Curcumin New Promising MPN Study

[EPguy]

Heads up , this post is dense, long, and detailed.

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There is a great thread going, initially about NAC supplement. It veered to Curcumin with Hunter's always knowledgeable influence.

healthunlocked.com/mpnvoice...

Hunter referenced a study, the full version being:

(Study #1, 2009) altmedrev.com/wp-content/up...

I have comments on it below.

I was further motivated to look for some MPN vs Curc studies. This one came up:

(Study #2, 2019) onlinelibrary.wiley.com/doi...

A most compelling argument for Curc. It is not in Vivo (real people) but all studies start in the lab and this safe agent should not require long safety studies.

It is a rare report being very technical but I can reasonably follow. I've found this is a sign of a better quality study, and it further notes consistent results with prior work, a good sign. It also meets my arbitrary cutoff of 2017 for freshness in MPN work.

Likely there are or will be clinical trials going on like the current NAC trial we know about. Any links are welcome. I am inclined to start Curc supp.

Here are my comments, 1st study #1, then the newer study #2.

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Curcumin study #1 from 2009

The complete report noted by Hunter is:

altmedrev.com/wp-content/up...

Some comments on it.

Curc needs added agents for bioavaility. The product Hunter is using claims "up to 46x greater absorption" showing the subject is being addressed by supp makers, esp since this date of 2009.

<<Because of curcumin’s rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavaility>>

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Some of the anti-inflammatory effects are relevant to molecules also noted with NAC, one example is TNF alpha, so they may share some similar benefits. However NAC and Curc operate differently, so you will be doing something different between these supps:

nutritionandmetabolism.biom...

<< Both curcumin, a component of the spice turmeric, and N-acetylcysteine (NAC), an antioxidant, inhibit activation of NF-κB by inflammatory stimuli, albeit by different mechanisms>>

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Rheumatoid arthritis

In rats << Intraperitoneal injection of an extract containing 4 mg total curcuminoids/kg/day for four days prior to arthritis induction significantly inhibited joint inflammation in both the acute (75%) and chronic (68%)

phases.>>

Hunter has found this real benefit.

Osteoarthritis

Similarly, member riteandscooter1 has found a benefit for osteoarthritis. <<Assessment every two weeks during the study demonstrated significant

improvements in pain severity (p<0.001) and disability scores (p<0.05)>> This was on real people, but included other supps in the formula so << Curcumin’s role in this improvement cannot be confirmed due to the other botanicals

and zinc in the treatment compound>>

I try to test one supp at a time if possible.

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Cancer

<< The impact of curcumin’s anti-inflammatory effects on carcinogenesis in humans remains to be determined. However, animal research demonstrates inhibition at all three stages of carcinogenesis – initiation, promotion, and progression>>

<< Currently there are nine ongoing clinical trials investigating the benefits of curcumin as a therapy for various cancers>> Note again the old 2009 date, there should be some results.

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Safe Dose

<<In every published clinical trial, curcumin appears to be extremely safe, even at doses up to 8 g daily>>

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Curc may affect certain chemo drugs, both + and -. This could be relevant to HU, but it is not called out here. My guess is any issue would show up in blood counts.

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Conclusion

<< The primary obstacle to utilizing curcumin therapeutically has been its limited systemic bioavailability>>

It seems this has been addressed with current formulas, but details matter which one you get. Both Hunter and ritaandscooter1 have selected their preferred options.

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Study #2

A study specific to what we care about and full of neat stuff:

onlinelibrary.wiley.com/doi...

This study used MPN patient blood samples.

<< Previous studies showed that curcumin can suppress JAK2/STAT signalling pathways in different type of cancer and injuries.>>

A new target for MPN therapy addressed by Curc:

<< recent studies identified the role of mTOR pathway in MPNs… This pathway has been found deregulated particularly in megakaryocytes of MPNs patients >>

<< curcumin was able to dissociate Raptor from mTOR …Our results suggest that curcumin inhibits proliferation and activates cell death program by modulating JAK2/STAT and mTORC1 pathways >>

I don’t know these details, but we now know to care about mTOR and Curc is showing good effects on mTOR.

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There are references to HEL cells throughout, I think these are a type of research cell used since the 80’s for various experiments.

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To my understanding, it had a dramatic effect of killing (apoptosis) bad Jak2 cells. See Figure 1 here. At higher Curc doses most bad cells are dead (Fig. 1B) .

