Coronavirus Infection – ACE2, UV, Tryptophan, And Hemoglobin Oxygen Binding

[Diokine]

Why do some disease patients have markedly elevated levels of ferritin?



One of the reported symptoms of initial coronavirus infection is bowel disturbances. ACE2 is a key enzyme of the renin-angotensin system, critical in maintaining vascular competence during various stresses. ACE2 is present in high amounts in the lungs, arteries, heart, kidney, and intestines. Intestinal depletion of ACE2 activity leads to defective amino acid transport, especially of the amino acid tryptophan. Severe deficiency of tryptophan and its associated actions on UV fluorescence and hemoglobin could critically impact oxygen absorption and delivery.

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ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.

Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.


Selected Microbes Light the Flame
The authors used a mouse model in which the gene that encodes angiotensin-converting enzyme 2 (ACE2) was knocked out (ACE2 knockout mice); ACE2, associated with a beneficial role in the cardiovascular system, digests angiotensin differently from its homolog ACE, the target in the renin-angiotensin system of ACE-inhibitor drugs used to lower blood pressure. The intestinal architecture did not unveil differences between the ACE2 knockout and wild-type animals. However, a chemical challenge induced a more pronounced inflammatory response in the colon of ACE2 knockout mice than in the wild-type controls. When wild-type mice were put on a protein-free diet, the chemically induced inflammatory lesions were as severe as those in the mutant mice, suggesting a role for nutrients in modulating the inflammatory response. In the ACE2 knockout mice, biodisposition of dietary amino acids was diminished, probably because the intestine and kidney of the mice do not express the transporter B0AT1, which mediates the uptake of neutral amino acids such as tryptophan. Lack of this essential amino acid in the diet markedly promoted inflammation after chemical irritation. Conversely, supplementing tryptophan as a dipeptide—a form of this amino acid that does not rely on B0AT1 for uptake by gut cells—ameliorated chemically induced inflammation. The authors concluded that gut depletion of tryptophan in the ACE2 knockout mice enhanced susceptibility to inflammation.

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So disruption of ACE2 in the gut is linked with altered biome, with its associated neurological implications, leading to inflammation and bowel disturbances. The specific loss of ACE2 leads to significantly disrupted amino acid absorption and processing, especially of the amino acid tryptophan.

Tryptophan specifically fluoresces under the influence of ultra-violet (UV) radiation, and is a critical component of Hemoglobin. The oxygen binding capacity of hemoglobin is enhanced by specific tryptophan binding sites and by UV light. Areas of local stress or infection fine tune their reaction via free tryptophan, increasing delivery of oxygen needed for immunodefensive reactions.

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Serotonin as a photoprotector of the oxygen-transporting function of hemoglobin
Oxygen-binding properties of human hemoglobin modified by UV-light (240-400 nm) in dose range (1.51 + 6.04) x 10(2) J/m2 together with serotonin (10(-4) M) has been studied by means of spectrophotometry. UV-radiation results in increase of the oxygen affinity of hemoglobin. Serotonin displays the photoprotective effect on the hemoglobin oxygen-transport function. Mechanisms of photoprotection of the biogenic amine are proposed for discussion.

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During infectious adaptive processes and other stressors, tryptophan handling is markedly altered. Tryptophan is typically bound to albumin, and alteration of these binding kinetics is critically important for managing subtle immune processes. Unbound tryptophan and its metabolites, controlled in part by local stressed environments, are critically important modulators of the immune response.

Tryptophan is mostly metabolized by either tryptophan hydroxylase (TPH,) generating serotonin, or tryptophan dioxygenase (TDO,) generating kynurenic acid. Stress or infection typically amplifies the activity of tryptophan dioxygenase. Importantly, tryptophan dioxygenase binds oxygen.

Infection with effective coronavirus depletes ACE2 and reduces its activity. This critically reduces amino acid absorption, especially tryptophan. Infection response processes increase cortisol, attenuate TPH activity, and increase TDO activity. Stress response alters albumin binding, releasing free tryptophan which is rapidly utilized by TDO, also consuming oxygen. Continued depletion of tryptophan decreases oxygen binding capacity of hemoglobin. This can progress to critical impairment of oxygen binding and delivery.

 

[Diokine]

Acute changes in glomerular albumin filtration during systemic infusion of angiotensin II – a multiphoton microscopy study
Antiproteinuric effects of ACE inhibitors have classically been assigned to their hemodynamic effects. Here we assess the acute effects of angiotensin II (AngII) on albumin glomerular sieving coefficient (GSC) in young anesthetized Munich Wister Froemter rats using intravital microscopy. Alexa-Fluor-594 albumin was injected i.v. and fluorescence intensities were determined in glomerular capillaries and in Bowman’s space (BS). The albumin GSC was then calculated according to: GSC = (intensity BS – intensity background)/(intensity capillaries – intensity background). GSC was measured before and during constant infusion of Ang II (27 ng/min/g BW). Baseline MAP averaged 90±4 mm Hg and stabilized at 130+/−11 mm Hg during AngII infusion. Capillary flow velocity was reduced during AngII infusion. Albumin GSC averaged 0.00038+/−.00009 at baseline and increased by 263+/−34% within 10 min after constant AngII infusion. During AngII infusion, de novo fluorescence was observed in the proximal tubules indicating uptake of filtered Alexa-albumin. These effects were abolished when a bolus of the AT1 antagonist losartan (9.9 μg/g BW) was injected prior to AngII. In control experiments (saline infusion) no significant changes in MAP, GSC or tubular fluorescence were observed. In summary, AngII causes rapid increases in glomerular albumin filtration, which are presumably mediated by angiotensin AT1 receptors.


Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A randomized clinical trial.
A significant 25% relative reduction in the albumin excretion rate occurred after 5 weeks of the 50-mg losartan dose, with further improvement over the subsequent 5 weeks with the 100-mg dose (relative reduction, 34%). In the losartan group, creatinine clearance did not improve and blood pressure decreased slightly. Side effects did not differ between treatment groups.


The potential use of albumin in COVID-19 patients
Albumin downregulates the expression of the ACE2 receptors (3) and has been shown to improve the ratio of arterial partial pressure of oxygen/fraction of inspired oxygen in patients with acute respiratory distress syndrome as soon as 24 hours after treatment and with an effect that persisted for at least seven days (4). Moreover, researchers who have studied the clinical characteristics of Covid-19 patients have reported again and again that lower serum albumin levels were associated with an increased risk of death, even to suggest that “albumin therapy might be a potential remedy”(5).

Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Decrease in lymphocyte count, serum total protein, serum albumin, high-density lipoprotein cholesterol (HDL-C), ApoA1, CD3+T%, and CD8+T% were found to be valuable in predicting the transition of COVID-19 from mild to severe illness.

 

[Diokine]

The reports of disrupted sense of taste and smell being an early indicator of infection progression may be associated with reductions in tryptophan and tryptophan hydryoxylase.

