More ammo for my fellow neuroendocrine partisans:https://www.nature.com/articles/srep41271 …
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And here’s a wild one for you infectious-disease freaks: intracellular parasites like toxoplasma & malaria induce IDO1 to evade immune attack. http://www.jbc.org/content/287/24/20197.full.pdf …
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As you might expect for an effect found in depression & anxiety, IDO1 expression goes up under conditions of psychological stress, in both mice and humans. https://scholar.google.com/scholar?start=10&q=ido1+knockout+mouse&hl=en&as_sdt=0,5#d=gs_qabs&u=%23p%3DACukYlo7kMkJ …
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IDO1 also seems to suppress the body’s regenerative abilities— IDO1 knockout mice grow their livers back faster after partial hepatectomy. https://scholar.google.com/scholar?start=10&q=ido1+knockout+mouse&hl=en&as_sdt=0,5#d=gs_qabs&u=%23p%3DzEW9P6U0EtsJ …
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If tryptophan-to-kynurenine metabolism does all these bad things — makes us anxious, susceptible to tumors and parasites, worse at healing from injuries— why do we have it?
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Immunosuppression can be useful for a wild animal in conditions of physical danger. If you’re fleeing for your life, you want to divert resources away from healing and body maintenance so you can devote more to being alert and running fast.
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This is good news for us humans who might want to use medical technology to reverse immunosuppression; the evolutionary rationale matters less to modern humans in safe conditions, so we shouldn’t necessarily expect an intrinsic tradeoff causing bad side effects.
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The other advantage of immune suppression is in preventing autoimmune disease, which indeed TDO and IDO seem to do.
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IDO1 inhibitors by themselves have shitty response rates in human cancer trials, but you’d expect that, given that IDO1 is only one of three enzymes catalyzing the same step in tryptophan/kynurenine metabolism!https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068130/ …
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IDO1 knockout mice are also resistant to diet-induced obesity; kynurenine affects metabolic disease too!https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851598/ …
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Endotoxin administration induces depression-like behaviors in mice (depression can be a response to inflammation or infection) ... but not in IDO1 knockout mice!https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-10-87 …
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As I learned from ICU nurse friends, “if you ain’t got pressure, you ain’t got shit.” The most urgent and deadly problem in sepsis, traumatic injury, and other medical emergencies is the loss of blood pressure. Guess what’s responsible for it? Kynurenine! https://scholar.google.com/scholar?start=40&q=ido1+knockout+mouse&hl=en&as_sdt=0,5#d=gs_qabs&u=%23p%3DEnV2KXf45XQJ …
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What happens to a human with TDO2 deficiency? In this case study, high levels of tryptophan and serotonin but no apparent health problems.https://www.sciencedirect.com/science/article/abs/pii/S1096719217300641 …
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You know how activated microglia play an important role in neurodegeneration (from things like Alzheimer’s and head trauma)? Kynurenine is involved here too! Microglia turn tryptophan into kynurenine and thence to the neurotoxin quinolinic acid. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1217971/pdf/8973572.pdf …
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It’s primarily activated macrophages and microglia (and not, say, neurons or astrocytes) that produce quinolinic acid, which is found elevated in brain infection, head trauma, Huntington’s, and AIDS dementia.https://journals.lww.com/neuroreport/Abstract/1997/01200/Activated_human_microglia_produce_the_excitotoxin.11.aspx …
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Quinolinic acid is an NMDA agonist, which means it spreads brain damage by excessively “exciting” neurotransmitter receptors, letting so many highly reactive calcium ions into the neuron that they kill it. This process has a role in virtually every neurodegenerative disease.
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Moreover, quinolinic acid makes brain tumors more resistant to oxidative stress (like radiation, chemo, or the body’s own immune defenses. ://cancerres.aacrjournals.org/content/canres/73/11/3225.full.pdf.)
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Viruses can induce kynurenine production; here, influenza increases TDO and IDO expression & kynurenine production in rat brains: https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=TDO+virus&btnG=#d=gs_qabs&u=%23p%3DM_fb6QYy0QYJ …
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TDO, IDO, kynurenine, and quinolinic acid are found elevated in various viral infections: HIV, hepatitis B and C, herpesviruses, etc.https://journals.sagepub.com/doi/full/10.4137/IJTR.S26862 …
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Why? Tryptophan depletion is itself an immune defense against some bacteria and viruses. In response to viral infection, the body produces IFN-gamma, which activates IDO and TDO, which make kynurenine. Unfortunately, kynurenine has all the nasty effects mentioned upthread.
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So if you have a *chronic* viral infection, you’re going to keep pumping out kynurenines as a side effect of trying to kill the virus, which cause immunosuppression, which makes you more susceptible to viral infection...it’s a vicious cycle!
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What kinds of drugs inhibit IDO and TDO? Well, azole antifungals (like ketoconazole) and the MAOI antifungal phenelzine (also known as Nardil, the Flame of the West) https://scholar.google.com/scholar?start=20&q=ido1+inhibitor&hl=en&as_sdt=0,5#d=gs_qabs&u=%23p%3DYbQyk8FoSIMJ …
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The antiviral acyclovir is also an IDO1 inhibitor:https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-7-44 …
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Acyclovir inhibits TDO too:https://link.springer.com/article/10.1007%2Fs11011-008-9095-4 …
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And so does the antibiotic minocycline:https://www.sciencedirect.com/science/article/abs/pii/S1043466617303848 …
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End of conversation
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