<< This data confirmed the FACS analysis and indicated that curcumin induced apoptosis in a dose-dependent manner in JAK2 V617F-mutated cell line>>

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Curc is really good to inhibit, or even stop, the STAT pathways that make trouble in MPN:

<< we observed that phosphorylation of STAT5 was 60% reduced, while STAT3 was extremely sensitive to curcumin-mediated JAK2 inhibition and its phosphorylation decreased to 20% even at the lower curcumin dose and was completely blocked at higher concentrations>>

A good actor (SOCS-1 and 3) is enhanced by Curc, being increased by up to 7 times (SOCS-1) and doubled (SOCS-3):

<< Furthermore, the protein expression of SOCS-1 and SOCS-3, negative regulators of JAK/STAT pathway, resulted clearly up-regulated after curcumin treatment>> They confirmed this result at least two ways.

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The newly MPN relevant pathway mTORC1:

My minimal understanding is Curc can stop this mTORC problem entirely at high enough doses:

<< Our results indicated that curcumin affects the principal modulator of mTORC1: AKT… its (mTORC’s) principal activator PDK was inhibited by low dose curcumin and it appeared unphosphorylated at the maximum concentration utilized>>

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They tested Curc in samples from real MPN patients to compare to the HEL cell sample tests. << The results were in accordance with in vitro analysis (HEL cells) …These results suggest that curcumin treatment affects JAK/STAT pathway and induces apoptosis in cells from JAK2 V617F mutated patients.>> In Fig. 4, (see Reply below for this figure) the tall black bar lower right shows an obvious, if complicated, effect of Curc on Jak2.

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Conclusions, Discussion

This study is new and worth our attention:

<< the effects of this phytochemical (Curc) on JAK2-mutated cells have been poorly studied until now.>>

Results are consistent with prior work, this is always a good thing:

<< Our data are in accordance to what has been already published by Chen and colleagues>>

Also consistent with prior studies << we showed that curcumin strongly inhibited the proliferation and induced apoptosis in a dose and time-dependent manner in HEL cells. Furthermore, we found that curcumin markedly reduced JAK2 phosphorylation and, consequently, the activation of its downstream effectors STAT3 and STAT5 in HEL cells>>

**Rux resistance, this is interesting, Curc might help Rux resistance by inhibiting one of the trouble makers << These small kinases (PIM 1-3) are known to be involved in leukemogenesis and in ruxolitinib resistance in MPNs cells>>

Another example of consistent and good results re the newly relevant mTORC:

<< In agreement with the results obtained by Beevers et al in human rhabdomyosarcoma cells, our results in HEL cells showed that curcumin negatively regulated the mTORC1 complex formation… This data are in accordance with the hypothesis that mTORC1 is a JAK2 downstream pathway and it is involved in MPNs pathogenesis >>

Further evidence of good effects << The curcumin effect was strengthened by the observation that CD177, an antigen over expressed in neutrophils of the majority of MPNs patients, was down-regulated by curcumin>>

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More discussion of Rux limitations (certain bad cells don't rely just on Jak2 allele) and potential Curc benefit for Rux:

<< Ishida et al demonstrated that HEL cells are only partially dependent on JAK2 V617F for survival and this may explain the very limited effect of ruxolitinib and its inefficiency to eradicate JAK2-mutated clone in MPNs patients… curcumin affects both proliferation and survival of HEL cells, suggesting that its role in MPNs could be more effective in blocking neoplastic cells with respect to the common JAK2 inhibitors, such as ruxolitinib >>

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Prior mTORC inhibitors are useful but have side effects, Curc might do the same thing without these effects

<< mTORC1 inhibitors can cause numerous side effects that could prevent their use. In contrast, curcumin turned out to be safe and non-toxic in many different trials so its use for MPNs treatment could represent an excellent alternative to common mTORC1 inhibitors >>

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<< this study showed that curcumin exerts an antitumor effect on human JAK2-mutated cells by inducing apoptosis and inhibition of proliferation, through the regulation of both JAK2/STAT and mTORC1 pathways. These findings suggest that curcumin seems to be a promising nutraceutical compound that should be further evaluated in different pharmaceutical formulation for the treatment of MPNs.>>

[EPguy]

Fig. 4 from Study #2

Curcumin Fig. 4

[Elizka]

Wonderful summary, EPguy. And thank you to Hunter. I saw this research awhile back and have been taking Meriva by Throne for a couple of years.

