PART 2 - AN IL8 INVESTIGATIONIn Part 1 we tackled a basic...

PART 2 - AN IL8 INVESTIGATION

In Part 1 we tackled a basic definition of what an Interleukin is. We saw that it can result in many adverse outcomes if left unchecked. But at the same time we still need some of it as a bodily warning system. A trigger to act. We then delved into some great observations as to what iPPS can do for these inflammatory markers once they are out of control.

Part 2 seeks to build on this base...we will discover more about the pathetic standard of care, we will observe other such biomarkers and what iPPS can do. We will also tackle a very unusual inflammatory condition.

Lets pick up with a quote on the drug Dexamethasone:


"Another established side effect of Dexamethasone is that it can cause steroid induced psychiatric reactions, including psychosis, mood changes, behavioural disturbance and cognitive dysfunction. These symptoms can develop within days of a 5 mg single dose even in those who have no psychiatric history."^2b

GFAP - MARKER

Another biomarker is one that is called GFAP. GFAP stands for Glial Fibrillary Acidic protein.⁸ To be precise, it is a gene that effectively issues instructions to cells as to what to produce.

The way to think of GFAP's is like the architects of the Sydney Harbour Bridge. (Yes yes Edski, its also similar to your Golden Gate Bridge).

The GFPA gene effectively provides the instructions for making a protein called GFAP which in turn makes filament proteins that provide the strength and support to cells.


All those thick fibre of metal cables that support and suspend the bridge platform on which thousands of cars and trucks and even trains (Sydney) pass over each and every day. Not unlike this, GFAP protein lends itself via binding to support the astroglial cells. What are these? These are cells that in turn support and nourish the all important cells in the brain and yes, the spinal cord. I'm talking important tissues here indeed.



_{Equating to a bridge supported by high tensile strength cabling, not completely unlike the fibrous nature of GFAP production.}

So how about a pic⁷ displaying not one, but three distinct areas of the brain and what our iPPS does...





What you are viewing above is a reduction of neural inflammatory markers as a direct result of PPS. The "Squigglies" as stated by Dr Simonaro are much less pronounced after PPS treatment in rat's brains. Let me state fro the record, once the appropriate authorities get wind of this and realise what they have, its going to have material ramifications for us. Watch this space indeed, but also do have patience. This stuff can take time eh'? One day it will translate for us (my views) and many will wonder who were the first few shareholders that caught on to this one early enough to make something of it.


WHY DOES IT WORK?

Before I even tackle the WHY...I want you to know why is the WHY important? We don't really need to know why it works...we just need to know itdoeswork, at least in maybe 20%...maybe 30% of the patients. (In actual fact some almost90%patients get at leastsomeefficacy).

When I invest I don't just want the POSTIVIES...yeah I want to hear about the NEGATIVES, yes you know who you are, all those guys that think I'm way too upramping...those guys that incorrectly say I never look at the negatives. I now only DONT ignore the negatives, I call for them. I want YOU to bring them to us and show me what they are so we can carefully research them to see if if we have a problem.

Where am I going with this? iPPS for the positive has strong Anti Inflammatory properties, but for all you DOWN rampers....it is NON IMMUNOSUPPRESSANT. What does that mean, it means one of the reasons we don't see many or any material side effects is that it is not simply blocking out these interleukins, its downregulating them....you should not (in my opinion) simply cut off...block ALL IL activity. That would actually be counterproductive. The body still needs *some* IL's. IL6 is the best example. If you are new tome...read this --->The good the bad and the ugly for a clear argument on why we still need some of the IL's. Blocking them totally can be equally disastrous as evidenced by the results of drugs that are total blockers such as Tanezumab. Great efficacy, on err... par with us....But the cost was too high in terms of side effects and despite it leading to just 2.5% or so of additional joint replacements in the drug cohort during the trial, it was deemed too much for the FDA to accept.


