key: cord-0927467-v1pjv93r authors: Boretti, Alberto; Banik, Bimal Krishna title: Intravenous Vitamin C for reduction of cytokines storm in Acute Respiratory Distress Syndrome date: 2020-04-21 journal: PharmaNutrition DOI: 10.1016/j.phanu.2020.100190 sha: ce5f5bca2fc5a9261e33ba2d9da278ad48cb0401 doc_id: 927467 cord_uid: v1pjv93r Abstract The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines' storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease. achievable concentration of less than 300 µM. However, this control was bypassed with IV administration of the vitamin, resulting in a very high level of Vit-C plasma concentration (up to 20 mM) [46, 47] . Additional research suggested that pharmacological concentrations of ascorbate as achieved with IV administration may result in cell death in numerous cancer cell lines [48] . Health care practitioners who had participated in complementary and alternative medicine conferences in 2006 and 2008 were debated on the benefits/risks of high-dose IV Vit-C in patients. A total of 199 participants were chosen and out of which 172 were taken Vit-C. Specifically, IV Vit-C was recommended to fight against infection, cancer, and fatigue [49] . In the early 1970s, a case study was conducted with 50 cancer patients who were taken a high dose of ascorbic acid [41] . Conventional therapies were applied to these patients, but these were not successful. On this basis, these patients were recommended to take ascorbic acid. Different doses and schedules were used. For example, some patients were given IV ascorbic acid (10 g/day for 10 successive days), a few were given higher dose amounts, and some were chosen to give oral ascorbic acid (10 g/day) or a combination of both. A wide variety of responses were found. Dome of them had no or minimal response and some of them had tumor regression and tumor hemorrhage. Despite this important observation, a lack of control study prevented making any conclusion on the health benefits of ascorbic acid treatment. From a limited study published in 1975, it is apparent that one of the patients experienced tumor regression [60] . The patient who had reticulum cell sarcoma exhibited improvement due to the treatment with ascorbic acid. A reduction of the daily dose of ascorbic acid was not helpful since symptoms of the disease appeared. Notably, remission was successfully achieved again after the same patient was given a higher initial dose of ascorbic acid. A larger study of terminal cancer patients treated with ascorbate was conducted in 1976. In this investigation, 100 terminal cancer patients [41] were given ascorbate through an acceptable and scientific way (10 g/day for 10 days IV, then repeated orally). The health conditions of these patients were evaluated concerning 1,000 matched control patients from the same clinic. Interestingly, the average survival time for ascorbate-treated patients was considerably much higher (300 days) than that of the matched control group [42, 43] . Two randomized investigations using placebo-controlled trials were performed. In these studies, cancer patients were taken either 10 g of oral Vit-C or placebo daily until signs of cancer go away. At the end of these investigations, no significant differences in clinical results were found between the two ascorbate-and placebo-treated groups [44, 45] . A study disclosed three case reports on cancer patients who received IV Vit-C as their main medicines. During Vit-C uptake, the patients were also given other materials including vitamins, minerals, and botanicals. It was claimed that the cases are analyzed following the National Cancer Institute (NCI) Best Case Series procedures. Histopathologic tests found weak prognoses for these patients. But the survival period of these patients went up after being treated with IV Vit-C [61] . Vit-C was given from 15 g to 65 g, once or twice a week, for several months to these patients. Two studies demonstrated that IV Vit-C treatment helps to improve the quality of life and decreases the side effects associated with cancer [62, 63] . Systematic studies identified that the doses of Vit-C to volunteers or cancer patients can be up to 1.5 g/kg. No toxicity risks were seen (for example, glucose-6-phosphate dehydrogenase deficiency, renal diseases or urolithiasis). These studies identified that plasma concentrations of Vit-C can be much higher with IV administration than that of oral administration. The concentration was maintained for approximately 4 hours [46, 47] . A phase I study investigated the safety and efficiency of dual drug therapy by combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects were evaluated in this study. The patients received IV gemcitabine (1000 mg for 30 