[EPguy in reply to Elizka]

Have you found any clear and specific benefits upon using it?

It seems the mfrs all compete on how many X more absorption they get, this one claims 29X while the other one claims 46. I suspect it might be like SPF sunscreen, diminishing returns as it get very high. But to the point, it may be Curc is getting attn lately precisely because they now know how to make it adequately bio available.

In a mostly unrelated note, I am finding the sustained release NAC to be not effective with minor exceptions, while the regular NAC seems better. But details matter, and likely it's something specific to the way these are made.

[Elizka in reply to EPguy]

Yes, I feel I have less muscle stiffness, my fingers are more mobile, and I have fewer headaches or eye pain.

[EPguy in reply to Elizka]

That's very specific and good news. My husband tried it for leg stiffness, pains, so far nothing improved. I said to give it more time, but seems here those getting any benefit are doing so quickly.

I'm on it now too, and off the NAC to keep with one-at-a-time. Curc may be helping, but I'll know more with more time. I'm after the malaise more than specific pains.

[DottyDaisy]

Thank you both for all this research.I confess I've only skimmed it as yet, but I always take information from this group, particularly from Hunter, very seriously.

I've copied the whole post to save elsewhere for further study. Maybe while I'm confined to barracks during recovery from surgery.

I am very grateful. Warmly, Daisy

[DJK12]

I'm not medically qualified but might I just add a word of caution about curcumin/turmeric supplements? I find the specialised hospital pharmacists very alert to interactions of drugs on both my GP or Consultant's prescriptions, but of course they can't see what supplements I might be taking.

I have looked at curcumin in the past and been concerned about problems as I'm on a blood thinner and so avoided it, but this NHS specialist pharmacy site also urges care with chemo/immunosuppressants/anticoagulants/statins amongst others:sps.nhs.uk/articles/advisin...

Eating it as part of a balanced diet appears to be no problem but that is in small amounts. I appreciate the jury is probably out about this and medical knowledge is moving fast, but some of our drugs are so powerful that care is needed and my first port of call would be the hospital pharmacist for advice.

[beetle in reply to DJK12]

This is just another example of the minefield we negotiate on a regular basis. I agree with your note of caution and have read that turmeric also has properties similar to aspirin in term of sticky platelets. I’m sorry I can’t find the reference to this right now. At times I feel overwhelmed by the conflicting advice/opinions out there as I realise research is bringing up new data all the time. I have a great deal of respect for ETGuy and Hunter who manage to get their heads round some pretty complicated articles and then pass them on to us in a simplified form. I thank them both

[Adlon57 in reply to beetle]

I was having terrible problems with my reaction to AZ vaccine 2021 to my schwannomatosis, and broken skull injury, [caused via double seizure in 2018], Hunter recommended turmeric, as aspirin might be too dangerous to my other conditions and medication, proved very successful, going though various mixtures of turmeric/curcumin; curcumin and turmeric black pepper proved most successful [Tescos own brand Turmeric & vitamin d was easily the worst, (0.3% turmeric extract?) ] 👍Hunter

[EPguy in reply to Adlon57]

Good info. Your result is consistent that details matter. Assuming a person is a candidate for benefits, which Curc is selected makes a difference for whether it may work.

[Adlon57 in reply to EPguy]

Have been in touch with my two specialists; Epilepsy and Schwannomatosis, about the benefits of turmeric/curcumin, they both have listened, believe me, hopefully use my experiences which have been dramatic, to further good use?

[EPguy in reply to Adlon57]

Can you say which conditions Curc is exactly helping? Or is it more generally just feeling better?

[Adlon57 in reply to EPguy]

The reaction to AZ vaccine, heart flutters [common side effect of vaccine, heart monitor test proved negative], it developed two schwannomas, on my left arm, making it swell and shake, my broken skull from 2018 was causing ongoing balance/equilibrium issues [could not walk uphill, dizziness], which the vaccine worsened, due to possible reaction to aspirin and my epilepsy medications etc, started circa september turmeric instead, that with the wearing off of vaccines 9th Feb and 23rd April 2021, [no reaction to pfizer booster vaccine 23rd Nov 2021] the balance/equilibrium issues improved, I tried various turmeric/curcumin concoctions since then curcumin and turmeric black pepper proved most successful [Tescos own brand Turmeric & vitamin d was easily the worst, (0.3% turmeric extract?) which I used last month, dizzy spells walking upstairs and getting off chairs, old symptoms from last year, although not as bad but certainly noticeable! ] Using curcumin last four days noticeable return of good signs, ! My left arm has improved but likliehood due to effects of vaccine wearing off? Curcumin/Turmeric proved most successful to my skull injury, I was getting equilibrium effects after the double seizure in Jan. 2018, I thought at first it was small auras to new epilepsy medication, starting at that time [Vimpat and Briviact] I'm a lazy bugger so never really energetic, I ignored these 'dizzy spells' even noticed when walking uphill in 2018, but definitely heightened after AZ vaccine 2021, I can walk uphill now, no dizzy spells hopefully from now on

