WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

[pattismith]

Thank you and I forgot to ask for how much time were you taking it? I do have some questions as to how one should be taking TUDCA :

-Is it better to take one single dose?
-Should it be taken across the day (say every 8 hours)
-Should it be taken with food?
Note that for a medication called UDCA (Ursodeoxycholic acid) there is evidence suggesting that one single dose at bedtime has the best effect.

Do you think TUDCA or UDCA are equivallent regarding to relieving ER stress?

 

[mariovitali]

Do you think TUDCA or UDCA are equivallent regarding to relieving ER stress?

From the studies I saw, TUDCA has a better effect

 

[datadragon]

High WASF3 disrupts Mitochondrial function while blocking ER stress lowered WASF3 levels and restored mitochondrial function. (Butyrate inhibits ER stress as mentioned but also zinc https://pubmed.ncbi.nlm.nih.gov/32549180/ ). High Copper seems it dramatically increased the expression levels of Grp78, CRT, and ATF4, resulting in ER stress (GRP78 increases WASF3) https://pubmed.ncbi.nlm.nih.gov/27502587/ https://link.springer.com/article/10.1007/s11356-023-27924-z https://www.sciencedirect.com/science/article/abs/pii/S0304389421018677 while any loss of bioavailable (usable) copper at the same time due to the lowering of Zinc and Vitamin A (and subsequently ceruloplasmin production) during inflammation and infection is going to result in disruption of mitochondrial function.

Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?​

Both oxidative and endoplasmic nreticulum stress should be dealt with.

High homocysteine induces endoplasmic reticulum (ER) stress as mentioned by Mario awhile back https://pubmed.ncbi.nlm.nih.gov/15243582/ but it also increases NLRP3 inflammasome and downregulates peroxisome proliferator-activated receptor (PPAR) expression (PPAR-a and PPAR-y) https://pubmed.ncbi.nlm.nih.gov/28394319/ https://link.springer.com/article/10.1186/1475-2891-3-4

ER Stress activates the NLRP3 inflammasome so yes there is a vicious cycle https://pubmed.ncbi.nlm.nih.gov/32447438/ https://pubmed.ncbi.nlm.nih.gov/31687078/ https://www.hindawi.com/journals/omcl/2019/3462530/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079978/

NLRP3 over activation lowers SHANK3 levels as does zinc deficiency. The protein encoded by the SHANK3 gene, a gene that regulates intestinal barrier function is regulated by zinc, and SHANK3 also regulates zinc uptake in the gut so there is the vicious cycle. The leaky gut and changes in the microbiome composition and function toward a more inflammatory state with increased propionate (propionic acid) and decreased butyrate (butyric acid) are part of those downstream effects, along with signs of neuroinflammation in the brain from the research. So now we have our low butyrate levels. I mentioned that PPARs need zinc to function and PPAR-a lowers NLRP3 and increases anti-inflammatory allopregnanolone - Allopregnanolone also tamps down chemokines and cytokines, such as NFkB, HMGB1, MCP-1 and TNF-a, all of which are part of the immune system and involved in many different inflammatory diseases.

The endoplasmic reticulum (ER) and mitochondria are physically connected to form dedicated structural domains known as mitochondria-associated ER membranes (MAMs), which participate in fundamental biological processes, including lipid and calcium (Ca2+) homeostasis, mitochondrial dynamics and other related cellular

mitochondria and ER are connected via mitochondria-associated ER membranes (MAM). Results found that excessive Cu (Copper) disrupted MAM integrity, reduced the co-localization of IP3R and VDAC1, and significantly changed the MAM-related factors levels (Grp75, Mfn2, IP3R, MCU, PACS2, and VDAC1), leading to MAM dysfunction. We further found that Cu exposure induced mitochondrial dysfunction via decreasing the ATP level and the expression levels of COX4, TOM20, SIRT1, and OPA1 and up-regulating Parkin expression level. Meanwhile, Cu exposure dramatically increased the expression levels of Grp78, CRT, and ATF4, resulting in ER stress. Overall, these findings demonstrated MAM plays the critical role in Cu-induced kidney mitochondrial dysfunction and ER stress, which deepened our understanding of Cu-induced nephrotoxicity. https://link.springer.com/article/10.1007/s11356-023-27924-z https://pubmed.ncbi.nlm.nih.gov/33248829/ ...Thanks Duck

 

[datadragon]

I wish it wasn't true but I am seeing that fructose does cause ER stress.

