Search Results (76)

The betel nut is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. Arecoline is an active ingredient from the areca nut. It has many pharmacological effects and can affect the central nervous system. In this study, we found that arecoline can relieve fatigue behavior. Objective: This research aims to estimate the anti-fatigue effects of arecoline and explore its underlying mechanisms using a murine model of central fatigue precipitated by sleep deprivation (SD). Methods: Seventy-two male C57BL/6 mice were randomly assigned to six groups: a control group, an SD-induced fatigue model group, a group that received Rhodiola Rosea capsules (2.5 mg/kg), and three arecoline groups, which were administered at low, medium, and high doses (10, 20, and 40 mg/kg, respectively). Following 28 days of continuous administrations, the effects of arecoline on mouse fatigue-related behaviors were assessed by behavioral tests, including grip strength, rotarod performance, and weight-bearing swimming endurance. The release levels of the related biochemical markers were measured by enzyme-linked immunosorbent assays (ELISAs). Western blotting was employed to quantify the expression levels of nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), sequestosome-1 (p62), and NADPH quinone oxidoreductase 1 (NQO1) in the gastrocnemius muscle. Results: Arecoline administration notably enhanced grip strength, delayed the onset of fatigue as evidenced by extended latencies in rotarod tests, and increased the duration of weight-bearing swimming in mice. In the elevated plus maze, arecoline obviously decreased both the number of entries and the total distance traveled in the open arms. Arecoline markedly decreased the contents of creatine kinase, blood urea nitrogen, lactate dehydrogenase, triglycerides, and cholesterol in the serum, while it elevated the levels of total testosterone, lactate dehydrogenase, and immunoglobulin G. Furthermore, it significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase in the gastrocnemius muscle, reduced malondialdehyde levels, augmented hippocampal SOD and CAT activity, and elevated glycogen stores in both liver and muscle tissues. Neurotransmitter levels showed significant increases, cytokine levels were markedly reduced, and the expressions of Nrf2, Keap1, NQO1, p62, and HO-1 in brain tissues were significantly upregulated. Conclusions: This study demonstrates that arecoline has anti-fatigue activity, and the specific mechanisms are associated with elevating glucose and lipid metabolism levels, relieving oxidative stress damage, inhibiting neuroinflammatory response, and regulating neurotransmitter levels and the Keap1/Nrf2/HO-1 signaling pathway. The research provides a new direction for arecoline’s potential in preventing and improving fatigue. Full article

We reported that a 31-amino-acid Zfra protein (zinc finger-like protein that regulates apoptosis) blocks neurodegeneration and cancer growth. Zfra binds WW domain-containing oxidoreductase (WWOX) to both N- and C-termini, which leads to accelerated WWOX degradation. WWOX limits the progression of neurodegeneration such as Alzheimer’s disease (AD) by binding tau and tau-hyperphosphorylating enzymes. Similarly, Zfra binds many protein targets and accelerates their degradation independently of ubiquitination. Furthermore, Zfra4-10 peptide strongly prevents the progression of AD-like symptoms in triple-transgenic (3xTg) mice during aging. Zfra4-10 peptide restores memory loss in 9-month-old 3xTg mice by blocking the aggregation of a protein cascade, including TPC6AΔ, TIAF1, and SH3GLB2, by causing aggregation of tau and amyloid β. Zfra4-10 also suppresses inflammatory NF-κB activation. Zfra-activated Hyal-2+ CD3- CD19- Z cells in the spleen, via Hyal-2/WWOX/Smad4 signaling, are potent in cancer suppression. In this perspective review, we provide mechanistic insights regarding how Zfra overrides WWOX to induce cancer suppression and retard AD progression via Z cells. Full article

In recent years, research on the discovery of natural compounds with potent antioxidant properties has resulted in growing interest in these compounds due to their potential therapeutic applications in oxidative-stress-related diseases. Argan oil, derived from the kernels of a native tree from Morocco, Argania spinosa, is renowned for its rich composition of bioactive compounds, prominently tocopherols, polyphenols, and fatty acids. Interestingly, a large body of data has shown that several components of argan oil activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, playing a crucial role in the cellular defense against oxidative stress. Activation of this Nrf2 pathway by argan oil components leads to the increased expression of downstream target proteins like NAD(P)H quinone oxidoreductase (NQO1), superoxide dismutase (SOD), heme oxygenase 1 (HO-1), and catalase (CAT). Such Nrf2 activation accounts for several health benefits related to antioxidant defense, anti-inflammatory effects, cardiovascular health, and neuroprotection in organisms. Furthermore, the synergistic action of the bioactive compounds in argan oil enhances the Nrf2 pathway. Accordingly, the modulation of the Kelch-like ECH associated protein 1 (Keap1)/Nrf2 signaling pathway by these components highlights the potential of argan oil in protecting cells from oxidative stress and underlines its relevance in dietetic prevention and therapeutic applications. This review aims to provide an overview of how major compounds in argan oil activate the Nrf2 pathway, updating our knowledge on their mechanisms of action and associated health benefits. Full article