🤞 Although have been informed last July that my next seizure will probably be my last, not really surprising after 400 + of the things in 52 years?

[EPguy in reply to Adlon57]

You've been thru all of it, I see your many posts. Wishing you comforts.

Anything that can help you feel better must be great, and it is good news that Curc is helping various of them at least some.

It seems your latest Curc using started 4 days ago with benefits showing already. The new Curc formulations may use forms of pepper and other add-ons to enhance its effects, you seem to have successfully found them.

There do seem to be more issues with the AZ vax, it's most risk with non-elderly women, but clearly not exclusive to that. So sorry you have experienced some of these effects.

[Beup in reply to DJK12]

Thanks! EPguy for posting and explaining, as you stated, this "promising" information. I'm sold! I copied and pasted and printed information from you and Hunter. I am learning so much. To DJK12's point: I recently saw a MPN specialist in NYC and I asked her about supplements like NAC, and she was not on board with supplement use in general. She only recommended use if a specific deficiency was seen in bloodwork, such as vitamin D. She cautioned about the possibility of impure ingredients without FDA approval. She did recommend the Mediterranean diet. The only supplement I take is a probiotic, but she said I could get some of that just by eating yogurt.

After reading many posts here on the positive effects of turmeric, a while back I started keeping my organic turmeric spice bottle with my salt and pepper. I add a dash here and there in many recipes. I read online that pepper, quercetin rich foods like apples and berries, and fats help to increase bioavailability.

[EPguy in reply to Beup]

As you can see in my response to DJK12, I define deficiency more broadly than most Drs. Misery is a very big deficiency that I feel is worth certain risk to cure.

As in many posts, Drs often look only at the labs, we live with a broader reality.

Agree on the probiotic, I actually call them "Yogurt pills". I'm not a dairy person so I do take when it feels the right thing to do.

[Beup in reply to EPguy]

I hear what you are saying. I agree. It will be good for me to see Dr. Fleischman's results on NAC project and then decide. Unless it is done... not sure where your chart is from. I saw same numbers for NAC in a smaller chart she showed in her diet presentation and she mentioned an ongoing lab NAC project. It's funny, in another chart from her diet study she lists rice, alcohol, baked goods, dairy, and pasta as being associated with decreased symptom burden!?!

[EPguy in reply to Beup]

Here is the link for that table. It was an internet survey:

ashpublications.org/blood/a...

[EPguy in reply to DJK12]

I agree, just because we can buy it at the local shop does not mean it's not real medicine with real effects; plus and minus.

Even more on the point, the recent formulations are much better at making it do its good or bad, sort of like modern pot, weed is way more potent than 40+ years ago. (I last tried it about that long ago) In the table here that I've posted before, NAC looks good with the largest symptom reduction. Curc less so. But I now suspect this is -before- the stronger formulations of Curc were in wide use. My take is if one wants the most benefit of Curc, the new high potency formulas are best, but it will go with proportionate added risk of being more effective.

With all that, if I can improve the misery that goes with my MPN, I'll weigh that heavily vs any risk. We do same with HU, Rux, INF etc. But I do coordinate with my MPN Dr. He's ok with NAC, not so keen on Probiotics, but ok for me to take that. A reality check, he is strongly against Resveratrol, which I agree based on my readings. I have posted on a promising study of Resv a while ago, but that stuff is not DIY.

NAC-Curc

[Jennytheb in reply to EPguy]

Interesting seeing the results for Vitamin D in your table above, perhaps more should be given to that, perhaps fewer negative results?

[EPguy in reply to Jennytheb]

Vit D shows a slightly worse outcome than without D, symptom score of 3.44 vs 3.36. Not much diff but at least by this criteria, adding more Vit D does not stand out.

But we have seen posts where too low Vit D can be a problem, so at least it's worth checking your Vit D at some point.