"Because cases of joint destruction and total joint replacement continue to rise after 1year of treatment, we consider the trajectory of this risk, when extrapolated to years of therapy, to be uncertain." ⁹

- FDA 2021


As mentioned, we do need some IL-8, but there is a limit. It was found on one study that burn victims that recovered from their injuries had a limited amount of IL8, those that didn't continued to have an excessive amount of IL8 present, in fact ther researchers in this case suggested the cut off to be around 234 pg/ml."A more recent study has shown that in 468 paediatric burn patients, concentrations of IL-8 that met or exceeded a cut off limit of 234 pg/ml were associated with higher independence of MOF, sepsis and mortality".¹⁰
THE IL1 BONUS

While investigating IL8 I came across the other IL's in fact in the Appendix B you will see them all listed with a brief (non Mozz) blurb of what they all do. The one I wanted to specifically point you was IL-1.


"IL- 1 causes lymphocyte activation, macrophage stimulation, increased leukocyte/endothelial adhesion, fever due to hypothalamus stimulation, and release of acute phase proteins by the liver. It may also cause apoptosis in many cell types and cachexia".³


I get shivers down my spine when I see the word apoptosis, its not a word you want to see when dealing with biology....it means cell death. IL-1 actually lowers pain thresholds and leads to tissue damage. Its another nasty that we want to control.

So here we are sitting here today waiting patiently for OA and MPS to playout....but Paradigmers, while I wait patiently, I have eyes on further away prizes.... Yeah I'm talking DMOAD but I'm also talking other inflammatory led indications....IL-1 is the perfect example. Experiments have been done via blocking IL-1, this led to the conclusion that this resulted in less severity of diseases....some of which included diseases that were considered to be inflammatory.⁴


Examples?


This is the mind blowing bit....

Type 2 Diabetes

Heart Failure


...and wait for it......sitting down?



Loss of hearing.


Have a look at those three indicators above:

1) Type2 diabetes is estimated to be a 58.7 Billion dollar market by 2025 with a compound growth rate of 6.5%.⁵ It affects some 37 million Americans right now.⁶

2) Heart Failure, well we already know this is the number 1 killer in the world...but did you know we have already started tackling it?
Proof please Mozz, where are you getting this from?





3) Hearing loos?

Mate, perhaps not many are affected by this (around 15 out of every 100,000 people ¹⁴ ) but think of the level of benefit we could one day provide.


Hearing loss can be an inflammatory condition? Wait till I tell my friend @avemaria, he is the one that keeps reminding me of the some 2000 inflammatory type conditions there are to address.



CONCLUSION

We've seen just how destructive IL 8 can be. We have seen the ramifications but we have also seen what a great biomarker it is for what's happening in the serum and in the brain. If we can reduce the levels of IL - 8 in an inflammatory setting and reduce it safely....well its an entire new branch of available and intriguing possibilities....lucrative?

Well if YOU had a degenerative brain condition and you were offered two solutions, one with a list of possible side effects too long for a Mozz post, compared to another Drug that's new but has virtually NO side effects and certainly no Adverse Show stopping side effects, I know which one I would choose!

Yes I, like you want everything to go up here and NOW....but it is the long long term where this story looks the brightest. Stay patient.



As usual, DYOR


APPENDIX A


Dexamethosone side effects
Reference:https://www.mayoclinic.org/drugs-supplements/dexamethasone-oral-route/side-effects/drg-20075207

Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

·Aggression

·agitation

·anxiety

·blurred vision

·decrease in the amount of urine

·dizziness

·fast, slow, pounding, or irregular heartbeat or pulse

·headache

·irritability

·mental depression

·mood changes

·nervousness

·noisy, rattling breathing

·numbness or tingling in the arms or legs

·pounding in the ears

·swelling of the fingers, hands, feet, or lower legs

·trouble thinking, speaking, or walking

·troubled breathing at rest

·weight gain

Incidence not known

·Abdominal or stomach cramping and/or burning (severe) or pain

·backache

·bloody, black, or tarry stools

·cough or hoarseness

·darkening of the skin

·decrease in height

·decreased vision

·diarrhea

·dry mouth

·eye pain

·eye tearing

·facial hair growth in females

·fainting

·fatigue

·fever or chills

·flushed, dry skin

·fractures

·fruit-like breath odor

·full or round face, neck, or trunk

·heartburn and/or indigestion (severe and continuous)

