Oxidation and "Unconventional” Approaches to Infection

Nonpharmacological approaches can be useful to control infectious diseases. Historically infection has been successfully managed with oxidation therapy methods that support the body's own innate defenses. Several modalities include ozone and hyperbaric oxygen therapy, ultraviolet blood irradiation (UBI), intravenous hydrogen peroxide, and ascorbate therapies. Oxidation therapies are virtually 100% safe, and repeatedly reported as highly and quickly effective in quelling infection (bacterial and viral) either as stand-alone therapies or adjunctive with drugs. They are directly and indirectly germicidal, and modulate the immune system via pro-oxidant signaling molecules. Oxidation therapies especially enhance oxygen delivery and metabolism, critical for all infection defenses. Ozone has remitted Ebola, COVID-19, and bacterial infections. UBI defeated most preantibiotic era infections in hospitals. Not being drug therapy, the effects of oxidation defenses, used by planetary animal life for millions of years, are not diminished by antibiotic-resistant organisms. Oxidation, depending on delivery method, can be very inexpensive and third world adaptable. This chapter summarizes the use of these key modalities, by exploring known published literature. © 2022 Elsevier Inc. All rights reserved.

Comparison of UVC Sensitivity and Dectin-2 Expression Between Malignant and Non-malignant Cells.

BACKGROUND/AIM: Rapid spread of COVID-19 resulted in the revision of the value of ultraviolet C (UVC) sterilization in working spaces. This study aimed at investigating the UVC sensitivity of eighteen malignant and nonmalignant cell lines, the protective activity of sodium ascorbate against UVC, and whether Dectin-2 is involved in UVC sensitivity. MATERIALS AND METHODS: Various cell lines were exposed to UVC for 3 min, and cell viability was determined using the MTT assay. Anti-UV activity was determined as the ratio of 50% cytotoxic concentration (determined with unirradiated cells) to 50% effective concentration (that restored half of the UV-induced loss of viability). Dectin-2 expression was quantified using flow cytometry. RESULTS: The use of culture medium rather than phosphate-buffered saline is recommended as irradiation solution, since several cells are easily detached during irradiation in phosphate-buffered saline. Oral squamous cell carcinoma cell lines showed the highest UV sensitivity, followed by neuroblastoma, glioblastoma, leukemia, melanoma, lung carcinoma cells, and normal oral and dermal fibroblasts. Human dermal fibroblasts were more resistant than melanoma cell lines; however, both expressed Dectin-2. Sodium ascorbate at micromolar concentrations eliminated the cytotoxicity of UVC in these cell lines. CONCLUSION: Normal cells are generally UVC-resistant compared to corresponding malignant cells, which have higher growth potential. Dectin-2 protein expression itself may not be determinant of UVC sensitivity.

Vitamin C Deficiency in Blood Samples of COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) is the most notable pandemic of the modern era. A relationship between ascorbate (vitamin C) and COVID-19 severity is well known, whereas the role of other vitamins is less understood. The present study compared the blood levels of four vitamins in a cohort of COVID-19 patients with different severities and uninfected individuals. Serum concentrations of ascorbate, calcidiol, retinol, and α-tocopherol were measured in a cohort of 74 COVID-19 patients and 8 uninfected volunteers. The blood levels were statistically compared and additional co-morbidity factors were considered. COVID-19 patients had significantly lower plasma ascorbate levels than the controls (p-value < 0.001), and further stratification revealed that the controls had higher levels than fatal, critical, and severe COVID-19 cases (p-values < 0.001). However, no such trend was observed for calcidiol, retinol, or α-tocopherol (p-value ≥ 0.093). Survival analysis showed that plasma ascorbate below 11.4 µM was associated with a lengthy hospitalization and a high risk of death. The results indicated that COVID-19 cases had depleted blood ascorbate associated with poor medical conditions, confirming the role of this vitamin in the outcome of COVID-19 infection.

Mini -Review of the Significance of Vitamin-C in the Management of Novel Corona Virus

