Peptides / Bioregulators

[cl-user]

These are 5/16 31G insulin needles

[Steve_Combi]

I’m about to start an experiment with LL 37

Our daughter (51y/o) has ischemic bladder due to recurring UTI’s that don’t resolve. Or UTI’s due to ischemia, not sure about the chicken and egg part of this one. So I got some IL 37 in today and she will start on Monday or as soon as I’ve sorted out dosing. If anyone here has any experience with this peptide, I’m all ears! (or eyes )

LL-37, the master antimicrobial peptide, its multifaceted role from combating infections to cancer immunity

https://www.sciencedirect.com/science/article/abs/pii/S0924857924003145b

The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent

Little peptide, big effects: the role of LL-37 in inflammation and autoimmune...

One of the antibiotics she was prescribed 5 years ago caused her to be “floxed”

Floxed by Cipro at 22: ‘A Bomb Went Off in My Body’

We are hoping for relief for both or even one of these conditions. She is just finishing up a 4 week TA-1 routine but no great improvement yet.

edited to remove mis-leading info on IL37 and added more info on LL 37

[Bicep]

I’m confused about whether you’re looking at the peptide LL37 or interleukin IL37. It sounds like the latter. But LL37 is a great one and antimicrobial, made by many cells in the body. I’m curious how it comes out if you can buy that stuff. I’m interested. IL 37, I have no idea if this is a peptide.

[Steve_Combi]

@Bicep

peptide LL37 or interleukin IL37

What I have is LL 37 peptide

My post on this is way off base LoL! for some reason I got the 2 mixed up. I’ll edit that post to clarify that.

I checked with my supplier and they don’t have IL37 but they do have an interesting selection of anti-virals.

[Ludovic]

I came across this very interesting article about the peptide Thymosin beta-4 and the heart. I plan to use this peptide the day after 3 hour long trail runs I do every 2 weeks because i have genetic hypertrophic cardiomyopathy;

https://www.sciencedirect.com/science/article/pii/S1567576923000644#s0040

[Steve_Combi]

@Ludovic

peptide Thymosin beta-4

There are 3 versions available;
TB500 (frag 1-4)
TB500 (frag 17-23)
TB500 (Full 43)

Frag = fragment, this is commonly done with peptides, to isolate a portion of the full peptide and use fragments for specific functions. I’ve been taking TB500 (frag 1-4) every morning (evry 2 months I take a week off) for about 15 months, in combination with BPC-157

The full version is the complete peptide of TB-4, not commonly available
Most common is TB500 (frag 1-4) with (frag 11-23) second in availability.

Utilizing Developmentally Essential Secreted Peptides Such as Thymosin Beta-4...

[Davin8r]

@Steve_Combi

The full version is the complete peptide of TB-4, not commonly available

Hey Steve, everything I’ve read says the opposite – that TB4 is the one universally available and the “real” TB500 (the frag) is nearly impossible to find. Are you sure you’ve got that right?

[Steve_Combi]

@Steve_Combi

I’m about to start an experiment with LL 37

Our daughter (51y/o) has ischemic bladder due to recurring UTI’s

I’m impressed with LL 37, it has helped our daughter in a very short period of time, and she has been doing a UTI test every couple of days and seeing positive results but…

It’s not fully resolved yet and seems to be 2 steps forward and 1 back for her. Probably due to being on various antibiotics 6 to 7 times a year for the past 8 years and most likely hosting a variety of resistant pathogens. Once we see where this goes I’ll post the test results.

For me, I’ve been fighting a little thing for nearly 2 years that has been “chronic” it presents for 4 to 5 days a week, rarely more than 3 days without being present. Since I started LL 37 I’ve been free of this thing for 10 days now. Super happy with that result.

My reason for getting this one is is that it is anti-microbial, anti-viral and anti-fungal. Since most infectious pathogens modify our immune system to be able to “hide”, we can become more susceptible to that pathogen, Some of these like EBV are in us forever. with 90% of humans being infected with this one.

My thought process was to, hopefully, clear out any residual pathogens in the hopes that my immune system would become more robust.

Many of these residual pathogens and the modifications they make are root causes of various disease and conditions.

A study published in Nature Genetics details similar clusters suggesting that EBV also plays a role in six other diseases: multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease

Epstein-Barr Virus Linked to Seven Serious Diseases | Breakthrough Discoveries

[Steve_Combi]

@Davin8r

that TB4 is the one universally available and the “real” TB500 (the frag) is nearly impossible to find. Are you sure you’ve got that right?

There is some confusion on this one due to the terminology used online.

The TB500’s are typically fragments of Tb-4 but due to ease of online marketing all TB500’s have become generically known as Thymosin b-4, so three “versions”

If we start with the “real” Thymosin beta-4 we can see it is a 43 amino peptide that our body makes. Unless other wise specified the TB500’s are fragments, so the one known as TB500 (Full) or (Full 43) or (Full 43aa) would be the “real” Tb-4

If you see TB500 available online, check to see which version it is.

Thymosin beta-4

[cl-user]

According to ChatGPT the Frag 1-4 is the least useful one:

@ChatGPT o1

• TB500 (Frag 1–4): Very short, uncertain biological effect, minimal data.

• TB500 (Frag 17–23): Commonly sold “active fragment”; reputed to deliver many of the tissue-repair benefits attributed to Thymosin Beta-4 by focusing on the actin-binding domain.