·increased hunger

·increased thirst

·increased urination

·loss of appetite

·loss of sexual desire or ability

·lower back or side pain

·menstrual irregularities

·muscle pain or tenderness

·muscle wasting or weakness

·nausea

·pain in the back, ribs, arms, or legs

·painful or difficult urination

·skin rash

·sleeplessness

·sweating

·trouble healing

·trouble sleeping

·unexplained weight loss

·unusual tiredness or weakness

·vision changes

·vomiting

·vomiting of material that looks like coffee grounds

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your healthcare professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:


.More common

·Increased appetite


.

Incidence not know

·Abnormal fat deposits on the face, neck, and trunk

·acne

·dry scalp

·lightening of normal skin color

·red face

·reddish purple lines on the arms, face, legs, trunk, or groin

·swelling of the stomach area

·thinning of the scalp hair

Other side effects not listed may also occur in some patients. If you notice any other effects,check with your healthcare professional.

APPENDIX B

Interleukin breakdown

Reference: (https://www.ncbi.nlm.nih.gov/books/NBK499840/)

Function

Interleukin-1 (IL-1)

Macrophages, large granular lymphocytes, B cells, endothelium, fibroblasts, and astrocytes secrete IL-1. T cells, B cells, macrophages, endothelium and tissue cells are the principal targets. IL-1 causes lymphocyte activation, macrophage stimulation, increased leukocyte/endothelial adhesion, fever due to hypothalamus stimulation, and release of acute phase proteins by the liver. It may also cause apoptosis in many cell types and cachexia.[2][3][4][5]

Interleukin-2 (IL-2)

T cells produce IL-2. The principal targets are T cells. Its primary effects are T-cell proliferation and differentiation, increased cytokine synthesis, potentiating Fas-mediated apoptosis, and promoting regulatory T cell development. It causes proliferation and activation of NK cells and B-cell proliferation and antibody synthesis. Also, it stimulates the activation of cytotoxic lymphocytes and macrophages.[6][7]

Interleukin-3 (IL-3)

T cells and stem cells make IL-3. It functions as a multilineage colony-stimulating factor.[8][9]

Interleukin-4 (IL-4)

CD4+T cells (Th2) synthesize IL-4, and it acts on both B and T cells. It is a B-cell growth factor and causes IgE and IgG1 isotype selection. It causes Th2 differentiation and proliferation, and it inhibits IFN gamma-mediated activation on macrophages. It promotes mast cell proliferation in vivo.[7]

Interleukin-5 (IL-5)

CD4+T cells (Th2) produce IL-5, and its principal targets are B cells. It causes B-cell growth factor and differentiation and IgA selection. Besides, causes eosinophil activation and increased production of these innate immune cells.[1]

Interleukin-6 (IL-6)

T and B lymphocytes, fibroblasts and macrophages make IL-6. B lymphocytes and hepatocytes are its principal targets. IL-6 primary effects include B-cell differentiation and stimulation of acute phase proteins.[1][10][1]

Interleukin-7 (IL-7)

Bone marrow stromal cells produce IL-7 that acts on pre-B cells and T cells. It causes B-cell and T-cell proliferation.[11]

Interleukin-8 (IL-8)

Monocytes and fibroblasts make IL-8. Its principal targets are neutrophils, basophils, mast cells, macrophages, and keratinocytes. It causes neutrophil chemotaxis, angiogenesis, superoxide release, and granule release.[12]

Interleukin-9 (IL-9)

Th9, Th2, Th17, mast cells, NKT cells, and regulatory T cells produce this cytokine. It enhances T-cell survival, mast cell activation and synergy with erythropoietin.[13]

Interleukin-10 (IL-10)

