. However, only few studies have addressed the impact of STR variation on phenotypic variation at both the organismal and molecular levels. Potential driving forces underlying the high mutation rates of STRs also remain largely unknown. Here, we leverage the recently generated expression and STR variation data among wild Caenorhabditis elegans strains to conduct a genome-wide analysis of how STRs affect gene expression variation. We identify thousands of expression STRs (eSTRs) showing regulatory effects and demonstrate that they explain missing heritability beyond SNV-based expression quantitative trait loci. We illustrate specific regulatory mechanisms such as how eSTRs affect splicing sites and alternative splicing efficiency. We also show that differential expression of antioxidant genes and oxidative stresses might affect STR mutations systematically using both wild strains and mutation accumulation lines. Overall, we reveal the interplay between STRs and gene expression variation by providing novel insights into regulatory mechanisms of STRs and highlighting that oxidative stress could lead to higher STR mutation rates.

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Oxidative stress is one of the elements causing aging and related diseases. Inhibiting Nrf2 activity or increasing oxidative pressure can replicate the deficits of premature aging. SIRT6 is one of the few proteins that can regulate both life span and aging. Deletion of SIRT6 in human cells impairs the antioxidant capacity of cells, which results in the accumulation of intracellular reactive oxygen species and DNA oxidation products. Characterization of the binding of Nrf2 with SIRT6 is critical for understanding the modulation of Nrf2-correlated cell activities by SIRT6. The yeast two-hybrid experiments showed that the binding of Nrf2 with SIRT6 is mediated by Neh1 and Neh3 domains. The elimination of the Neh1 and Neh3 domains decreased the binding stability and free energy, according to the molecular dynamic analysis. The roles of theses domains in mediating the binding were confirmed by co-immunoprecipitation. In cells transfected with the small interfering RNA (siRNA) targeting the Nrf2 Neh1 domain and plasmids overexpressing domain-mutant Nrf2, it was discovered that Nrf2 lost its activity to stimulate the transcription of antioxidant genes in the absence of Neh1 and Neh3 domains.

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Long-term acclimation temperature effects on biomarkers of oxidative stress, metabolic stress, expression of heat shock proteins (Hsps), and warm-temperature acclimation related 65-kDa protein (Wap65) were evaluated in the threatened chocolate mahseer (Neolissochilus hexagonolepis). Fifteen-day-old larvae were acclimated to different water temperatures (15, 19, 23-control group, 27, and 31 °C) for 60 days prior to the sampling for quantification of mRNA, enzyme, nitric oxide, and malondialdehyde (MDA) content. Acclimation to 31 °C increased the basal mRNA level of glutathione S-transferase alpha 1 (GSTa1), and activities of catalase (CAT), glutathione reductase (GR), and GST enzymes and but downregulated the expression of superoxide dismutase 1 (SOD1) in the whole-body homogenate. Other antioxidant genes, i.e., CAT and GPx1a, were unaffected at 31 °C, and nitric oxide (NO) concentration was significantly lower. In contrast, fish acclimated to 15 °C showed an upregulated transcript level of all the antioxidant genes and no significant difference in the CAT, GR, and GST enzymes. Activities of the metabolic enzymes, aspartate transaminase (AST) and alanine transaminase (ALT), were significantly lower at 15 °C. The expression of Hsp47 was upregulated at both 15 and 31 °C groups, whereas Hsp70 was elevated at 27 and 31 °C groups. Wap65-1 transcription did not show significant variation in treatment groups compared to control. Fish in the high (31 °C) and low-temperature (15 °C) acclimation groups were capable of maintaining oxidative stress by modulating their antioxidant transcripts, enzymes, and Hsps.

