Oxidative stress in metabolic dysfunction-associated steatotic liver disease (MASLD): How does the animal model resemble human disease?

Despite decades of research, the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is still not completely understood. Based on the evidence from preclinical models, one of the factors proposed as a main driver of disease development is oxidative stress. This study aimed to search for the resemblance between the profiles of oxidative stress and antioxidant defense in the animal model of MASLD and the group of MASLD patients. C57BL/6J mice were fed with the Western diet for up to 24 weeks and served as the animal model of MASLD. The antioxidant profile of mice hepatic tissue was determined by liquid chromatography-MS3 spectrometry (LC-MS/MS). The human cohort consisted of 20 patients, who underwent bariatric surgery, and 6 controls. Based on histological analysis, 4 bariatric patients did not have liver steatosis and as such were also classified as controls. Total antioxidant activity was measured in sera and liver biopsy samples. The hepatic levels of antioxidant enzymes and oxidative damage were determined by Western Blot. The levels of antioxidant enzymes were significantly altered in the hepatic tissue of mice with MASLD. In contrast, there were no significant changes in the antioxidant profile of hepatic tissue of MASLD patients, except for the decreased level of carbonylated proteins. Decreased protein carbonylation together with significant correlations between the thioredoxin system and parameters describing metabolic health suggest alterations in the thiol-redox signaling. Altogether, these data show that even though the phenotype of mice closely resembles human MASLD, the animal-to-human translation of cellular and molecular processes such as oxidative stress may be more challenging.

Physiological and oxidative stress response of carrot (Daucus carota L.) to jumping plant-louse Bactericera trigonica Hodkinson (Hemiptera: Psylloidea) infestation.

BACKGROUND: Carrot is an important vegetable crop grown worldwide. The major economic problem in carrot cultivation is yellow disease caused by Bactericera trigonica, which induces biotic stress and has the greatest impact on crop productivity. Comprehensive studies on the mechanism of carrot defense response to biotic stress caused by B. trigonica infestation have yet to be conducted. METHODS: The changes in photosynthetic pigments, proline, TPC, H2O2 and MDA content, DPPH radical scavenging ability, and antioxidant enzyme activity of SOD, CAT, and POX in carrot leaves in response to insect sex (female and male), rapid response (during the first six hours), and long-term response to B. trigonica infestation were evaluated. RESULTS: The results of our study strongly suggest that B. trigonica infestation causes significant changes in primary and secondary metabolism and oxidative status of carrot leaves. Photosynthetic pigment content, TPC, and DPPH and CAT activities were significantly reduced in carrot leaves in response to insect infestation. On the other hand, proline, H2O2 content, and the activity of the antioxidant enzymes superoxide dismutase and peroxidase were increased in carrot leaves after B. trigonica infestation. The results indicate that B. trigonica attenuates and delays the oxidative stress responses of carrot, allowing long-term feeding without visible changes in the plant. Carrot responded to long-term B. trigonica infestation with an increase in SOD and POX activity, suggesting that these enzymes may play a key role in plant defense mechanisms. CONCLUSIONS: This is the first comprehensive study strongly suggesting that B. trigonica infestation causes significant changes in primary and secondary metabolism and an attenuated ROS defense response in carrot leaves that enables long-term insect feeding. The information provides new insights into the mechanisms of carrot protection against B. trigonica infestation.

Calcineurin B-like protein ZmCBL8-1 promotes salt stress resistance in Arabidopsis.

MAIN CONCLUSION: ZmCBL8-1 enhances salt stress tolerance in maize by improving the antioxidant system to neutralize ROS homeostasis and inducing Na+/H+ antiporter gene expressions of leaves. Calcineurin B-like proteins (CBLs) as plant-specific calcium sensors have been explored for their roles in the regulation of abiotic stress tolerance. Further, the functional variations in ZmCBL8, encoding a component of the salt overly sensitive pathway, conferred the salt stress tolerance in maize. ZmCBL8-1 is a transcript of ZmCBL8 found in maize, but its function in the salt stress response is still unclear. The present study aimed to characterize the protein ZmCBL8-1 that was determined to be composed of 194 amino acids (aa) with three conserved EF hands responsible for binding Ca2+. However, a 20-aa fragment was found to be missing from its C-terminus relative to another transcript of ZmCBL8. Results indicated that it harbored a dual-lipid modification motif MGCXXS at its N-terminus and was located on the cell membrane. The accumulation of ZmCBL8-1 transcripts was high in the roots but relatively lower in the leaves of maize under normal condition. In contrast, its expression was significantly decreased in the roots, while increased in the leaves under NaCl treatment. The overexpression of ZmCBL8-1 resulted in higher salt stress resistance of transgenic Arabidopsis in a Ca2+-dependent manner relative to that of the wild type (WT). In ZmCBL8-1-overexpressing plants exposed to NaCl, the contents of malondialdehyde and hydrogen peroxide were decreased in comparison with those in the WT, and the expression of key genes involved in the antioxidant defense system and Na+/H+ antiporter were upregulated. These results suggested that ZmCBL8-1 played a positive role in the response of leaves to salt stress by inducing the expression of Na+/H+ antiporter genes and enhancing the antioxidant system to neutralize the accumulation of reactive oxygen species. These observations further indicate that ZmCBL8-1 confers salt stress tolerance, suggesting that transcriptional regulation of the ZmCBL8 gene is important for salt tolerance.