Mechanistically, Fructose promoted the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 to activate the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. https://pubmed.ncbi.nlm.nih.gov/35495917/

Fructose is known to induce uric acid production by increasing ATP degradation to AMP, a uric acid precursor and thus, within minutes after fructose infusion, serum uric acid levels rise https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197219/

Gout-associated uric acid crystals activate NLRP3 https://www.frontiersin.org/articles/10.3389/fimmu.2019.02538/full

Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome https://journals.sagepub.com/doi/full/10.1177/17590914211018100

viruses can trigger a biochemical pathway, known as the immune complement system...Complement activation then elicits secretion of both IL-1β and IL-18 via activation of the NLRP3 inflammasome https://pubmed.ncbi.nlm.nih.gov/23817414/. Under pathological conditions, NLRP3 inflammasome activation is initiated by host recognition of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451233/

Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines. This study revealed that intracellular TXNIP protein is a critical regulator of activation of the fructose-induced NLRP3 inflammasome, which can be effectively blocked by the antioxidants quercetin and ascorbic acid (Vitamin C). https://pubmed.ncbi.nlm.nih.gov/28326454/

FXR levels in the liver inversely correlated with the extent of NLRP3 inflammasome activation. Fxr deficiency in mice augmented the ability of ER stress to induce NLRP3 and thioredoxin-interacting protein (TXNIP), whereas FXR ligand activation prevented it, ameliorating liver injury. farnesoid X receptor (FXR) activation inhibits ER stress-induced NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in hepatocytes. In patients with hepatitis B virus (HBV)-associated hepatic failure or non-alcoholic fatty liver disease, and in mice with liver injury, FXR levels in the liver inversely correlated with the extent of NLRP3 inflammasome activation. https://pubmed.ncbi.nlm.nih.gov/30208322/

 

[Violeta]

I had hoped the fructose damage to the liver was only from high fructose corn syrup, but I guess not. I had been eating watermelon (a lot) for two days and now regret it. I did have the return of some pain in one of my knees.

Berberine helps with ER issues.

The therapeutic effects of berberine against different diseases: A review on the involvement of the endoplasmic reticulum stress​

It has been reported that BBR can decrease apoptosis and inflammation following different pathological conditions, which might be mediated by targeting ER stress pathways. In this manuscript, we reviewed the protective potential of BBR against several diseases, such as metabolic disorders, cancer, intestinal diseases, cardiovascular, liver, kidney, and central nervous system diseases, in both in vivo and in vitro studies.

https://pubmed.ncbi.nlm.nih.gov/35778942/

 

[datadragon]

glutamate activates the NLRP3 inflammasome via induction of ER oxidative stress https://pubmed.ncbi.nlm.nih.gov/31129157 NLRP3 inflammasome activation leads to endoplasmic reticulum stress which causes high WASF3 and disrupts Mitochondrial function, while blocking ER stress lowered WASF3 levels and restored mitochondrial function.