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The present study was carried out to investigate the effects of bamboo leaf extract (BLE) on energy metabolism, antioxidant capacity, and biogenesis of broilers' small intestine mitochondria. A total of 384 one-day-old male Arbor Acres broiler chicks were randomly divided into four groups with six replicates each for 42 d. The control group was fed a basal diet, whereas the BLE1, BLE2, and BLE3 groups consumed basal diets with 1.0, 2.0, and 4.0 g/kg of BLE, respectively. Some markers of mitochondrial energy metabolism including isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase and some markers of redox system including total superoxide dismutase, malondialdehyde, and glutathione were measured by commercial colorimetric kits. Mitochondrial and cellular antioxidant genes, mitochondrial biogenesis-related genes, and mitochondrial DNA copy number were measured by quantitative real-time-polymerase chain reaction (qRT-PCR). Data were analyzed using the SPSS 19.0, and differences were considered as significant at P < 0.05. BLE supplementation linearly increased jejunal mitochondrial isocitrate dehydrogenase (P < 0.05) and total superoxide dismutase (P < 0.05) activity. The ileal manganese superoxide dismutase mRNA expression was linearly affected by increased dietary BLE supplementation (P < 0.05). Increasing BLE supplementation linearly increased jejunal sirtuin 1 (P < 0.05) and nuclear respiratory factor 1 (P < 0.05) mRNA expression. Linear (P < 0.05) and quadratic (P < 0.05) responses of the ileal nuclear respiratory factor 2 mRNA expression occurred with increased dietary BLE levels. In conclusion, BLE supplementation was beneficial to the energy metabolism, antioxidant capacity, and biogenesis of small intestine mitochondria in broilers. The dose of 4.0 g/kg BLE demonstrated the best effects.

The intensive breeding model of broilers exposes broilers directly to oxidative stress, which is associated with mitochondrial dysfunction. Some researches have shown that bamboo leaf extract (BLE) exhibited antioxidant capacity both in vitro and vivo. However, few researches have been conducted to explore the effects of BLE supplementation on small intestine mitochondrial functions in broilers. The study aimed to evaluate whether BLE can improve energy metabolism, antioxidant capacity, and biogenesis of broilers' small intestine mitochondria. All broilers were randomly divided into four groups. The control (CTR) group was fed a basal diet, and the three experimental groups of BLE1, BLE2, and BLE3 were fed the basal diet supplemented with 1.0, 2.0, and 4.0 g of BLE per kg of feed between 1 d and 42 d of age, respectively. Based on our results, we obtained interesting evidence that BLE supplementation enhanced metabolic efficiency of small intestine mitochondria in broilers.

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Fibre plays an important role in diluting dietary energy density. Fibre is also implicated in the regulation of appetite, perhaps through direct effects in the brain. However, there is little information on this effect in pigs. Therefore, this study was conducted to investigate the effect of fibre type in regulating the expression of genes involved in appetite control, inflammation and antioxidant defence in the hypothalamus of weaned piglets. A total of 64 Duroc × Landrace × Yorkshire barrows at 37 days old were blocked by body weight and allotted to two dietary treatments, supplementation with either 0.25% cellulose (Solka-Floc) or inulin (INU) for 28 days, after which animals were killed for analysis. Pigs fed INU had a tendency (p = 0.06) for reduced feed intake in the first week, although this effect disappeared in subsequent weeks. Pigs supplemented with INU had lower expression of dopamine (dopamine receptor D2), serotonin (5-hydroxytryptamine receptor 1B), free fatty acid (GPR43) and neuropeptide Y receptor Y2 receptors in the hypothalamus (p < 0.05). Expression of the tryptophan hydroxylase 2 gene in the hypothalamus also tended (p = 0.09) to be lower for pigs fed INU. The abundance of antioxidant defence genes, superoxide dismutase (SOD1) and catalase, were greater (p < 0.05) but that of a proinflammatory gene, interleukin 1ß, was lower (p < 0.05) in the hypothalamus of pigs fed INU. Therefore, consumption of INU causes downregulation of inflammation in the hypothalamus and regulation of the abundance of serotonin or dopamine receptors, and may also increase antioxidant defence through upregulation of SOD and catalase in weaned piglets.