Some others that look ok are herbals, antioxidants and Zinc. But as always, some can have risks.

[EPguy in reply to DJK12]

It seems that Curc is by itself safe, based on the 1st report note: "In every published clinical trial, curcumin appears to be extremely safe, even at doses up to 8 g daily".

But the concern we MPNs have is effects of any supp that is specific to our condition and meds. PLT regularly shows up as a concern. So it does pay to coordinate with your qualified expert.

[Lettie_WP]

What kind of dosage saw positive results?

[EPguy in reply to Lettie_WP]

This was in vitro, (test tube) vs in a person or mouse. So to have real medical guidance it would need a dose finding phase for Curc; this is exactly what's happening right now with the NAC trial.

What gets my attn is the real results we see in the small sample from our MPN group here.

[Meatloaf9]

I asked my mpn specialist last Dec about taking turmeric. He said a recent study found no benefit for mpn patients. I did not ask for the reference to the article. I have been taking turmeric since 2018, various brands, in that time my AB went from 27 to 50. I still take it, not sure why. Good luck to all.

[Wyebird]

Thanks I tried it once but bruised easily, now I suffer from arthritis and I’m on Peg I think I’ll try it again

[gravityyaoi]

Traditional Chinese Medicine hospitals in China have been doing a lot of work on MPN research in regard to the use of natural herbal compound formulas. Here's a couple other articles that are interesting.

Here's a study for an experimental herbal formula that's been constructed to possibly help treat polycythemia vera:

sciencedirect.com/science/a...

The above study states that the saikosaponins in the herb Chai Hu was found to have the same clinical effects as ruxolitinib but with less incident of side effects and the other herbs have been chosen based on active constituents.

Here's one showing a compound from indigo inducing apoptosis in mutated Jak2 cells:

jeccr.biomedcentral.com/art...

One of the treatments I've read about for leukemia that's being co-opted for other MPNs is a compound of concentrated indigo precipitate mixed with realgar as the indigo upregulates the body's production of interferon-a and the arsenic trioxide in the realgar binds to the malignant cells making it easier for the interferon-a to attack. Sadly you'll never see this treatment in the West due to the toxicity of realgar and the indigo can cause gastritis symptoms when used along without other protective herbal compounds. Chinese medicine focuses on a whole-body picture so other herbs are added to protect the patient during treatment, so technically everyone would be treated differently in the end. which is something we sorely lack over in the West.

[EPguy in reply to gravityyaoi]

Good info. The 1st report is short and seems to be a summary of something. I can't process it too well.

The 2nd one is neat and reads sort of like the one for Curc, showing that ZT55 is also worthy of further study. It is a problem however to get attn in the West for all the good opportunities that can be found from traditional meds.

We see in countless reports "...is worth further study" The guys in charge have their priorities and we wait for them to choose.

[gravityyaoi in reply to EPguy]

Yes, it's basically a verification report of markers and active components in the herbal formula through mass spectrometry, linking active components to chemical pathways and verifying that the formula and particularly saikosaponin-a induced apoptosis of erythroblasts via Jak/Stat inhibition.

The discussion section of the article does have a good point about the role of oxidative stress in the role of pathogenesis in these diseases, which I believe is the reason some people don't tolerate or find results readily with just single drug therapies. There's also the factor that fibrosis starts to form in some cases, providing poor micro-circulation within the marrow and further preventing medicines from treating what they should.

I've also read reports where the mutated Jak2 cells inhibit pro-apoptopic molecules like BAX and caspases which just prevent them from being destroyed by the body. Clearly multi-targeted approaches are needed, and it's unfortunate that supplements are discouraged as many of the herbs with 'blood-moving' properties that are used to treat cancers and marrow diseases in China, have been found also improve circulation and inhibit tissue fibrosis in addition to inhibiting thrombus formations.

As for the ATO, it's used in China along with indigo, or Qing Dai, which is also in the above formula they're trying to use to treat PV. The same formula with ATO and indigo is used to treat the hepatosplenomegaly that pops up in these illnesses, sometimes even in a topical cream applied over the organ through the skin, so there's absolutely a wider picture of oxidative stress and irregulated immune function in the body which relies on both the liver and the spleen to function properly.

