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1.
Transport of Vitamin C in Cancer.
Muñoz-Montesino, C, Peña, E, Roa, FJ, Sotomayor, K, Escobar, E, Rivas, CI
Antioxidants & redox signaling. 2021;(1):61-74
Abstract
Significance: 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. Recent Advances: Several studies performed recently in vivo and in vitro 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. Critical Issues: 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. Future Directions: 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. Antioxid. Redox Signal. 35, 61-74.
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2.
Adjunctive treatments for the management of septic shock - a narrative review of the current evidence.
Donovan, K, Shah, A, Day, J, McKechnie, SR
Anaesthesia. 2021;(9):1245-1258
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Abstract
Septic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta-blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta-blocker therapy may have beneficial cardiac and non-cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.
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Clinical efficacy and safety of oral and intravenous vitamin C use in patients with malignant diseases.
Hoppe, C, Freuding, M, Büntzel, J, Münstedt, K, Hübner, J
Journal of cancer research and clinical oncology. 2021;(10):3025-3042
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Abstract
BACKGROUND Vitamin C, also called ascorbic acid, is a water-soluble antioxidant and free radical scavenger. It is required in the body for numerous metabolic functions and is involved in the development of proteins and connective tissue. METHODS In April 2020, a systematic search was carried out on five electronic databases (Medline, Embase, Cochrane, Cinahl, PsycINFO) to find studies on the use, efficacy and safety of a complementary therapy with vitamin C in oncological patients. RESULTS Out of the initial 23,195 search results, 21 studies with 1961 patients were included in this review. Five of the included studies (n = 417) were randomized controlled trials (RCTs). The remaining 16 studies belonged to a lower class of evidence. The patients who were treated with vitamin C suffered from various malignant diseases, some in an advanced and palliative stage. Vitamin C was applied intravenously or orally. It was either the only treatment or was combined with chemo- or radiotherapy. Endpoints included the development of the disease-related symptoms, quality of life, mortality, progression-free survival and safety of vitamin C. The studies were of moderate quality and showed either no effect of vitamin C or a positive trend, although this has rarely been statistically proven in group comparisons. No or only slight side effects with both oral and intravenous administration of vitamin C were reported. CONCLUSION Oral intake of vitamin C does not appear to have any effect in patients with malignancies. Data are heterogeneous for intravenous administration. There are no RCTs with statistical group comparisons.
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New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.
Testa, U, Pelosi, E, Castelli, G
Hematology/oncology and stem cell therapy. 2021;(3):179-191
Abstract
Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C.
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Vitamin C and Cell Death.
Szarka, A, Kapuy, O, Lőrincz, T, Bánhegyi, G
Antioxidants & redox signaling. 2021;(11):831-844
Abstract
Significance: Persistent oxidative stress is a common feature of cancer cells, giving a specific weapon to selectively eliminate them. Ascorbate in pharmacological concentration can contribute to the suspended formation of hydroxyl radical via the Fenton reaction; thus, it can be an important element of the oxidative stress therapy against cancer cells. Recent Advances: The main components of ascorbate-induced cell death are DNA double-strand breaks via the production of hydroxyl radical and ATP depletion due to the activation of poly (ADP-ribose) polymerase 1. Presumably, DNA damage can be the primary contributor to the anticancer activity of pharmacological ascorbate, as opposed to the rupture of bioenergetics. The caspase independency of high-dose ascorbate-induced cell death proposed the possible involvement of several types of cell death, such as ferroptosis, necroptosis, and autophagy. Critical Issues: Ascorbate can target at least two key molecular features of cancer cells as a part of the anticancer therapy: the intrinsic or acquired resistance to cell death and the dysregulated metabolism of cancer cells. It seems probable that different concentrations of ascorbate alter the nature of induced cell death. Autophagy and necroptosis may play a role at intermediate concentrations, but caspase-independent apoptosis may dominate at higher concentrations. However, ascorbate behaves as an effective inhibitor of ferroptosis that may have crucial importance in its possible clinical application. Future Directions: The elucidation of the details and the links between high-dose ascorbate-induced cancer selective cell death mechanisms may give us a tool to form and apply synergistic cancer therapies. Antioxid. Redox Signal. 34, 831-844.
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The Role of Vitamin C in Two Distinct Physiological States: Physical Activity and Sleep.