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Reactive oxygen species (ROS) are normal products of a number of biochemical reactions and are important signaling molecules. However, at the same time, they are toxic to cells and have to be strictly regulated by their antioxidant systems. The etiology and pathogenesis of many diseases are associated with increased ROS levels, and many external stress factors directly or indirectly cause oxidative stress in cells. Within this context, the overexpression of genes encoding the proteins in antioxidant systems seems to have become a viable approach to decrease the oxidative stress caused by pathological conditions and to increase cellular stress resistance. However, such manipulations unavoidably lead to side effects, the most dangerous of which is an increased probability of healthy tissue malignization or increased tumor aggression. The aims of the present review were to collect and systematize the results of studies devoted to the effects resulting from the overexpression of antioxidant system genes on stress resistance and carcinogenesis in vitro and in vivo. In most cases, the overexpression of these genes was shown to increase cell and organism resistances to factors that induce oxidative and genotoxic stress but to also have different effects on cancer initiation and promotion. The last fact greatly limits perspectives of such manipulations in practice. The overexpression of GPX3 and SOD3 encoding secreted proteins seems to be the "safest" among the genes that can increase cell resistance to oxidative stress. High efficiency and safety potential can also be found for SOD2 overexpression in combinations with GPX1 or CAT and for similar combinations that lead to no significant changes in H2O2 levels. Accumulation, systematization, and the integral analysis of data on antioxidant gene overexpression effects can help to develop approaches for practical uses in biomedical and agricultural areas. Additionally, a number of factors such as genetic and functional context, cell and tissue type, differences in the function of transcripts of one and the same gene, regulatory interactions, and additional functions should be taken into account.

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Chronic gut inflammation in Crohn's disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression.

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Mass rearing of insects of high biological quality is a crucial attribute for the successful implementation of sterile insect release programs. Various ontogenetic stages of Spodoptera litura (Fabr.) were treated with a range of low doses of ionizing radiation (0.25-1.25 Gy) to assess whether these gamma doses could elicit a stimulating effect on the growth and viability of developing moths. Doses in the range of 0.75 Gy to 1.0 Gy administered to eggs positively influenced pupal weight, adult emergence, and growth index, with a faster developmental period. The enhanced longevity of adults derived from eggs treated with 0.75 Gy and 1.0 Gy, and for larvae and pupae treated with 1.0 Gy, indicated a hormetic effect on these life stages. Furthermore, the use of these hormetic doses upregulated the relative mRNA expression of genes associated with longevity (foxo, sirtuin 2 like/sirt1, atg8) and viability/antioxidative function (cat and sod), suggesting a positive hormetic effect at the transcriptional level. These results indicated the potential use of low dose irradiation (0.75-1 Gy) on preimaginal stages as hormetic doses to improve the quality of the reared moths. This might increase the efficiency of the inherited sterility technique for the management of these lepidopteran pests.

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Avian musculoaponeurotic fibrosarcoma (Maf) proteins play an important role in Nrf2/Keap1 signaling pathway, which mainly resist the oxidant stress. The members of sMaf have a high homology basic leucine zipper (bZIP) and lack trans activation domain, and could interact with other transcriptional regulatory factors as a molecular chaperone. In this study, a full-length MafG-like gene was cloned from Procambarus Clarkii, designated as PcMafG-like, which consisted of an ORF length of 246 bp encoding 82 amino acids, a 5' untranslated region (UTR) of 483 bp, and a 3' UTR of 111 bp. The domain of PcMafG-like had a bZIP-Maf domain that binds to DNA. The cDNA sequence of PcMafG-like was 99 % similar to that of Penaeus vannamei. The mRNA of PcMafG-like was expressed in all tested tissues, and the highest expression was in muscle tissue. Under stimulation of Cu2+ and Cd2+, PcMafG-like was significantly up-regulated in hepatopancreas and gill, and the same result was testified by situ hybridization. The representative antioxidant genes, CAT, GPx and CZ-SOD, were significantly induced by Cu2+; CAT and GPx was induced by Cd2+. PcMafG-dsRNA significantly inhibited the expression of these up-regulated genes, but also inhibited the expression of other detected genes CZ-SOD, GST-θ and GST-1like. The antioxidant effect of PcMafG-like was further verified by oxidative stress markers (T-SOD, CuZnSOD, GPx, CAT, GSH and MDA) kits. Cu2+ and Cd2+ could induce the contents of these oxidative stress markers (MDA, GSH, CZ-SOD, CAT in Cu2+/Cd2+ treated group, and GSH-Px in Cd2+ group), while interference of PcMafG-like significantly inhibited the up-regulation. Furthermore, hematoxylin-eosin staining experiments showed that the degree of pathological damage was dose-dependent and time-dependent, and the pathological damage was more serious after dsRNA interfered with PcMafG-like. In addition, subcellular localization showed that PcMafG-like gene existed in nucleus. The recombinant protein PcMafG-like was expressed and purified in prokaryotic expression. The affinity analysis of promoter by agarose gel electrophoresis suggested that PcMafG-like could bind with CAT promoter in vitro. This indicated that PcMafG-like could activate antioxidant genes.

