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Oral Diseases Sep 2016Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron... (Review)
Review
Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron donor and acts as a cofactor for fifteen mammalian enzymes. Two sodium-dependent transporters are specific for ascorbic acid, and its oxidation product dehydroascorbic acid is transported by glucose transporters. Ascorbic acid is differentially accumulated by most tissues and body fluids. Plasma and tissue vitamin C concentrations are dependent on amount consumed, bioavailability, renal excretion, and utilization. To be biologically meaningful or to be clinically relevant, in vitro and in vivo studies of vitamin C actions have to take into account physiologic concentrations of the vitamin. In this paper, we review vitamin C physiology; the many phenomena involving vitamin C where new knowledge has accrued or where understanding remains limited; raise questions about the vitamin that remain to be answered; and explore lines of investigations that are likely to be fruitful.
Topics: Ascorbic Acid; Humans; In Vitro Techniques; Oral Health; Recommended Dietary Allowances
PubMed: 26808119
DOI: 10.1111/odi.12446 -
Oxidative Medicine and Cellular... 2022Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells...
Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.
Topics: Humans; AMP-Activated Protein Kinases; Ascorbic Acid; Ferroptosis; Glutathione; Heme Oxygenase-1; Iron; NF-E2-Related Factor 2; Nuclear Respiratory Factor 1; Pancreatic Neoplasms; Piperazines
PubMed: 35915609
DOI: 10.1155/2022/5361241 -
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 -
Science (New York, N.Y.) Dec 2015More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured...
More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.
Topics: Adenomatous Polyposis Coli Protein; Animals; Ascorbic Acid; Cell Line, Tumor; Colorectal Neoplasms; Dehydroascorbic Acid; Female; Glucose Transporter Type 1; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Glycolysis; Humans; Mice; Mice, Mutant Strains; Mice, Nude; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Xenograft Model Antitumor Assays; ras Proteins
PubMed: 26541605
DOI: 10.1126/science.aaa5004 -
Antioxidants & Redox Signaling Jan 2019Hexokinases are key enzymes that are responsible for the first reaction of glycolysis, but they also moonlight other cellular processes, including mitochondrial redox... (Review)
Review
SIGNIFICANCE
Hexokinases are key enzymes that are responsible for the first reaction of glycolysis, but they also moonlight other cellular processes, including mitochondrial redox signaling regulation. Modulation of hexokinase activity and spatiotemporal location by reactive oxygen and nitrogen species as well as other gasotransmitters serves as the basis for a unique, underexplored method of tight and flexible regulation of these fundamental enzymes. Recent Advances: Redox modifications of thiols serve as a molecular code that enables the precise and complex regulation of hexokinases. Redox regulation of hexokinases is also used by multiple parasites to cause widespread and severe diseases, including malaria, Chagas disease, and sleeping sickness. Redox-active molecules affect each other, and the moonlighting activity of hexokinases provides another feedback loop that affects the cellular redox status and is hijacked in malignantly transformed cells.
CRITICAL ISSUES
Several compounds affect the redox status of hexokinases in vivo. These include the dehydroascorbic acid (oxidized form of vitamin C), pyrrolidinium porrolidine-1-carbodithioate (contraceptive), peroxynitrite (product of ethanol metabolism), alloxan (a glucose analog), and isobenzothiazolinone ebselen. However, very limited information is available regarding which amino acid residues in hexokinases are affected by redox signaling. Except in cases of monogenic diabetes, direct evidence is absent for disease phenotypes that are associated with variations within motifs that are susceptible to redox signaling.
FUTURE DIRECTIONS
Further studies should address the propensity of hexokinases and their disease-associated variants to participate in redox regulation. Robust and straightforward proteomic methods are needed to understand the context and consequences of hexokinase-mediated redox regulation in health and disease.
