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s_r_constantin's profile
Sarah Constantin
Sarah Constantin
Sarah Constantin
@s_r_constantin

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Sarah Constantin

@s_r_constantin

Math/ML/data-science person now working on solving aging...and helping with COVID19?! Founder, LRI and Daphnia Labs. Married to @oscredwin

Be
srconstantin.posthaven.com
Joined February 2019

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    Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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    More ammo for my fellow neuroendocrine partisans:https://www.nature.com/articles/srep41271 …

    9:47 AM - 29 Nov 2019
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    • Stephen Malina Semaj ‘somewhat “civil’ servant” Franz Ronay Patrick Corbett Pernilla Ekström Ricardo Ciarán Pedro Ivan Lopez Cole Hudson
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      2. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        TDO2 knockout mice are apparently normal except that they show less anxiety & more neurogenesis than wild type mice: https://onlinelibrary.wiley.com/doi/pdf/10.1002/npr2.12006 …

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      3. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        Pharmacological inhibition of TDO2 in mice prevents tumor progression by encouraging immune response against the tumor graft: https://www.pnas.org/content/pnas/109/7/2497.full.pdf …

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      4. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        TDO2 knockout mice also show more exploratory activity and better performance on some cognitive tasks.https://www.sciencedirect.com/science/article/pii/S0166432816303722 …

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      5. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        TDO and IDO are the enzymes that break down tryptophan into kynurenine. High kynurenine and kynurenine-to-tryptophan ratios are found in tons of age-related & psychiatric diseases; in invertebrates, TDO knockouts are long-lived; tumors have elevated IDO expression.

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      6. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        Part of the picture may be that tryptophan-to-kynurenine metabolism is immune suppressive. TDO and IDO knockout mice have stronger innate immune responses to endotoxin.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/ …

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      7. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        This is suggestive for cancer because the innate immune response to endotoxin is also how the immune system attacks tumors, and in fact stimulating this pathway (bacteriotherapy, TNF-alpha, IL-2, etc) can be very effective cancer treatment.

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      8. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        IDO knockout mice show less excitotoxicity in response to neurotoxins: https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=ido1+knockout+mouse&btnG=#d=gs_qabs&u=%23p%3DTd62rMbUAicJ …

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      9. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      10. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      11. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      12. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      13. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      14. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      15. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      16. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      17. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      18. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      19. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      20. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      21. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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 …

        1 reply 1 retweet 1 like
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      22. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      23. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      24. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      25. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      26. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      27. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      28. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      29. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      30. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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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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      31. Sarah Constantin‏ @s_r_constantin 29 Nov 2019
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        Acyclovir inhibits TDO too:https://link.springer.com/article/10.1007%2Fs11011-008-9095-4 …

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