Electrostatic fermentation avoids the cellular redox imbalance of traditional fermentation, but knowledge gaps exist. This study explores the impact of electrostatic fermentation on the growth, volatile profile, and genetic response of Saccharomyces pastorianus Saflager S-23. The applied voltage (15 and 30 V) in the electrostatic fermentation system increased the growth and substrate utilization of S. pastorianus while decreasing ethanol production. The aromas typically associated with traditional fermentation, such as alcoholic, grape, apple, and sweet notes, were diminished, while aromas like roses, fruits, flowers, and bananas were augmented in electrostatic fermentation. RNA-seq analysis revealed upregulation of genes involved in cell wall structure, oxidoreductase activity, and iron ion binding, while genes associated with protein synthesis, growth control, homeostasis, and membrane function were downregulated under the influence of applied voltage. The electrostatic fermentation system modulates genetic responses and metabolic pathways in yeast, rendering it a promising method for tailored beer production. Demonstrating feasibility under industrial-scale and realistic conditions is crucial for advancing towards commercialization. Full article

This work describes the design and synthesis of three series of hybrids of thienopyrimidines and sulfonamides. Dihydrofolate reductase enzyme was selected as a target for the in-silico screening of the synthesized thienopyrimidine–sulfonamide hybrid as an antibacterial, while squalene epoxidase was selected as an antifungal target protein. All screened compounds showed promising binding affinity ranges, with perfect fitting not exceeding 1.9 Å. The synthesized compounds were tested for their antimicrobial activity using agar well diffusion and minimum inhibitory concentration tests against six bacterial strains in addition to two Candida strains. Compounds 8iii and 12ii showed varying degrees of inhibition against Staphylococcus aureus and Escherichia coli bacterial strains, whereas the best antifungal activity against Candida was displayed by compound 8iii. Compound 12ii, the cyclohexathienopyrimidine coupled with sulfadiazine at position 3, has the best antibacterial activity, which is consistent with molecular docking results at the active site of the oxidoreductase protein. Interestingly, compound 12ii also has the highest docking binding energy at the antifungal squalene epoxidase active site. Investigating the physicochemical properties of the synthesized hybrids revealed their high tolerability with cell membranes, and moderate to poor oral bioavailability, and that all are drug-like candidates, among which 4i, the cyclohexathieno[2,3-d] pyrimidine core with sulphaguanidine incorporated at position 4, recorded the best score (1.58). Full article

This experiment aimed to investigate the mitigating effect of CUR on the growth performance and liver and intestinal health of broilers fed AFB1-contaminated diets. In this study, 320 one-day-old healthy male Arbor Acres (AA) broilers were randomly divided into four groups, including the Control group (fed the basal diet), the AFB1 group (fed the AFB1-contaminated diet containing 1 mg/kg AFB1), the AFB1+CUR group (fed the AFB1-contaminated diet with 500 mg/kg CUR), and the CUR group (fed the basal diet containing 500 mg/kg CUR), with eight replicates of ten animals per group and a 28 d experimental period. In terms of the growth performance, the addition of 500 mg/kg CUR significantly improved AFB1-induced significant reductions in the final body weight on day 28 and mean daily gain (p < 0.05) and increased the ratio of the mean daily feed intake to mean daily weight gain in broilers (p < 0.05). In terms of liver health, significant improvements in liver histological lesions occurred in broilers in the AFB1+CUR group compared to the AFB1 group, with significantly higher glutathione peroxidase (GSH-Px), catalase (CAT), and total superoxide dismutase (T-SOD) activities (p < 0.05) and significantly higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), heme oxygenase 1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1) gene expression (p < 0.05). In terms of intestinal health, CUR addition significantly increased the relative length of ileum (p < 0.05), significantly elevated the height of ileal villi (p < 0.05), significantly reduced D-Lactate (D-LA) and diamine oxidase (DAO) activities in broiler serum (p < 0.05), significantly increased GSH, CAT, and T-SOD activities in ileal tissues (p < 0.05), and significantly elevated the expression of Nrf2, HO-1, and NQO-1 genes (p < 0.05) compared to the AFB1 group. In conclusion, CUR showed a protective effect against damage to the liver and intestine caused by AFB1 in broilers through the Nrf2 signaling pathway, thereby improving the growth performance of broilers exposed to AFB1. Full article