Topics: Animals; Hexokinase; Humans; Mitochondria; Oxidation-Reduction; Signal Transduction
PubMed: 29742915
DOI: 10.1089/ars.2017.7255 -
Antioxidants & Redox Signaling Jul 2021Vitamin C is a powerful antioxidant that has an intricate relationship with cancer and has been studied for more than 60 years. However, the specific mechanisms that... (Review)
Review
Vitamin C is a powerful antioxidant that has an intricate relationship with cancer and has been studied for more than 60 years. However, the specific mechanisms that allow malignant cells to uptake, metabolize, and compartmentalize vitamin C remain unclear. In normal human cells, two different transporter systems are responsible for its acquisition: glucose transporters (GLUTs) transport the oxidized form of vitamin C (dehydroascorbic acid) and sodium-coupled ascorbic acid transporters (SVCTs) transport the reduced form (ascorbic acid [AA]). In this study, we review the mechanisms described for vitamin C uptake and metabolization in cancer. Several studies performed recently and have provided the scientific community a better understanding of the differential capacities of cancer cells to acquire vitamin C: tumors from different origins do not express SVCTs in the plasma membrane and are only able to acquire vitamin C in its oxidized form. Interestingly, cancer cells differentially express a mitochondrial form of SVCT2. Why tumors have reduced AA uptake capacity at the plasma membrane, but develop the capacity of AA transport within mitochondria, remains a mystery. However, it shows that understanding vitamin C physiology in tumor survival might be key to decipher the controversies in its relationship with cancer. A comprehensive analysis of the mechanisms by which cancer cells acquire, compartmentalize, and use vitamin C will allow the design of new therapeutic approaches in human cancer. 35, 61-74.
Topics: Antioxidants; Ascorbic Acid; Dehydroascorbic Acid; Glucose Transport Proteins, Facilitative; Humans; Mitochondria; Neoplasms; Sodium-Coupled Vitamin C Transporters
PubMed: 33607936
DOI: 10.1089/ars.2020.8166 -
Journal of Cellular Physiology Nov 2019For a long time, the effect of vitamin C on cancer cells has been a controversial concept. From Linus Pauling's studies in 1976, it was proposed that ascorbic acid (AA)... (Review)
Review
For a long time, the effect of vitamin C on cancer cells has been a controversial concept. From Linus Pauling's studies in 1976, it was proposed that ascorbic acid (AA) could selectively kill tumor cells. However, further research suggested that vitamin C has no effect on tumor survival. In the last decade, new and emerging functions for vitamin C have been discovered using the reduced form, AA, and the oxidized form, dehydroascorbic acid (DHA), independently. In this review, we summarized the latest findings related to the effects of DHA on the survival and metabolism of tumor cells. At the same time, we put special emphasis on the bystander effect and the recycling capacity of vitamin C in various cellular models, and how these concepts can affect the experimentation with vitamin C and its therapeutic application in the treatment against cancer.
Topics: Ascorbic Acid; Biological Transport; Dehydroascorbic Acid; Humans; Neoplasms; Oxidation-Reduction
PubMed: 30963581
DOI: 10.1002/jcp.28637 -
Frontiers in Neuroscience 2023Different studies have established the fundamental role of vitamin C in proliferation, differentiation, and neurogenesis in embryonic and adult brains, as well as in... (Review)
Review
Different studies have established the fundamental role of vitamin C in proliferation, differentiation, and neurogenesis in embryonic and adult brains, as well as in cell models. To fulfill these functions, the cells of the nervous system regulate the expression and sorting of sodium-dependent vitamin C transporter 2 (SVCT2), as well as the recycling of vitamin C between ascorbic acid (AA) and dehydroascorbic acid (DHA) via a bystander effect. SVCT2 is a transporter preferentially expressed in neurons and in neural precursor cells. In developmental stages, it is concentrated in the apical region of the radial glia, and in adult life, it is expressed preferentially in motor neurons of the cerebral cortex, starting on postnatal day 1. In neurogenic niches, SVCT2 is preferentially expressed in precursors with intermediate proliferation, where a scorbutic condition reduces neuronal differentiation. Vitamin C is a potent epigenetic regulator in stem cells; thus, it can induce the demethylation of DNA and histone H3K27m3 in the promoter region of genes involved in neurogenesis and differentiation, an effect mediated by Tet1 and Jmjd3 demethylases, respectively. In parallel, it has been shown that vitamin C induces the expression of stem cell-specific microRNA, including the Dlk1-Dio3 imprinting region and miR-143, which promotes stem cell self-renewal and suppresses expression of the methyltransferase gene Dnmt3a. The epigenetic action of vitamin C has also been evaluated during gene reprogramming of human fibroblasts to induced pluripotent cells, where it has been shown that vitamin C substantially improves the efficiency and quality of reprogrammed cells. Thus, for a proper effect of vitamin C on neurogenesis and differentiation, its function as an enzymatic cofactor, modulator of gene expression and antioxidant is essential, as is proper recycling from DHA to AA by various supporting cells in the CNS.
