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1.
Pharmacological Ascorbate as a Means of Sensitizing Cancer Cells to Radio-Chemotherapy While Protecting Normal Tissue.
Schoenfeld, JD, Alexander, MS, Waldron, TJ, Sibenaller, ZA, Spitz, DR, Buettner, GR, Allen, BG, Cullen, JJ
Seminars in radiation oncology. 2019;(1):25-32
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Abstract
Chemoradiation has remained the standard of care treatment for many of the most aggressive cancers. However, despite effective toxicity to cancer cells, current chemoradiation regimens are limited in efficacy due to significant normal cell toxicity. Thus, efforts have been made to identify agents demonstrating selective toxicity, whereby treatments simultaneously sensitize cancer cells to protect normal cells from chemoradiation. Pharmacological ascorbate (intravenous infusions of vitamin C resulting in plasma ascorbate concentrations ≥20 mM; P-AscH-) has demonstrated selective toxicity in a variety of preclinical tumor models and is currently being assessed as an adjuvant to standard-of-care therapies in several early phase clinical trials. This review summarizes the most current preclinical and clinical data available demonstrating the multidimensional role of P-AscH- in cancer therapy including: selective toxicity to cancer cells via a hydrogen peroxide (H2O2)-mediated mechanism; action as a sensitizing agent of cancer cells to chemoradiation; a protectant of normal tissues exposed to chemoradiation; and its safety and tolerability in clinical trials.
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2.
Transporter oligomerisation: roles in structure and function.
Cecchetti, C, Pyle, E, Byrne, B
Biochemical Society transactions. 2019;(1):433-440
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Abstract
Oligomerisation is a key feature of integral membrane transporters with roles in structure, function and stability. In this review, we cover some very recent advances in our understanding of how oligomerisation affects these key transporter features, with emphasis on a few groups of transporters, including the nucleobase ascorbate transporters, neurotransmitter sodium symporters and major facilitator superfamily members.
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3.
Vitamin C for Type 2 Diabetes Mellitus and Hypertension.
Das, UN
Archives of medical research. 2019;(2):11-14
Abstract
It is suggested that supplementation of vitamin C reduces hyperglycemia and lowers blood pressure in hypertensives by enhacing the formation of prostaglandin E1 (PGE1), PGI2 (prostacyclin), endothelial nitric oxide (eNO), and restore essential fatty acid (EFA) metabolism to normal and enhance the formation of lipoxin A4 (LXA4), a potent anti-inflammatory, vasodilator and antioxidant. These actions are in addition to the ability of vitamin C to function as an antioxidant. In vitro and in vivo studies revealed that PGE1, PGI2 and NO have cytoprotective and genoprotective actions and thus, protect pancreatic β and vascular endotheilial cells from the cytotoxic actions of endogenous and exogenous toxins. AA, the precursor of LXA4 and LXA4 have potent anti-diabetic actions and their plasma tissue concentrations are decreased in those with diabetes mellitus and hypertension. Thus, vitamin C by augmenting the formation of PGE1, PGI2, eNO, LXA4 and restoring AA content to normal may function as a cytoprotective, anti-mutagenic, vasodilator and platelet anti-agregator actions that explains its benefical action in type 2 diabetes mellitus and hypertension.
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Chronic venous disease: from symptoms to microcirculation.
Senra Barros, B, Kakkos, SK, De Maeseneer, M, Nicolaides, AN
International angiology : a journal of the International Union of Angiology. 2019;(3):211-218
Abstract
The recently published European Venous Forum (EVF) Guidelines 2018 update on the management of chronic venous disorders of the lower limbs has focused on several new aspects: a new place for early symptoms, new data on microcirculation alterations, and a re-evaluation of veno-active drugs (VADs), based on new criteria. The symposium "Chronic Venous Disease (CVD): From Symptoms to Microcirculation", held at the annual meeting of the EVF on 28 June 2018 in Athens, Greece, highlighted this perspective by answering three questions: What do symptoms mean and how do they influence our choice of investigations? Is there a link between symptoms and microcirculation alterations? How to choose the right VAD for the right patient based on the updated EVF guidelines? The answers given led the speakers to three conclusions: early symptoms reveal the initial stage of CVD and patients with C0S disease should be properly diagnosed, investigated, and treated; damage to the microcirculation is likely to be the first evidence of the onset of venous disease; Ruscus+HMC+VitC has proven efficacy in randomized controlled trials, and has been given a strong recommendation (Grade 1A) by the 2018 EVF guidelines for treatment of pain, heaviness, feeling of swelling, paresthesia, and edema, and should be considered as one of the preferred treatments to relieve these symptoms in CVD patients.
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Vitamin C: A Natural Inhibitor of Cell Wall Functions and Stress Response in Mycobacteria.