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Simvastatin (SIM) is one of the most widely used lipid-lowering drugs and consequently has been frequently detected in various waters. However, its potential adverse effects and toxic mechanisms on non-target organisms such as Daphnia magna (D. magna) remain still unclear. In the present study, the expressions of Nrf2 and antioxidant genes including Keap1, HO-1, GCLC, GST, SOD, CAT, GPx5, GPx7, GRx, TRX, TrxR, and Prx1 in D. magna exposed to SIM for 24 h, 48 h, and 96 h were investigated. The changes of SOD, CAT, GST, and GPx enzymatic activities, and the GSH and MDA content under SIM for 48-h exposure were also addressed. Results showed that the expression of Nrf2 was inhibited at 24 h but induced at 96 h, displaying a time- and/or dose-dependent relationship under SIM exposure. In contrast, Keap1 exhibited induction at 24 h. HO-1 showed significant induction under SIM exposure for different time. SOD generally displayed an induction trend under SIM exposure for different periods. GPX5 expression showed significant induction under SIM exposure, particularly at 24 h in 5 µg L-1 increasing 15 folds of the control. But GPX7 expression generally displayed inhibition except in 5 µg L-1. Trx and TrxR showed different induction or inhibition, which was depended on the exposure time and concentration. Prx1 displayed significant induction in most SIM groups. In addition, the decreasing GSH and increasing MDA content also indicated oxidative stress of SIM exposure. Overall, SIM exposure affected the expression of Nrf2 and antioxidant-related genes and altered the redox homeostasis of D. magna, even may cause the morphological changes such as shorten spine and abnormal development eye.

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BACKGROUND: Oxidative stress plays a critical role in tumorigenesis, tumor development, and resistance to therapy. A systematic analysis of the interactions between antioxidant gene expression and the prognosis of patients with sarcoma is lacking but urgently needed. METHODS: Gene expression and clinical data of patients with sarcoma were derived from The Cancer Genome Atlas Sarcoma (training cohort) and Gene Expression Omnibus (validation cohorts) databases. Least absolute shrinkage, selection operator regression, and Cox regression were used to develop prognostic signatures for overall survival (OS) and disease-free survival (DFS). Based on the signatures and clinical features, two nomograms for predicting 2-, 4-, and 6-year OS and DFS were established. RESULTS: On the basis of the training cohort, we identified five-gene (CHAC2, GPX5, GSTK1, PXDN, and S100A9) and six-gene (GGTLC2, GLO1, GPX7, GSTK1, GSTM5, and IPCEF1) signatures for predicting OS and DFS, respectively, in patients with sarcoma. Kaplan-Meier survival analysis of the training and validation cohorts revealed that patients in the high-risk group had a significantly poorer prognosis than those in the low-risk group. On the basis of the signatures and other independent risk factors, we established two models for predicting OS and DFS that showed excellent calibration and discrimination. For the convenience of clinical application, we built web-based calculators (OS: https://quankun.shinyapps.io/sarcDFS/). CONCLUSIONS: The antioxidant gene signature models established in this study can be novel prognostic predictors for sarcoma.