Introduction: A newly discovered COVID-19 is a communicable disease which is caused by corona virus. The corona virus disease 2019 pandemic has affected 100 million people in the worldwith just about 22,69,466 deaths occurred to date.In management of covid-19 Vitamin C has various physiological functions, many of which are includes immunomodulatory,antioxidant, anti-inflammatory and antithrombotic functions. In the systematic reviewwe reviewed the feasibility of accessible evidence on significance of nutrient C in treatment of patients with corona virus. Methods: To accessing the importance of vitamin C in patients with corona virus we taken already various research published article, meta-analysis,systematic review and randomized control trails on role of nutrient C. The web of science, pubmedand scopus were obtained and using specified search query.For producing the graph and plots weworking on R-studio application. Results: We were looking different wellsprings of role of vitamin and Coronavirus. The time frame from 2020-2021 an inquiry created found of 254 reports from 173 Sources (Journals, Books,article and so forth) the quantity of writers included 1477, Authors of single-composed archives were 17, multi-wrote records were 1460, writers per archive was 5.81and co-writers per archive was 6.26. The Collaboration Index and Average references per archive was 6.16 and5.6. Conclusion: In this article after finding of many article we evaluated the significance roles of vitamin C as a multiple functions of antiviral, antioxidant, and immunosuppressed. Although in the fight against corona virus there is currently no proof from completed randomized controlled trials to decisively and specifically indicate a role for vitamin supplementation. Some study has proved there is strong scientific evidence, builded on learning of vitamin physiology, pharmacology. Battle against this worldwide pandemic some clinical studies of ARDS and infection to preferable a role for vitamins C. A valuable number of ongoing studies should provide solid evidence to inform and decision-makers and researchers shortly. © The Electrochemical Society

On the origin of nitrosylated hemoglobin in COVID-19: Endothelial NO capture or redox conversion of nitrite?: Experimental results and a cautionary note on challenges in translational research.

In blood, the majority of endothelial nitric oxide (NO) is scavenged by oxyhemoglobin, forming nitrate while a small part reacts with dissolved oxygen to nitrite; another fraction may bind to deoxyhemoglobin to generate nitrosylhemoglobin (HbNO) and/or react with a free cysteine to form a nitrosothiol. Circulating nitrite concentrations in healthy individuals are 200-700 nM, and can be even lower in patients with endothelial dysfunction. Those levels are similar to HbNO concentrations ([HbNO]) recently reported, whereby EPR-derived erythrocytic [HbNO] was lower in COVID-19 patients compared to uninfected subjects with similar cardiovascular risk load. We caution the values reported may not reflect true (patho)physiological concentrations but rather originate from complex chemical interactions of endogenous nitrite with hemoglobin and ascorbate/N-acetylcysteine. Using an orthogonal detection method, we find baseline [HbNO] to be in the single-digit nanomolar range; moreover, we find that these antioxidants, added to blood collection tubes to prevent degradation, artificially generate HbNO. Since circulating nitrite also varies with lifestyle, dietary habit and oral bacterial flora, [HbNO] may not reflect endothelial activity alone. Thus, its use as early marker of NO-dependent endothelial dysfunction to stratify COVID-19 patient risk may be premature. Moreover, oxidative stress not only impairs NO formation/bioavailability, but also shifts the chemical landscape into which NO is released, affecting its downstream metabolism. This compromises the endothelium's role as gatekeeper of tissue nutrient supply and modulator of blood cell function, challenging the body's ability to maintain redox balance. Further studies are warranted to clarify whether the nature of vascular dysfunction in COVID-19 is solely of endothelial nature or also includes altered erythrocyte function.

Hypothesis: Mutual dependency of ascorbate and calcidiol for optimal performance of the immune system

For a proper functioning, immune cells require sufficient levels of ascorbate and calcidiol in the blood. Upon activation, immune cells increase their internal conversion of calcidiol to calcitriol. In general, calcitriol can affect the expression of ca. 3% of the genes in the human genome. Among the gene products are a number of Fe (II)-and 2-oxoglutarate-dependent dioxygenases functioning as demethylases of histones, DNA, RNA and ribosomes in epigenetic gene regulation. These dioxygenases require millimolar concentrations of ascorbate for activity. Immune cells contain 1-4 mM ascorbate. It is hypothesized here that there is a mutual dependency of ascorbate and calcidiol for optimal performance of the human immune system. Early signs for this thesis are in literature, but were not yet recognized. Daily intake of both compounds to keep the plasma levels to ca. 75 mu M for ascorbate and to at least 75 nM for calcidiol, will reduce the risk of serious disease after infections. This applies in particular to infected individuals with prolonged elevated levels of neutrophils. Reports state that such subjects are often deficient in either ascorbate (vitamin C) or calcidiol (vitamin D-3), but none of the studies considered the levels of both at the same time.

Vitamin C Plasma Levels Associated with Inflammatory Biomarkers, CRP and RDW: Results from the NHANES 2003-2006 Surveys.