Mammalian Taste Bud Cells Utilize Extragemmal 5-Hydroxy-L-Tryptophan to Biosynthesize the Neurotransmitter Serotonin
Thus, our results suggest that the overall bodily 5-HTP level in the plasma and nervous system can regulate taste buds’ physiological function, and provide an important molecular mechanism connecting these peripheral taste organs with the circulatory and nervous systems.


Low plasma tryptophan is associated with olfactory function in healthy elderly community dwellers in Japan
Lower plasma Trp levels were associated with a decrease in olfactory function in functionally competent older individuals. Because olfactory dysfunction predicts age-related diseases, low plasma Trp levels may represent a clinical sign of disease risk in elderly people.

 

[Diokine]

Tryptophan, histidine, hemoglobin, lupus

Tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase (TDO and IDO) are oxygen dependent enzymes that catalyze the conversion of tryptophan to N-Formyl-L-kynurenine. This complex metabolism of tryptophan is critical for immune modulation. Tumor environments express high levels of TDO and IDO, rapidly consuming tryptophan. This is tied in with UV-fluorescence, which is used a complex signalling system to modulate immune system cytokines. Systemic lupus erythematosus is an autoimmune disease characterized by several symptoms, including rash. IDO and TDO activity are greatly increased in lupus.

Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season

Classically, exposure to ultraviolet radiation aggravates symptoms of lupus. Histidine is an essential amino acid associated with lupus. Upon exposure to UV radiation, unbound histidine is catabolized to urocanic acid, which is also associated with lupus.

Fluorescent light activates the immunomodulator cis-urocanic acid in vitro: implications for patients with systemic lupus erythematosus

Histidine and tryptophan share a imidazole and indole ring respectively, and this allows them to form a special chemical bond called a pi-bond. This special bond is very important for many processes in the body. Histidine especially is critically important in the oxygen-binding capacity of hemoglobin. The picture we have here is a complex, delicate balance of tryptophan and histidine in cellular processes. Disruptions of tryptophan metabolism, as in large scale immune activation, can disrupt histidine capacity as well.

Distal Histidine Stabilizes Bound O2 and Acts as a Gate for Ligand Entry in Both Subunits of Adult Human Hemoglobin*

In 1970, Perutz (1) proposed that the distal histidines located at the E7 helical positions,3 αHis-58 and βHis-63, play crucial structural roles for regulating both the affinities and rates of O2 binding to adult human hemoglobin (HbA).4 These ideas were based on the suggestion by Pauling (2) that His(E7) could stabilize bound O2 by donating a hydrogen bond to the partial negative charge on the superoxide-Fe(III)-like FeO2 complex and on the idea by Perutz and Mathews (3) that the distal histidine could also be acting as gate for ligand entry and exit. Studies of model heme compounds and naturally occurring globins with His(E7) replacements suggested strongly that the distal histidine also plays a key role in discrimination between O2 and CO binding (4,–,9).

Chloroquine disrupts immune catabolism of tryptophan

Chloroquine is an anti-malarial drug used in the treatment of lupus. While it has many mechanisms of action, one important one is its capacity to modify catabolism of tryptophan.

Antimalarial drug chloroquine counteracts activation of indoleamine (2,3)-dioxygenase activity in human PBMC

Antimalarial chloroquine is also used for the treatment of immune-mediated diseases. The interference of chloroquine with interferon-γ-induced tryptophan breakdown and neopterin production has been investigated in human peripheral blood mononuclear cells (PBMC) in vitro. Micromolar concentrations (2–50 μM) of chloroquine dose-dependently suppressed mitogen-induced tryptophan breakdown in PBMC but not in the myelomonocytic THP-1-Blue cell line, after 48 h of treatment. In stimulated PBMC, neopterin production was super-induced by 10 μM chloroquine, while it was significantly suppressed at a concentration of 50 μM. These anti-inflammatory effects may relate to the therapeutic benefit of chloroquine in inflammatory conditions and may widen the spectrum of its clinical applications.

Quinine is similar, and has similar actions on plasma tryptophan, though the specific action on IDO or TDO are not studied.

Quinine interactions with tryptophan and tyrosine in malaria patients, and implications for quinine responses in the clinical setting

Consistent with competition for uptake from plasma into cells, plasma tryptophan and tyrosine levels increased ≥2-fold during quinine therapy. Plasma quinine levels in individual plasma samples were significantly and positively correlated with tryptophan and tyrosine in the same samples. Control studies indicated no effect on phenylalanine. Chloroquine treatment of Plasmodium vivax-infected patients did not affect plasma tryptophan or tyrosine. During quinine treatment, plasma tryptophan was significantly lower (and quinine significantly higher) in patients experiencing adverse drug reactions.

I think one important mechanism of action of chloroquine in treating the severe immune response from coronavirus disease is to decrease the activity of TDO and IDO, increasing plasma levels of tryptophan. This has the action of increasing blood UV reactivity, stabilizing histidine bonding and promoting the oxygen binding capacity of hemoglobin.

 

[TheSir]

Hemoglobin has iron in it. Covid causes iron to be dumped from hemoglobin into the bloodstream, overburdening organs and glands.

Separation of iron and hemoglobin has another major effect of making oxygen unable to attach to hemoglobin and thus unable to get into cells, lowering body oxygenation. Lowered oxygenation is essentially the same as being physically unfit, so Covid is basically an unfitness simulator with a touch of iron toxicity. That's why people feel out of breath and fatigued even though being fine otherwise. Those with excellent oxygenation would experience the exact opposite: lightness of movement and endless energy.

You could say Covid is anti-peat: the virus.

 

[Diokine]

Is hypoxia a compensatory mechanism to reduce activity of TDO during excessive immune activation?

One concerning presentation of coronavirus disease is rapid decompensation and convulsions. The mechanisms for this have not been fully elucidated. Some degree of CNS involvement is apparent, but what are the major factors? Kynurenic acid is created from tryptophan and oxygen by TPO and IDO. Kynurenic acid itself is classically neuroprotective and anti-convulsive. During stress, inflammation, or immune reactions, microglia in the brain can catabolize kynurenic acid to quinolinic acid, a potent nuerotoxin which has been associated with seizures. This conversion to quinolinic acid is catalyzed by Kynurenine 3-monooxygenase, and requires oxygen. Treatment with hyperbaric oxygen is sometimes associated with seizures which have been linked to excessive production of quinolinic acid.

Tryptophan dioxygenase also requires oxygen. I hypothesize there is a compensatory feedback loop between arterial oxygen tension and TDO/IDO activation during systemic immune activation. Reduced oxygen tension lowers TDO/IDO activity, inversely hyperoxia increases activity. I suspect there may be a loss of feedback sensitivity leading to excessive consumption of O2, and I also suspect encouraging hyperoxia during severe immune challenge may be detrimental to recovery.

Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway
O2 •– SCAVENGING BY IDO – AN ANTIOXIDANT DEFENSE?