Th2 cells produce IL-10. Its principal targets are Th1 cells. It causes inhibition of IL-2 and interferon gamma. It decreases the antigen presentation, and MHC class II expression of dendritic cells, co-stimulatory molecules on macrophages and it also downregulates pathogenic Th17 cell responses. It inhibits IL-12 production by macrophages.[14][15]

Interleukin-11 (IL-11)

Bone marrow stromal cells and fibroblasts produce IL-11. The IL-11 principal targets are hemopoietic progenitors and osteoclasts. The IL-11 primary effects include osteoclast formation, colony stimulating factor, raised platelet count in vivo, and inhibition of pro-inflammatory cytokine production.[16]

Interleukin-12 (IL-12)

Monocytes produce IL-12. Its principal targets are T cells. It causes induction of Th1 cells. Besides, it is a potent inducer of interferon gamma production by T lymphocytes and NK cells.[16]

Interleukin-13 (IL-13)

CD4+T cells (Th2), NKT cells and mast cells synthesize IL-13. It acts on monocytes, fibroblasts, epithelial cells and B cells. The IL-13 significant effects are B-cell growth and differentiation, stimulates isotype switching to IgE. It causes increased mucus production by epithelial cells, increased collagen synthesis by fibroblasts and inhibits pro-inflammatory cytokine production. Also, IL-13 works together with IL-4 in producing biologic effects associated with allergic inflammation and in defense against parasites.[17]

Interleukin-14 (IL-14)

T cells produce IL-14, and its principal effects are stimulation of activated B cell proliferation and inhibition of immunoglobulin secretion.

Interleukin-15 (IL-15)

Monocytes, epithelium, and muscles make IL-15. It acts on T cells and activated B cells. It causes the proliferation of both B and T cells. It causes NK cell memory and CD8+ T cell proliferation.

Interleukin-16 (IL-16)

Eosinophils and CD8+T cells synthesize IL-16. Its principal target is CD4+ T cells. It causes CD4+ T cell chemoattraction.

Interleukin-17 (IL-17)

This cytokine is produced by Th-17. It acts on epithelial and endothelial cells. IL-17 main effects are the release of IL-6 and other pro-inflammatory cytokines. It enhances the activities of antigen-presenting cells. It stimulates chemokine synthesis by endothelial cells.[18][19]

Interleukin-18 (IL-18)

Macrophages mostly make IL-18, which can be produced by hepatocytes and keratinocytes. Its principal target is a co-factor in Th1 cell induction. It causes interferon gamma production and enhances NK cell activity.

Interleukin-19 (IL-19)

Th2 lymphocytes synthesize IL-19 and acts on resident vascular cells in addition to immune cells. It is an anti-inflammatory molecule. It promotes immune responses mediated by regulatory lymphocytes and has substantial activity on microvascular.[20]

Interleukin-20 (IL-20)

Immune cells and activated epithelial cells secrete IL-20. It acts on epithelial cells. It plays a vital role in the cellular communication between epithelial cells and the immune system under inflammatory conditions.

Interleukin-21 (IL-21)

NK cells and CD4+ T lymphocytes make IL-21. It acts on various immune cells of innate and the adaptive immune systems. IL-21 promotes B and T lymphocyte proliferation and differentiation. It enhances NK cell activity.[21]

Interleukin-22 (IL-22)

Different cells in both innate and acquired immunities produce IL-22, but the primary sources are T cells. Th22 cell is a new line of CD4+ T cells, which differentiated from naive T cells in the presence of various pro-inflammatory cytokines including IL-6. IL-22 inhibits IL-4 production. It also has essential functions in mucosal surface protection and tissue repair.[22]

Interleukin-23 (IL-23)

Macrophages and dendritic cells mainly synthesize IL-23. It acts on T cells causing maintenance of IL-17 producing T cells.[19]

Interleukin-24 (IL-24)

Monocytes, T and B cells mostly make IL-24. It causes cancer-specific cell death, causes wound healing and protects against bacterial infections and cardiovascular diseases.[23]

Interleukin-25 (IL-25)

Dendritic cells produced predominantly IL-25. It acts on various types of cells, including Th2 cells. It stimulates the synthesis of Th2 cytokine profile including IL-4 and IL-13.[24]

Interleukin-26 (IL-26)

It is strongly associated inflammatory activity with IL-26. Th17 cells produce this interleukin. It acts on epithelial cells and intestinal epithelial cells. It induces IL-10 expression, stimulates the production of IL-1-beta, IL-6, and IL-8 and causes Th17 cell generation.