This study examined the genes related to immunity, metabolism, and antioxidants that may interact with the prevalence of postpartum endometritis in Ossimi sheep. We used fifty endometritis-positive Ossimi sheep and fifty that appeared to be normal. For the purpose of taking blood samples, each ewe had its jugular vein pierced. Nucleotide sequence differences for the immunological (alpha-2-macroglobulin, toll-like receptor 2, transforming growth factor beta, interleukin 1 receptor-associated kinase 3, high-mobility group box 1, Fc alpha and Mu receptor, and inducible nitric oxide synthase), metabolic (ADAM metallopeptidase with thrombospondin type 1 motif 20, potassium sodium-activated channel subfamily T member 2, Mitogen-activated protein kinase kinase kinase 4, FKBP prolyl isomerase 5, and relaxin family peptide receptor 1), and antioxidant (superoxide dismutase, catalase, NADH: ubiquinone oxidoreductase subunit s5, and Heme oxygenase-1) genes were found among sheep with endometritis and those in good condition utilizing PCR-DNA sequencing. Fisher’s exact test revealed a significant difference in the probability of dispersal of all significant nucleotide changes between ewe groups with and without endometritis (p ˂ 0.01). In endometritis ewes, there was a considerable up-regulation of the expression levels of A2M, TLR2, IRAK3, HMGB1, FCAMR, iNOS, ADAMTS20, KCNT2, MAP3K4, FKBP5, RXFP1, and HMOX1. Conversely, there was a down-regulation of the genes that encode TGF-β, SOD, CAT, and NDUFS5. The kind of marker and its frequency in postparturient endometrtits significantly impacted the transcript levels of the indicators under analysis. The results validate that nucleotide changes and gene manifestation outlines in these candidates are significant predictors of the prevalence of endometritis in sheep. Full article

Protein import and oxidative folding within the intermembrane space (IMS) of mitochondria relies on the MIA40–ERV1 couple. The MIA40 oxidoreductase usually performs substrate recognition and oxidation and is then regenerated by the FAD-dependent oxidase ERV1. In most eukaryotes, both proteins are essential; however, MIA40 is dispensable in Arabidopsis thaliana. Previous complementation experiments have studied yeast mia40 mutants expressing a redox inactive, but import-competent versions of yeast Mia40 using A. thaliana ERV1 (AtERV1) suggest that AtERV1 catalyzes the oxidation of MIA40 substrates. We assessed the ability of both yeast and Arabidopsis MIA40 and ERV1 recombinant proteins to oxidize the apo-cytochrome reductase CCMH and the cytochrome c oxidase assembly protein COX19, a typical MIA40 substrate, in the presence or absence of glutathione, using in vitro cysteine alkylation and cytochrome c reduction assays. The presence of glutathione used at a physiological concentration and redox potential was sufficient to support the oxidation of COX19 by AtERV1, providing a likely explanation for why MIA40 is not essential for the import and oxidative folding of IMS-located proteins in Arabidopsis. The results point to fundamental biochemical differences between Arabidopsis and yeast ERV1 in catalyzing protein oxidation. Full article

Since the ethanol extract of Alisma orientale Juzepzuk (EEAO) suppresses lung inflammation by suppressing Nuclear Factor-kappa B (NF-κB) and activating Nuclear Factor Erythroid 2-related Factor 2 (Nrf2), we set out to identify chemicals constituting EEAO that suppress lung inflammation. Here, we provide evidence that among the five most abundant chemical constituents identified by Ultra Performance Liquid Chromatography (UPLC) and Nuclear Magnetic Resonance (NMR), alismol is one of the candidate constituents that suppresses lung inflammation in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model and protects mice from ALI-like symptoms. Alismol did not induce cytotoxicity or reactive oxygen species (ROS). When administered to the lung of LPS-induced ALI mice (n = 5/group), alismol decreased the level of neutrophils and of the pro-inflammatory molecules, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1), Interferon-gamma (IFN-γ), and Cyclooxygenase-2 (COX-2), suggesting an anti-inflammatory activity of alismol. Consistent with these findings, alismol ameliorated the key features of the inflamed lung of ALI, such as high cellularity due to infiltrated inflammatory cells, the development of hyaline membrane structure, and capillary destruction. Unlike EEAO, alismol did not suppress NF-κB activity but rather activated Nrf2. Consequently, alismol induced the expression of prototypic genes regulated by Nrf2, including Heme Oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamyl cysteine ligase catalytic units (GCLC). Alismol activating Nrf2 appears to be associated with a decrease in the ubiquitination of Nrf2, a key suppressive mechanism for Nrf2 activity. Together, our results suggest that alismol is a chemical constituent of EEAO that contributes at least in part to suppressing some of the key features of ALI by activating Nrf2. Full article