Increasing evidence suggests that cumulative oxidative tissue injury induced by reactive oxygen and nitrogen species contributes to degenerative or inflammatory processes such as ageing, cancer, arthritis, cataracts, neurological disorders (e.g. Alzheimer’s disease), diabetes mellitus, and atherosclerosis.193–195 To counteract the potentially damaging effects of reactive oxygen and nitrogen species, organisms possess a variety of co-operatively acting antioxidant defense mechanisms which consist of enzymes (e.g. superoxide dismutase, catalase, glutathione peroxidase), non-enzymatic, transition metal binding proteins (e.g. ferritin, transferrin, ceruloplasmin, metallothionein), and non-proteinaceous, small molecular weight antioxidants (e.g. vitamin C, bilirubin, α-tocopherol or ubiquinol-10). Several antioxidant defenses are up-regulated upon exposure of cells to oxidative stress and are also subject to control by cytokines (e.g. heme oxygenase196,197). Increased levels of O2 •– are toxic to mammalian cells and microbes. There is recent evidence that such toxicity is the result of oxidation of iron-sulfur clusters by O2 •–, resulting in release of Fe2+ that in the presence of H2 O2 catalyzes the formation of the highly reactive hydroxyl radical.198,199 Mitochondrial aconitase appears to be a sensitive and critical target for O2 •– in cells.200,201 O2 •– may also exhibit toxicity in a transition metal ion-independent fashion via its rapid reaction with • NO to form the strong oxidant peroxynitrite.202,203 As IDO scavenges O2 •– it has been proposed that the dioxygenase may represent an inducible, cytosolic antioxidant defense primarily under the control of IFNγ. 30,204,205 For this to be physiologically relevant, high concentrations of IDO would be required considering the rate constant of reaction of superoxide dismutase (SOD) with O2 •– is approximately 1000-fold greater than that exhibited by IDO (i.e. kSOD ~ 2 x 109 M–1s–1 versus kIDO ~ 2–8 x 106 M–1s–1).206 Indeed, in vivo induction of IDO by LPS in the lungs of rabbits, but not rats and mice,204,207 increased the resistance to paraquat- and oxygen-induced pulmonary damage.204 The species specificity of the protective effect was consistent with pulmonary IDO being induced to a 170-fold greater degree in rabbits than rats and mice.204 In support for O2 •– scavenging by IDO, addition of a SOD-inhibitor enhanced IDO activity 4-fold in lung slices of rabbits, but not rat and mice. Furthermore, paraquat and hyperoxia enhanced IDO activity in rabbit lungs 5-fold in the presence of the SOD inhibitor. These results suggest that IDO can be increased in vivo to a level sufficiently high to scavenge O2 •– and, thereby, exhibit antioxidant activity.204 The pathogenesis of influenza virus in lungs is associated with oxidative stress.155,208,209 Increased induction of IDO and other antioxidant enzymes (heme oxygenase-1, glutathione peroxidase and manganese SOD) have been reported in lungs of influenza-infected mice with progression of the disease.209 A recent study suggests that the time of increased heme oxygenase-1, but not IDO, activity coincides with decreased lung tissue damage in mice infected with influenza.209 It, therefore, appears that the extent to which IDO is induced may be species specific and determines whether the oxygenase represents an inducible antioxidant defense.

 

[Diokine]

It is very interesting to me the metaphorical connections between the organism response to infection and the global reaction we are witnessing. It is becoming apparent that the rate of death we are seeing is directly proportional to the aberrant reaction of immune response patterns, along with some of the care provided in hospitals. A competent organism has feedback mechanisms in place to limit the effect of reactionary patterns, thus preventing the excursion of the system beyond a point where competent reaction is possible.

Chronic adaptations to fungal infections, viral interference, gut inflammation, poor diet and nutrition, environmental poisons, and improper light hygiene render these systems unable to properly modulate. This excessive global immune activation we are seeing is the logical next step in the chain of derangement.

The key is to restore sensitivity, not encourage greater flux in a dysfunctional system.

 

[Diokine]

Hemoglobin has iron in it. Covid causes iron to be dumped from hemoglobin into the bloodstream, overburdening organs and glands.

The iron in hemoglobin is bound by what is called the proximal histidine - F8 residue, while bound oxygen is stabilized by the distal histidine E7. Loss of this binding would result in Fe2+ liberation. I think disruption in histidine - tryptophan association and loss of UV sensitvity may account for some of this.

 

[ecstatichamster]

people who died in the Wuhan paper had 3 times higher serum ferritin.

Also much higher WBC count.

 

[RealNeat]

The iron in hemoglobin is bound by what is called the proximal histidine - F8 residue, while bound oxygen is stabilized by the distal histidine E7. Loss of this binding would result in Fe2+ liberation. I think disruption in histidine - tryptophan association and loss of UV sensitvity may account for some of this.

Any benefit from these compounds which show efficacy for sickle cell anemia?

Sickle Cell Disease and Phenylketonuria (PKU): You May Have the Genes, But Your Diet Determines Your Symptoms

 

[Diokine]

Is there a link between tryptophan, eosinophilia-myalgia syndrome, and pulmonary insult?


Eosinophilia-myalgia syndrome is a rare condition sometimes associated with consumption of supplements containing different forms of tryptophan. Some of the symptoms are remarkably similar to “coronavirus disease,” specifically dry cough, fever, and dyspnea. I think this syndrome represents a critical alteration in tryptophan metabolism, with its effects on UV sensitivity and immune modulation. Unnatural and rare tryptophan (aromatic amino acid) metabolites may contribute to significant disruption or amplification of tryptophan-handling enzymes, which commonly presents with severe adverse pulmonary symptoms.



Dyspnea and Pulmonary Function in the L-Tryptophan-Associated Eosinophilia-Myalgia Syndrome

We reviewed the pulmonary history, dyspnea ratings, and pulmonary function test results in 16 patients with L-tryptophan-induced eosinophilia myalgia syndrome to determine the correlation between reported pulmonary complaints and pulmonary function abnormalities. All patients reported pulmonary symptoms. Dyspnea, seen in 14 of 16 (87 percent) patients, was the most common symptom. The severity of dyspnea was graded by the baseline dyspnea index and the oxygen cost diagram. Pulmonary function testing including maximal static inspiratory and expiratory pressures were measured. The DCO was diminished in 12 of 16 (75 percent) patients. The MSIP was decreased in seven out of ten (70 percent) and the MSEP was decreased in nine out of ten (90 percent) of those patients tested. There was a statistically significant correlation between the severity of dyspnea as graded by the BDI and OCD, and the decrease in DCO. These results and a review of the literature of the pulmonary manifestations of EMS lead us to conclude that patients with EMS have a high prevalence of dyspnea, and it appears to be caused by both lung parenchymal involvement, as well as respiratory muscle weakness.



Acute eosinophilic pulmonary disease associated with the ingestion of L-tryptophan-containing products.
A series of four patients with pulmonary infiltrates, pleural effusions, hypoxemia, peripheral eosinophilia, and symptoms of dyspnea, fatigue, and weakness is reported. Lung tissue obtained in three patients revealed interstitial pneumonitis, small-to-medium-vessel mixed-cell vasculitis, and alveolar exudate of histiocytes and eosinophils. All patients reported ingestion of L-tryptophan-containing products at a time when an association between L-tryptophan and the eosinophilia-myalgia syndrome was established. This clinical pattern of pulmonary involvement may be part of the continuum of the eosinophilia-myalgia syndrome. The pathophysiology of this syndrome and the relationship with the ingestion of L-tryptophan-containing products have not yet been identified.