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Objective: The impact of various environmental stresses on native Apis cerana cerana fitness has attracted intense attention in China. However, the defence responses of A. cerana cerana to different stressors are poorly understood. Here, we aimed to elucidate the regulatory mechanism mediated by the tumorous imaginal discs (Tid) protein of A. cerana cerana (AccTid) in response to stressors. Methods: We used some bioinformatics softwares to analyse the characterisation of Tid. Then, qRT-PCR, RNA interference and heat resistance detection assays were used to explore the function of Tid in stress response in A. cerana cerana. Results: AccTid is a homologous gene of human Tid1 and Drosophila Tid56, contains a conserved J domain and belongs to the heat shock protein DnaJA subfamily. The level of AccTid induced expression was increased under temperature increases from 40°C to 43°C and 46°C, and AccTid knockdown decreased the heat resistance of A. cerana cerana, indicating that the upregulation of AccTid plays an important role when A. cerana cerana is exposed to heat stress. Interestingly, contrary to the results of heat stress treatment, the transcriptional level of AccTid was inhibited by cold, H2O2 and some agrochemical stresses and showed no significant change under ultraviolet ray and sodium arsenite stress. These results suggested that the requirement of A. cerana cerana for Tid differs markedly under different stress conditions. In addition, knockdown of AccTid increased the mRNA levels of some Hsps and antioxidant genes. The upregulation of these Hsps and antioxidant genes may be a functional complement of AccTid knockdown. Conclusion: AccTid plays a crucial role in A. cerana cerana stress responses and may mediate oxidative damage caused by various stresses. Our findings will offer fundamental knowledge for further investigations of the defence mechanism of A. cerana cerana against environmental stresses.

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BACKGROUND: Cervical cancers are usually treatable if detected in early stages by a combination of therapies. However, the prognosis of cervical cancer patients with metastasis remains unfavorable due to the fact that most of the cervical carcinomas are either resistant to anticancer drugs or show signs of relapse after initial treatment. Therefore, it is important to control the chemoresistance as it is the key to develop effective treatment options for cervical cancer. OBJECTIVE: The current study aimed at evaluating the differential responses of cervical cancer cells to anti-cancer drugs and assessed whether the differences in the expression profiles of antioxidant genes regulated by nuclear factor erythroid-2-related factor 2 (NRF2), led to the variations in the sensitivities of the cancer cells to treatment. METHODOLOGY: Three cervical cancer cell lines were investigated for their differences in NRF2 pathway by measuring the gene expression and enzyme activity. The differences in the sensitivity to anti-cancer drugs and variation in ROS profile was also evaluated. The addition of exogenous drugs to manipulate the intracellular ROS and its effect on NRF2 pathway genes was also investigated. RESULTS: HeLa and SiHa cells were more sensitive to cisplatin and oxaliplatin treatment than C33A cells. HeLa and SiHa cells had significantly lower NRF2 gene levels, NQO1 enzyme activity and basal GSH levels than C33A cells. Levels of ROS induced were higher in HeLa than C33A cells. CONCLUSION: Overall, the differences in the cellular levels of antioxidant regulatory genes led to the differential response of cervical cancer cells to anti-cancer drugs.

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BACKGROUND: Pomegranate is an ancient fruit containing Punicalagin, which has known as an effective antioxidant. Pomegranate peel was recognized as a phenol and tannin source, and pomegranate seed contains unique fatty acid (Punicic acid). Limited information exists about the influences of pomegranate peel and seed on antioxidant enzymes and proteins in the male reproduction system. This study was performed to determine the pomegranate peel and seed effects on the expression of antioxidant genes and DJ-1 protein in ram's testis. MATERIALS AND METHODS: In this experimental study, twenty-one mature Iranian rams were randomly divided into three groups (n=7 in each group), and fed experimental diets consisted of a control diet (C), a diet containing dry pomegranate seed pulp (S), and a diet containing pomegranate peel (P) for 80 days. All rams were offered isoenergetic and isonitrogenous rations. Testicular tissue samples were collected, and expression of Gpx1, Gpx4, Prdx4, Prdx5, and Sod2 genes was quantified by real-time polymerase chain reaction (RT-PCR). In addition, western blotting was used to evaluate DJ-1 expression at the protein level. RESULTS: Gpx1 and Sod2 mRNA levels in the peel group were significantly (P<0.05) higher than control. Prdx5 mRNA level was increased (P<0.05) in the seeds group than in the control group. Gpx4 and Prdx4 expression were statistically not affected significantly by the experimental diet. Data analysis showed a significant (P<0.05) increase (1.5-fold) in the expression level of DJ-1 in peel groups than in control. CONCLUSION: The expression of antioxidant genes and DJ-1 protein in ram testes are more influenced by pomegranate peel than seed.