In my personal case, I've responded very poorly to the available drug options, HU giving me such bad brain fog I could barely move around, interferon just didn't do anything but worsen my anxiety, and my platelet count actually raised on anagrelide, and when they upped the dose of that, they spiked further as well as giving me horrible gastritis and nerve damage along with chronic fatigue and pain. I also hadn't had any incidences of erythramelalgia until after anagrelide either. So my acupuncturist and I have been trying to treat all of it with herbs and acupuncture the last couple of years, and my platelets have dropped to below 800 which they haven't been that low in over 5 years. Of course I wouldn't advise people to go this route without medication, but I do believe it's worth using supplemental therapy to keep everything else in check or mitigate the side-effects we experience.

[EPguy in reply to gravityyaoi]

Your note on oxidative stress is on the point. These guys are esp focused there:

mpnlab.org/

They are doing the NAC dosing study. On its long path, NAC was noted for MPN potential at least far back as 2013 and only now is there any formal human clinical work on it.

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I'm an inventor by profession and the lesson here is similar: ideas are relatively easy ("cheap" to use the impolite term) but making them reality is hard. You need skill, patience, partners, luck and time, not always in that order. Medicine is that x 10, I think that's why we are mostly on our own for most of the supps we want to try.

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I have read of ATO use in Chinese meds, I think it has a good future esp if the guys with the milder oral formula make it happen.

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Yours is quite the journey with no regular therapies working. Can you say exactly which INF brand or formula you tried? To my knowledge only two, PEG and Besremi, have been commonly used successfully in recent times for MPN.

Have you done a full gene sequence? (NGS) You might have some unusual things going on.

[gravityyaoi in reply to EPguy]

Thank you for the link, I'll check into it. I know NAC is used to treat pulmonary fibrosis and have seen articles where the same pathways it affects seem to work similarly to some anti-fibrosis herbs I've read about. They are right about JAK2 mutation making itself resistant to destruction and creating a hospitable environment for MPNs to thrive.

I'm of a similar mind when it comes to supplementation and we have to figure out what will work for each of us.

I read an article a while about about flax oil inhibiting arsenic-based cardiac damage, so that may be something good to keep in mind if ATO treatment becomes available.

Pegasys was what I tried, and it hadn't helped any and aggravated my anxiety and gave me some abnormal thoughts of suicide that I didn't have before, so I'm reluctant to try Besremi as well since my levels seem to be decreasing steadily over time. I haven't looked into gene sequencing though.

Here's some more articles I've gathered the past couple of years since there's been some mention of mTOR and other mechanisms in MPNs along with some articles about herbal active components that are being linked to these pathways. Hopefully they can be of help to someone here and sorry in advance if they've been discussed before, I don't frequent here often, haha.

Jak2 mutation upregulates interleukin-6 production via excess p-Stat3 and pkm1 stabilization in macrophages:

frontiersin.org/articles/10...

Emodin downregulates IL-6 and excess p-Stat3 that leads to anti-apoptosis environment (This goes along with the above study and emodin is found in Da Huang, He Shou Wu, Hu Zhang, and Jue Ming Zi):

aacrjournals.org/mct/articl...

Oleanolic acid induces pkm2 to pkm1 switch, inhibits mTOR phosphorylation (found in Nu Zhen Zi and often used to treat leukemia and other marrow conditions, a small tidbit from an article about herbs used to inhibit cancers):

journals.plos.org/plosone/a...

Atractylenoside-i inhibited AKT/PI3K/mTOR pathway to induce apoptosis and promoted caspase activation to upregulate apoptosis as well as downregulating IL-6 and other inflammatory processes (the MPN Labs studies mentioned these pathways as well):

cmjournal.biomedcentral.com...

Shows that AKT activation is a process in Jak2 mutated cell transformations (goes with above article):

pubmed.ncbi.nlm.nih.gov/212...

Shows that jak2 mutation induced MAPK activity is regulated by PI3K in proliferation (goes with above article on atractylenoside-i)

ncbi.nlm.nih.gov/pmc/articl...

Resveratrol (found in the Chinese herb Hu Zhang in high amounts) induced apoptosis in jak2 mutant tumor cells with 1.5-7x greater selectivity than those without, also synergized with jak2 inhibitor ruxolitinib, in lab cultures it inhibited polycythemia vera erythroid colonies:

pubmed.ncbi.nlm.nih.gov/263...

Angelica sinensis inhibits jak2 activity similarly to ruxolitinib and weakened anti-apoptopic effects of jak2 overexpression:

tjpr.org/admin/123899007981...