Syal, K, Chatterji, D
Advances in experimental medicine and biology. 2018;:321-332
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, has re-emerged as a threat to human race. Conventional antibiotic treatments are failing due to different stress response strategies adopted by bacterial pathogens. Since time immemorial, Vitamin C is known to protect against pathogens by boosting immunity in humans. Recently, Vitamin C has been shown to directly kill M. tuberculosis including multiple drug-resistant strains by generation of oxidative radicals through Fenton's reaction. Concurrently, it inhibits (p)ppGpp-mediated stringent response thus effectively shutting down long-term survival and persistence in mycobacteria. Here, we have discussed historical perspective and recent evidences on Vitamin C-mediated inhibition of several key pathways of M. tuberculosis such as (p)ppGpp synthesis and mycobacterial cell wall function. Several cell wall components including mycolic acids are critical for mycobacterial virulence. We observed downregulation of various mycolic acids in M. smegmatis upon treatment with Vitamin C, and data have been presented here. Vitamin C has been shown to inhibit the biofilm growth as well as disrupt the formed biofilm in mycobacteria. Additionally, Vitamin C role in cell-mediated and humoral immunity has been elucidated. Vitamin C is toxic at high concentration; therefore we have proposed the idea of derivatizing Vitamin C in order to lower the minimal inhibition concentration (MIC) necessary to target M. tuberculosis.
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6.
Vitamins for Prevention of Contrast-induced Acute Kidney Injury: A Systematic Review and Trial Sequential Analysis.
Xu, Y, Zheng, X, Liang, B, Gao, J, Gu, Z
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018;(5):373-386
Abstract
BACKGROUND To date, universally accepted preventive measures for contrast-induced acute kidney injury (CI-AKI) do not exist, and they warrant further research. OBJECTIVE The purpose of this study was to evaluate the efficacy of vitamins, including vitamin C and E, for prevention of CI-AKI. METHODS We electronically searched the MEDLINE, EMBASE, and Cochrane databases. The outcome of interest was the incidence of CI-AKI. RESULTS A total of 19 studies were included in this meta-analysis. Pooled analysis showed that vitamin C plus saline [relative risk (RR) = 0.63, 95% confidence interval (CI) 0.49-0.82, p = 0.0005] and vitamin E plus saline (RR = 0.39, 95% CI 0.24-0.62, p < 0.0001) significantly reduced the incidence of CI-AKI compared to saline alone. The effect of vitamin C plus saline was further confirmed by trial sequential analysis (TSA). However, TSA indicated that more trials are required to confirm the efficacy of vitamin E plus saline. There was no significant difference in preventing CI-AKI between vitamin C and N-acetylcysteine (NAC) (RR = 0.90, 95% CI 0.47-1.71, p = 0.75), between vitamin C plus NAC and saline (RR = 0.62, 95% CI 0.30-1.30, p = 0.20), as well as between vitamin C plus NAC and NAC (RR = 0.97, 95% CI 0.49-1.92, p = 0.93). CONCLUSIONS Vitamin C plus saline administration is effective at reducing the risk of CI-AKI. Evidence for the use of vitamin E plus saline in this context is encouraging, but more trials are required. Furthermore, this meta-analysis and TSA indicated insufficient power to draw a definitive conclusion on the effect of vitamin C plus NAC, versus saline or NAC alone, which needs to be explored further.
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Inflammatory and oxidative stress parameters as potential early biomarkers for silicosis.
Nardi, J, Nascimento, S, Göethel, G, Gauer, B, Sauer, E, Fão, N, Cestonaro, L, Peruzzi, C, Souza, J, Garcia, SC
Clinica chimica acta; international journal of clinical chemistry. 2018;:305-313
Abstract
Workers involved in mining activities are exposed to crystalline silica, which leads to constant pulmonary inflammatory reactions and severe oxidative damage, resulting in silicosis. In this work, we aimed to evaluate inflammatory and oxidative stress parameters as potential early biomarkers of effect to assess crystalline silica toxicity in workers who had occupational exposure during mining. We enrolled 38 workers exposed to crystalline silica (WECS), 24 individuals with silicosis (IWS), and 30 occupationally unexposed workers (OUW), a total of 92 participants. The WECS were divided into 2 groups, according to the time of exposure: 19 workers with 1-15 years of occupational exposure (WECS I) and 19 workers with >16 years of occupational exposure (WECS II). The inflammatory parameters assessed were L-selectin, β-2 integrin, and intercellular adhesion molecule-1 (ICAM-1) surface protein expression in lymphocytes and monocytes, complement C3 and C4, high sensitivity C-reactive protein (hsCRP), and adenosine deaminase (ADA) in serum. Plasma levels of malondialdehyde (MDA) and serum levels of vitamin C were determined as biomarkers of oxidative stress. Biochemical and hematological parameters were also investigated. L-selectin surface protein expression was significantly decreased in the WECS II group (p < 0.05), indicating the importance of this immune system component as a potential marker of crystalline-silica-induced toxicity. The MDA levels were significantly increased in the WECS I, WECS II, and IWS groups compared to the OUW group (p < 0.05). Vitamin C levels were decreased, while C3, hsCRP, ADA, and aspartate aminotransferase (AST) levels were increased in the IWS group compared to the OUW group (p < 0.05). Glucose and urea levels were significantly higher in the WECS I, II, and IWS groups compared to the OUW group (p < 0.05). Negative partial association was found between L-selectin and time of exposure (p < 0.001), supporting the relevance of this biomarker evaluation in long-term exposure to crystalline silica. Significant associations were also observed among inflammatory and oxidative stress biomarkers. Therefore, our results demonstrated the relevance of L-selectin as a potential peripheral biomarker for monitoring crystalline silica-induced toxicity in miners after chronic exposure, before silicosis has developed. However, more studies are necessary for better understanding of the use L-selectin as an early biomarker in exposed workers.
