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play a role during the initial chemotactic response of neutrophils shortly after infection

following vitamin C supplementation, a 20% increase in neutrophil chemotactic activity was observed

also contributes to the phagocytosis and killing of microbes by neutrophils

low levels of vitamin C occurring in high-stress situations

maturation, proliferation, and viability of T cells have all been shown to be upregulated by the presence of normal physiologic concentrations of vitamin C

Vitamin C has been shown to directly affect the number of Igs released from B cells

vitamin C among healthy young adult males showed a significant increase in serum levels of IgA, IgG, and IgM

effects of high-dose vitamin C on cytokine levels in cancer patients, finding decreased amounts of the cytokines Interleukin-1 alpha (IL-1 alpha), IL-2, IL-8, and tumor necrosis factor-alpha (TNF-alpha) after high-dose vitamin C infusion

when vitamin C was supplemented with vitamin E in healthy adults, it increased the production of cytokines IL-1 beta and TNF-alpha

vitamin C acts to modulate the levels of cytokines to prevent them from fluctuating in either direction

vitamin C also acts as an important antioxidant to the cells of the immune system.

human leukocytes, neutrophils, in particular, possess the ability to transport the oxidized form of vitamin C across its membrane to use as a defense mechanism against ROS produced during an immune response

Vitamin C also can recover other endogenous antioxidants in the body such as vitamin E and glutathione, returning them to their active state

vitamin C can decrease the activation of NF-kB

can reduce harmful nitrogen-based compounds such as N-nitrosamines and nitrosamides, both of which are carcinogenic 

subjects taking oral vitamin C supplementation saw a 60% to 90% reduction in oxidative stress compared to a placebo control

subjects infused with vitamin C alone had a 516% increase in glutathione levels compared to subjects not provided the 500 mg daily supplementation

hydroxylating proline and lysine

mature and stabilize the tissue of a healing wound

healing

oral surgery

improved soft tissue regeneration

vitamin C increases the mRNA levels of type I and type III collagen in the human dermis

Studies have demonstrated that those with low levels of vitamin C are at a significantly higher risk of respiratory infection compared to those with normal levels

viral cold duration was reduced by about 8% in adults and 13.5% in children using prophylactic daily doses of 200 mg of oral vitamin C

prophylactically supplementing vitamin C decreases the risk of infection with respiratory viruses such as the common cold

combined with probiotics, oral vitamin C supplementation showed a 33% decrease in the incidence of respiratory tract infections in preschool-age children [

high-dose oral supplementation of vitamin C managed to prevent or reduce symptoms if taken before or just after the onset of cold- or flu-like symptoms

improvements in oxygen saturation and decreased IL-6 levels (a marker of inflammation) in the treatment group compared to the control group

8 g doses of oral vitamin C

there is a negative correlation between age and serum levels of vitamin C

Patients with COVID-19 will likely also experience depletion in serum levels of vitamin C as a direct result of the upregulation of the immune system to combat the infection

Colunga et al. suggested that oral vitamin C can be combined with oral Quercetin, an antiviral flavonoid, to improve Quercetin’s ability to block viral membrane fusion of SARS-CoV-2

high doses of 1-2 g/day of oral vitamin C could prevent other upper respiratory infections

It appears vitamin C supplementation by itself does not provide a striking benefit in preventing COVID-19 infection for those without a deficiency

Hiedra et al. were able to show decreases in inflammatory biomarkers, such as D-dimer and ferritin

some evidence to support that prophylactic use of vitamin C helps reduce the severity of respiratory infection symptoms once a subject has already been infected

oral vitamin C in combination with zinc provided the largest amount of antibody titers 42 days

linear relationship between days of vitamin C therapy and survival duration

other studies were unable to find any definitive improvement concerning therapy with vitamin C

Fowler et al. aimed to see if a high-dose vitamin C infusion would benefit patients affected by ARDS, but they were unable to conclude that vitamin C infusion, compared to a placebo, could decrease vascular inflammation and damage in ARDS

in a sample of 67 COVID-19-positive ICU patients, 82% of them displayed plasma vitamin C levels below 0.4 mg/dL

continuous vitamin C infusion at a rate of 60 mg/kg/day for four days decreased the need for mechanical ventilation and vasopressor use but had no significant effect on overall mortality

Carr et al. suggested that high-dose IV vitamin C is most effective when treating sepsis as septic patients receiving the normal daily recommendations through diet still showed decreased vitamin C levels

High-dose IV vitamin C treatment has also been shown by Kakodkar et al. to decrease syndecan-1, an endothelial glycocalyx that contributes to mortality in septic patients

combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure

combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure

reduced overall mortality

reduced overall mortality

propose the use for high-dose vitamin C to aid in the treatment of septic shock-induced hypotension

treatment of severe sepsis using a high dose (up to 200 mg/kg/day) of IV vitamin C was explored in phase I, a double-blind, randomized, placebo-controlled trial by Fowler et al. [75]. Their findings included a reduction in SOFA scores and decreased vascular injury compared to a placebo control group, all while showing minimal adverse side effects

Maintaining a daily intake of 75 and 100 mg for men and women, respectively, as recommended by the U.S. Institute of Medicine

surgery per se can promote cancer metastasis through a series of local and systemic events

surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers

After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear

infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients

Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis

Surgery-induced cancer metastasis has been well established in animal models

tumor cell dissemination, tumor-favoring immune responses, and neoangiogenesis

the surgical resection of primary tumors is beneficial is controversial

CTCs abruptly increase just after surgery

Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer

excessive glucocorticoids negatively modulate immune functions

immune surveillance against tumors is considered to be impaired by surgical stress

In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla

NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids

In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases

primary tumors may secrete angiogenic inhibitors as well as angiogenic activators

second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.

double-edged sword

HIF-1 in neutrophils plays a critical role in NETosis and bacteria-killing activity

neutrophils play various roles in the initiation and progression of cancer

NETosis

many inflammatory and neoplastic diseases

formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1

NETosis has been highlighted as an inflammatory event that promotes cancer metastasis

Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves

A series of these events is called NETosis.

neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins

innate immune response against infection

Neutrophils are the most abundant type of granulocytes, comprising 40–70% of all white blood cells

two types of NEToses, suicidal (or lytic) NETosis and vital NETosis

Suicidal NETosis mainly depends on the production of reactive oxygen species (ROS)

Since neutrophils die during this process, it is called suicidal NETosis.

vital NETosis

vital NETosis occurs independently of ROS production

Vital NETosis can be induced by Gram-negative bacteria. LPS

NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia

neutrophils actively undergo NETosis in the tumor microenvironment

Hypoxia

NETosis plays a pivotal role in noninfectious autoimmune diseases,

cytokines

tumor-derived proteases

tumor exosomes

NETosis generally actively progresses in the tumor microenvironment.

the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.

NETosis is a defense system to protect the body from invading pathogens

when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences

plasma levels of NETosis markers are elevated after major surgeries

local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases

NETs promote metastasis at multiple steps

NETs loosen the ECM and capillary wall to promote the intravasation of cancer cells

NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow

NETs promote the local invasion of cancer cells by degrading the extracellular matrix (ECM)

neutrophil elastase, matrix metalloproteinase 9, and cathepsin G

NETs also promote the intravasation of cancer cells

millions of tumor cells are released into the circulation every day,

NETs can wrap up CTCs with platelets

β1-integrin plays an important role in the interaction between CTCs and NETs

NET-platelet-CTC aggregates.

After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late

NETs are believed to participate in the reactivation of dormant cancer cells in metastatic regions

NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells