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ACS Nano Aug 2023Ions play a vital role in regulating various biological processes, including metabolic and immune homeostasis, which involves tumorigenesis and therapy. Thus, the...
Ions play a vital role in regulating various biological processes, including metabolic and immune homeostasis, which involves tumorigenesis and therapy. Thus, the perturbation of ion homeostasis can induce tumor cell death and evoke immune responses, providing specific antitumor effects. However, antitumor strategies that exploit the effects of multiion perturbation are rare. We herein prepared a pH-responsive nanomodulator by coloading curcumin (CU, a Ca enhancer) with CaCO and MnO into nanoparticles coated with a cancer cell membrane. This nanoplatform was aimed at reprogramming the tumor microenvironment (TME) and providing an antitumor treatment through ion fluctuation. The obtained nanoplatform, called CM NPs, could neutralize protons by decomposing CaCO and attenuating cellular acidity, they could generate Ca and release CU, elevating Ca levels and promoting ROS generation in the mitochondria and endoplasmic reticulum, thus, inducing immunogenic cell death. Mn could decompose the endogenous HO into O to relieve hypoxia and enhance the sensitivity of cGAS, activating the cGAS-STING signaling pathway. In addition, this strategy allowed the reprogramming of the immune TME, inducing macrophage polarization and dendritic cell maturation via antigen cross-presentation, thereby increasing the immune system's ability to combat the tumor effectively. Moreover, the as-prepared nanoparticles enhanced the antitumor responses of the αPD1 treatment. This study proposes an effective strategy to combat tumors via the reprogramming of the tumor TME and the alteration of essential ions concentrations. Thus, it shows great potential for future clinical applications as a complementary approach along with other multimodal treatment strategies.
Topics: Humans; Calcium; Manganese; Hydrogen Peroxide; Manganese Compounds; Tumor Microenvironment; Oxides; Immunotherapy; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 37530575
DOI: 10.1021/acsnano.3c01215 -
Redox Biology Jul 2023Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells... (Review)
Review
Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells generally represent a higher oxidant level, which suggests a dual therapeutic strategy by regulating redox status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, pro-oxidant therapy exhibits a great anti-cancer capability, attributing to a higher oxidant accumulation within cancer cells, whereas antioxidant therapy to restore redox homeostasis has been claimed to fail in several clinical practices. Targeting the redox vulnerability of cancer cells by pro-oxidants capable of generating excessive reactive oxygen species (ROS) has surfaced as an important anti-cancer strategy. However, multiple adverse effects caused by the indiscriminate attacks of uncontrolled drug-induced OS on normal tissues and the drug-tolerant capacity of some certain cancer cells greatly limit their further applications. Herein, we review several representative oxidative anti-cancer drugs and summarize their side effects on normal tissues and organs, emphasizing that seeking a balance between pro-oxidant therapy and oxidative damage is of great value in exploiting next-generation OS-based anti-cancer chemotherapeutics.
Topics: Humans; Antioxidants; Reactive Oxygen Species; Oxidative Stress; Oxidation-Reduction; Oxidants; Neoplasms
PubMed: 37224697
DOI: 10.1016/j.redox.2023.102754 -
PloS One 2023Deficiency of silent information regulator 1 (SIRT1) can trigger inflammation, mitochondrial malfunctioning, and apoptosis through the hypothalamic-pituitary-ovarian...
BACKGROUND
Deficiency of silent information regulator 1 (SIRT1) can trigger inflammation, mitochondrial malfunctioning, and apoptosis through the hypothalamic-pituitary-ovarian axis, producing poor quality oocytes, leading to infertility. Normal vitamin D (VD) levels promote SIRT1 activity required for optimal fertility, and low levels of either may result in fertility problems owing to cell-membrane de-stabilization, increased autophagy, DNA damage leading to increased reactive oxygen species and mitochondrial dysfunction. Therefore, in this study, we want to estimate the levels of VD, SIRT1 and antioxidants (MnSOD; manganese superoxide dismutase, GR; glutathione reductase, visfatin) and oxidants (adrenaline & cortisol) in individuals living with infertility and explore the association of VD with SIRT1 expression (levels), antioxidants, and oxidants contributing to infertility in women. The significance of this study is that it highlights the importance of maintaining optimal levels of VD for reproductive health in females.
METHODS
This cross-sectional study included 342 (135 infertile and 207 fertile) female subjects. Serum levels of MnSOD, SIRT1, visfatin, GR, VD, adrenaline, and cortisol were analyzed by ELISA and were compared in fertile and infertile samples using the Mann Whitney U test.
RESULTS
There were significantly high levels of VD, SIRT1, GR, MnSOD and visfatin in fertile female participants. However, mean adrenaline and cortisol levels were higher in infertile samples with a significant negative correlation with VD. A significant negative correlation of VD with MnSOD, SIRT1, visfatin and GR was observed (p <0.01). In VD subset groups, MnSOD levels were significantly high in VD sufficient groups however, adrenaline and cortisol levels were significantly high in groups suffering from VD deficiency.
