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Cell Death & Disease Sep 2023Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly...
Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is possible to recover sensitivity to ferroptosis in certain cellular models. Here, we discovered that co-treatment with the metabolically stable ferroptosis inducer imidazole ketone erastin (IKE) and the oxidized form of vitamin C, dehydroascorbic acid (DHAA), is a powerful therapy that induces ferroptosis in tumor cells previously resistant to IKE-induced ferroptosis. We determined that DHAA and IKE + DHAA delocalize and deplete GPX4 in tumor cells, specifically inducing lipid droplet peroxidation, which leads to ferroptosis. Moreover, in vivo, IKE + DHAA has high efficacy with regard to the eradication of highly aggressive tumors such as glioblastomas. Thus, the use of IKE + DHAA could be an effective and safe therapy for the eradication of difficult-to-treat cancers.
Topics: Humans; Ferroptosis; Dehydroascorbic Acid; Lipid Droplets; Neoplasms; Cell Death; Lipid Peroxidation
PubMed: 37752118
DOI: 10.1038/s41419-023-06153-9 -
Scientific Reports Sep 2023To explore potential metabolomics biomarkers in predicting post-herpetic neuralgia (PHN) induced by herpes zoster (HZ). A total of 90 eligible patients were...
To explore potential metabolomics biomarkers in predicting post-herpetic neuralgia (PHN) induced by herpes zoster (HZ). A total of 90 eligible patients were prospectively enrolled and assigned into an acute pain (ACP) group and a PHN group. Serum samples were collected before clinical intervention to perform metabolomics profiling analyses using gas chromatography mass spectrometry (GC-MS). Key metabolites were identified using partial least squares discriminant analysis (PLS-DA). A binary logistic regression was used to build a combined biomarker model to predict PHN from ACP. The discriminating efficiency of the combined biomarker model was investigated and validated by internal validation. Six metabolites were identified as the key metabolites related to PHN. All these metabolites (N-Acetyl-5-hydroxytryptaMine, glucose, dehydroascorbic acid, isopropyl-beta-D-thiogalactopyranoside, 1,5-anhydro-D-sorbitol, and glutamic acid) were found elevated in the PHN group. Pathway analyses showed that glucose-alanine cycle, tryptophan metabolism, tyrosine metabolism, lactose degradation, malate-aspartate shuttle were top five metabolic pathways evolved in PHN. The AUC was 0.85 (95% CI 0.76-0.93) for the combined biomarker model, and was 0.91 (95% CI 0.84-1.00) for the internal validation data set to predict PHN. Metabolomics analyses of key metabolites could be used to predict PHN induced by HZ.
Topics: Humans; Neuralgia, Postherpetic; Chickenpox; Varicella Zoster Virus Infection; Metabolomics; Herpes Zoster; Acute Pain; Glucose
PubMed: 37697028
DOI: 10.1038/s41598-023-42363-z -
Free Radical Biology & Medicine Sep 2023An excessive blood level of homocysteine (HcySH) is associated with numerous cardiovascular and neurodegenerative disease conditions. It has been suggested that direct...
An excessive blood level of homocysteine (HcySH) is associated with numerous cardiovascular and neurodegenerative disease conditions. It has been suggested that direct S-homocysteinylation, of proteins by HcySH, or N-homosteinylation by homocysteine thiolactone (HTL) could play a causative role in these maladies. In contrast, ascorbic acid (AA) plays a significant role in oxidative stress prevention. AA is oxidized to dehydroascorbic acid (DHA) and if not rapidly reduced back to AA may degrade to reactive carbonyl products. In the present work, DHA is shown to react with HTL to produce a spiro bicyclic ring containing a six-membered thiazinane-carboxylic acid moiety. This reaction product is likely formed by initial imine condensation and subsequent hemiaminal product followed by HTL ring opening and intramolecular nucleophilic attack of the resulting thiol anion to form the spiro product. The reaction product was determined to have an accurate mass of 291.0414 and a molecular composition CHNOS containing five double bond equivalents. We structurally characterized the reaction product using a combination of accurate mass tandem mass spectrometry, 1D and 2D-nuclear magnetic resonance. We also demonstrated that formation of the reaction product prevented peptide and protein N-homocysteinylation by HTL using a model peptide and α-lactalbumin. Furthermore, the reaction product is formed in Jurkat cells when exposed to HTL and DHA.