In vascular plants, the final photosynthetic electron transfer from ferredoxin (Fd) to NADP⁺ is catalyzed by the flavoenzyme ferredoxin:NADP⁺ oxidoreductase (FNR). FNR is recruited to thylakoid membranes via an integral membrane protein TROL (thylakoid rhodanese-like protein) and the membrane associated protein Tic62. We have previously demonstrated that the absence of TROL triggers a very efficient superoxide (O₂^•−) removal mechanism. The dynamic TROL–FNR interaction has been shown to be an apparently overlooked mechanism that maintains linear electron flow before alternative pathway(s) is(are) activated. In this work, we aimed to further test our hypothesis that the FNR–TROL pair could be the source element that triggers various downstream networks of chloroplast ROS scavenging. Tandem affinity purification followed by the MS analysis confirmed the TROL–FNR interaction and revealed possible interaction of TROL with the thylakoid form of the enzyme ascorbate peroxidase (tAPX), which catalyzes the H₂O₂-dependent oxidation of ascorbate and is, therefore, the crucial component of the redox homeostasis system in plants. Further, EPR analyses using superoxide spin trap DMPO showed that, in comparison with the wild type, plants overexpressing TROL (TROL OX) propagate more O₂^•− when exposed to high light stress. This indicates an increased sensitivity to oxidative stress in conditions when there is an excess of membrane-bound FNR and less free FNR is found in the stroma. Finally, immunohistochemical analyses of glutathione in different Arabidopsis leaf cell compartments showed highly elevated glutathione levels in TROL OX, indicating an increased demand for this ROS scavenger in these plants, likely needed to prevent the damage of important cellular components caused by reactive oxygen species. Full article

Chloride intracellular ion channel (CLIC) proteins exist as both soluble and integral membrane proteins, with CLIC1 capable of shifting between two distinct structural conformations. New evidence has emerged indicating that members of the CLIC family act as moonlighting proteins, referring to the ability of a single protein to carry out multiple functions. In addition to their ion channel activity, CLIC family members possess oxidoreductase enzymatic activity and share significant structural and sequence homology, along with varying overlaps in their tissue distribution and cellular localization. In this study, the 2-hydroxyethyl disulfide (HEDS) assay system was used to characterize kinetic properties, as well as the temperature and pH profiles of three CLIC protein family members (CLIC1, CLIC3, CLIC4). We also assessed the effects of the drugs rapamycin and amphotericin B, on the three CLIC proteins’ enzymatic activity in the HEDS assay. Our results demonstrate CLIC1 to be highly heat-sensitive, with optimal enzymatic activity observed at neutral pH7 and at a temperature of 37 °C, while CLIC3 had higher oxidoreductase activity in more acidic pH5 and was found to be relatively heat stable. CLIC4, like CLIC1, was temperature sensitive with optimal enzymatic activity observed at 37 °C; however, it showed optimal activity in more alkaline conditions of pH8. Our current study demonstrates individual differences in the enzymatic activity between the three CLIC proteins, suggesting each CLIC protein is likely regulated in discrete ways, involving changes in the subcellular milieu and microenvironment. Full article