Acute respiratory failure as a manifestation of eosinophilia-myalgia syndrome associated with L-tryptophan intake*
-A 61-year-old woman presented with a one-week history of progressive dyspnea, dry cough, and fever.
-Arterial blood gas analysis (room air): pH = 7.55; arterial oxygen tension = 53 mmHg; arterial carbon dioxide tension = 23 mmHg; peripheral oxygen saturation (SpO2) = 91%;

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Please note, this arterial oxygen tension would be considered critically low at this level of peripheral oxygen saturation. This is almost a defining characteristic of “coronavirus infection.”
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-Initial computed tomography scan of the chest (Figure 2): diffuse areas of consolidation in the left lung (with volumetric loss and air bronchograms), peripheral consolidations, and areas of ground-glass attenuation in the right lung;
-The patient was initially treated for severe community-acquired pneumonia, with antibiotic therapy (ceftriaxone and levofloxacin) and oxygen therapy. After one week, she still presented fever, hypoxemia, and dyspnea upon minimal exertion, without radiological improvement. There was an increase in eosinophilia in the blood (2670 cells/mm3, 16%), which, in conjunction with the pleural eosinophilia and eosinophilia in the BAL, motivated the treatment with 125 mg of methylprednisolone every 6 hours.



There is a link between eosinophilia-myalgia syndrome and toxic oil syndrome, a similarly rare condition that shares some of the same symptoms. These syndromes have been linked to various intermediate aromatic amino acid compounds. It is possible that association with different residues present on products of industrial contamination can seriously impact crucial portions of tryptophan metabolism.


3-(Phenylamino)alanine, a novel aniline-derived amino acid associated with the eosinophilia-myalgia syndrome: a link to the toxic oil syndrome?


While the mechanisms still aren’t well defined, I think the evidence is clear that disruptions in tryptophan metabolism, initiated by viral infection, environmental factors, stress, or chronic immune activation, can progress to severe respiratory distress.

 

[Diokine]

@Tarmander


Could tryptophan metabolites from the gut microbiome contribute to severe pulmonary complications?



The clinical presentations of persons supposedly infected with and suffering from coronavirus disease are varied, but the most sensational ones include reports of severe hypoxia, hemological disturbances, and pulmonary injury, sometimes leading to death. The reasons behind why some people are infected and apparently experience no symptoms, and why some people progress to life-threating respiratory distress, are not clear. Some of the reported symptoms and clinical finding are similar to symptoms reported in eosinophilia-myalgia syndrome, which similarly presents with widely varied symptoms. The respiratory symptoms in particular, are strikingly similar in many ways. This syndrome has been associated with intake of L-tryptophan from a single source, and specific contaminants have been closely linked to the development of the disease.


Association of tryptophan with respiratory distress is not new, and has also been associated in ruminant cattle. Acute bovine pulmonary edema and emphysema, also called Fog Fever, is associated with an abrupt change in pasture and feeding conditions, specifically movement to pasture with high levels of green grass. This green grass is especially high in tryptophan, and the bacteria in the rumen of the cattle metabolize the tryptophan to indoleacetic acid and then to 3-methylindole (skatole) which has been associated with the severe pulmonary edema and respiratory distress seen.


Prevention of tryptophan-induced acute bovine pulmonary oedema and emphysema (fog fever).
The pathogenesis of acute bovine pulmonary oedema and emphysema (ABPE) is related to the ruminal formation of 3-methylindole (3MI) from L-tryptophan (TRP), a naturally occurring amino acid and constituent of forage. The objectives of the present study were to determine whether monensin and lasalocid, both polyether antibiotics, were effective in reducing ruminal conversion of TRP to 3MI in vivo and to confirm that reduction in ruminal conversion of TRP to 3MI prevented tryptophan induced ABPE. Sixteen mature Hereford cows were assigned to one of four groups and given TRP to induce ABPE. Group 1 was given 100 mg monensin orally twice daily starting one day before and ending four days after TRP dosing. Group 2 was given 200 mg monensin once daily and group 3 was given 100 mg lasalocid twice daily. Group 4, the control, was given only TRP without further treatment. All control cows developed clinical signs of respiratory disease and lesions of ABPE; one control cow died of ABPE. Mean ruminal 3MI concentrations in control cows reached a peak of 36.4 micrograms per ml. Clinical signs of pulmonary disease appeared in two cows treated with lasalocid and one died. Mean ruminal 3MI in these animals peaked at 38.8 micrograms per ml. No clinical signs of respiratory disease were observed in any of the monensin treated cows and at necropsy there were no pulmonary lesions of ABPE. Mean ruminal 3MI concentrations in monensin treated cows did not exceed 8.9 micrograms per ml. In all groups plasma 3MI concentrations generally reflected ruminal 3MI concentrations but at lower concentrations. The results of this experiment demonstrate that reduction in ruminal 3MI formation by monensin prevents tryptophan induced ABPE.


Coronavirus infection requires the interaction of what is termed the “spike” protein, a tryptophan rich residue which binds to the ACE2 receptor located in the cellular membrane. These ACE2 receptors have been studied to form dimers with B0AT1, a sodium dependent transporter of amino acids, required for intestinal uptake of tryptophan. Association of coronavirus spike protein with ACE2 – B0AT1 complexes allows for infection of a cell.


Structure of dimeric full-length human ACE2 in complex with B0AT1
Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV), directly interacting with the spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019- nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. B0AT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with B0AT1. The complex, assembled as a dimer of ACE2-B0AT1 heterodimers, exhibits open and closed conformations due to the shifts of the peptidase domains (PDs) of ACE2. A newly resolved Collectrin-like domain (CLD) on ACE2 mediates homodimerization. Structural modelling suggests that the ACE2-B0AT1 complex can bind two S proteins simultaneously, providing important clues to the molecular basis for coronavirus recognition and infection.



Disruption of this ACE2 – B0AT1 complex in the gut by coronavirus interference would make the intestines unable to transport tryptophan into circulation. This has the effect of lowering serum tryptophan and increasing urinary excretion of tryptophan via effects on the kidneys. Importantly, this has the effect of introducing unabsorbed tryptophan and other amino acids into the colonic lumen, subjecting them to further degradation by bacterial and fungal species. Depending on the species involved and state of colonic health, several toxic tryptophan degradation products can be produced, including 3-methylindole.


In conclusion, disruption of ACE2 – B0AT1 complex by coronavirus spike protein interference can increase free tryptophan levels in the colon, leading to production of toxic degradation products. These toxic products have been directly linked to severe respiratory complications in both humans and cattle. The vast differences in colonic health and microbiome compositions in the population could explain the differences in symptoms seen. Additionally, this mechanism is not dependent on infection from coronavirus, and in fact many causes could contribute to similar types of disease. This evidence also provides a link for the mechanism of a maladaptive microbiome being a principle cause of manifold disease, from diabetes, autoimmune conditions, and chronic fatigue, to cancer, Alzheimer's, and dementia.