Although undisputed for its anti-inflammatory and immune system boosting properties, vitamin C remains an inconsistently investigated nutrient in the United States. However, subclinical inadequacies may partly explain increased inflammation and decreased immune function within the population. This secondary analysis cross-sectional study used the 2003-2006 NHANES surveys to identify more clearly the association between plasma vitamin C and clinical biomarkers of acute and chronic inflammation C-reactive protein (CRP) and red cell distribution width (RDW). From plasma vitamin C levels separated into five defined categories (deficiency, hypovitaminosis, inadequate, adequate, and saturating), ANOVA tests identified significant differences in means in all insufficient vitamin C categories (deficiency, hypovitaminosis, and inadequate) and both CRP and RDW in 7607 study participants. There were also statistically significant differences in means between sufficient plasma vitamin C levels (adequate and saturating categories) and CRP. Significant differences were not identified between adequate and saturating plasma vitamin C levels and RDW. Although inadequate levels of vitamin C may not exhibit overt signs or symptoms of deficiency, differences in mean levels identified between inflammatory biomarkers suggest a closer examination of those considered at risk for inflammatory-driven diseases. Likewise, the subclinical levels of inflammation presented in this study provide evidence to support ranges for further clinical inflammation surveillance.

Vitamin C and COVID-19 treatment: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Vitamin C has been used as an anti-oxidant in various diseases including viral illnesses like coronavirus disease (COVID-19). METHODS: Meta-analysis of randomized controlled trials (RCT) investigating the role of vitamin C supplementation in COVID-19 was carried out. RESULTS: Total 6 RCTs including n = 572 patients were included. Vitamin C treatment didn't reduce mortality (RR 0.73, 95% CI 0.42 to 1.27; I2 = 0%; P = 0.27), ICU length of stay [SMD 0.29, 95% CI -0.05 to 0.63; I2 = 0%; P = 0.09), hospital length of stay (SMD -0.23, 95% CI -1.04 to 0.58; I2 = 92%; P = 0.57) and need for invasive mechanical ventilation (Risk Ratio 0.93, 95% CI 0.61 to 1.44; I2 = 0%; P = 0.76). Further sub-group analysis based on severity of illness (severe vs. non-severe), route of administration (IV vs. oral) and dose (high vs. low) failed to show any observable benefits. CONCLUSION: No significant benefit noted with vitamin C administration in COVID-19. Well-designed RCTs with standardized control group needed on this aspect.

Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19.

Sepsis induced by bacteria or viruses can result in multiorgan dysfunction, which is a major cause of death in intensive care units. Current treatments are only supportive, and there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti-inflammatory, anticoagulant and immune modulatory actions, so it is a rational treatment for sepsis. Here, we summarise data that support the use of megadose vitamin C as a treatment for sepsis and COVID-19. Megadose intravenous sodium ascorbate (150 g per 40 kg over 7 h) dramatically improved the clinical state and cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a clinically relevant ovine model of Gram-negative bacteria-induced sepsis. In a critically ill COVID-19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. These findings suggest that megadose vitamin C should be trialled as a treatment for sepsis and COVID-19.

Proximity Labeling for the Identification of Coronavirus-Host Protein Interactions.

Biotin-based proximity labeling circumvents major pitfalls of classical biochemical approaches to identify protein-protein interactions. It consists of enzyme-catalyzed biotin tags ubiquitously apposed on proteins located in close proximity of the labeling enzyme, followed by affinity purification and identification of biotinylated proteins by mass spectrometry. Here we outline the methods by which the molecular microenvironment of the coronavirus replicase/transcriptase complex (RTC), i.e., proteins located within a close perimeter of the RTC, can be determined by different proximity labeling approaches using BirAR118G (BioID), TurboID, and APEX2. These factors represent a molecular signature of coronavirus RTCs and likely contribute to the viral life cycle, thereby constituting attractive targets for the development of antiviral intervention strategies.

What Can Cellular Redox, Iron, and Reactive Oxygen Species Suggest About the Mechanisms and Potential Therapy of COVID-19?

Accumulating evidence suggests that there are important contributions to coronavirus disease (COVID-19) from redox imbalance and improperly coordinated iron, which cause cellular oxidative damage and stress. Cells have developed elaborate redox-dependent processes to handle and store iron, and their disfunction leads to several serious diseases. Cellular reductants are important as reactive oxygen species (ROS) scavengers and to power enzymatic repair mechanisms, but they also may help generate toxic ROS. These complicated interrelationships are presented in terms of a cellular redox/iron/ROS triad, including ROS generation both at improperly coordinated iron and enzymatically, ROS interconvertibility, cellular signaling and damage, and reductant and iron chelator concentration-dependent effects. This perspective provides the rational necessary to strongly suggest that COVID-19 disrupts this interdependent triad, producing a substantial contribution to the ROS load, which causes direct ROS-induced protein and phospholipid damage, taxes cellular resources and repair mechanisms, and alters cellular signaling, especially in the more critical acute respiratory distress syndrome (ARDS) phase of the infection. Specific suggestions for therapeutic interventions using reductants and chelators that may help treat COVID-19 are discussed.