Anserine is a naturally occurring histidine dipeptide with significant antioxidant activities. This study aimed to investigate the preventive mechanism of anserine on tert-butyl hydroperoxide (TBHP)-induced liver damage in a normal human liver cell line (L-02 cells). The L-02 cells were pretreated with anserine (10, 20, and 40 mmol/L) and then induced with 400 μmol/L of TBHP for 4 h. The results showed that the survival rates of L-02 cells and the contents of GSH were significantly increased with the pretreatment of anserine; the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the extracellular fluid were sharply decreased; and the formation of reactive oxygen species (ROS), nuclear fragmentation, and apoptosis were significantly inhibited. In addition, anserine could bind to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) with a binding force of −7.2 kcal/mol; the protein expressions of nuclear factor-erythroid 2-related factor-2 (Nrf2), quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and Bcl-2 were upregulated by anserine in TBHP-induced L-02 cells, with the downregulation of p-JNK and caspase-3. In conclusion, anserine might alleviated liver injury in L-02 cells via regulating related proteins in the Keap1-Nrf2 and JNK-Caspase-3 signaling pathways. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized primarily by a decline in cognitive function. However, the etiopathogenesis of AD is unclear. N6-methyladenosine (m6A) is abundant in the brain, and it is interesting to explore the relationship between m6A and AD causes. In this paper, the gene expression of METTL3 and NDUFA10 were found to correlate with the Mini-mental State Examination (MMSE), which is a clinical indicator of the degree of dementia. METTL3 is involved in post-transcriptional methylation and the formation of m6A. NDUFA10 encodes the protein with NADH dehydrogenase activity and oxidoreductase activity in the mitochondrial electron transport chain. The following three characteristics were observed in this paper: 1. The lower the expression level of NDUFA10, the smaller the MMSE, and the higher the degree of dementia. 2. If the expression level of METTL3 dropped below its threshold, the patient would have a risk of AD with a probability close to 100%, suggesting a basic necessity for m6A to protect mRNA. 3. The lower the expression levels of both METTL3 and NDUFA10, the more likely the patient would suffer from AD, implying the coherence between METTL3 and NDUFA10. Regarding the above discovery, the following hypothesis is presented: METTL3 expression level is downregulated, then the m6A modification level of NDUFA10 mRNA is also decreased, thereby reducing the expression level of NDUFA10-encoded protein. Furthermore, the abnormal expression of NDUFA10 contributes to the assembly disorder of mitochondrial complex I and affects the process of the electron respiratory chain, with the consequent development of AD. In addition, to confirm the above conclusions, the AI Ant Colony Algorithm was improved to be more suitable for discovering the characteristics of AD data, and the SVM diagnostic model was applied to mine the coherent effects on AD between METTL3 and NDUFA10. In conclusion, our findings suggest that dysregulated m6A leads to altered expression of its target genes, thereby affecting AD’s development. Full article

Although bacterial thioredoxin reductase-like ferredoxin/flavodoxin NAD(P)⁺ oxidoreductases (FNRs) are similar in terms of primary sequences and structures, they participate in diverse biological processes by catalyzing a range of different redox reactions. Many of the reactions are critical for the growth, survival of, and infection by pathogens, and insight into the structural basis for substrate preference, specificity, and reaction kinetics is crucial for the detailed understanding of these redox pathways. Bacillus cereus (Bc) encodes three FNR paralogs, two of which have assigned distinct biological functions in bacillithiol disulfide reduction and flavodoxin (Fld) reduction. Bc FNR2, the endogenous reductase of the Fld-like protein NrdI, belongs to a distinct phylogenetic cluster of homologous oxidoreductases containing a conserved His residue stacking the FAD cofactor. In this study, we have assigned a function to FNR1, in which the His residue is replaced by a conserved Val, in the reduction of the heme-degrading monooxygenase IsdG, ultimately facilitating the release of iron in an important iron acquisition pathway. The Bc IsdG structure was solved, and IsdG-FNR1 interactions were proposed through protein–protein docking. Mutational studies and bioinformatics analyses confirmed the importance of the conserved FAD-stacking residues on the respective reaction rates, proposing a division of FNRs into four functionally unique sequence similarity clusters likely related to the nature of this residue. Full article

Ferroptosis participates in the occurrence and development of neurological disorders. Modulating ferroptosis may have therapeutic potential in nervous system diseases. Therefore, TMTbased proteomic analysis in HT-22 cells was performed to identify erastin–induced differentially expressed proteins. The calcium-transporting ATP2B3 (ATP2B3) was screened as a target protein. ATP2B3 knockdown markedly alleviated the erastin–induced decrease in cell viability and elevated ROS (p < 0.01) and reversed the up-regulation of oxidative stress-related proteins polyubiquitin-binding protein p62 (P62), nuclear factor erythroid 2-related factor2 (NRF2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase-1 (NQO1) protein expression (p < 0.05 or p < 0.01) and the down−regulation of Kelch-like ECH-associated protein 1(KEAP1) protein expression (p < 0.01). Moreover, NRF2 knockdown, P62 inhibition, or KEAP1 overexpression rescued the erastin–induced decrease in cell viability (p < 0.05) and increase in ROS production (p < 0.01) in HT-22 cells, while simultaneous overexpression of NRF2 and P62 and knockdown of KEAP1 partially offset the relief effect of ATP2B3 inhibition. In addition, knockdown of ATP2B3, NRF2, and P62 and overexpression of KEAP1 significantly down-regulated erastin–induced high expression of the HO-1 protein, while HO-1 overexpression reversed the alleviating effects of ATP2B3 inhibition on the erastin–induced decrease in cell viability (p < 0.01) and increase in ROS production (p < 0.01) in HT-22 cells. Taken together, ATP2B3 inhibition mediates the alleviation of erastin–induced ferroptosis in HT-22 cells through the P62–KEAP1–NRF2–HO-1 pathway. Full article