minutes, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). No adverse effects were observed for ascorbic acid treatment. Five subjects received fewer than 18 of the proposed 24 ascorbate infusions. In three patients the disease was continued. Imaging tests were performed on nine patients to assess tumor size. This showed that the health situation was stable in each of them [64] . A 2013 phase I clinical investigation studied the effects of combining ascorbate with gemcitabine in the treatment of stage IV pancreatic cancer. During each 4-week cycle, patients were given gemcitabine weekly for 3 weeks and ascorbate for 4 weeks with a specific dose. This study found a progression-free and overall survival period. The combination of drug treatment was acceptable well [54] . In 2014, a phase I/IIA clinical trial measured the toxicities of two systems. The first one was combined IV ascorbate with carboplatin and the second one was ascorbate paclitaxel in stage III/IV ovarian cancer. More than 24 patients were chosen to receive either chemotherapy alone or chemotherapy and IV Vit-C. The chemotherapy was given for 6 months and IV Vit-C was continued for 12 months. Interestingly, IV Vit-C reduced chemotherapy-related toxicities [65] . A phase I/II clinical trial of high-dose IV Vit-C with numerous chemotherapeutic agents was conducted in 2015. This study was performed to evaluate multiple factors. Some important targets were to evaluate associated adverse effects, to determine the pharmacokinetic activities of Vit-C, to understand the clinical potential, to evaluate changes in mood and behavior and to assess the lifestyle [66] . A high-dose of IV Vit-C was analyzed in 14 patients. The procedures performed were tolerated well and were safe. A few temporary side effects were seen: increased urinary flow, thirst, nausea, vomiting, and chilling. It was important to note that an administration of chemotherapeutic agents did not alter the plasma concentration of Vit-C. A few patients were benefitted from this treatment because they experience temporary stable disease, demonstrate more activity with additional energy. However, since the group was small, no general conclusions from this study were drawn [66] . Recently, [67] , a phase I study was evaluated to evaluate the safety, bioavailability, and efficiency of high-dose IV Vit-C in combination with chemotherapy regimens mFOLFOX6 or FOLFIRI. These were a combination of well-known J o u r n a l P r e -p r o o f agents: oxaliplatin, leucovorin, and 5-fluorouracil or leucovorin, 5-fluorouracil and irinotecan hydrochloride. This study was conducted on 36 patients with metastatic colorectal or gastric cancer. The principal aims were to evaluate the maximum-tolerated dose. Another goal was to determine the phase II dose of ascorbic acid with co-administration with mFOLFOX6 or FOLFIRI. Initially, all patients were given an identical chemotherapy treatment for 14 days with Vit-C infusions. Later, the concentration of ascorbic acid was altered for the dose-escalation investigation. This study demonstrated no dose-limiting toxicity. Therefore, a maximum-tolerated dose was not identified from this investigation. However, a dose of 1.5 g/kg for ascorbic acid was recommended for this phase II study. No adverse side effects were observed and the treatments were acceptable to the patients. Based on the success, a randomized phase III investigation is under progress. The goal of this study is to determine the clinical power of ascorbic acid against metastatic colorectal cancer in combination with mFOLFOX6 with or without bevacizumab [67] . Several studies were performed small doses of IV ascorbic acid treatment (1000 mg) with arsenic trioxide regimens, and mixed results were obtained [68, 69, [70] . Clinical investigations of ascorbate in combination with arsenic trioxide were reported [36] . Patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) were treated in two clinical trials [71, 72] . The patients in both of these trials were undergone conventional therapy along with IV Vit-C. IV Vit-C was administered under radiation therapy and in the presence of temozolomide. The toxicity and overall survival rate of the patients were favorable. The NSCLC clinical trial was a phase II procedure that has 14 patients with advanced cancer. These patients were also given both chemotherapy and IV Vit-C. The results of this investigation were also favorable. Many trials with IV Vit-C in a combination with other medicines are under active investigation. Accordingly, 5 trials are being conducted by scientists at Iowa University, 4 phase II studies and 1 phase IB/II trial. The 4 phase II clinical trials are focused to identify the efficiency of high-dose ascorbic acid combined with