Acute immune activation suppresses oxidative phosphorylation-mediated ATP production and favors Warburg glycolysis, a state that is coupled with increased succinate levels. Notably, both of these changes facilitate NLRP3 inflammasome activation. high levels of the metabolite succinate can support IL-1β expression by stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) for IL-1 β transcript expression to occur. This process has recently shown to be inhibited by the anti-inflammatory metabolite itaconate, a TCA cycle off-shoot metabolite that is produced by decarboxylation of cis-aconitate of the TCA cycle by the enzyme immune responsive gene 1. Itaconate inhibits the activity of succinate dehydrogenase and mitochondrial respiration in LPS-activated macrophages, concurrently, decreasing LPS-induced mtROS. Itaconate can also activate the anti-inflammatory cellular programming of nuclear factor erythroid 2-related factor 2 (Nrf2) via alkylation of cysteine residues on the protein KEAP1. Additionally, itaconate can inhibit LPS-induced IL-1β secretion by impairing glycolytic flux via targeting glycolytic enzymes GAPDH or fructose-bisphosphate aldolase A https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463618/ @HTester Succinate accumulation, along with the induction of the glycolytic enzyme hexokinase-1, increases the activity of the respiratory chain complex II, promotes the production of mROS, stabilizes HIF-1α, regulates the transcription of pro-IL-1β, and activates the NOD-like receptor protein 3 (NLRP3) inflammasome, increasing the production of IL-1β (which increases c-reactive protein). https://forums.phoenixrising.me/threads/an-acod1-genomics-question.90574/#post-2441131

Exercise appears to have different effects on NLRP3 inflammasome (inflammation). In the case of chronic exercise with high intensity such as what occurs in many athletics/sports, a significant INCREASE in expression of gene, NLRP3 and serum levels of IL-1β, IL-18 cytokines were observed. Chronic exercise with moderate intensity such as walking however, significantly REDUCED the expression of NLRP3 gene and subsequent serum levels of IL-1β, IL-18 cytokines. So there are differences in intensive vs light exercise with intensive pouring additional fuel on the fire of inflammation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524053/

 

[hapl808]

Thank you and I forgot to ask for how much time were you taking it? I do have some questions as to how one should be taking TUDCA :

-Is it better to take one single dose?
-Should it be taken across the day (say every 8 hours)
-Should it be taken with food?
Note that for a medication called UDCA (Ursodeoxycholic acid) there is evidence suggesting that one single dose at bedtime has the best effect.

I was taking it for less than a month I think, and usual dose was just 250mg with the main meal of the day (right beforehand). Seemed like it might help with digestion from my research, but wasn't sure.

Yeah, very complicated to figure out. Maybe I'll revisit TUDCA - don't recall any bad effects, and maybe improved digestion. For me, any mental or physical exertion leads to messed up digestion for days, so I have a number of things I'm always trying to see:

1. How is my regular digestion (not during any crash).
2. How does a supplement affect my crash threshold.
3. How does a supplement affect my crash symptoms (digestion, headache, etc).

Hard to figure out any trends or truisms.

 

[dannybex]

@hapl808

Again, I am not suggesting that this is THE solution for ME/CFS, I described what I did and that within months I got my life back.

Correct me if I'm wrong, but it's my understanding you had post-finasteride syndrome, not ME/CFS?

 

[dannybex]

Fructose ingestion is one of the worst things you can do if you have liver issues

In HIGH amounts, yes.

In normal amounts, it's not an issue. Only 2-3% – is converted to fat via de novo lipogenesis.

From this review:

"At present, short-term intervention studies however suggest that a high-fructose intake consisting of soft drinks, sweetened juices, or bakery products can increase the risk of metabolic and cardiovascular diseases. There is, however, no objective ground to support that moderate intake of fructose, or of fructose consumed with fruits or honey, is unsafe."

And here's the conclusion of another study:

"These data suggest that when fructose is consumed as part of a typical diet in normally consumed sweeteners, such as sucrose or HFCS, ectopic fat storage in the liver or muscles is not promoted."