Interleukin-27 (IL-27)

T cells make IL-27 that activates STAT-1 and STAT-3, which regulates immune responses. IL-27 stimulates IL-10 production. It is a pro-inflammatory molecule and upregulates type-2 interferon synthesis by natural killer cells.[10]

Interleukin-28 (IL-28)

Regulatory T-cells synthesize IL-28, which acts on keratinocytes and melanocytes. It stimulates cell presentation of viral antigens to CD8+T lymphocytes. IL-28 also upregulates TLR-2 and TLR-3 expression. IL-28 enhances the keratinocyte capacity to recognize pathogens in the healthy skin.

Interleukin-29 (IL-29)

IL-29 is a type-3 interferon and produced by virus-infected cells, dendritic cells, and regulatory T-cells. It upregulates viral protective responses. Virus-infected cells may regulate IL-29 genome.

Interleukin-30 (IL-30)

Monocytes mainly produce IL-30 in response to TLR agonists including bacterial LPS. It acts on monocytes, macrophages, dendritic cells, T and B lymphocytes, natural killer cells, mast cells, and endothelial cells.[10]

Interleukin-31 (IL-31)

IL-31 is produced mainly by Th2 cells and dendritic cells. It is a proinflammatory cytokine and a chemotactic factor that direct polymorphonuclear cells, monocytes, and T cells to inflammatory lesions. IL-31 induces chemokines production and synthesis of IL-6, IL-16, and IL-32.

Interleukin-32 (IL-32)

IL-32 is a pro-inflammatory molecule. Natural killer cells and monocytes mainly produce it. IL-32 induces the synthesis of various cytokines including IL-6, and IL-1beta. It inhibits IL-15 production.[25]

Interleukin-33 (IL-33)

Mast cells and Th2 lymphocytes express IL-33 that acts on various innate and immune cells including dendritic cells and T and B lymphocytes. It mediates Th2 responses and therefore participates in the protection against parasites and type-I hypersensitivity reaction.

Interleukin-34 (IL-34)

Various phagocytes and epithelial cells synthesize Interleukin-34 (IL-34). It enhances IL-6 production and participates in the differentiation and development of antigen-presenting cells including microglia.[26]

Interleukin-35 (IL-35)

Regulatory B cells mainly secrete it. One of the primary functions of this interleukin is its involvement in lymphocyte differentiation. It exhibits an immune-suppressive effect.

Interleukin-36 (IL-36)

Phagocytes mainly make IL-36. It acts on T lymphocytes and NK cells regulating the IFN-γ synthesis. It stimulates the hematopoiesis and expression of both MHC class I and II molecules as well as intracellular adhesion molecules (ICAM)-1.

Interleukin-37 (IL-37)

IL-37 plays an essential role in the regulation of the innate immunity causing immunosuppression. Phagocytes and organs including the uterus, testis, and thymus express it. IL-37 upregulates immune responses and inflammation in autoimmune disorders.