CONCLUSIONS
Deficiency of VD is associated with a decrease in SIRT1 and other antioxidants, which may deter natural reproductive functions leading to infertility. Further studies are required to determine the cause-effect relationship of VD deficiency on conception and interpretation of the involved mechanism.
Topics: Humans; Female; Vitamin D; Antioxidants; Sirtuin 1; Nicotinamide Phosphoribosyltransferase; Hydrocortisone; Cross-Sectional Studies; Vitamins; Infertility, Female; Vitamin D Deficiency; Oxidants
PubMed: 37428803
DOI: 10.1371/journal.pone.0287727 -
Redox Biology Jul 2023During cardiac ischemia-reperfusion, excess reactive oxygen species can damage mitochondrial, cellular and organ function. Here we show that cysteine oxidation of the...
During cardiac ischemia-reperfusion, excess reactive oxygen species can damage mitochondrial, cellular and organ function. Here we show that cysteine oxidation of the mitochondrial protein Opa1 contributes to mitochondrial damage and cell death caused by oxidative stress. Oxy-proteomics of ischemic-reperfused hearts reveal oxidation of the C-terminal C786 of Opa1 and treatment of perfused mouse hearts, adult cardiomyocytes, and fibroblasts with HO leads to the formation of a reduction-sensitive ∼180 KDa Opa1 complex, distinct from the ∼270 KDa one antagonizing cristae remodeling. This Opa1 oxidation process is curtailed by mutation of C786 and of the other 3 Cys residues of its C-terminal domain (Opa1). When reintroduced in Opa1 cells, Opa1 is not efficiently processed into short Opa1 and hence fails to fuse mitochondria. Unexpectedly, Opa1 restores mitochondrial ultrastructure in Opa1 cells and protects them from HO-induced mitochondrial depolarization, cristae remodeling, cytochrome c release and cell death. Thus, preventing the Opa1 oxidation occurring during cardiac ischemia-reperfusion reduces mitochondrial damage and cell death induced by oxidative stress independent of mitochondrial fusion.
Topics: Animals; Mice; Cell Death; Coronary Artery Disease; Cysteine; Hydrogen Peroxide; Myocardial Reperfusion Injury; Optic Atrophy, Autosomal Dominant; Oxidative Stress
PubMed: 37224696
DOI: 10.1016/j.redox.2023.102755 -
Neurobiology of Disease Mar 2024Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono‑oxygenase 3 (FMO3).... (Review)
Review
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono‑oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications.
Topics: Humans; Stroke; Inflammation; Oxides; Methylamines
PubMed: 38286388
DOI: 10.1016/j.nbd.2024.106423 -
Biomolecules & Biomedicine Nov 2023Current research supports the evidence that the gut microbiome (GM), which consist of gut microbiota and their biologically active metabolites, is associated with... (Review)
Review
Current research supports the evidence that the gut microbiome (GM), which consist of gut microbiota and their biologically active metabolites, is associated with atherosclerosis development. Trimethylamine-N-oxide (TMAO), a metabolite produced by the GM through trimethylamine (TMA) oxidation, significantly enhances the formation and vulnerability of atherosclerotic plaques. TMAO promotes inflammation and oxidative stress in endothelial cells, leading to vascular dysfunction and plaque formation. Dimethyl-1-butanol (DMB), iodomethylcholine (IMC) and fluoromethylcholine (FMC) have been recognized for their ability to reduce plasma TMAO by inhibiting trimethylamine lyase, a bacterial enzyme involved in the choline cleavage anaerobic process, thus reducing TMA formation. Conversely, indole-3-carbinol (I3C) and trigonelline inhibit TMA oxidation by inhibiting flavin-containing monooxygenase-3 (FMO3), resulting in reduced plasma TMAO. The combined use of inhibitors of choline trimethylamine lyase and flavin-containing monooxygenase-3 could provide novel therapeutic strategies for cardiovascular disease prevention by stabilizing existing atherosclerotic plaques. This review aims to present the current evidence of the roles of TMA/TMAO in atherosclerosis as well as its potential therapeutic prevention aspects.
Topics: Humans; Plaque, Atherosclerotic; Endothelial Cells; Atherosclerosis; Lyases; Choline; Oxides
PubMed: 37337893
DOI: 10.17305/bb.2023.8893 -
Scientific Reports Jun 2023In present work, the degradation behavior of tea catechins on various commercial glazes was elucidated for the first time. Four kinds of Japanese typical commercial...