common anticancer molecules. These studies with ascorbate are also progressing with many cancer cell lines. These include studies on non-small cell lung cancer therapy under radiation therapy and in the presence of carboplatin and paclitaxel; metastatic pancreatic adenocarcinoma in the presence of gemcitabine and nab-paclitaxel; pancreatic adenocarcinoma in the presence of gemcitabine and radiation therapy, and glioblastoma in the presence of temozolomide and radiation therapy. Another phase IB/II trial is investigating the safety and clinical performance of high-dose ascorbate with radiation therapy against soft tissue sarcoma. Numerous studies used IV ascorbic acid at a fixed dose of 1000 mg with various amounts of arsenic trioxide as anticancer therapy. It was expected that the pro-oxidant character of IV ascorbic acid can improve the effects of arsenic trioxide by a sensitization process of the malignant cells to arsenic's cytotoxic nature [72] . The combination therapies worked well. Some benefits against multiple myeloma were observed. However, the role of Vit-C in this was not determined [73] [74] [75] . In contrast, similar combination regimens were not effective and resulted in side effects, including the progression of the disease with particular cancer. Moreover, no anticancer effects against metastatic J o u r n a l P r e -p r o o f colorectal cancer [76] and metastatic melanoma were determined [77] . Since these trials were not placebo-controlled, the role of ascorbic acid to the results is unclear. Intravenous (IV) high-dose ascorbic acid was well-tolerated in clinical trials [46] , [78] , [74] , [71] , [73] , [64] . It was speculated that ascorbic acid may accelerate renal failure in patients with preexisting renal disorders [49] . Glucose-6phosphate dehydrogenase (G-6-PD) deficient patients were not good candidates to have high doses of Vit-C due to hemolysis [50] [51] [52] . Vit-C was able to improve the bioavailability of iron. A large dose of Vit-C was not recommended for patients with hemochromatosis [53] . Vit-C in high doses reacted with a few anticancer compounds. These interactions were detected in preclinical studies. A phase I clinical investigation examined the feasibility of using high-dose IV ascorbate and gemcitabine in stage IV pancreatic cancer patients. It was important to know that the combination formula was well tolerated by patients. No adverse effects were observed [54] . In vitro and in vivo animal studies indicated ascorbate can alter the mechanism of the drug. For example, ascorbate with bortezomib altered the action of the medicine as a proteasome inhibiting agent and blocked bortezomibmediated cell death [55] [56] [57] . This interaction was observed with a low concentration of Vit-C (40 mg/kg/day) to animals. The cell culture study on blood plasma with Vit-C (1 g/day) also demonstrated a large decrease in bortezomib's growth inhibitory effect against multiple myeloma cells. The plasma of healthy volunteers was analyzed. This amount had blocked the drug's inhibitory properties against the 20S proteasome [57] . On the other hand, a study that utilized mice harboring human prostate cancer cell xenografts did not find any good effect of oral Vit-C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of this medicine [58] . Studies showed that dehydroascorbic acid, an oxidized form of Vit-C alters the cytotoxic properties of some chemotherapy drugs [59] . But, the concentration of dehydroascorbic acid is found to be low in dietary supplements and foods. Despite some controversial results over the years, Vit-C had proven to have anticancer effects when given intravenously at high concentrations [79] . Some reports on the anticancer activities of Vit-C were dependent on the use of immune-deficient mice. These studies were conducted to examine the direct effects of ascorbate on tumors. It was found that the effects of Vitamin C are much stronger in the presence of an intact immune system [79] . These observations suggested a combination treatment which requires evaluation in patients. The antiviral properties of Vit-C were recently reviewed [80] . Vit-C was used for the treatment of hypovitaminosis C in malnourished patients. A combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) worked well in the treatment of patients with sepsis and septic shock [81] . There were 29 ongoing or completed clinical trials with Vit-C administration in sepsis. The effectiveness of Vit-C in preventing common cold [82] and other health disorders J o u r n a l P r e -p r o o f was questioned [83] [84] . The ascorbic acid therapy for acute inflammatory disorders was based upon numerous biological studies following many decades of research. The current interest in Vit-C