Vitamin C-An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19.

There are limited proven therapies for COVID-19. Vitamin C's antioxidant, anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections, including COVID-19, and the mechanisms of action in infectious disease, including support of the stress response, its role in preventing and treating colds and pneumonia, and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8 g/day) may reduce the incidence and duration of respiratory infections and intravenous vitamin C (6-24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients' vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised persons with COVID-19.

The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19.

Investigation into the role of vitamin C in the prevention and treatment of pneumonia and sepsis has been underway for many decades. This research has laid a strong foundation for translation of these findings into patients with severe coronavirus disease (COVID-19). Research has indicated that patients with pneumonia and sepsis have low vitamin C status and elevated oxidative stress. Administration of vitamin C to patients with pneumonia can decrease the severity and duration of the disease. Critically ill patients with sepsis require intravenous administration of gram amounts of the vitamin to normalize plasma levels, an intervention that some studies suggest reduces mortality. The vitamin has pleiotropic physiological functions, many of which are relevant to COVID-19. These include its antioxidant, anti-inflammatory, antithrombotic and immuno-modulatory functions. Preliminary observational studies indicate low vitamin C status in critically ill patients with COVID-19. There are currently a number of randomized controlled trials (RCTs) registered globally that are assessing intravenous vitamin C monotherapy in patients with COVID-19. Since hypovitaminosis C and deficiency are common in low-middle-income settings, and many of the risk factors for vitamin C deficiency overlap with COVID-19 risk factors, it is possible that trials carried out in populations with chronic hypovitaminosis C may show greater efficacy. This is particularly relevant for the global research effort since COVID-19 is disproportionately affecting low-middle-income countries and low-income groups globally. One small trial from China has finished early and the findings are currently under peer review. There was significantly decreased mortality in the more severely ill patients who received vitamin C intervention. The upcoming findings from the larger RCTs currently underway will provide more definitive evidence. Optimization of the intervention protocols in future trials, e.g., earlier and sustained administration, is warranted to potentially improve its efficacy. Due to the excellent safety profile, low cost, and potential for rapid upscaling of production, administration of vitamin C to patients with hypovitaminosis C and severe respiratory infections, e.g., COVID-19, appears warranted.

Ascorbate as Prophylaxis and Therapy for COVID-19-Update From Shanghai and U.S. Medical Institutions.

BACKGROUND: No validated treatments have been identified for the COVID-19 pandemic virus; several are currently in randomized clinical trials. Diagnostic instruments are rapidly evolving. Symptoms range from those of a common cold to acute respiratory distress syndrome (ARDS), to sepsis arising from the flood of inflammatory bacterial and viral pathogens in the blood. Mortality generally arises from cytokine storms of uncontrolled inflammation, oxidative injury, and damage to the alveolar-capillary barrier, with secondary bacterial infection. To address the indisputably urgent need for therapeutics for COVID-19, a specialized interdisciplinary medical panel convened in Shanghai in March 2020 to consider all relevant clinical and experimental evidence on the possible utility of intravenous (IV) ascorbate in the treatment of COVID-19-related ARDS. METHODS: The panel convened multidisciplinary medical experts and reviewed all relevant in vitro, in vivo, clinical studies and randomized controlled trials on IV ascorbate and issued a consensus report on 23 March 2020 noting that substantial differences in serum concentrations of ascorbate are achieved through IV administration in contrast with the oral route. FINDINGS: The Shanghai panel, and a parallel medical group in Guangzhou, are advising the use of high-dose IV ascorbate for the treatment of ARDS, along with other supportive therapies, including Vitamin D and zinc. We report preliminary progress in using this treatment for 50 consecutive cases treated in Shanghai hospitals, consistent with earlier reports from a meta-analysis of the use of IV ascorbate to treat sepsis. We provide an instructive clinical anecdote regarding a single family where one elderly member with cardiac and other major comorbidities developed and survived ARDS-related sepsis following daily treatments that included 15 g of IV ascorbate. None of her adult caregivers who had ingested between 2 and 10 g of ascorbate daily developed COVID-19.

Excess Ascorbate is a Chemical Stress Agent against Proteins and Cells.

Excess ascorbate (as expected in intravenous treatment proposed for COVID-19 management, for example) oxidizes and/or degrades hemoglobin and albumin, as evidenced by UV-vis spectroscopy, gel electrophoresis, and mass spectrometry. It also degrades hemoglobin in intact blood or in isolated erythrocytes. The survival rates and metabolic activities of several leukocyte subsets implicated in the antiviral cellular immune response are also affected. Excess ascorbate is thus an unselective biological stress agent.