In present work, the degradation behavior of tea catechins on various commercial glazes was elucidated for the first time. Four kinds of Japanese typical commercial glaze powders (Oribe /Namako/Irabo /Toumei) based on Fe/Mg /Cu /Ti oxides were utilized and deposited on ceramic tiles. Tea solution extracted from green tea leaves at 80 °C and then utilized for the examination of degradation behavior with glazes to meet a nearly identical condition in human daily tea drinking with ceramicwares. It was found that the degradation of tea catechins significantly dependent on the chemical structure of glazes, that is: Fe/Cu/Mg oxides contained glazes can promote the degradation of epigallocatechin, epicatechin, epigallocatechin gallate and epicatechin gallate, while Ti oxide contained glaze stimulated the degradation of epigallocatechin gallate selectively. Coloring pigments were produced in degraded tea solutions, whose color shows glaze dependent property. We presume that these color pigments can be assigned as oxytheotannin, especially theaflavin and its oxides as well as thearubigins, that produced through the polymerization of intermediate free radical catechin and/or the ortho-quinone generated by catalytic effect of glaze oxides worked as Lewis's acids. The specific function of glazes on degradation of catechins discovered here not only provides principal information for design and development of functional materials but also bring new impacts on daily tea drinking and long-term human health-related issues.
Topics: Humans; Catalysis; Catechin; Oxides; Tea
PubMed: 37380665
DOI: 10.1038/s41598-023-37480-8 -
Cardiovascular Diabetology Jul 2023The relationship between sodium glucose co-transporter 2 inhibitors (SGLT2i) and trimethylamine N-oxide (TMAO) following acute myocardial infarction (AMI) is not yet...
INTRODUCTION
The relationship between sodium glucose co-transporter 2 inhibitors (SGLT2i) and trimethylamine N-oxide (TMAO) following acute myocardial infarction (AMI) is not yet explored.
METHODS
In this secondary analysis of the EMMY trial (ClinicalTrials.gov registration: NCT03087773), changes in serum TMAO levels were investigated in response to 26-week Empagliflozin treatment following an AMI compared to the standard post-MI treatment. Additionally, the association of TMAO changes with clinical risk factors and cardiorenal biomarkers was assessed.
RESULTS
The mean age of patients (N = 367) was 57 ± 9 years, 82% were males, and 14% had type 2 diabetes. In the Empagliflozin group, the median TMAO value was 2.62 µmol/L (IQR: 1.81) at baseline, 3.74 µmol/L (2.81) at 6 weeks, and 4.20 µmol/L (3.14) at 26 weeks. In the placebo group, the median TMAO value was 2.90 µmol/L (2.17) at baseline, 3.23 µmol/L (1.90) at 6 weeks, and 3.35 µmol/L (2.50) at 26 weeks. The serum TMAO levels increased significantly from baseline to week 6 (coefficient: 0.233; 95% confidence interval 0.149-0.317, p < 0.001) and week 26 (0.320, 0.236-0.405, p < 0.001). The average increase in TMAO levels over time (p = 0.007) was significantly higher in the Empagliflozin compared to the Placebo group. Age was positively associated with TMAO, whereas eGFR and LVEF were negatively associated with TMAO.
CONCLUSIONS
Our results are contrary to existing experimental studies that showed the positive impact of SGLT2i on TMAO precursors and cardiovascular events. Therefore, we recommend further research investigating the impact of SGLT2i therapy on acute and long-term changes in TMAO in cardiovascular cohorts.
Topics: Male; Humans; Middle Aged; Aged; Female; Diabetes Mellitus, Type 2; Myocardial Infarction; Sodium-Glucose Transporter 2 Inhibitors; Oxides
PubMed: 37475009
DOI: 10.1186/s12933-023-01920-6 -
Free Radical Biology & Medicine Sep 2023Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous...
Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br), or thiocyanate (SCN) as substrates. AECs exposed to GOX/MPO/SCN (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br diverged significantly from GOX/MPO/SCN for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br-treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.
Topics: Humans; Child, Preschool; Thiocyanates; Peroxidase; Cystic Fibrosis; Bromides; Chlorides; Oxidants; Antioxidants; Hypochlorous Acid; Epithelial Cells; Metabolomics
PubMed: 37356776
DOI: 10.1016/j.freeradbiomed.2023.06.021 -
Frontiers in Immunology 2024The innate immune response represents the first-line of defense against invading pathogens. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been... (Review)
Review
The innate immune response represents the first-line of defense against invading pathogens. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in various aspects of innate immune function, which involves respiratory bursts and inflammasome activation. These reactive species widely distributed within the cellular environment are short-lived intermediates that play a vital role in cellular signaling and proliferation and are likely to depend on their subcellular site of formation. NADPH oxidase complex of phagocytes is known to generate superoxide anion radical (O ) that functions as a precursor for antimicrobial hydrogen peroxide (HO) production, and HO is utilized by myeloperoxidase (MPO) to generate hypochlorous acid (HOCl) that mediates pathogen killing. HO modulates the expression of redox-responsive transcriptional factors, namely NF-kB, NRF2, and HIF-1, thereby mediating redox-based epigenetic modification. Survival and function of immune cells are under redox control and depend on intracellular and extracellular levels of ROS/RNS. The current review focuses on redox factors involved in the activation of immune response and the role of ROS in oxidative modification of proteins in macrophage polarization and neutrophil function.
Topics: Hydrogen Peroxide; Oxidation-Reduction; Superoxides; Oxidative Stress; Hypochlorous Acid; Immunity, Innate
PubMed: 38515749
DOI: 10.3389/fimmu.2024.1359600