 

[datadragon]

yes I have severe deficiency (undetectable) MBL. This lead to a constant proinflammatory state.​

Mannan-binding lectin deficiency augments hepatic endoplasmic reticulum stress through IP3R-controlled calcium release​

Human mannose-binding lectin (MBL) is encoded by the MBL2 gene and is a key player in innate immunity. Human mannose-binding lectin 2 is directly regulated by peroxisome proliferator-activated receptors via a peroxisome proliferator responsive element In this study, we showed that PPARα and PPARγ up-regulate the expression of human MBL2.... https://pubmed.ncbi.nlm.nih.gov/23711995/​

Interestingly, Zinc is needed for PPARs: Zinc increases the gene expression of A20 and PPAR-a, the two zinc finger proteins with anti-inflammatory properties and all PPAR agonists tested lost their potency to downregulate the TNF-a induced inflammatory response in zinc-deficient cells. However, if zinc was added back, all PPAR agonists significantly downregulated the TNF-mediated induction of inflammatory transcription factors NF-B and AP-1 and significantly reduced the expression of their target genes, VCAM-1 and IL-6.​

Edit: new link https://www.sciencedirect.com/science/article/pii/S0022316623029346?via=ihub​

@pattismith ​

In normal amounts, it's not an issue. Only 2-3% – is converted to fat via de novo lipogenesis.

Fructose upregulates NLRP3 inflammasome and uric acid so its a potential problem more when someone is already in a high inflammatory state adding additional fuel to the fire. Those dealing with ME/CFS, an infection, an inflammatory condition or gout perhaps might want to avoid potential triggers like that in that state and otherwise just be mindful that its one of many contributors to inflammation.

Fruit does contain fructose, a type of sugar. But when you eat a piece of fruit, the fructose comes packaged with fiber, vitamins, antioxidants, magnesium, potassium, & other phytonutrients, likely chromium as well. These nutrients work together to reduce inflammation, prevent DNA damage, & improve vascular & immune function GENERALLY, slashing your risk of disease. Its the processing in some cases that takes out all the cofactors and gives you sugar in isolation without molasses that contains magnesium for example. Again just more mindful when dealing with overactive inflammation, if your not you can enjoy in moderation - at least I do. Molasses, which is removed from the sugar cane in refinement, contains up to 25% of the RDA for magnesium in one tablespoon. Sugar has none unless you get something like turbinado that has the molasses and use turbinado added to something.

​

 

[pattismith]

In this study, we showed that PPARα and PPARγ up-regulate the expression of human MBL2.... https://pubmed.ncbi.nlm.nih.gov/23711995/​

Interestingly, Zinc is needed for PPARs: Zinc increases the gene expression of A20 and PPAR-a, the two zinc finger proteins with anti-inflammatory properties and all PPAR agonists tested lost their potency to downregulate the TNF-a induced inflammatory response in zinc-deficient cells. However, if zinc was added back, all PPAR agonists significantly downregulated the TNF-mediated induction of inflammatory transcription factors NF-B and AP-1 and significantly reduced the expression of their target genes, VCAM-1 and IL-6. https://academic.oup.com/jn/article/134/7/1711/4688619​

@pattismith ​

Thank you

 

[mariovitali]

Correct me if I'm wrong, but it's my understanding you had post-finasteride syndrome, not ME/CFS?

Post Finasteride syndrome turned to ME/CFS because I gradually developed PEM . Many PFS patients also had the same fate as me.

Quite possibly this is happening with COVID19 and LongCOVID is ME/CFS

 

[datadragon]

It seems the 'zinc is needed for ppars' is no longer on the journals site I linked but the study is here also and free to view/download.
https://www.sciencedirect.com/science/article/pii/S0022316623029346?via=ihub

@pattismith @mariovitali

 

[Violeta]

In HIGH amounts, yes.

In normal amounts, it's not an issue. Only 2-3% – is converted to fat via de novo lipogenesis.

From this review:

"At present, short-term intervention studies however suggest that a high-fructose intake consisting of soft drinks, sweetened juices, or bakery products can increase the risk of metabolic and cardiovascular diseases. There is, however, no objective ground to support that moderate intake of fructose, or of fructose consumed with fruits or honey, is unsafe."

And here's the conclusion of another study:

"These data suggest that when fructose is consumed as part of a typical diet in normally consumed sweeteners, such as sucrose or HFCS, ectopic fat storage in the liver or muscles is not promoted."