Topics: Humans; Dehydroascorbic Acid; Neurodegenerative Diseases; Peptides; Homocysteine
PubMed: 37385568
DOI: 10.1016/j.freeradbiomed.2023.06.031 -
Frontiers in Microbiology 2023The production of pyocyanin by increases its virulence, fitness and biofilm formation. Pyocyanin is also a redox molecule and we hypothesize that ascorbic acid being an...
The production of pyocyanin by increases its virulence, fitness and biofilm formation. Pyocyanin is also a redox molecule and we hypothesize that ascorbic acid being an antioxidant will interact with pyocyanin. The main objective of this study was to investigate the potential interaction of ascorbic acid with pyocyanin, and also to investigate the impact of ascorbic acid in combination with Furanone-30 on quorum sensing and biofilm formation of . When incubated with ascorbic acid, hyperchromic and hypsochromic shifts in pyocyanin absorbance peaks at 385 nm and 695 nm were observed. In the presence of dehydroascorbic acid and citric acid, these shifts were absent, indicating that the intrinsic antioxidant property of ascorbic acid was probably essential in binding to pyocyanin. NMR spectroscopy showed shifts in H NMR pyocyanin peaks between 8.2 to 5.8 ppm when incubated in the presence of ascorbic acid. Density Functional Theory (DFT) supported potential interactions between the -CHOH or -OH moieties of ascorbic acid with the -C=O moiety of pyocyanin. The pyocyanin-ascorbic acid complex impaired pyocyanin binding to DNA. Ascorbic acid combined with furanone-30 elevated quorum-sensing inhibition in , which was directly associated with significantly reduced virulence, adhesion, aggregation and biofilm formation and enhanced antibiotic-mediated bacterial killing. This study demonstrated that the antioxidant ascorbic acid directly binds to pyocyanin, modulates its structure and results in disruption of biofilm formation and associated tolerance to antibiotics.
PubMed: 37520362
DOI: 10.3389/fmicb.2023.1166607 -
Stem Cell Research & Therapy Jan 2024After myocardial infarction, the lost myocardium is replaced by fibrotic tissue, eventually progressively leading to myocardial dysfunction. Direct reprogramming of...
BACKGROUND
After myocardial infarction, the lost myocardium is replaced by fibrotic tissue, eventually progressively leading to myocardial dysfunction. Direct reprogramming of fibroblasts into cardiomyocytes via the forced overexpression of cardiac transcription factors Gata4, Mef2c, and Tbx5 (GMT) offers a promising strategy for cardiac repair. The limited reprogramming efficiency of this approach, however, remains a significant challenge.
METHODS
We screened seven factors capable of improving direct cardiac reprogramming of both mice and human fibroblasts by evaluating small molecules known to be involved in cardiomyocyte differentiation or promoting human-induced pluripotent stem cell reprogramming.
RESULTS
We found that vitamin C (VitC) significantly increased cardiac reprogramming efficiency when added to GMT-overexpressing fibroblasts from human and mice in 2D and 3D model. We observed a significant increase in reactive oxygen species (ROS) generation in human and mice fibroblasts upon Doxy induction, and ROS generation was subsequently reduced upon VitC treatment, associated with increased reprogramming efficiency. However, upon treatment with dehydroascorbic acid, a structural analog of VitC but lacking antioxidant properties, no difference in reprogramming efficiency was observed, suggesting that the effect of VitC in enhancing cardiac reprogramming is partly dependent of its antioxidant properties.
CONCLUSIONS
Our findings demonstrate that VitC supplementation significantly enhances the efficiency of cardiac reprogramming, partially by suppressing ROS production in the presence of GMT.
Topics: Humans; Mice; Animals; Reactive Oxygen Species; Ascorbic Acid; Antioxidants; Cellular Reprogramming; T-Box Domain Proteins; MEF2 Transcription Factors; Myocytes, Cardiac; Vitamins; Fibroblasts
PubMed: 38229180
DOI: 10.1186/s13287-023-03615-x -
BMC Plant Biology Sep 2023Salt stress is one of the key factors limiting rice production. Alginate oligosaccharides (AOS) enhance plant stress resistance. However, the molecular mechanism...
BACKGROUND
Salt stress is one of the key factors limiting rice production. Alginate oligosaccharides (AOS) enhance plant stress resistance. However, the molecular mechanism underlying salt tolerance in rice induced by AOS remains unclear. FL478, which is a salt-tolerant indica recombinant inbred line and IR29, a salt-sensitive rice cultivar, were used to comprehensively analyze the effects of AOS sprayed on leaves in terms of transcriptomic and metabolite profiles of rice seedlings under salt stress.