focuses on bacterial sepsis and septic shock in patients. More than 300 scientific and clinical studies supported mechanistic data to use Vit-C against this disease [85, 86] . Some other additional role of Vit-C in the treatment of viral diseases is also possible. The biological concepts and evidence for the use of Vit-C in viral infections are described here. Numerous studies identified that Vit-C in high dosages is virucidal [83] . This conclusion was based on in-vitro experiments. In the presence of copper and/or iron, high doses of Vit-C showed virucidal activity. This was explained through the formation of hydrogen peroxide and other radical initiators [87, 88] . Moreover, the low pH value of the system was responsible for the in-vitro antiviral effects of Vit-C. Despite these studies, the in vivo virucidal activity of Vit-C was not confirmed. It was well established that Vit-C is a powerful antioxidant and it can exert pro-oxidant effects at high concentrations. The generation of reactive oxygen species through the reduction of transition metal is possible [89] . It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans invitro through an iron-catalyzed Fenton reaction [90] . An iron chelator 2,2′-bipyridyl inhibited this effect. An experiment demonstrated that Vit-C can decrease the viral load of the Ebstein-Barr virus (EBV) [91] . This observation suggested multiple mechanisms are involved in Vit-C-controlled anti-vital therapy. The activity of antigens and load was reduced through pre-treatment of human foreskin fibroblast and endothelial cells with ascorbate before cytomegalovirus (CMV) infection [92] . This observation was failed to reproduce when ascorbate is added after the infection. The immunomodulatory activities of Vit-C were responsible for this effect. In general, Ascorbic acid is concentrated in leucocytes, lymphocytes, and macrophages [93, 94] . Chemotaxis was improved by Vit-C [95] [96] [97] . The neutrophil phagocytic activity and oxidative death were also enhanced [95] [96] [97] . Lymphocyte proliferation was also accelerated [95] [96] [97] . The rate-determining last step of ascorbic acid biosynthesis in animals is L-Gulono-γ-lactone oxidase or the isomeric Gulo form. Mutations in the gene of this enzyme prevented anthropoid primates and guinea pigs to synthesize this molecule. The effects of Vit-C in viral infections were studied via a Gulo (-/-) knockout mice system. It was shown that nasal inoculation of the H3N2 influenza virus is fatal in Gulo (-/-) mice in comparison to wild type mice [97] . Anti-viral cytokine interferon (IFN)-α/β became lower. However, the viral titers in the lung of ascorbic acidinsufficient Gulo (-/-) mice became more abundant [97] . The pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1)-α/β, and infiltration of inflammatory cells was increased in the lung. These results were corrected in Gulo (-/-) mice repleted with ascorbic acid before viral exposure occurs. Most probably, an impaired phosphorylation process of signal transducers and activators of transcription (STATs) was responsible for the decreased generation of IFN in Gulo (-/-) mice [98] . It was found that Gulo (-/-) mice as compared to wild type mice have an impaired immune response with higher lung pathological dysfunction when exposed to influenza H1N1 virus [98] . It was shown that restraint-stressed mice with H1N1-induced pneumonia have a dose-dependent reduction of J o u r n a l P r e -p r o o f mortality in the presence of ascorbate. Histopathological lung sections also demonstrated reduced problems in the treated mice [99] . An administration of Vit-C was helpful to recover mitochondrial membrane potential and gene expression of pro-inflammatory cytokines. Ascorbic acid was reported to have clinical activity against numerous other viruses including poliovirus, Venezuelan equine encephalitis, human lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV) and rabies virus in addition to demonstrating activity against influenza and herpes virus [100] [101] [102] [103] [104] [105] [106] [107] . It is known that most of the infections activate phagocytes with the generation of reactive oxygen species (ROS). The ROS has a key role in deactivating viruses. Some of the ROS harm the host cells that cause viral-induced host injury. Respiratory syncytial virus (RSV) infects the upper and lower respiratory tract in infants and children. RSV infection of airway epithelial cells accelerates ROS production and this inhibits the concentration of the lung antioxidant enzymes. The oxidant-antioxidant amount and proportion in cells are critical to RSV pulmonary toxicity [108] . Lung pulmonary inflammation and injury are considerably reduced by the administration of antioxidants [109] . Ascorbic acid is a powerful antioxidant and therefore, it scavenges oxygen free radicals and restores other cellular antioxidants. These include tetrahydrobiopterin and α-tocopherol [94] . The hypothesis that Vit-C may become beneficial in the treatment of viral infections is based on two concepts. Patients with infectious diseases do not have a sufficient level of Vit-C due to metabolic consumption [110] . Vit-C has immunomodulating properties in patients with viral infections. This is possible by increasing the production of α/β interferons and downregulating the synthesis of proinflammatory cytokines. Despite that Vit-C have beneficial effects in viral infections no solid clinical data exists on this topic. Pauling suggested that Vit-C can be used for the treatment of the common cold. On this basis, most of the randomized controlled trials (RCTs') targeted the role of Vit-C in the prevention and treatment of the cold symptoms. In an analysis of 29 RCTs, Vit-C failed to reduce cold disease [82] . No consistent effects of Vit-C were observed also on the duration of colds in patients. Several studies, however, complicated the interpretation of these data. infection takes place due to the reactivation of the latent Varicella-Zoster virus (VZV). This is particularly predominant because of the loss of cell-induced immunity with age. The concentration of ascorbic acid in plasma is decreased in post-herpetic neuralgia patients compared to healthy persons [111] . An RCT study was conducted with 41 patients who were subjected to IV Vit-C (50mg/kg on days 1, 3 and 5) or placebo [111] . It was found that those patients who were taken IV Vit-C have experienced less pain. In a non-blinded RCT, the role of ascorbic acid on acute herpetic pain and postherpetic neuralgia were evaluated [112] . Eighty-seven patients were given 5g of IV ascorbic acid on the first, third and fifth days or placebo. Interestingly, a few differences between the groups were observed. The treated group with Vit-C demonstrated a lower incidence of postherpetic neuralgia and a lower pain score. Vit-C is mostly concentrated in the aqueous humor of the anterior chamber of the eye. A retrospective cohort J o u r n a l P r e -p r o o f investigation indicated that oral Vit-C reduced the risk of herpes simplex keratitis in combination with an oral antiviral drug [111] . It was concluded only a few months before the start of the CoV19 epidemic that there is an urgent need for novel research about the application of IV Vit-C, targeting the management of infectious diseases [80] . Influenza A virus causes epidemics and pandemics that kill thousands of people every year. Experimental studies demonstrate a beneficial effect of ascorbic acid against influenza. Patients with respiratory disorders due to infection by influenza were treated with histone acetyltransferase (HAT) without corticosteroids. Remarkably, these patients showed rapid improvement after the initiation of HAT. Corticosteroids, on the other hand, have a complex role in the treatment of infection. As a result, corticosteroids may not be a standard choice in patients with influenza A infection [113, 114] . Effective clinical trials are necessary to investigate the use of Vit-C against infections due to influenza, RSV, herpes, and other viral illnesses. A large dose of IV ascorbic acid can be one treatment of choices for Covid19 pneumonia [115] . A report on this disease indicates the severity. For example, a 26% ICU admission and a 4.3% mortality rate are observed among 138 cases [116] . It is believed that ARDS is the main mechanism for Covid19's action. This is followed by increased oxidative stress because of the release of free radicals and cytokines. Considering this mechanism of the process, a large dose of Vit-C should play a key role in the management of Covid19. A study indicates out of 99 Covid19 patients, 17 of them developed ARDS [117] . Eleven patients passed away due to multiple organ failure [117] . This death was explained due to increased oxidative stress and cytokine generation that lead to ARDS. Like influenza, coronaviruses are pandemic viruses that injure lung drastically [118] . This viral infection generates a "storm" of cytokines that reacts with the endothelial cells of the lung. This interaction causes neutrophil infiltration and enhances oxidative stress and damages the function of the lung barrier [118] . ARDS is characterized by strong hypoxemia. This is propagated because of multiple reasons. Uncontrolled inflammation, oxidative injury, and damage to the alveolarcapillary barrier are the main reasons [119] . The severe increased oxidative stress causes pulmonary injuries: lung injury (ALI) and ARDS. ALI and ARDS are key factors responsible for substantially high morbidity and mortality [120, 121] . An increase of C-reactive protein (hsCRP), an indicator of inflammation and oxidative stress is seen among Covid19 patients [122] . The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) is a major regulator of antioxidant response element (ARE) driven cytoprotective protein expression. It is believed that the activation of Nrf2 signaling pathways plays a crucial role in preventing cells and tissues to undergo oxidative stress. 