Thank you, Danny, that made me breathe a sigh of relief.

And also, I will try to stick to lower carb fruit and small amounts of honey.

 

[pattismith]

It seems the 'zinc is needed for ppars' is no longer on the journals site I linked but the study is here also and free to view/download.
https://www.sciencedirect.com/science/article/pii/S0022316623029346?via=ihub

@pattismith @mariovitali

Zinc is also needed for metalloprotease like MMP9 and these metalloprotease may lower MBL levels..;

Hypothyroidism also lower MBL levels.

Otherwise, genetic is the main factor for low MBL and it's the reason for my low level.

Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency​

 

[mariovitali]

Regarding MBL :

MBL generates ER Stress and is also a cause of Liver Injury.

https://twitter.com/i/web/status/1695776654981836976

 

[datadragon]

Zinc is also needed for metalloprotease like MMP9 and these metalloprotease may lower MBL levels..;

Yes, and zinc is needed for the PPARs that regulate MBL levels. Matrix metalloproteinases as modulators of inflammation and innate immunity https://www.nature.com/articles/nri1418/ Zinc is needed for thyroid as well as Vitamin A. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes - Retinoid X receptor requires Vitamin A. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone). https://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor

Butyrate inhibits IDO1 and the short chain fatty acid (SCFA) butyrate induced Aryl Hydrocarbon receptor (AhR) activity and the transcription of AhR-dependent genes (AHR) https://www.nature.com/articles/s41598-018-37019-2 and https://www.nature.com/articles/s41598-017-10824-x Butyrate suppresses IFN-y https://pubmed.ncbi.nlm.nih.gov/15145607/

I just found however that AHR also regulates cellular zinc uptake, and that zinc is an integral part of AHR signalling processes https://www.biorxiv.org/content/10.1101/2022.11.03.515052v1 AHR negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription https://www.nature.com/articles/ncomms5738 other immune cells are also affected by butyrate but less studied such as mast cells, dendritic cells and T cells. so its more of a regulator as covered here https://forums.phoenixrising.me/threads/an-acod1-genomics-question.90574/post-2441131

Zinc is involved with Vitamin A metabolism to active forms which also leads to ceruloplasmin production that makes both copper and iron bioavailable (usable). We see in this thread that a high unbound copper and low zinc and butyrate can lead to ER stress, higher WASF3 levels and disrupts mitochondrial function. Zinc is also involved with conversion to active B6 and getting into the cell, a cofactor for glutathione, and subsequently b12 metabolism needs glutathione which would lower methylation. https://forums.phoenixrising.me/thr...-van-konynenburg-documents.90623/post-2441698

Zinc is lowered by NLRP3 overactivation that reduces zinc uptake in the gut by lowering SHANK3 levels and also induces inflammatory cytokines that sequester zinc and consequently reduces zinc availability further during inflammation or infection. https://forums.phoenixrising.me/thr...-b6-production-utilization.57030/post-2440317

Zinc homeostasis is tightly regulated by zinc transporters and metallothioneins that control zinc concentration and its distribution in individual cells and contributes to zinc signaling. zinc directly binds STAT3 and inhibits its phosphorylation by Janus kinases (JAK) and does so without affecting the kinase activity of JAK proteins. Furthermore, the structure of STAT3 itself is altered by the zinc binding. Zinc suppresses autoimmune diseases by inhibiting STAT3 activation. Zinc directly binds STAT3, altering its structure. The structurally altered STAT3 molecule cannot effectively transduce the IL-6 signaling pathway; this pathway is critical for autoimmune diseases involving Th17 cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286780/

Glutamate signaling is needed to establish memory and learning. Age-related decreases in the GLUTAMATE NMDA NR2B subunit correlate with memory deficits. It also appears that the loss of Shank3 via zinc deficiency that is required for its function or lowered from NLRP3 over activation interacts with NMDA receptors. Since SHANK3 is concentrated in glutamatergic synapses, it interacts with all prominent glutamate receptors, such as NMDA, AMPA, and mGlu receptors. SHANK3 also indirectly interacts with Neuroligins (NLGN), a family of post-synaptic adhesion molecules. Most of these interactions are indirect and mediated by post-synaptic proteins such as GKAP, Homer PSD95 etc. InsG3680 Shank3 mutant mice show disruptions of glutamatergic signaling as compared to WT controls. https://www.nature.com/articles/s41398-021-01612-3 I see also that moderate to severe intellectual disability, epilepsy, schizophrenia are all connected to shank3.