Interleukin-38 (IL-38)

Il-38 acts on T cells and inhibits the synthesis of IL-17 and IL-22. The placenta, tonsil's B lymphocytes, spleen, skin, and thymus widely express IL-38.[27]

Interleukin (IL-39)

B lymphocytes mainly produce IL-39. It acts on neutrophils inducing their differentiation or expansion.[28]

Interleukin-40 (IL-40)

IL-40 is produced in the bone marrow, fetal liver, and by activated B cells. IL-40 plays a vital role in the development of humoral immune responses.[29]

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Clinical Significance

Clinical significance of some cytokines are listed below:[1][28][29][30]

• IL-1 acts on the hypothalamus to induce fever and is therefore called an endogenous pyrogen. It operates on hepatocytes to increase synthesis of specific serum proteins, such as amyloid A protein and fibrinogen. It causes fall in blood pressure or shock in large amounts. Corticosteroids inhibit the IL-1 effect.
• Gene knockout mouse studies have provided evidence that the primary IL-2 function in vivo is the suppression of T responses. Mice lacking IL-2 or its receptor (CD25) develop lymphadenopathy and T cell-mediated autoimmunity.
• Knockout mice lacking IL-10 develop inflammatory bowel disease, probably because of uncontrolled activation of macrophages reacting to enteric microbes.
• IL-12 overproduction causes allergic disorders. Corticosteroids inhibit the effects of IL-12.
• IL-19 may be used to induce angiogenesis in ischemic tissue.
• The administration of IL-21 may be considered for use as a preventive and therapeutic approach when dealing with Th2-mediated allergic diseases.
• IL-26 shows high expression in psoriatic skin lesions, colonic lesions from individuals with inflammatory bowel disease and synovia of individuals with rheumatoid arthritis. It may constitute a promising target to treat chronic inflammatory disorders.
• IL-27 was found to exerts anti-inflammatory effects in several experimental autoimmune models. IL-27 treatment suppressed autoimmune diabetes.
• IL-28 may be sufficient treatment of HCV patients.
• IL-29 is a marker of osteoarthritis as joint inflammation implicates it.
• IL-36 also seems to play a significant role in human psoriasis. In psoriatic lesion tissues, IL-36 levels were found to be elevated, and generalized pustular psoriasis was also discovered, which is rare and life-threatening.
• In lupus patients were elevated IL-37 levels in comparison with healthy controls, and mucocutaneous and renal involvement was correlated with high disease activity.
• Recent studies point to an association between IL-38 and autoimmune diseases. Its role in carcinogenesis or cancer growth is unclear.
• IL-39 secreted by activated B cells may be a critical pro-inflammatory cytokine and a potential therapeutic target for the treatment of autoimmune diseases such as systemic lupus erythematosus.
• IL-40 expression in several human B-cell lymphomas suggests that it may play a role in the pathogenesis of these diseases.

REFERENCES

0] https://www.hindawi.com/journals/iji/2011/908468/
1] https://www.spandidos-publications.com/10.3892/ijo.2015.3234
2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827827/
2a] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cerebrospinal-fluid
2b] https://www.nature.com/articles/s41415-020-2238-7
3] https://www.ncbi.nlm.nih.gov/books/NBK499840/
4] https://www.ncbi.nlm.nih.gov/books/NBK499840/
4]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644509/
5] https://drug-dev.com/global-type-2-diabetes-market-set-to-almost-double-to-58-7-billion/#:~:text=The%20global%20type%202%20diabetes,research%20and%20consulting%20firm%20GlobalData
6] 58-7-billion/#:~:text=The%20global%20type%202%20diabetes,research%20and%20consulting%20firm%20GlobalData.
6] https://www.cdc.gov/diabetes/basics/type2.html#:~:text=More%20than%2037%20million%20Americans,adults%20are%20also%20developing%20it.
7]
8] https://medlineplus.gov/genetics/gene/gfap/
9] https://www.healio.com/news/rheumatology/20210325/fda-panel-rejects-pfizers-tanezumab-for-osteoarthritis-pain-over-riskbenefit-doubts#:~:text=%E2%80%9CTanezumab%20carries%20the%20risk%20of,of%20therapy%2C%20to%20be%20uncertain.
10] Biomarkers in Burn Patient Care. Amina El Ayadi, ... Celeste C. Finnerty, in Total Burn Care (Fifth Edition), 2018.
11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428389/
12] https://pubmed.ncbi.nlm.nih.gov/21454676/