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Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc.
Corrao, S, Mallaci Bocchio, R, Lo Monaco, M, Natoli, G, Cavezzi, A, Troiani, E, Argano, C
Nutrients. 2021;(4)
Abstract
More than one year has passed since the first cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus were reported in Wuhan (China), rapidly evolving into a global pandemic. This infectious disease has become a major public health challenge in the world. Unfortunately, to date, no specific antivirals have been proven to be effective against COVID-19, and although a few vaccines are available, the mortality rate is not decreasing but is still increasing. One therapeutic strategy has been focused on infection prevention and control measures. In this regard, the use of nutraceutical supports may play a role against some aspect of the infection, particularly the inflammatory state and the immune system function of patients, thus representing a strategy to control the worst outcomes of this pandemic. For this reason, we performed an overview including meta-analyses and systematic reviews to assess the association among melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers using three databases, namely, MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews. According to the evidence available, an intake of 50,000 IU/month of vitamin D showed efficacy in CRP. An amount of 1 to 2 g per day of vitamin C demonstrated efficacy both in CRP and endothelial function, and a dosage of melatonin ranging from 5 to 25 mg /day showed good evidence of efficacy in CRP, TNF and IL6. A dose of 50 mg/day of elemental zinc supplementation showed positive results in CRP. Based on the data reported in this review, the public health system could consider whether it is possible to supplement the current limited preventive measures through targeted nutraceutical large-scale administration.
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Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins-Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions.
Valachová, K, Rapta, P, Moura, NMM, Batinic-Haberle, I, Šoltés, L
International journal of molecular sciences. 2021;(16)
Abstract
High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three ortho isomeric Mn(III) substituted N-alkyl- and alkoxyalkylpyridylporphyrins or para isomeric Mn(III) N-methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The ortho compounds MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001) and MnTnHex-2-PyP5+ are able to redox cycle with ascorbate whereby producing H2O2 which is subsequently coupled with Cu(I) to produce the •OH radical essential for HA degradation. Conversely, with the para analog, MnTM-4-PyP5+, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active ortho isomeric Mn(III) porphyrins.
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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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Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19.
Bae, M, Kim, H
Molecules (Basel, Switzerland). 2020;(22)
Abstract
Low levels of micronutrients have been associated with adverse clinical outcomes during viral infections. Therefore, to maximize the nutritional defense against infections, a daily allowance of vitamins and trace elements for malnourished patients at risk of or diagnosed with coronavirus disease 2019 (COVID-19) may be beneficial. Recent studies on COVID-19 patients have shown that vitamin D and selenium deficiencies are evident in patients with acute respiratory tract infections. Vitamin D improves the physical barrier against viruses and stimulates the production of antimicrobial peptides. It may prevent cytokine storms by decreasing the production of inflammatory cytokines. Selenium enhances the function of cytotoxic effector cells. Furthermore, selenium is important for maintaining T cell maturation and functions, as well as for T cell-dependent antibody production. Vitamin C is considered an antiviral agent as it increases immunity. Administration of vitamin C increased the survival rate of COVID-19 patients by attenuating excessive activation of the immune response. Vitamin C increases antiviral cytokines and free radical formation, decreasing viral yield. It also attenuates excessive inflammatory responses and hyperactivation of immune cells. In this mini-review, the roles of vitamin C, vitamin D, and selenium in the immune system are discussed in relation to COVID-19.
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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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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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Intravenous vitamin C in the treatment of allergies: an interim subgroup analysis of a long-term observational study.
Vollbracht, C, Raithel, M, Krick, B, Kraft, K, Hagel, AF
The Journal of international medical research. 2018;(9):3640-3655
Abstract
UNLABELLED Objective Oxidative stress appears to be a key factor in the pathogenesis of allergic diseases and a potential therapeutic target in allergy treatment. Allergic diseases are reportedly associated with reduced plasma levels of ascorbate, which is a key physiological antioxidant. Ascorbate prevents excessive inflammation without reducing the defensive capacity of the immune system. Methods An interim analysis of a multicenter, prospective, observational study was conducted to investigate the change in disease-specific and nonspecific symptoms (fatigue, sleep disorders, depression, and lack of mental concentration) during adjuvant treatment with intravenous vitamin C (Pascorbin®; Pascoe, Giessen, Germany) in 71 patients with allergy-related respiratory or cutaneous indications. Results Between the start and end of treatment, the mean sum score of three disease-specific symptoms decreased significantly by 4.71 points and that of four nonspecific symptoms decreased significantly by 4.84 points. More than 50% of patients took no other allergy-related medication besides vitamin C. Conclusions Our observations suggest that treatment with intravenous high-dose vitamin C reduces allergy-related symptoms. Our observations form a basis for planning a randomized controlled clinical trial to obtain more definitive evidence of the clinical relevance of our findings. We also obtained evidence of ascorbate deficiency in allergy-related diseases. TRIAL REGISTRATION Clinical Trials NCT02422901.
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Patterns of Death in Patients with Sepsis and the Use of Hydrocortisone, Ascorbic Acid, and Thiamine to Prevent These Deaths.
Marik, PE
Surgical infections. 2018;(8):812-820
Abstract
Background: In general, patients with sepsis die from the host response to the infecting pathogen rather than from the infecting pathogen itself. Four patterns of death have been identified in sepsis, namely vasoplegic shock, single-organ respiratory failure (acute respiratory distress syndrome [ARDS]), multi-system organ failure (MSOF), and persistent MSOF with ongoing inflammation and immunosuppression with recurrent infections (persistent inflammation-immunosuppression and catabolism syndrome [PICS]). To improve the outcome of sepsis adjunctive therapies that modulate the immune system have been tested; these therapies that have targeted specific molecules or pathways have universally failed. Conclusion: We propose that the combination of hydrocortisone, intravenous ascorbic acid, and thiamine (HAT therapy), which synergistically targets multiple pathways, restores the dysregulated immune system and organ injury, and reduces the risk of death and organ failure following sepsis.
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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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Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction.
Barabutis, N, Khangoora, V, Marik, PE, Catravas, JD
Chest. 2017;(5):954-962
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Abstract
BACKGROUND Sepsis refers to the dysregulated host immune response elicited by microbial infections resulting in life-threatening organ dysfunction. Sepsis represents a medical challenge, since it is associated with a rate of death as high as 60%. Septic shock is strongly associated with vascular dysfunction and elevated pulmonary capillary permeability. We recently reported that the combination of hydrocortisone (HC), ascorbic acid (vitC), and thiamine dramatically improves outcomes and reduces mortality in patients with sepsis. In the present study, we provide experimental evidence in support of the hypothesis that the combination of HC and vitC enhances endothelial barrier function. METHODS Human lung microvascular endothelial cells were exposed to lipopolysaccharide (LPS) in the absence or presence of HC and vitC. RESULTS LPS alone induced profound hyperpermeability, as reflected in decreased values of transendothelial electrical resistance. vitC alone did not exhibit barrier enhancement properties nor did it affect the LPS-induced hyperpermeability. Similarly, HC alone exhibited only a minor barrier-enhancing and protective effect. Conversely, the combination of HC and vitC, either as before or after treatment, dramatically reversed the LPS-induced barrier dysfunction. The barrier-protective effects of HC and vitC were associated with reversal of LPS-induced p53 and phosphorylated cofilin downregulation and LPS-induced RhoA activation and myosin light chain phosphorylation. CONCLUSIONS These data provide a novel mechanism of endothelial barrier protection and suggest one possible pathway that may contribute to the therapeutic effects of HC and vitC in patients with sepsis.