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8.
Compartment-Specific Importance of Ascorbate During Environmental Stress in Plants.
Zechmann, B
Antioxidants & redox signaling. 2018;(15):1488-1501
Abstract
SIGNIFICANCE Ascorbate is an essential antioxidant in plants. Total contents and its redox state in organelles are crucial to fight and signal oxidative stress. Recent Advances: With quantitative immunoelectron microscopy and biochemical methods, highest ascorbate contents have recently been measured in peroxisomes (23 mM) and the cytosol (22 mM), lowest ones in vacuoles (2 mM), and intermediate concentrations (4-16 mM) in all other organelles. CRITICAL ISSUES The accumulation of ascorbate in chloroplasts and peroxisomes is crucial for plant defense. Its depletion in chloroplasts, peroxisomes, and mitochondria during biotic stress leads to the accumulation of reactive oxygen species (ROS) and the development of chlorosis and necrosis. In the apoplast and vacuoles, ascorbate is the most important antioxidant for the detoxification of ROS. The cytosol acts as a hub for ascorbate metabolism as it reduces its oxidized forms that are produced in the cytosol or imported from other cell compartments. It is a sink for ascorbate that is produced in mitochondria, distributes ascorbate to all organelles, and uses ascorbate to detoxify ROS. As ascorbate and its redox state are involved in protein synthesis and modifications, it can be concluded that ascorbate in the cytosol senses oxidative stress and regulates plant growth, development, and defense. FUTURE DIRECTIONS Future research should focus on (1) dissecting roles of ascorbate in vacuoles and the lumen of the endoplasmic reticulum, (2) identifying the physiological relevance of ascorbate transporters, and (3) correlating current data with changes in the subcellular distribution of related enzymes, ROS, and gene expression patterns.
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9.
Modeling the degradation kinetics of ascorbic acid.
Peleg, M, Normand, MD, Dixon, WR, Goulette, TR
Critical reviews in food science and nutrition. 2018;(9):1478-1494
Abstract
Most published reports on ascorbic acid (AA) degradation during food storage and heat preservation suggest that it follows first-order kinetics. Deviations from this pattern include Weibullian decay, and exponential drop approaching finite nonzero retention. Almost invariably, the degradation rate constant's temperature-dependence followed the Arrhenius equation, and hence the simpler exponential model too. A formula and freely downloadable interactive Wolfram Demonstration to convert the Arrhenius model's energy of activation, Ea, to the exponential model's c parameter, or vice versa, are provided. The AA's isothermal and non-isothermal degradation can be simulated with freely downloadable interactive Wolfram Demonstrations in which the model's parameters can be entered and modified by moving sliders on the screen. Where the degradation is known a priori to follow first or other fixed order kinetics, one can use the endpoints method, and in principle the successive points method too, to estimate the reaction's kinetic parameters from considerably fewer AA concentration determinations than in the traditional manner. Freeware to do the calculations by either method has been recently made available on the Internet. Once obtained in this way, the kinetic parameters can be used to reconstruct the entire degradation curves and predict those at different temperature profiles, isothermal or dynamic. Comparison of the predicted concentration ratios with experimental ones offers a way to validate or refute the kinetic model and the assumptions on which it is based.
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A review of micronutrients in sepsis: the role of thiamine, l-carnitine, vitamin C, selenium and vitamin D.
Belsky, JB, Wira, CR, Jacob, V, Sather, JE, Lee, PJ
Nutrition research reviews. 2018;(2):281-290
Abstract
Sepsis is defined as the dysregulated host response to an infection resulting in life-threatening organ dysfunction. The metabolic demand from inefficiencies in anaerobic metabolism, mitochondrial and cellular dysfunction, increased cellular turnover, and free-radical damage result in the increased focus of micronutrients in sepsis as they play a pivotal role in these processes. In the present review, we will evaluate the potential role of micronutrients in sepsis, specifically, thiamine, l-carnitine, vitamin C, Se and vitamin D. Each micronutrient will be reviewed in a similar fashion, discussing its major role in normal physiology, suspected role in sepsis, use as a biomarker, discussion of the major basic science and human studies, and conclusion statement. Based on the current available data, we conclude that thiamine may be considered in all septic patients at risk for thiamine deficiency and l-carnitine and vitamin C to those in septic shock. Clinical trials are currently underway which may provide greater insight into the role of micronutrients in sepsis and validate standard utilisation.