RESULTS
In this experiment, exogenous application of AOS increased SOD, CAT and APX activities, as well as GSH and ASA levels to reduce the damage to leaf membrane, increased rice stem diameter, the number of root tips, aboveground and subterranean biomass, and improved rice salt tolerance. Comparative transcriptomic analyses showed that the regulation of AOS combined with salt treatment induced the differential expression of 305 and 1030 genes in FL478 and IR29. The expressed genes enriched in KEGG pathway analysis were associated with antioxidant levels, photosynthesis, cell wall synthesis, and signal transduction. The genes associated with light-trapping proteins and RLCK receptor cytoplasmic kinases, including CBA, LHCB, and Lhcp genes, were fregulated in response to salt stress. Treatment with AOS combined with salt induced the differential expression of 22 and 50 metabolites in FL478 and IR29. These metabolites were mainly related to the metabolism of amino and nucleotide sugars, tryptophan, histidine, and β -alanine. The abundance of metabolites associated with antioxidant activity, such as 6-hydroxymelatonin, wedelolactone and L-histidine increased significantly. Combined transcriptomic and metabolomic analyses revealed that dehydroascorbic acid in the glutathione and ascorbic acid cycles plays a vital role in salt tolerance mediated by AOS.
CONCLUSION
AOS activate signal transduction, regulate photosynthesis, cell wall formation, and multiple antioxidant pathways in response to salt stress. This study provides a molecular basis for the alleviation of salt stress-induced damage by AOS in rice.
Topics: Transcriptome; Seedlings; Antioxidants; Oryza; Salt Stress; Glutathione; Oligosaccharides
PubMed: 37770835
DOI: 10.1186/s12870-023-04470-x -
Animal Reproduction Science May 2024The incidence of bovine endometritis, which has a negative impact on the reproduction of dairy cows, has been recently increasing. In this study, the differential...
The incidence of bovine endometritis, which has a negative impact on the reproduction of dairy cows, has been recently increasing. In this study, the differential markers and metabolites of healthy cows and cows with endometritis were analyzed by measuring blood biochemical indicators and immune factors using biochemical and enzyme-linked immunosorbent assay kits combined with nontargeted metabolomics. The LC-QTOF platform was used to evaluate the serum metabolomics of healthy cows and cows with endometritis after 21-27 days of calving. The results showed that glucose, free fatty acid, calcium, sodium, albumin, and alanine aminotransferase levels were significantly lower in the serum of cows with endometritis than in healthy cows (P < 0.05). However, the serum potassium, interleukin-1, interleukin-6, and tumor necrosis factor levels were significantly higher in cows with endometritis (P < 0.05). In addition, the serum metabolome data analysis of the two groups showed that the expression of 468 metabolites was significantly different (P < 0.05), of which 291 were upregulated and 177 were downregulated. These metabolites were involved in 78 metabolic pathways, including amino acid, nucleotide, carbohydrate, lipid, and vitamin metabolism pathways; signal transduction pathways, and other biological pathways. Taken together, negative energy balance and immune activation, which are related to local abnormalities in amino acid, lipid, and carbohydrate metabolism, were the important causes of endometritis in dairy cows. Metabolites such as glucose, carnosine, dehydroascorbic acid, L-malic acid, tetrahydrofolic acid, and UDP-glucose may be used as key indicators in the hematological diagnosis and treatment of endometritis in dairy cows.
Topics: Female; Cattle; Animals; Endometritis; Cattle Diseases; Metabolomics; Biomarkers
PubMed: 38564886
DOI: 10.1016/j.anireprosci.2024.107460 -
Nutrients Aug 2023The influence of the diet and nutritional status of milk donors on the nutritional composition of donor human milk (DHM) is unknown. The present study aimed to determine...