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Focus on ascorbic acid Sodium ascorbate kills Candida albicans in vitro via iron-catalyzed fenton reaction: importance of oxygenation and metabolism Inhibitory effects of 6-O-acylated L-ascorbic acids possessing a straightor branched-acyl chain on epstein-barr virus activation In vitro inhibition of human cytomegalovirus replication in human foreskin fibroblasts and endothelial cells by ascorbic acid 2-phosphate Vitamin C and Immune Function Role of vitamin C in the function of the vascular endothelium Ascorbic acid and the immune response Killing of S.aureus in murine peritoneal macrophages by ascorbic acid along with antibiotics chloramphenicol or ofloxacin: correlation with inflammation Vitamin C is an essential factor on the anti-viral immune response through the production of interferon-alpha/beta at the initial stage of influenza A virus (H3N2) infection Vitamin C deficiency increases the lung pathology of influenza virus-infected gulo-/-mice A new mechanism of vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental venezuelan equine encephalitis Persistent parvovirus B19 viremia with chronic arthralgia treated with ascorbic acid: a case report Ascorbic acid has superior ex vivo antiproliferative, cell deathinducing and immunomodulatory effects over IFN-alpha in HTLV-1-associated myelopathy Intermittent high-dose vitamin C therapy in patients with HTLV-I associated myelopathy NF-kappa B-independent suppression of HIV expression by ascorbic acid In vitro inactivation of human immunodeficiency virus by ascorbic acid Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells Prevention of rabies by vitamin C Viral-mediated in hibition of antioxidant enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation Vitamin C for the treatment of sepsis: the scientific rationale Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain A study of intravenous administration of vitamin C in the treatment of acute herpetic pain and postherpetic neuralgia Corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis Effect of corticosteroid therapy on influenza-related mortality: a systematic review and metaanalysis Early Large Dose Intravenous Vitamin C is the Treatment of Choice for 2019-nCov Pneumonia Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome HIPK1 Interference Attenuates Inflammation and Oxidative Stress of Acute Lung Injury via Autophagy Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace Zhonghua Jie He He Hu Xi Za Zhi Zhonghua Jiehe He Huxi Zazhi Chin J Tuberc Respir Dis 43(0):E005, 2020 Role of Nrf2 and Its Activators in Respiratory Diseases Vitamin C in the critically ill -indications and controversies High Dose Vitamin C and Influenza: A Case Report Protective activity of ascorbic acid at influenza infection Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1 Direct pulmonary delivery of solubilized curcumin reduces severity of lethal pneumonia Targeting cancer vulnerabilities with high-dose vitamin C Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis. Free Radic Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid Pharmacological ascorbate suppresses growth of gastric cancer cells with GLUT1 overexpression and enhances the efficacy of oxaliplatin through redox modulation Effect of high-dose vitamin C infusion in a glucose-6-phosphate dehydrogenase-deficient patient. Case Rep Restoration of TET2 function blocks aberrant self-renewal and leukemia progression Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer Ascorbate regulates haematopoietic stem cell function and leukaemogenesis Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma The association between ascorbate and the hypoxia-inducible factors in human renal cell carcinoma requires a functional Von Hippel-Lindau protein Vitamin C sensitizes melanoma to BET inhibitors High-dose intravenous vitamin C treatment for COVID-19 Covid-19-Navigating the Uncharted Potential interventions for novel coronavirus in China: a systematic review Clinical features and outcomes of 221 patients with COVID-19 in Wuhan, China Outcome reporting from protocols of clinical trials of Coronavirus Disease The authors received no funding and have no conflict of interest to declare.