Butyrate is involved with memory, autoantibodies, suppresses demyelination and enhances remyelination .
https://forums.phoenixrising.me/threads/bc007-what-are-your-thoughts.87520/post-2442283

People who were missing the SHANK3 gene and mice that lacked part of the gene had difficulty falling asleep even when sleepy which can occur also with zinc deficiency and high inflammation levels (NLRP3 over activation) that lower Shank3 levels. Shank3 is an important modulator of sleep and clock gene expression.
https://elifesciences.org/articles/42819 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974951/

 

[datadragon]

Added:

Butyrate is involved with memory, autoantibodies, suppresses demyelination and enhances remyelination .
https://forums.phoenixrising.me/threads/bc007-what-are-your-thoughts.87520/post-2442283

Butyrate, a gut-derived environmental signal, regulates tyrosine hydroxylase gene expression via a novel promoter element https://pubmed.ncbi.nlm.nih.gov/16165221/ (dopamine)

Zinc and Vitamin A are needed for thyroid. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes - Retinoid X receptor (RXR) requires Vitamin A. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone). Vitamin A is crucial in activating Retinoid X Receptors (RXR), which is also required for PPAR activation. https://pubmed.ncbi.nlm.nih.gov/23440512/ https://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor zinc (and Vitamin A) is needed for the PPARs that regulate MBL levels.

Vitamin A and D also work in synergy throughout the body including for immunity which is compromised upon loss of Vitamin A. https://www.medicalnewstoday.com/articles/219513#1 Vitamin D binds to its receptor (VDR) and dimerizes (combine with a similar molecule to form a dimer) with the retinoid X receptor (RXR), which is a retinoic acid (vitamin A) receptor. RXR is needed to activate the vitamin D receptor (VDR) and the Thyroid Hormone Receptor (THR) and peroxisome proliferator–activated receptor (PPARs).

Without sufficient vitamin A, vitamin D is unable to properly fulfill some of its functions. [In the cell, VDR binds 1,25(OH)2D, and the complex interacts with the retinoid X receptor to form a 1,25(OH)2D*VDR*retinoid X receptor heterodimer complex. This complex can bind vitamin D–responsive elements in the promoter regions of target genes.] https://pubmed.ncbi.nlm.nih.gov/9790574/ https://link.springer.com/article/10.1007/s10552-004-1661-4

PPARa has pain lowering properties (which require zinc and Vitamin A). PPARα-mediated pathway triggering TRPV1 channel activation and desensitization, and highlight a novel mechanism which might contribute to the analgesic effects shown by PPARα agonists in vivo. https://forums.phoenixrising.me/thr...acute-pain-nejm-08-03-2023.90696/post-2442397

 

[SlamDancin]

@datadragon Just started Tribuytrin (sp?), it’s a supposed prodrug form of Butyrate. I’ll let you know if I notice any benefits

 

[Forummember9922]

Just a quick note hopefully not derailing
From
https://onlinelibrary.wiley.com/doi/10.1002/jmv.25963

“Previous studies showed that ER stress was modulated by herpes simplex virus types 1 (HSV-1) infection to facilitate viral replication. Here, we investigated the effect of TUDCA on HSV-1 infection of HEC-1-A cells and showed that both replication and multiplication of the virus were inhibited by TUDCA in a dose dependent manner.”

Surely other viruses or pathogens are attempting this as well. Humans need a firmware update, pretty unimpressive security.