Hi - do you guys have any insights/experience on inhibiting p-selectin and glioblastoma?
https://www.sciencedaily.com/releases/2021/04/210412101853.htm
https://www.youtube.com/watch?v=yxra4mZgjS0
Hi, I have no experience with inhibiting p selecting, but these may be interesting:
https://www.nature.com/articles/aps200859.pdf?origin=ppub
Kind regards,
Daniel
Heparin: Great Value in Cancer Treatment
https://cancertreatmentsresearch.com/heparin-great-value-in-cancer-treatment
P-selectin binds to heparan sulfate and fucoidans. Both are sulfated polysaccharides. Heparan sulfate is a member of the glycosaminoglycan family of carbohydrates and is very closely related in structure to heparin.
Heparin, commonly known as an anticoagulant, is a highly sulfated form of heparan sulfate. Both consist of a variably sulfated repeating disaccharide unit.
The most common disaccharide unit within heparan sulfate is composed of a glucuronic acid (It is found in many gums such as gum arabic, xanthan, and kombucha tea) linked to N-acetylglucosamine.
Heparin is a strong inhibitor of heparanase, the enzyme that breaks down heparan sulfate, so inhibiting heparanase means inhibiting p-selectin.
Compounds that may decrease expression of P-selectin:
- Aspirin *
- Tretinoin
- Amlodipine
- Cimetidine *
- Clopidogrel
- Diclofenac
- Enalapril
- Genistein *
- Nebivolol
- Parthenolide/Feverfew *
- Pravastatin
- Progesterone
- Resveratrol
- Rosuvastatin
- Sertraline
- Simvastatin
- Testosterone
https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=737162
5-HT2A antagonists, Cyproheptadine and pizotifen, inhibit P-selectin expression in human platelets.
https://pubmed.ncbi.nlm.nih.gov/24466319
Dipyridamole, a blood thinner, prevents P-selectin expression in the vascular beds.
https://pubmed.ncbi.nlm.nih.gov/11149578
Anti-platelet, anti-thrombotic, anti-histamine, anti-serotonin, anti-depressant, anti-migraine drugs appear to decrease P-selectin expression!
https://pubmed.ncbi.nlm.nih.gov/23736780/
Effects of magnoline on P-selectin's expression in diabetic rats and its reno-protection
Systematic Review and Meta-Analysis of the Effect of Statins on Circulating E-Selectin, L-Selectin, and P-Selectin
The pleiotropic effects of statins might involve preventing inflammatory cell adhesion to the endothelium, which is a critical step in the pathogenesis of atherosclerosis. We conducted a systematic review and meta-analysis of the effects of statins on the circulating cell adhesion molecules E-Selectin, L-Selectin, and P-Selectin. A literature search was conducted in PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 61 studies, statins significantly reduced P-selectin (standard mean difference, SMD = −0.39, 95% CI −0.55 to −0.22, p < 0.001; moderate certainty of evidence), L-selectin (SMD = −0.49, 95% CI −0.89 to −0.10, p = 0.014; very low certainty of evidence), and E-Selectin (SMD = −0.73, 95% CI −1.02 to −0.43, p < 0.001; moderate certainty of evidence), independently of baseline lipid profile and other study and patient characteristics. The corresponding pooled SMD values in sensitivity analysis were not substantially altered when individual studies were sequentially removed. Simvastatin had a significant lowering effect on both P-selectin and E-selectin. Therefore, statins significantly reduce circulating selectins. Further studies are required to investigate whether selectin lowering mediates cardiovascular risk reduction with these agents.
https://www.mdpi.com/2227-9059/9/11/1707
Interesting, Simvastatin is made from the fungus Aspergillus terreus. It's a lipophilic statin, which I guess is an anion (negative charge), because heparan sulfate is also an anion and we know that p-selectin binds to it.
Unfortunately, there is no online tool to determine the lipophilic/hydrophilic and anionic/cationic properties of a drug!
P-selectin expression is induced by two distinct mechanisms. First, P-selectin is synthesized by megakaryocytes and endothelial cells, where it is sorted into the membranes of secretory granules. When megakaryocytes and endothelial cells are activated by agonists such as thrombin, P-selectin is rapidly translocated to the plasma membrane from granules. Secondly, increased levels of P-selectin mRNA and protein are induced by inflammatory mediators such as tumor necrosis factor-a (TNF-a), Lipopolysaccharide (LPS), and interleukin-4 (IL-4). Although TNF-a and LPS increase levels of both mRNA and protein in murine models, they do not appear to affect mRNA in human endothelial cells, while IL-4 increases P-selectin transcription in both species. The elevated synthesis of P-selectin may play an important role in the delivery of protein to the cell surface. In ischemic stroke patients, plasma P-selectin concentration was reported to be highly correlated to plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator activity.
https://en.wikipedia.org/wiki/P-selectin
Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. This is fundamental for the leeches' habit of feeding on blood, since it keeps a host's blood flowing after the worm's initial puncture of the skin.Hirudin is the most potent natural inhibitor of thrombin. Unlike antithrombin, hirudin binds to and inhibits only the activated thrombin, with a specific activity on fibrinogen. Therefore, hirudin prevents or dissolves the formation of clots and thrombi (i.e., it has a thrombolytic activity), and has therapeutic value in blood coagulation disorders, in the treatment of skin hematomas and of superficial varicose veins, either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such as heparin, as it does not interfere with the biological activity of other serum proteins, and can also act on complexed thrombin.
https://en.wikipedia.org/wiki/Hirudin
Therefore, Leech therapy may be an option to contain P-selectin!