Shows TGF-b signaling contributes to Jak2 mutation clonal dominance:

ashpublications.org/blood/a...

Salvia/Astragalus compound exerts anti-fibrosis effect via TGF-b pathways (goes with above article, and NAC seems to work via this pathways as well):

sciencedirect.com/science/a...

These along with the ones I posted earlier seem to be showing great strides in research are being made in China when it comes to herbal supplements and how they affect multiple pathways all at once and there's been reports of remission being achieved with either single herbal therapy or combined with medication.

[EPguy in reply to gravityyaoi]

The mental health issue you had a top hazard with INF and it makes sense that you cannot use that agent. I have been paying very close attn to this in my start of Bes. Besremi has no specific indication of better results here and you would try that only with the closest watch of yourself and experts. There could be a supp somewhere that would help but this is a high risk test that is not at all a do it yourself project.

Some current research on MPN vaxes has some intended to "unmask" the Jak2 alleles. We had a recent thread on that. In contrast CALR is inherently more visible and is right now subject to a phase 1 trial of CAR-T therapy as I recall.

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Some random comments on the articles:

In the 1st link the star is C188-9 to control STAT3 and thus IL-6, one of the molecules we care about. . We can hope this agent will be part of future MPN trials.

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The one on Akt is specific to MPN and is directed to the agent LY294002. They note increased jak2 mutant mouse survival with the agent.

This reminds me of the mouse study that has been posted for NAC that was one reason the NAC studies are happening.

<<...NAC extends the lifespan of mice with MPN through a mechanism independent of cytoreduction.>>

ncbi.nlm.nih.gov/pmc/articl...

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The link on Resveratrol brings to mind the post:

healthunlocked.com/mpnvoice...

combining it with Rux had great results. For resv as a supp it seems more risky than some of the others, and my Dr, who is ok with supps in general, strongly advised to avoid casual use of this one.

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It makes sense China has an advantage in research on traditional meds, since it is well known and long used there. It's not exactly same as supplements since these have been tested for certain uses for a very long time and thus used safely as actual medicine, just not in the conventional way that science currently directs. It likely requires some modern attention to know the effect on the molecular issues that are a modern discovery, this is exactly the point of some of your links.

As with so many promising developments, it will require late stage clinical trials to get any of them in wide use in many countries. It would be exciting to see such results in ASH or the like. As I've noted, right now there are increasingly more new agents of interest than there are resources to study them, even with our condition getting all the money that "Cancer" tends to attract. (that's another post, the renaming of MPD as MPN Cancer opened up lots of new $ for our, and corporate, benefit).

In the meantime if there are MPN patients in China using these agents for benefit right now it would be great to hear their stories.

[gravityyaoi in reply to EPguy]

The poor bioavailability of resveratrol seems to be getting studied as well. It was found that when combined with a component of licorice the absorption rate was increased:

pubs.acs.org/doi/10.1021/ac...

And apparently this component in question is made by the body naturally via intestinal bacterial when licorice is consumed:

pubmed.ncbi.nlm.nih.gov/891...

Just shows the complex way in how all this works together. But his might be something to consider for those who do wish to try supplementing with resveratrol.

[EPguy in reply to gravityyaoi]

I also see your ref to ATO (arsenic). It's actually discussed in this post:

healthunlocked.com/mpnvoice...

And in this post re a trial on it:

healthunlocked.com/mpnvoice...

<<--ATO-INF <<These results have led to the planning of IFN and arsenic based clinical trial approaches for MPN patients.>> So unspecified experts are on top of this exciting new finding. We can hope to see a recruitment notice some time in the future.>>

--

There is also a new oral ATO under development that should be safer than prior versions:

<<ORH-2014 at 15 mg is safe, bioavailable, and provides the required arsenic exposure compared to intravenous arsenic trioxid>>

pubmed.ncbi.nlm.nih.gov/315...

--

So ATO-INF could be in our future.

[Island-Lady]

This is all super interesting. It brings up the question wouldn’t it be direct and effective to use rapamycin as an mTOR inhibitor? I know it is early days but it is being tested with other cancers.

[EPguy in reply to Island-Lady]

I had not heard of either of these before this. With mTOR now implicated in our concerns, anything that might address it is worth considering.

Problem is opportunities are multiplying faster than the resources to study them. At least for supps, we're sort of on our own. We are all part of a trial of sorts right here as we discuss them. If a supp is known to be generally safe and our qualified expert advisors agree, we will be learning from each other as we try various of them.