The influence of the diet and nutritional status of milk donors on the nutritional composition of donor human milk (DHM) is unknown. The present study aimed to determine the nutritional profile of DHM and the associations between donors' dietary intake and nutritional status and the micronutrient and lipid composition in DHM. For this purpose, 113 donors completed a food frequency questionnaire, provided a five-day weighed dietary record, and collected milk for five consecutive days. Nutrient determinations in donors' erythrocytes, plasma, urine, and milk were performed. Multiple linear regressions were conducted for the evaluation of the associations. We highlight the following results: DHM docosahexaenoic acid (DHA) was positively associated with donors' plasma DHA content and donors' DHA intake (R 0.45, < 0.001). For every 1 g/day DHA intake, an increase of 0.38% in DHA content and 0.78% in total omega-3 content was observed in DHM (R 0.29, < 0.001). DHM saturated fatty acids were positively associated with erythrocyte dimethyl acetals, plasma stearic acid, fatty acids intake, and breastfeeding duration and negatively associated with erythrocyte margaroleic acid (R 0.34, < 0.01). DHM cholecalciferol was associated with plasma cholecalciferol levels and dairy intake (R 0.57, < 0.01). Other weaker associations were found for free thiamin, free riboflavin, pyridoxal, dehydroascorbic acid, and the lipid profile in DHM. In conclusion, the diet and nutritional status of donors influence the fatty acid profile and micronutrient content of DHM.
Topics: Female; Humans; Milk, Human; Micronutrients; Eating; Fatty Acids, Omega-3; Fatty Acids; Docosahexaenoic Acids; Nutrients; Trace Elements
PubMed: 37571421
DOI: 10.3390/nu15153486 -
Journal of Plant Physiology Jul 2023Numerous studies report different types of responses following exposure of plants to high frequency electromagnetic fields (HF-EMF). While this phenomenon is related to...
Numerous studies report different types of responses following exposure of plants to high frequency electromagnetic fields (HF-EMF). While this phenomenon is related to tissue heating in animals, the situation is much less straightforward in plants where metabolic changes seem to occur without tissue temperature increase. We have set up an exposure system allowing reliable measurements of tissue heating (using a reflectometric probe and thermal imaging) after a long exposure (30 min) to an electromagnetic field of 2.45 GHz transmitted through a horn antenna (about 100 V m at the plant level). We did not observe any heating of the tissues, but we detected rapid increases (60 min) in the accumulation of transcripts of stress-related genes (TCH1 and ZAT12 transcription factor) or involved in ROS metabolism (RBOHF and APX1). At the same time, the amounts of hydrogen peroxide and dehydroascorbic acid increased while glutathione (reduced and oxidized forms), ascorbic acid, and lipid peroxidation remained stable. Therefore, our results unambiguously show that molecular and biochemical responses occur rapidly (within 60min) in plants after exposure to an electromagnetic field, in absence of tissue heating.
Topics: Animals; Arabidopsis; Electromagnetic Fields; Plants; Hydrogen Peroxide; Lipid Peroxidation
PubMed: 37210775
DOI: 10.1016/j.jplph.2023.153999 -
The Analyst Nov 2023Affinity assays allow direct detection of DNA methylation events without requiring a special sequence. However, the signal amplification of these methods heavily depends...
Affinity assays allow direct detection of DNA methylation events without requiring a special sequence. However, the signal amplification of these methods heavily depends on nanocatalysts and bioenzymes, making them suffer from low sensitivity. In this work, alkaline phosphatase (ALP)-assisted chemical redox cycling was employed to amplify the sensitivity of fluorescence affinity assays for DNA methylation detection using Ru@SiO@MnO nanocomposites as fluorescent probes. In the ALP-assisted chemical redox cycling reaction system, ALP hydrolyzed 2-phosphate-L-ascorbic acid trisodium salt (AAP) to produce AA, which could reduce MnO nanosheets to form Mn, making the fluorescence recovery of Ru@SiO nanoparticles possible. Meanwhile, AA was oxidized to dehydroascorbic acid (DHA), which was re-reduced by tris(2-carboxyethyl) phosphine (TCEP) to trigger a redox cycling reaction. The constantly generated AA could etch large amounts of MnO nanosheets and greatly recover Ru@SiO fluorescence, amplifying the signal of the fluorescence assay. Employing the proposed ALP-assisted chemical redox cycling signal amplification strategy, a sensitive affinity assay for DNA methylation detection was achieved using ALP encapsulated liposomes that were linked with the 5mC antibody (Ab) to bind with methylated sites. A detection limit down to 2.9 fM was obtained for DNA methylation detection and a DNA methylation level as low as 0.1% could be distinguished, which was superior to conventional affinity assays. Moreover, the affinity assays could detect DNA methylation more specifically and directly, implying their great potential for the analysis of tumor-specific genes in liquid biopsy.
Topics: Alkaline Phosphatase; DNA Methylation; Fluorescence; Manganese Compounds; Silicon Dioxide; Oxides; Oxidation-Reduction
PubMed: 37842979
DOI: 10.1039/d3an01383a