Group items matching

in title, tags, annotations or url

it is clear that E2 can stimulate antibody production by B cells, probably by inhibiting T cell suppression of B cells

In cycling women, the largest quantities of Ig were detected before ovulation

In contrast, E2 at high concentrations leads to a suppression of B-lymphocyte lineage precursors

E2 at periovulatory to pregnancy serum levels is able to stimulate antibody secretion under healthy conditions but also in autoimmune diseases, whereas similar serum levels of E2 lead to a suppression of bone marrow B cell lineage precursors

In chronic inflammatory disorders, where B cells play a decisive role, E2 would promote the disease when autoaggressive B cells are already present, whereas chronically elevated E2 would inhibit initiation of an autoimmune disease when no such B cells are available. This might be a good reason why particularly B cell-dependent diseases such as SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis appear in women in the reproductive years, predominantly, in the third or fourth decades of life

Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases

IFN-γ, IL-12, and TNF were allocated to Th1 reactions

IL-4, IL-5, and IL-10 to Th2 responses

antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17

no direct effects of estrogens on Th17 cells or IL-17 secretion have been described until now.

So-called Th17 cells producing IL-17 are the main T cells responsible for chronic inflammation.

Because IFN-γ has been allocated a Th17-inhibiting role (Fig. 1⇑), its increase by E2 at pregnancy doses and the E2-mediated inhibition of TNF must be viewed as a favorable effect in chronic inflammation

in humans and mice, E2 at periovulatory to pregnancy levels stimulates IL-4, IL-10, and IFN-γ but inhibits TNF from CD4+ T cells

In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity

increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response

secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels

The dichotomous effect of E2 on IL-1β and TNF at high and low concentrations is most probably due to inhibition of NF-κB at high concentrations

experiments with mouse and rat macroglial and microglial cells demonstrate that E2 at proestrus to pregnancy levels exerts neuroprotective effects by increasing TGF-β and by inhibiting iNOS and NO release, and reducing expression of proinflammatory cytokines and prostaglandin E2 production.

E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal

It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation

important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF

low E2 concentrations were demonstrated to have no or even stimulatory effects

This renders a woman in the postmenopausal phase to a more proinflammatory situation

most in vitro studies demonstrated a stimulatory effect of E2 on secretion of IL-4, IL-10, and TGF-β typically at periovulatory to pregnancy levels

E2 at periovulatory to pregnancy levels has an ameliorating effect on chronic inflammatory diseases as long as B cell-dependent immunity or an overshooting fibrotic tissue repair process do not play a crucial pathogenic role. However, when the B cell plays an important role, E2 might even stimulate the disease process as substantiated by flare-ups in SLE during pregnancy

Short-term administration of E2 at pregnancy levels was shown to induce an inflammatory response specific to the lateral prostate of the castrated male rat

dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice

These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health

all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.

The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.

feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight

mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique

Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles

the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's

The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months

mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed

blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics

previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling

Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice

Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls

xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls

Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism

One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells

Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation

insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes

Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders

Physiological feedback loops apparently exist between microbes, host hormones, and immunity

The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression

studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism

We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.

Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.

Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium

L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells

the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH

intense inflammatory cell infiltration, edematous lamina propria, and mucosal sloughing. However, the pathogenicity of B. hominis in human intestine has only been elucidated from case reports and a case series study

changes in the gut microbiota induced by antibiotics alter neuroinflammation and amyloid deposition in a mouse model of AD

Our data suggest that amyloid proteins in the microbiota are involved in the origination and maintenance of neurodegenerative disease.

exposure to bacteria producing a functional extracellular amyloid protein enhances aggregation of AS in brain neurons in aged rats and in muscle cells in nematodes

AS aggregates seed aggregation of tau

involvement of the vagus nerve in PD

microgliosis, astrogliosis and enhanced expression of IL-6, TLR2 and TNF in the brain following curli exposure suggest the occurrence of an enhanced local sterile inflammatory response to AS in the brain.

the immune system in both AD and PD have now been extensively established

TLR2 activation through exposure to bacterial amyloid is pathogenic

Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration

Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid

ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu

H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents

The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.

Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate

Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration

Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations

For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.

It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.

There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.

H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections

Neutrophils generate H2O2 from superoxide,

i.v. ascorbate is effective in some viral infections

H2O2 is toxic to hepatitis C

Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.

Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose

As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,

Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm

Human Burkitt's lymphoma cells

We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines

Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration

plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption

For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion

All tested normal cells were insensitive to 20 mM ascorbate.

Lymphoma cells were selected because of their sensitivity to ascorbate

As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death

Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure

In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate

Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate

Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.

extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.

H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death

Superoxide dismutase was not protective

Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate

For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased

Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes

There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity

H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media

ascorbate radical is a surrogate marker for H2O2 formation.

whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable

The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.

The occurrence of one predicted complication, oxalate kidney stones, is controversial

In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis

ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.

ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation

data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant

More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis

NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2

The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.

nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface

Inhibition of inducible Nitric Oxide Synthase (iNOS)

NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.

Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS

tolerance in the immune system that decreases the immune response to antigens on the tumors

Freund’s adjuvant

increase in kinases in these cells which phosphorylate serine, and tyrosine

responsible for activation of many growth factors and enzymes

phosphorylated amino acids suppress iNOS activity

Hexokinase II

Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system

Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.

Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10

These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation

Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth

Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients

IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV

IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production

nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis

early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop

later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity

cGMP is increased by NO

NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases

the greater the malignancies and the greater the metastatic potential of these tumors

The greater the NO production in many types of tumors,

gynecological

elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility

The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.

T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells

last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.

intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.

In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state

Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity

Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells

Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further

Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases

COX 2 inhibitors or all trans-retinoic acid

Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect

interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis

In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)

these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target

colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable

The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment

The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD

In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal

Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum

We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro

The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic

The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well

Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).

we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.

Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.

In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment

This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.

The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s

Lyme, Connecticut.

Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere

approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6

Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)

‘post-treatment Lyme disease syndrome’ (PTLDS)

host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic

inflammatory responses to residual antigens from dead organisms

residual tissue damage following pathogen clearance;

autoimmune responses, possibly elicited by antigenic mimicry

Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses

Ten male rhesus macaques

half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.

Minimal and focal lymphoplasmacytic inflammation

inflammation was observed in the leptomeninges overlying a section of temporal cerebral cortex

Minimal localized lymphoplasmacytic choroiditis

Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces

Inflammation was observed in 56% (5/9) of the NHPs irrespective of treatment group

For all animals, inflammation was reserved to perineural tissue

The treatment lasted 28 days

Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs

A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal

mild, multifocal lymphoplasmacytic inflammation was observed in one doxycycline-treated animal

three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures

10% to -20% of human patients treated

Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)

and the rapid clearance of dead spirochetes in a murine model

higher doses may be needed to combat neuroborreliosis

NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)

increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis

Another indirect route of SARS-CoV-2-induced NET production is platelet activation

When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis

In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.

SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors

Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause

NETosis and NETs are increasingly recognized as causes of vascular injury

SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation

NET formation may be caused by activated platelets rather than SARS-CoV-2 itself

NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.

early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses

NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease

NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation

“cytokine storm”

SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19

NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response

patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]

COVID-19 NETs may act as potential inducers for autoimmune responses

have weakened adaptive immunity as well as a high level of inflammation

tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised

NETs have also been shown to enhance macrophage pyroptosis in sepsis

facilitating an immunosuppressive microenvironment

persistent immunosuppression may result in bacterial co-infection or secondary infection

can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes

NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection

Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness

NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells

decreased E-cadherin (an epithelial marker) expression

COVID-19 also has a long-term influence on tumor progression

Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19

patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis

awaken cancer cells

NETs have been shown to change the tumor microenvironment

enhance tumor progression and metastasis

vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response

vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS

vitamin C may also inhibit NETosis and NET production in COVID-19

Metformin

Vitamin C

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