Supplemental;
PUTATIVE MECHANISMS OF TOXICITY OF 3-METHYLINDOLE: From Free Radical to Pneumotoxicosis

 

[Tarmander]

@Tarmander


Could tryptophan metabolites from the gut microbiome contribute to severe pulmonary complications?



The clinical presentations of persons supposedly infected with and suffering from coronavirus disease are varied, but the most sensational ones include reports of severe hypoxia, hemological disturbances, and pulmonary injury, sometimes leading to death. The reasons behind why some people are infected and apparently experience no symptoms, and why some people progress to life-threating respiratory distress, are not clear. Some of the reported symptoms and clinical finding are similar to symptoms reported in eosinophilia-myalgia syndrome, which similarly presents with widely varied symptoms. The respiratory symptoms in particular, are strikingly similar in many ways. This syndrome has been associated with intake of L-tryptophan from a single source, and specific contaminants have been closely linked to the development of the disease.


Association of tryptophan with respiratory distress is not new, and has also been associated in ruminant cattle. Acute bovine pulmonary edema and emphysema, also called Fog Fever, is associated with an abrupt change in pasture and feeding conditions, specifically movement to pasture with high levels of green grass. This green grass is especially high in tryptophan, and the bacteria in the rumen of the cattle metabolize the tryptophan to indoleacetic acid and then to 3-methylindole (skatole) which has been associated with the severe pulmonary edema and respiratory distress seen.


Prevention of tryptophan-induced acute bovine pulmonary oedema and emphysema (fog fever).
The pathogenesis of acute bovine pulmonary oedema and emphysema (ABPE) is related to the ruminal formation of 3-methylindole (3MI) from L-tryptophan (TRP), a naturally occurring amino acid and constituent of forage. The objectives of the present study were to determine whether monensin and lasalocid, both polyether antibiotics, were effective in reducing ruminal conversion of TRP to 3MI in vivo and to confirm that reduction in ruminal conversion of TRP to 3MI prevented tryptophan induced ABPE. Sixteen mature Hereford cows were assigned to one of four groups and given TRP to induce ABPE. Group 1 was given 100 mg monensin orally twice daily starting one day before and ending four days after TRP dosing. Group 2 was given 200 mg monensin once daily and group 3 was given 100 mg lasalocid twice daily. Group 4, the control, was given only TRP without further treatment. All control cows developed clinical signs of respiratory disease and lesions of ABPE; one control cow died of ABPE. Mean ruminal 3MI concentrations in control cows reached a peak of 36.4 micrograms per ml. Clinical signs of pulmonary disease appeared in two cows treated with lasalocid and one died. Mean ruminal 3MI in these animals peaked at 38.8 micrograms per ml. No clinical signs of respiratory disease were observed in any of the monensin treated cows and at necropsy there were no pulmonary lesions of ABPE. Mean ruminal 3MI concentrations in monensin treated cows did not exceed 8.9 micrograms per ml. In all groups plasma 3MI concentrations generally reflected ruminal 3MI concentrations but at lower concentrations. The results of this experiment demonstrate that reduction in ruminal 3MI formation by monensin prevents tryptophan induced ABPE.


Coronavirus infection requires the interaction of what is termed the “spike” protein, a tryptophan rich residue which binds to the ACE2 receptor located in the cellular membrane. These ACE2 receptors have been studied to form dimers with B0AT1, a sodium dependent transporter of amino acids, required for intestinal uptake of tryptophan. Association of coronavirus spike protein with ACE2 – B0AT1 complexes allows for infection of a cell.


Structure of dimeric full-length human ACE2 in complex with B0AT1
Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV), directly interacting with the spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019- nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. B0AT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with B0AT1. The complex, assembled as a dimer of ACE2-B0AT1 heterodimers, exhibits open and closed conformations due to the shifts of the peptidase domains (PDs) of ACE2. A newly resolved Collectrin-like domain (CLD) on ACE2 mediates homodimerization. Structural modelling suggests that the ACE2-B0AT1 complex can bind two S proteins simultaneously, providing important clues to the molecular basis for coronavirus recognition and infection.



Disruption of this ACE2 – B0AT1 complex in the gut by coronavirus interference would make the intestines unable to transport tryptophan into circulation. This has the effect of lowering serum tryptophan and increasing urinary excretion of tryptophan via effects on the kidneys. Importantly, this has the effect of introducing unabsorbed tryptophan and other amino acids into the colonic lumen, subjecting them to further degradation by bacterial and fungal species. Depending on the species involved and state of colonic health, several toxic tryptophan degradation products can be produced, including 3-methylindole.


In conclusion, disruption of ACE2 – B0AT1 complex by coronavirus spike protein interference can increase free tryptophan levels in the colon, leading to production of toxic degradation products. These toxic products have been directly linked to severe respiratory complications in both humans and cattle. The vast differences in colonic health and microbiome compositions in the population could explain the differences in symptoms seen. Additionally, this mechanism is not dependent on infection from coronavirus, and in fact many causes could contribute to similar types of disease. This evidence also provides a link for the mechanism of a maladaptive microbiome being a principle cause of manifold disease, from diabetes, autoimmune conditions, and chronic fatigue, to cancer, Alzheimer's, and dementia.


Supplemental;
PUTATIVE MECHANISMS OF TOXICITY OF 3-METHYLINDOLE: From Free Radical to Pneumotoxicosis

pretty cool. Thanks for the heads up

 

[lvysaur]

Any benefit from these compounds which show efficacy for sickle cell anemia?

Sickle Cell Disease and Phenylketonuria (PKU): You May Have the Genes, But Your Diet Determines Your Symptoms

Really interesting stuff!

So the sickle cell trait, the yam thiocyanate, and malaria all evolved together. So it seems like the sickle cell probably would have been more abundant in an earlier time, before humans started farming yams. As yams became important, the trait became useless but not critically fatal--unless someone wasn't eating yams.

 

[Diokine]

@RealNeat

Any benefit from these compounds which show efficacy for sickle cell anemia?

Sickle Cell Disease and Phenylketonuria (PKU): You May Have the Genes, But Your Diet Determines Your Symptoms

This hypothesis has led to very interesting research, thank you. I suspect that the sickle cell trait may have developed in part as a result of chronically reduced tryptophan availability for incorporation into erythrocytes. This change in morphology may have conferred resistance against infection with malarial parasites.



Does infection with malaria parasite influence tryptophan metabolism?

Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria.


Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c+ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation
Tryptophan concentrations decreased at peak infection (mean, 28.5 ± 10.0 μmol/liter versus 47.3 ± 0.1 μmol/liter at baseline; P = 0.003) and further declined at 24 (21.2 ± 6.0 μmol/liter; P = 0.0006) and 48 (22.8 ± 8.6 μmol/liter; P = 0.002) h after treatment


Malaria parasite induces tryptophan-related immune suppression in mice.
Plasmodium spp. cause the worst parasitic diseases in humans and evade host immunity in complicated ways. Activated catabolism of tryptophan in dendritic cells is thought to suppress immunity, which is mediated by an inducible rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3 dioxygenase (IDO), via both tryptophan depletion and production of toxic metabolites. In various infections, including malaria, IDO is known to be activated but its biological significance is unclear; therefore, we investigated whether malaria parasites induce IDO to suppress host immune responses. We found that enzymatic activity of IDO was elevated systematically in our mouse malaria model, and was abolished by in vivo IDO inhibition with 1-methyl tryptophan. Experimental infection with Plasmodium yoelii showed that IDO inhibition slightly suppressed parasite density in association with enhanced proliferation and IFN-gamma production by CD4+ T cells in response to malaria parasites. Our observations suggest that induction of IDO is one of the immune mechanisms of malaria parasites.


What effects do malaria parasite infection have on erythrocyte morphology?


The role of the red blood cell in host defence against falciparum malaria: an expanding repertoire of evolutionary alterations
Second, the HbAS genotype decreases the adhesive properties of parasitized RBCs mediated through P. falciparum erythrocyte membrane protein 1 (PfEMP1). Altered cytoskeletal properties of HbS‐containing RBCs have been hypothesized to impact parasite protein trafficking to the RBC surface (Cyrklaff et al, 2011; Kilian et al, 2015), and thereby reduce cytoadhesion (Cholera et al, 2008). Third, the HbAS genotype has an effect on the immune system. It is postulated that reduced parasite invasion and growth in HbAS RBCs indirectly gives the immune system time to increase its activity and more effectively combat infection. There is also evidence to suggest that the HbAS genotype favourably alters the immune response directly by increasing phagocytosis of infected RBCs, or possibly through influencing the induction of inflammatory cytokines following endothelial activation (due to altered cytoadhesion properties)

Tryptophan-rich domains of Plasmodium falciparum SURFIN4.2 and Plasmodium vivax PvSTP2 interact with membrane skeleton of red blood cell

Plasmodium falciparum dramatically alters the morphology and properties of the infected red blood cells (iRBCs). A large group of exported proteins participate in these parasite-host interactions occurring at the iRBC membrane skeleton. SURFIN4.2 is one of iRBC surface protein that belongs to surface-associated interspersed protein (SURFIN) family. Although the intracellular tryptophan-rich domain (WRD) was proposed to be important for the translocation of SURFINs from Maurer’s clefts to iRBC surface, the molecular basis of this observation has yet to be defined.

Among P. falciparum proteins that contain tryptophan-rich residues are the SURFIN family proteins. SURFIN4.2 is one of the iRBC-exported proteins and is encoded by a small family of surface-associated interspersed (surf) genes consisting of 10 members in the P. falciparum genome [14]. Plasmodium falciparum SURFINs form one clade with the Plasmodium vivax subtelomeric transmembrane proteins (PvSTPs) [15]. The intracellular tryptophan-rich domains (WRDs) of SURFIN/PvSTP are related to the sequences of the intracellular regions of PfEMP1 and Pf332 [14]. SURFIN4.2 localizes to Maurer’s clefts and has been reported to be trafficked to the surface of the iRBC together with RIFIN and PfEMP1 [14]. Thus, SURFIN/PvSTP proteins are potential immune targets and malaria vaccine candidates [16, 17]. For another member SURFIN4.1, the N-terminal 50 amino acids, transmembrane domain, and adjacent intracellular region contain sufficient information for recruiting a recombinant protein into the classical ER/Golgi secretory pathway, and for efficient translocation across the PVM to the Maurer’s clefts [18]. The mechanism by which SURFIN proteins are anchored into the iRBC membrane has yet to be elucidated, but recombinant SURFIN4.2 possessing the intracellular WRD can be cleaved by surface treatment of iRBC with proteinase K, suggesting the WRD of SURFIN4.2 may be responsible for transport of the protein from Maurer’s clefts to the iRBC membrane [19]. Interestingly, intracellular region of Pf332 that is homologous to the SURFIN WRD is found to associate with actin filaments of RBC membrane skeleton [12]. In the case of PfEMP1, the intracellular VARC region (also known as the acidic terminal sequence, ATS) having homology with WRD binds to host spectrin-actin [4, 20, 21]. Thus, this study aimed to identify host RBC proteins that may associate with SURFIN4.2 WRD. This could provide an important insight into the molecular basis of trafficking of SURFIN proteins from Maurer’s cleft to iRBC surface. This study revealed binding of WRDs of SURFIN4.2 and PvSTP2 to RBC membrane skeleton proteins, and interactions between the second WRD of SURFIN4.2 with actin and spectrin.

Does tryptophan have any effect on sickle cell erythrocytes?

Liposome-loaded phenylalanine or tryptophan as sickling inhibitor: a possible therapy for sickle cell disease.
Phenylalanine or tryptophan entrapped in small unilamellar liposomes was used to transport Phe or Trp across the red blood cell membrane. The incorporation of Phe or Trp into RBCs via liposomes markedly inhibited and reversed the in vitro sickling of deoxy Hb S. Furthermore, normal and SS RBCs loaded with Phe or Trp did not exhibit significant change in osmotic fragility, mechanical fragility, autohemolysis, and glycolysis when compared to untreated RBCs. In addition, the oxygen affinity measured as the P50 and concentrations of 2,3-DPG and ATP were not affected by the incorporation of Phe or Trp into AA or SS RBCs. These results demonstrate that this liposomal transport system which transferred Phe and Trp into intact RBCs did not have any adverse effect on RBC metabolism and function, and may have therapeutic implications in the treatment of sickle cell disease.


Inhibition of sickle hemoglobin gelation by amino acids and related compounds.
The effects of amino acids, several aromatic compounds, and peptides on the gelation and solubility of deoxyhemoglobin S have been studied. The aromatic amino acids (tryptophan, phenylalanine, and possibly tyrosine) significantly inhibited the rate of gel formation and increased solubility. The dipeptide L-Thr-L-Phe, the tripeptide L-Lys-L-Phe-L-Phe, and various phenylalanine analogues (hydrocinnamic acid, phenethylamine, benzamine, and amphetamine) also inhibited gelation. However, aromaticity is not a sufficient condition for inhibiting gelation as shown by the fact that several aromatic compounds (acetylsalicylic acid, salicyclic acid, aniline, and phenol) enhanced gelation. Surprisingly, several oligopeptides (betaS1--12, betaS4--8, betaS3--13, and betaS4--10) also enhanced gelation. All of these additives follow the supersaturation relationship that the delay time for gelation is proportional to the ratio of the total hemoglobin concentration to the solubility of deoxyhemoglobin S to the nth power (n approximately 35). A possible mechanism for the action of these inhibitors is considered in terms of a specific site of interaction on the hemoglobin molecule. Although none of these compounds may prove to be efficacious in treatment of sickle cell anemia, they should yield information about the structure and process of formation of the deoxyhemoglobin S gel.

Hemoglobin S antigelation agents based on 5-bromotryptophan with potential for sickle cell anemia.
5-Bromotryptophan (5-BrTrp) is the most potent amino acid derivative reported in the literature to inhibit the gelation of hemoglobin S (from sickle cell anemia patients). Trp-Trp is also more potent than Trp as an antigelation agent. Therefore, we have prepared a series of dipeptides containing 5-BrTrp and evaluated the antigelation activity. 5-BrTrp-5-BrTrp is the most potent, i.e., 5.9 times the activity of Trp, followed by 5-BrTrp-Trp and then Trp-5-BrTrp. This improved antigelation potency for 5-BrTrp-5-BrTrp and 5-BrTrp-Trp is very significant and will be pursued further as lead compounds with potential for sickle cell anemia.

What effect does thiocyanate have?

While this is speculation at this point, I believe that thiocyanate may act to prevent protein aggregation, which helps to stablize sickle-trait hemoglobin. I suspect that this is part of tryptophans original role, in concert with UV radiation. Thiocyanate may act to reduce oxidative modification of amino-acid residues and may act to directly stabilize amino-acid complexes. This would support the use of other thiols such as N-acetyl-cysteine and lipoic acid.
@Terma

Factors affecting the physical stability (aggregation) of peptide therapeutics
2.7.6. Antioxidants and chelators
Peptide oxidation, which was described earlier in this review, is a major cause of chemical instability and also sometimes linked to physical stability. Amino acids such as methionine, cysteine, histidine, tyrosine and tryptophan in peptides are susceptible to oxidation under some conditions encountered during pharmaceutical development. Therefore, a number of antioxidants are used as excipients including ascorbic acid [191]. It has also been reported that sodium thiosulfate, methionine, catalase or platinum, and the chelating agents EDTA and DTPA are also effective in reducing the oxidation of biologics

The role of thiols and disulfides in protein chemical and physical stability

Inhibition effect of thiol-type antioxidants on protein oxidative aggregation caused by free radicals

 

[Regina]

Any benefit from these compounds which show efficacy for sickle cell anemia?

Sickle Cell Disease and Phenylketonuria (PKU): You May Have the Genes, But Your Diet Determines Your Symptoms

so cool. Really neat find.

 

[Terma]

Yeah your articles are super interesting, I just have to find time to go through. Quick mention for lupus because it's both high IDO but eventually they develop problems with KMO due to NADPH deficiency so kynurenine accumulates, wrote about this other threads, meaning if you thought this resembled lupus in any way then NAC is a kind of backdoor solution to prevent immune overactivation. One option nobody talks about is pharmacological pre-formed kynurenine supplementation or i.v. I forget (requiring some NADPH) to avoid serotonin synthesis, but no one's gonna do that.

 

[Peater Piper]

I found this through a google search, where it's speculated that hydroxychloroquine requires adequate zinc levels in order to be effective for treating COVID-19. I don't know enough about the topic to judge its validity:

Coronavirus Cases: Turning The Corner? | Peak Prosperity

 

[RealNeat]

What does all this mean for iron. Im still not super clear on the application of this. Iron balance is a tricky thing. Eating it specifically can cause a lot of damage since everything is also "contaminated" with it. I'm sure low iron really isn't the issue but rather things like improper vitamin A and copper along with ceruloplasmin. If iron is really the issue, then would blood letting help or hurt? Also what about blood transfusions and hyperbaric oxygen chambers?

 

[Diokine]

Does inflammatory bowel disease have any correlation between serious adverse pulmonary symptoms in coronavirus disease?





Uneventful course in IBD patients during SARS-CoV-2 outbreak in northern Italy

Based on our evaluation, as of March 23nd, we conclude that none of our patients with IBD was affected by a complicated SARS-CoV-2 related pneumonia. All our patients were advised to continue their current immunosuppressive regimen,. These findings warrant further investigation, to confirm our preliminary findings and allow implementing guidelines on the management of these patients during the SARS-CoV-2 global pandemic.

While data as of the publication of this article, April 13, 2020, is scare, some evidence is supporting the idea that patients either under treatment for or experiencing inflammatory bowel disease (IBD) have limited pulmonary symptoms. The mechanism for this hypothetical is currently unexamined.

Inflammatory bowel disease represents a complex change in immune regulation of bowel tissue, typically indicated by disruptions in inflammatory remediation and an accommodation towards persistent inflammatory states. Hypoxa-inducible factor 1, tryptophan, and vascular-endothelial growth factor patterns in those experiencing IBD point to a picture of sustained hypoxic environments within bowel tissue. I hypothesize that systemic accommodations to these hypoxic factors in patients with chronic IBD induce a state of resistance to catastrophic endothelial disruption by sudden changes in tryptophan catabolism and vascular homeostasis, progressing to severe cardiopulmonary presentation. In addition, some of the treatments for IBD may confer resistance through similar mechanisms.

Bowel injury results in inflammation. Chronic unremediated inflammation increases vascular permeability through increases in VEGF and HIF-1. This is associated with increases in expression of indoleamine-dioxygenase, an enzyme involved in immune modulation and the catabolism of tryptophan. Systemically, this represents an increase in vascular permeability and an increase in angiogenesis. Eventually, a quasi-equilibriated state is reached to allow the organism to maintain critical oxygenation. However, this comes at the expense of vascular competence. The specific mechanism for this hypothesis is not well examined, but fatigue in transient receptor potential receptors is one explanation. Fatigue in this system would render the endothelial network less responsive to the stimulus of hyper-activation of the immune response, which can lead to catastrophic vascular decompensation.


Specific Features of Vascular Endothelium in Patients with Severe Forms of Inflammatory Bowel Diseases

It is determined that, in IBD patients, endothelium dysfunction is manifested in an increase in the VEGF and DEC levels. The indicators of endothelial dysfunction are shown to be directly correlated with the serum markers of systemic inflammation. Therefore, VEGF and DEC values can be used not only as criteria for assessing the intensity of IBD, but also as predictors of a complicated disease course.

Vascular Endothelial Dysfunction in Inflammatory Bowel Diseases: Pharmacological and Nonpharmacological Targets

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are chronic inflammatory conditions involving primarily the gastrointestinal tract. However, they may be also associated with systemic manifestations and comorbidities. The relationship between chronic inflammation and endothelial dysfunction has been extensively demonstrated. Mucosal immunity and gastrointestinal physiology are modified in inflammatory bowel diseases, and these modifications are mainly sustained by alterations of endothelial function. The key elements involved in this process are cytokines, inflammatory cells, growth factors, nitric oxide, endothelial adhesion molecules, and coagulation cascade factors.

Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis, assessment and implications

Endothelial dysfunction is considered one of the etiological factors of inflammatory bowel disease (IBD). An inflammatory process leads to functional and structural changes in the vascular endothelium. An increase of leukocyte adhesiveness and leukocyte diapedesis, as well as an increased vascular smooth muscle tone and procoagulant activity is observed. Structural changes of the vascular endothelium comprise as well capillary and venule remodeling and proliferation of endothelial cells. Hypoxia in the inflammatory area stimulates angiogenesis by up-regulation of vascular endothelial growth factor, fibroblast growth factor and tumor necrosis factor-α. Inflammatory mediators also alter the lymphatic vessel function and impair lymph flow, exacerbating tissue edema and accumulation of dead cells and bacteria.

Markers of Hypoxia Correlate With Histologic and Endoscopic Severity of Colitis in Inflammatory Bowel Disease

HIF1α and metabolic reprogramming in inflammation

Hypoxia-inducible factor as an angiogenic master switch




What are the vascular implications of coronavirus disease?



Besides sensational serious adverse pulmonary symptoms, coronavirus disease presents with substantial evidence of endothelial disruption, including significant hematological disturbances and coagulopathy, including embolisms. I think abrupt changes in metabolism of tryptophan can explain this. Through various mechanisms, tryptophan and its catabolic products can induce significant changes in vascular competence. Modification of transient receptor potential (TRP) channels in endothelial cells is capable of causing catastrophic permeability, in the case of sepsis or other critical illness – leading to death. Specific tryptophan products are capable of augmenting or reversing these sequelae.


Is COVID-19 an endothelial disease? Clinical and basic evidence

The symptoms most commonly reported by patients affected by coronavirus disease 2019 (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g. high blood pressure, thrombosis, pulmonary embolism) seem to suggest that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ of COVID-19.

Roles of transient receptor potential channels in regulation of vascular and epithelial barriers

Transient receptor potential (TRP) channels are a ubiquitously expressed multi-family group of cation channels that are critical to signaling events in many tissues. Their roles have been documented in many physiologic and pathologic conditions. Nevertheless, direct studies of their roles in maintain barrier function in endothelial and epithelia are relatively infrequent. This seems somewhat surprising considering that calcium ion concentrations are known to regulate barrier function. This short review provides an introduction to TRP channels and reviews some of the work in which investigators directly studied the role of TRP channels in endothelial permeability to electric current, solute, or leukocytes during the inflammatory response.

Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice

Sepsis is characterized by systemic inflammation, edema formation and hypo-perfusion leading to organ dysfunction and ultimately death. Activation of the transient receptor potential vanilloid type 4 (TRPV4) channel is associated with edema formation and circulatory collapse. Here, we show that TRPV4 channels are involved in the hyper-inflammatory response and mortality associated with sepsis. Pharmacological inhibition of TRPV4 channels in mice reduced mortality in lipopolysaccharide and cecal-ligation-and-puncture models of sepsis, but not in a tumor necrosis factor-α (TNFα)-induced sepsis model. These protective effects of TRPV4 channel inhibition were attributable to prevention of the sepsis-induced surge of a broad spectrum of pro-inflammatory cytokines, including TNFα, interleukin (IL)-1 and IL-6 and subsequent preservation of endothelial cell function, including Ca2+ signaling, integrity and endothelium-dependent vasodilation. These results suggest that TRPV4 antagonists may be of therapeutic utility in the management of sepsis.

Structural mechanisms of transient receptor potential ion channels

Accelerated Tryptophan Degradation Predicts Poor Survival in Trauma and Sepsis Patients

We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients.

Regulation of Vascular Tone and Blood Pressure by a Tryptophan-Derived Tricyclic Hydroperoxide

In vitro, cis-WOOH but not trans-WOOH oxidizes protein kinase G1α (PKG1α) to a dimer in a reaction dependent on Cys42. Similarly, exposure of endothelium-denuded arteries to cis-WOOH dimerizes PKG1α. Such cis-WOOH-induced PKG1α dimerization is associated with arterial relaxation, whereas arteries from “redox dead” PKG1α-C42S knock-in mice are refractory to relaxation by cis-WOOH. Moreover, Trp-induced relaxation of IDO1-expressing and endothelium-intact arteries depends on PKG1α-Cys42 as corresponding segments from PKG1α-C42S knock-in mice do not relax, and it is attenuated by pretreatment with PEG-catalase. Together, our data indicate that in ‘inflamed arteries’, endothelial IDO1/H2O2 generate light (i.e., 1O2) in a dark reaction. This results in formation of a tricyclic Trp-derived hydroperoxide that signals relaxation via oxidative activation of PKG1α in vascular smooth muscle cells.

Protein kinase G oxidation is a major cause of injury during sepsis

Sepsis is a common life-threatening clinical syndrome involving complications as a result of severe infection. A cardinal feature of sepsis is inflammation that results in oxidative stress. Sepsis in wild-type mice induced oxidative activation of cGMP-dependent protein kinase 1 alpha (PKG Iα), which increased blood vessel dilation and permeability, and also lowered cardiac output. These responses are typical features of sepsis and their combined effect is a lowering of blood pressure. This hypotension, a hallmark of sepsis, resulted in underperfusion of end organs, resulting in their damage. A central role for PKG Iα oxidative activation in injury is supported by oxidation-resistant Cys42Ser PKG Iα knock-in mice being markedly protected from these clinical indices of injury during sepsis. We conclude that oxidative activation of PKG Iα is a key mediator of hypotension and consequential organ injury during sepsis.

What are the effects of some tryptophan metabolites on vascular competence?


Oxidation of protein kinase G by tryptophan-derived oxidation products is likely one major factor in progression of endothelial disruption and increased risk of death. Some products of tryptophan metabolism appear to exert potent endothelial effects, and it is apparent that study of this system is critical to understanding serious illness that may threaten the vascular system.

Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

We found that conditioned medium of endothelial cells inhibited cyclooxgenase-2 and interleukin-6 expression in macrophages stimulated with lipopolysaccharide. Analysis of conditioned medium extracts by liquid chromatography–mass spectrometry showed the presence of 5-methoxytryptophan (5-MTP), but not other related tryptophan metabolites. Furthermore, endothelial cell–derived 5-MTP suppressed lipopolysaccharide-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. Lipopolysaccharide suppressed 5-MTP level in endothelial cell-conditioned medium and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by the inhibition of lipopolysaccharide-induced endothelial leakage and suppression of lipopolysaccharide- or cecal ligation and puncture–mediated proinflammatory mediators overexpression. 5-MTP administration rescued lungs from lipopolysaccharide-induced damages and prevented sepsis-related mortality. Importantly, compared with healthy subjects, serum 5-MTP level in septic patients was decreased by 65%, indicating an important clinical relevance.

A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury

Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF

Melatonin inhibits nitric oxide production by microvascular endothelial cells in vivo and in vitro

Long-Lasting Priming of Endothelial Cells by Plasma Melatonin Levels


Are there other substances that can modify the catabolism of tryptophan, thus influencing endothelial health?

Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro
Influence of Immunosuppressive Agents on Tryptophan Degradation and Neopterin Production in Human Peripheral Blood Mononuclear Cells
Coffee Extracts Suppress Tryptophan Breakdown in Mitogen-Stimulated Peripheral Blood Mononuclear Cells