Study of the influence of disease duration on glutatione-dependent ensymes dynamics in patients with paranoid schizophrenia.

OBJECTIVE: Aim: The objective of the research was to conduct a comprehensive longitudinal analysis of the temporal dynamics of glutathione system functionality in individuals diagnosed with paranoid schizophrenia. Specifically, the research was focused on investigating variations in the profiles of glutathione-dependent enzymes, with meticulous consideration given to the duration of the illness. PATIENTS AND METHODS: Materials and Methods: The study group comprised 300 individuals officially diagnosed with 'Paranoid Schizophrenia,' subdivided into five subgroups, each consisting of 60 patients. The subgroups were defined as follows: Subgroup I included 60 patients with a disease duration ranging from 3 to 5 years; Subgroup II comprised 60 patients with a duration of 6 to 10 years; Subgroup III consisted of 60 patients with a duration of 11 to 15 years; Subgroup IV included 60 patients with a duration of 16 to 20 years; and Subgroup V encompassed 60 patients with a duration of 21 years and older. The comparison group comprised 20 patients diagnosed with "Primary psychotic episode". RESULTS: Results: The research demonstrates a consistent and noteworthy reduction in the enzymatic activities of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase in various Subgroups of paranoid schizophrenia patients. The observed declines are particularly prominent within the first 3-5 years of the illness, show casing statistically significant reductions. Patients with prolonged illness durations, especially surpassing 21 years, display substantial reductions in all three enzymes, suggesting a cumulative enzymatic impact associated with prolonged illness. CONCLUSION: Conclusions: The identification of critical periods of inhibition in the glutathione protection chain, provides valuable information about potential therapeutic interventions for individuals with paranoid schizophrenia.

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.

Effects of chemotherapeutic drugs on the antioxidant capacity of human erythroleukemia cells with MDR phenotype.

In this work, we identified that different chemotherapeutic drugs may select cells with different antioxidant capacities. For this, we evaluated the sensitivity of two multidrug-resistant (MDR) erythroleukemia cell lines: Lucena (resistant to vincristine, VCR) and FEPS (resistant to daunorubicin, DNR) derived from the same sensitive cell K562 (non-MDR) to hydrogen peroxide. In addition, we evaluated how the cell lines respond to the oxidizing agent in the absence of VCR/DNR. In absence of VCR, Lucena drastically decreases cell viability when exposed to hydrogen peroxide, while FEPS is not affected even without DNR. To analyze whether selection by different chemotherapeutic agents may generate altered energetic demands, we analyzed the production of reactive oxygen species (ROS) and the relative expression of the glucose transporter 1 gene (glut1). We observed that the selection through DNR apparently generates a higher energy demand than VCR. High levels of transcription factors genes expression (nrf2, hif-1α, and oct4) were kept even when the DNR is withdrawn from the FEPS culture for one month. Together, these results indicate that DNR selects cells with greater ability to express the major transcription factors related to the antioxidant defense system and the main extrusion pump (ABCB1) related to the MDR phenotype. Taking into account that the antioxidant capacity of tumor cells is closely related to resistance to multiple drugs, it is evident that endogenous antioxidant molecules may be targets for the development of new anticancer drugs.

Transcriptome analysis revealed molecular basis of cold response in Prunus mume.