Otocka-Kmiecik, A, Król, A
Nutrients. 2020;(12)
Abstract
This paper is a literature overview of the complex relationship between vitamin C and two opposing physiological states, physical activity and sleep. The evidence suggests a clinically important bidirectional association between these two phenomena mediated by different physiological mechanisms. With this in mind, and knowing that both states share a connection with oxidative stress, we discuss the existing body of evidence to answer the question of whether vitamin C supplementation can be beneficial in the context of sleep health and key aspects of physical activity, such as performance, metabolic changes, and antioxidant function. We analyze the effect of ascorbic acid on the main sleep components, sleep duration and quality, focusing on the most common disorders: insomnia, obstructive sleep apnea, and restless legs syndrome. Deeper understanding of those interactions has implications for both public health and clinical practice.
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Manipulation of Ascorbate Biosynthetic, Recycling, and Regulatory Pathways for Improved Abiotic Stress Tolerance in Plants.
Broad, RC, Bonneau, JP, Hellens, RP, Johnson, AAT
International journal of molecular sciences. 2020;(5)
Abstract
Abiotic stresses, such as drought, salinity, and extreme temperatures, are major limiting factors in global crop productivity and are predicted to be exacerbated by climate change. The overproduction of reactive oxygen species (ROS) is a common consequence of many abiotic stresses. Ascorbate, also known as vitamin C, is the most abundant water-soluble antioxidant in plant cells and can combat oxidative stress directly as a ROS scavenger, or through the ascorbate-glutathione cycle-a major antioxidant system in plant cells. Engineering crops with enhanced ascorbate concentrations therefore has the potential to promote broad abiotic stress tolerance. Three distinct strategies have been utilized to increase ascorbate concentrations in plants: (i) increased biosynthesis, (ii) enhanced recycling, or (iii) modulating regulatory factors. Here, we review the genetic pathways underlying ascorbate biosynthesis, recycling, and regulation in plants, including a summary of all metabolic engineering strategies utilized to date to increase ascorbate concentrations in model and crop species. We then highlight transgene-free strategies utilizing genome editing tools to increase ascorbate concentrations in crops, such as editing the highly conserved upstream open reading frame that controls translation of the GDP-L-galactose phosphorylase gene.
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Vitamin C in Plants: Novel Concepts, New Perspectives, and Outstanding Issues.
Foyer, CH, Kyndt, T, Hancock, RD
Antioxidants & redox signaling. 2020;(7):463-485
Abstract
Significance: The concept that vitamin C (l-ascorbic acid) is at the heart of the peroxide processing and redox signaling hub in plants is well established, but our knowledge of the precise mechanisms involved remains patchy at best. Recent Advances: Ascorbate participates in the multifaceted signaling pathways initiated by both reactive oxygen species (ROS) and reactive nitrogen species. Crucially, the apoplastic ascorbate/dehydroascorbate (DHA) ratio that is regulated by ascorbate oxidase (AO) sculpts the apoplastic ROS (apoROS) signal that controls polarized cell growth, biotic and abiotic defences, and cell to cell signaling, as well as exerting control over the light-dependent regulation of photosynthesis. Critical Issues: Here we re-evaluate the roles of ascorbate in photosynthesis and other processes, addressing the question of how much we really know about the regulation of ascorbate homeostasis and its functions in plants, or how AO is regulated to modulate apoROS signals. Future Directions: The role of microRNAs in the regulation of AO activity in relation to stress perception and signaling must be resolved. Similarly, the molecular characterization of ascorbate transporters and mechanistic links between photosynthetic and respiratory electron transport and ascorbate synthesis/homeostasis are a prerequisite to understanding ascorbate homeostasis and function. Similarly, there is little in vivo evidence for ascorbate functions as an enzyme cofactor.
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Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection.
Hoang, BX, Shaw, G, Fang, W, Han, B
Journal of global antimicrobial resistance. 2020;:256-262
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Abstract
Coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses increase oxidative stress in the body leading to cellular and tissue damage. To combat this, administration of high-dose vitamin C (ascorbic acid or ascorbate), in addition to standard conventional supportive treatments, has been shown to be a safe and effective therapy for severe cases of respiratory viral infection. Morbidity, mortality, infectiveness and spread of infectious diseases are dependent on the host-pathogen relationship. Given the lack of effective and safe antiviral drugs for coronaviruses, there should be more attention in supporting host immune defence, cytoprotection and immunoregulation. Implementation of high-dose vitamin C therapy could dramatically reduce the need for high doses of corticosteroids, antibacterials and antiviral drugs that may be immunosuppressive, adrenal depressive and toxic, complicating the disease course. In order to effectively fight the novel SARS-CoV-2 virus, medical professionals should explore readily available pharmaceutical and nutritional therapeutic agents with proven antioxidant, anti-inflammatory and immunosupportive properties. Supplemental vitamin C may also provide additional benefits for the prevention of viral infections, shorten the disease course and lessen complications of the disease.
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10.
Vitamin C and coronavirus.
Simonson, W
Geriatric nursing (New York, N.Y.). 2020;(3):331-332