PubMed: 37424994
DOI: 10.3389/fnins.2023.1155758 -
Pflugers Archiv : European Journal of... Sep 2020Glucose transport is intimately linked to red blood cell physiology. Glucose is the unique energy source for these cells, and defects in glucose metabolism or transport... (Review)
Review
Glucose transport is intimately linked to red blood cell physiology. Glucose is the unique energy source for these cells, and defects in glucose metabolism or transport activity are associated with impaired red blood cell morphology and deformability leading to reduced lifespan. In vertebrate erythrocytes, glucose transport is mediated by GLUT1 (in humans) or GLUT4 transporters. These proteins also account for dehydroascorbic acid (DHA) transport through erythrocyte membrane. The peculiarities of glucose transporters and the red blood cell pathologies involving GLUT1 are summarized in the present review.
Topics: Anemia, Hemolytic; Animals; Carbohydrate Metabolism, Inborn Errors; Erythrocytes; Glucose Transporter Type 1; Humans; Monosaccharide Transport Proteins
PubMed: 32474749
DOI: 10.1007/s00424-020-02406-0 -
Heart & Lung : the Journal of Critical... 2023There is currently a need to identify metabolomic responses to acute exercise in chronic obstructive pulmonary disease (COPD).
BACKGROUND
There is currently a need to identify metabolomic responses to acute exercise in chronic obstructive pulmonary disease (COPD).
OBJECTIVE
We investigated the metabolomic, oxidative, and inflammatory responses to constant (CE) and intermittent (IE) work rate exercises in COPD.
METHODS
Sixteen males with COPD performed a symptom-limited incremental cycle exercise test (ICE). Metabolomic, oxidative, and inflammatory responses to CE and IE (based on the performance of ICE) were analyzed in the plasma.
RESULTS
Fructose-6-phosphate, 3-phosphoglyceric acid, l-carnitine, and acylcarnitines levels were significantly decreased, whereas alpha-ketoglutaric, malic, 2-hydroxybutyric, and 3-hydroxybutyric acids were increased, after CE and IE (p<0.05). Increases in citric, isocitric, and lactic acids, as well as decreases in pyruvic and oxalic acids, were only present with IE (p<0.05). Isoleucine was decreased after both exercises (p<0.05). We observed an increase in inosine-5'-diphosphate, uric acid, ascorbic acid, and pantothenic acid, as well as a decrease in 5-hydroxymethyluridine, threonic acid, and dehydroascorbic acid, after IE (p<0.05). Catalase, reduced glutathione, and total antioxidant status difference values for both exercises were similar (p>0.05). The change in glutathione peroxidase (GPx) with CE was more significant than that with IE (p = 0.004). The superoxide dismutase change was greater with IE than with CE (p = 0.015). There were no significant changes in inflammatory markers after exercise (p>0.05).
CONCLUSION
CE and IE cause isoleucine, l-carnitine, and acylcarnitine levels to decrease, whereas ketone bodies were increased, thus indicating the energy metabolism shift from carbohydrates to amino acid utilization and lipid metabolism in COPD. Compared with CE, IE produces significant changes in more metabolomics in terms of carbohydrates, lipids, amino acids, nucleotides, and vitamins. Acute CE and IE alter circulating GPx levels in COPD.
Topics: Male; Humans; Isoleucine; Exercise; Carnitine; Pulmonary Disease, Chronic Obstructive; Oxidative Stress; Carbohydrates
PubMed: 36724589
DOI: 10.1016/j.hrtlng.2023.01.011