Japanese apricot (Prunus mume Sieb. et Zucc.) is a traditional woody flower and fruit tree restrictedly cultivated in northern area due to its inability to survive harsh winters and early springs. In the current study, RNA-seq and physiological assay were used to study the cold response of P. mume 'Xuemei'. A total of 4705 genes were identified as differentially expressed genes (DEGs) in the 21 pairwise comparisons among seven time points under 0 °C cold treatment, and 3678 of them showed differential levels compared with control at normal temperature. The gene expression profiles indicated that the number of upregulated genes increased with prolongation of treatment time throughout the whole 48 h. Hierarchical clustering suggested three obvious phases of the gene expression profiles. Gene ontology (GO) analysis of the 4705 DEGs resulted in 102 significantly enriched GO items in which the transcription activity was dominant. 225 DEGs were predicted to encode transcription factor (TF) genes. Some important TFs (ERF, CBF, WRKY, NAC, MYB, bHLH) were strongly induced during the whole cold treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that plant signal transduction pathways such as plant hormone and calcium (Ca2+) were notable. Metabolic pathways such as sugar metabolism, especially RFOs (raffinose family oligosaccharides) were activated, which was accompanied by the accumulation of soluble sugars. SOD and POD enzyme activities coupled with reactive oxygen species (ROS)-related gene expression profile implied a gradually induced ROS scavenging system under cold treatment. These results might shed light on the sensitivity to cold stress in Japanese apricot and provide new insights into hardiness studies in P. mume and its related species. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01376-2.

Application of Se-Met to CdTe QDs significantly reduces toxicity by modulating redox balance and inhibiting apoptosis.

Cadmium tellurium quantum dots (CdTe QDs) as one of the most widely used QDs have been reported the toxicity and biosafety in recent years, little work has been done to reduce their toxicity however. Based on the mechanisms of toxicity of CdTe QDs on liver target organs such as oxidative stress and apoptosis previously reported by other researchers, we investigated the mechanism of action of trace element selenium (Se) to mitigate the hepatotoxicity of CdTe QDs. The experimental results showed that Se-Met at 40-140 µg L-1 could enhance the function of intracellular antioxidant defense system and the molecular structure of related antioxidant enzymes by reduce the production of ROS by 45%, protecting the activity of antioxidants and up-regulating the expression of selenoproteins with antioxidant functions, Gpx1 increase 225% and Gpx4 upregulated 47%. In addition, Se-Met could alleviate CdTe QDs-induced apoptosis by regulating two apoptosis-inducing factors, as intracellular caspase 3/9 expression levels were reduced by 70% and 87%, decreased Ca2+ concentration, and increased mitochondrial membrane potential measurements. Overall, this study indicates that Se-Met has a significant protective effect on the hepatotoxicity of CdTe QDs. Se-Met can be applied to the preparation of CdTe QDs to inhibit its toxicity and break the application limitation.

Simultaneous Application of Red and Blue Light Regulate Carbon and Nitrogen Metabolism, Induces Antioxidant Defense System and Promote Growth in Rice Seedlings under Low Light Stress.

The purpose of this study is to determine the effect of light quality on growth, carbon and nitrogen metabolism, and antioxidant defense system of rice seedlings. Six light conditions were employed, including white (W), red (R), blue (B), combined LED of R and B at 3:1 (R3B1), combined LED of R and B at 1:1 (R1B1), as well as combined LED of R and B at 1:3 (R1B3). Combined application of red light and blue light could promote the growth of rice seedling leaves and roots under low light stress to varying degrees, increase the photosynthetic area by increasing the leaf area, improve the root characteristics by increasing the root volume, and increase the dry matter accumulation of rice seedlings. In addition, the combination of red light and blue light could increase carbon and nitrogen metabolites in rice seedling leaves, regulate the expression of genes related to carbon and nitrogen metabolism and enzyme activity, and enhance the antioxidant enzyme activity of rice seedlings. These results indicate that red light and blue light directly have synergistic effects which can regulate the carbon and nitrogen metabolism of rice seedlings, promote the morphogenesis of rice seedlings under low light stress, and promote growth, which has never been reported in previous studies. This study is a new discovery in the application of light quality in crop production and provides new avenues to enhance crop stress resistance. However, further study is needed to explore the physio-biochemical and molecular mechanisms of light quality in crop production.

Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro.

Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential of selected flavonoids in reducing carcinogen-induced reactive oxygen species (ROS) and DNA damage through the activation of nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2)/antioxidant response element (ARE) pathway was studied in vitro. Dose-dependent effects of pre-incubated flavonoids on pro-carcinogen 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKAc)-induced ROS and DNA damage in human bronchial epithelial cells were studied in comparison to non-flavonoids. The most effective flavonoids were assessed for the activation of Nrf2/ARE pathway. Genistein, procyanidin B2 (PCB2), and quercetin significantly suppressed the NNKAc-induced ROS and DNA damage. Quercetin significantly upregulated the phosphorylated protein kinase B/Akt. PCB2 significantly upregulated the activation of Nrf2 and Akt through phosphorylation. Genistein and PCB2 significantly upregulated the phospho-Nrf2 nuclear translocation and catalase activity. In summary, genistein and PCB2 reduced the NNKAc-induced ROS and DNA damage through the activation of Nrf2. Further studies are required to understand the role of dietary flavonoids on the regulation of the Nrf2/ARE pathway in relation to carcinogenesis.