]L-4, TNF-a, LPS and PAI-1 Inhibitors also help to reduce p-selectin production.
TNF-alpha Inhibitors
- Vagus nerve stimulation [92]
- Ketosis [93]
- Acute psychological stress [94] and Glucocorticoids/Cortisol [95] (not recommended)
- Calorie restriction [96]
- Yoga [97]
- Tai Chi [98]
- Wim Hof Breathing/Meditation [99]
- Cycling [98]
- Mediterranean diet [100]
- Elemental diet for lectin sensitive [101].
- Napping after sleep loss [102].
- Falling in love, having sex, nursing, and positive social encounters. All of these lead to increased oxytocin [103]. L Reuteri also increases oxytocin [104].
- LLLT [105, 106, 107]
- Elemental diet [101]/ Lectin avoidance diet if lectin sensitive
- Fish Oil/DHA+EPA [108]
- Fasting [109]
- Exercise
- PQQ [110]
- Curcumin [111, 112]
- EGCG [113]
- Cinnamon/Sodium Benzoate [114, 115]
- Black Cumin Seed Oil [116]
- Rooibos [117]
- Carob [118]
- Nicotinamide Riboside NAD+ [119]
- Kombucha [120]
- Hops (xanthohumol) [121]
https://selfhack.com/blog/supplements-lifestyle-factors-influence-tnf-interleukin-6-il-6
Factors that May Reduce LPS
1) Prebiotics
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@aliml2 if i read this correctly Simvastatin had the best effect and Atorvastatin didn't have any. If we use Simvastatin for the COC protocol i guess we double dip in this strategy also?
@aliml2 Some years ago I have considered having this as a continuous option and have concluded it has more disadvantages than advantages. Specifically during the years when some strong debates were going on between visitors. But on the other hand, this function is needed to correct typing errors etc., and as a result it has been made an option for (as I remember) 5 min after posting, or something like that. If the error is observed at a latter time, you let me know, and I will help with the correction.
If that edit only comes from time to time, I cannot do anything about it since we have no technical support (other than myself) as there is little support for the website from the readers (i like to thank Tim and Chris48 who recently supported the website). What we have is used to pay the web hosting. Therefore, I do what I can in the available time.
Thanks for understanding.
Kind regards,
Daniel
@aliml2 Some years ago I have considered having this as a continuous option and have concluded it has more disadvantages than advantages. Specifically during the years when some strong debates were going on between visitors. But on the other hand, this function is needed to correct typing errors etc., and as a result it has been made an option for (as I remember) 5 min after posting, or something like that. If the error is observed at a latter time, you let me know, and I will help with the correction.
If that edit only comes from time to time, I cannot do anything about it since we have no technical support (other than myself) as there is nearly zero support for the website from any of the readers. Therefore, I do what I can and the available time.
Thanks for understanding.
Kind regards,
Daniel
@daniel I'd buy your supplements for my own use or would recommend them here where I live but supplements sent via FedEx or other couriers just don't get thru customs here, only if they are sent via regular post but you don't have that shipping option. Would you consider adding such a shipping option?
@j we do have the option to send them via regular post (such as PostNL or Deutsche Post) but using such options, once we send them out we can only pray they get to the customer, since tracking is very poor, and it is very difficult to recover the money if it is lost.
This is why we typically prefer FedEx or UPS - speed, responsibility and clarity on every step while the parcel is moving.
However, we can test a small package, with Deutsche Post, and see if it gets through.
@j we do have the option to send them via regular post (such as PostNL or Deutsche Post) but using such options, once we send them out we can only pray they get to the customer, since tracking is very poor, and it is very difficult to recover the money if it is lost.
This is why we typically prefer FedEx or UPS - speed, responsibility and clarity on every step while the parcel is moving.
However, we can test a small package, with Deutsche Post, and see if it gets through.
Great! However, I only see the following shipping options:
Standard Shipping (DHL or FedEx, 6-20 business days)
Premium Shipping (FedEx, 3-10 business days)
Express Shipping (UPS, 1-6 business days)
My experience with the regular post is very good, and I have tried it from many corners of the world. I'd say 90% gets delivered. It does take longer but at least for me it's so much more convenient. Everything that is sent via the couriers is retained not only for tax purposes but in the case of supplements almost always I get a notice that I have to request permission from the local health authorities and that's way too much trouble.