[Mostew in reply to EPguy]

Very interesting debate. As some of you know I take Curcumin liquid capsules . Not had a problem with them and hope some good being done. So hard to tell .

Unfortunately most conventional medics are not well up on natural remedies…

[EPguy in reply to Mostew]

From some of the comments on the other posts , it seems which exact Curc we select makes a difference. Hunter noted clear results, but has found one brand to be his preferred one.

Have you tried various formulas?

[Mostew in reply to EPguy]

Morning Yes I have used Geronova R plus curcumin and now CBD vital liquid capsules

Because I don't have any REALLY troublesome symptoms I suppose I'm taking it to hopefully prevent getting worse ..

Just come across this . Have you heard of it ?

Do hope you have a better Saturday than last one ...

[EPguy in reply to Mostew]

That's great to have not much broken, could be the supps are helping to keep it that way.

I'm not familiar with Levagen. As I've posted, there are far more opportunities than there are resources to test them. So we must select priorities.

For now I opt to consider Curc in this slow process, in particular the one Hunter's searching has found effective at least for him.

In a twist, I'm having a correlation (can't say causation) to improvement while on Lysine and regular NAC at 500. If/when this correlation stops, I'll start testing the Curc I just got. Meantime my husband has opted to try the new Curc for his leg pains, he never took any supp before. I'll update if any results there.

Thanks for the Saturday concern, today is way better than last week. (that correlation I noted still going)

[Mostew in reply to EPguy]

Levagen®+ - The Body’s Most Effective Anti-inflammatory Agent And Beyond

[Bluetop in reply to EPguy]

Thanks for all this information. I started taking curcumin (after Okd it with haem) for about a year and it did seem to be gradually allowing the reduction of hydroxy. (dropping 2 hydroxy a week). Until one day my platelets etc had risen again. I persevered but had to accept the need to increase my hydroxy dose again. I still take cucumin but not on a daily basis. I find it very beneficial for other inflammations such as joint/muscle aches.

[EPguy in reply to Bluetop]

A pattern on the joint issues. In our small sample it seems to help most in that area, as it has been shown in the studies.

Did you reduce the Curc after the HU increase? Is there a concern about interaction with the HU? The bottle we have calls for 2 pills/day.

My husband, who has no MPN but plenty of leg pains, will try it as a result of what I've learned here.

So far I don't think any supp will fully replace our "real" meds, but if they add comfort and QoL that is very worth it.

[Bluetop]

Yes, I did reduce the curc after the HU increase -I maybe should have stuck with it to see if it would bring the bloods down again, but it is very reassuring to know I have something for general pains as I don't tolerate paracetamol well. I encouaged my son to try cucumin for his eczema (as this is another JAK-Stat pathway issue) -it didn't seem to help -though he does include tumeric in his cooking.

[EPguy in reply to Bluetop]

I'm currently having several days in a row of not feeling trashed. I'm still taking NAC. But it could be details matter here, I'm now convinced the long release 600 formula is no good for me, and actually seems to make things worse. On the 500 regular ones I've found them milder and maybe actually helping.

I'm taking 500mg/day and also a Lysine supp. I tried lysine bec I happen to have some, it's an amino acid that's broadly good for MPN, and it's very mild (not suppose to do much) I felt better right after a started the Lysine but this is correlation, not causation. And last Saturday happened, a majorly bad day (while on Lysine and still on the sustained NAC)

I've had three really bad days sine 2021, that was #3.

The combo Lysine + regular NAC might be helping. I may hold off the Curc till this combo stops correlating to good days.

[Bluetop in reply to EPguy]

Sorry you are having a run of bad days. You do seem to be monitoring carefully. I hope you find a good balance that works.

[EPguy in reply to Bluetop]

Thanks for concern.

I don't have obvious physical aliments (except post covid and near the time of my Dx) ; there are so many members here that are of stronger will than I.

But the mental toll of the malaise is hard, and when I get bad days my husband goes down that hole right with me. He sees it in my eyes. That is very hard.

What keeps us here in spirits is learning together and seeing new therapies coming on line for hope that our bad days may get softer. Just the past 6 months, at least in the US, it's Besremi, Vongo. And exciting trials of Bomedemstat, Rusfertide, and the list gets bigger every year for every country to look forward to.

[PhysAssist]

I shoulda known that you'd have already posted this report- plus added valuta!Thanks,

PA