Diokine
Member
- Joined
- Mar 2, 2016
- Messages
- 624
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.
---
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.
---
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.
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.
---
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.
---
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.
---
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.
---
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.
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