• TB500 (Full 43): Essentially the entire Thymosin Beta-4 sequence; could confer a broader functional profile but may differ in absorption, half-life, or synergy compared to the fragment.

In the current peptide marketplace, most references to “TB-500” are either the 17–23 fragment or a synthetic Tβ4 analog. If you encounter “Frag 1–4” or “Full 43,” proceed with caution, do ample research, and seek professional guidance to ensure safety and proper usage.
[…] About Frag 1-4:
The N-terminal region of Tβ4 does not traditionally contain the actin-sequestering motif, which is better characterized within the peptide’s central region.
it may not yield significant benefits in tissue repair or anti-inflammation.

[Steve_Combi]

@ChatGPT o1

• TB500 (Frag 1–4): Very short, uncertain biological effect, minimal data.

I prefer www.Undermind.ai for technical searches. It provides the referenced articles and studies but those links are lost in this cut and paste.

Detailed summary

The TB500 fragment 1-4 peptide (Ac-SDKP) has been consistently demonstrated in preclinical studies to exhibit significant antifibrotic, anti-inflammatory, and pro-angiogenic properties, with therapeutic potential in tissue regeneration across myocardial, pulmonary, cutaneous, and renal models, primarily through inhibition of TGF-β/Smad signaling and promotion of neovascularization [1, 2, 4, 11, 19, 28].

---

Crucial Findings: 1. Biological Activity and Mechanisms of Action

• Antifibrotic Effects:
  • Ac-SDKP prevents fibroblast-to-myofibroblast differentiation [9, 28] and inhibits collagen deposition across diverse organ models (heart, lungs, kidneys) by suppressing TGF-β/Smad signaling and connective tissue growth factor (CTGF) expression [4, 8, 28].
  • Specifically reduces organ fibrosis and extracellular matrix accumulation in myocardial infarction (MI), pulmonary fibrosis, silicosis, and diabetic nephropathy models [11, 13, 25].
• Anti-inflammatory Activity:
  • Downregulates NF-κB signaling and ICAM-1 expression, reducing macrophage and neutrophil recruitment and mitigating inflammation [8, 23, 26].
  • Switches macrophages to the M2 repair phenotype in myocardial and pulmonary injuries [19].
• Pro-angiogenic Activity:
  • Promotes endothelial cell migration, tube formation, and VEGF upregulation; induces capillary density in ischemic tissues [1, 2, 18].
  • Stimulates matrix metalloproteinase (MMP) activation to aid in tissue remodeling [18, 13].

2. Tissue Regeneration Benefits

• Cardiac Models:
  • Substantial reduction in myocardial fibrosis, improved left ventricular function, and prevention of cardiac rupture post-MI, attributed to decreased collagen deposition and enhanced capillary density [2, 10, 19, 20].
• Pulmonary Fibrosis:
  • In bleomycin-induced models, Ac-SDKP prevents and ameliorates fibrosis, reduces epithelial-mesenchymal transition (EMT), and improves histological and functional lung outcomes [4, 11, 16].
• Cutaneous Wounds:
  • Accelerates skin flap survival and wound repair via angiogenesis and enhanced re-epithelialization [1].
• Renal and Diabetic Fibrosis:
  • Prevents kidney fibrosis through endothelial-mesenchymal modulation and synergistic effects with ACE inhibitors in diabetes-associated organ damage [22, 25].

3. Preclinical Models and Delivery

• Effective in numerous animal studies (mice, rats) across fibrosis and tissue injury models, with methods ranging from systemic injections to localized biomaterial delivery (e.g., peptide hydrogels in myocardial infarction) [4, 12, 13].
• Challenges include Ac-SDKP instability due to rapid degradation by angiotensin-converting enzyme (ACE), mitigated by co-treatment with ACE inhibitors or analog modifications [7, 24].

4. Key Gaps and Translational Challenges

• Long-term Efficacy and Tissue-Specificity:
  • Limited data on chronic injury models, bone repair applications, and differentiation of effects across tissue microenvironments [15, 22].
• Pharmacokinetics:
  • Short half-life remains a barrier for stable therapeutic delivery, though biomaterial or analog advancements hold promise [12, 15].
• Mechanistic Refinement:
  • Further elucidation of the Tβ4-POP-Ac-SDKP cleavage pathway’s role in endogenous fibrosis resolution is needed [3].

---

Conclusion:

Ac-SDKP is a promising candidate for preclinical tissue regeneration due to its potent antifibrotic and angiogenic mechanisms. However, translational challenges, including stability and tissue-specific applicability, must be resolved to harness its therapeutic potential fully.

[cl-user]

@Steve_Combi

I prefer www.Undermind.ai for technical searches. It provides the referenced articles and studies but those links are lost in this cut and paste.

Looks much better than ChatGPT o1 for that kind of questions indeed. Trying my same initial prompt in it and then refined it. Here is what it says.
Interestingly, it’s similar to the answer it gave you except about the angiogenesis. It told you Pro-angiogenic Activity but it tells me Limited Role in Angiogenesis. the 1–4 fragment (Ac-SDKP) has minimal to no angiogenic activity.
I guess we will have to look at that deeper.

@Undermind.ai

Functional Roles of Ac-SDKP

The 1–4 fragment (Ac-SDKP) has distinct biochemical and pharmacological activities, most notably:

1. Anti-Fibrotic Actions:

• Ac-SDKP is a potent fibrogenesis inhibitor, particularly in cardiovascular, renal, and pulmonary models [7, 25].
• It suppresses the TGF-β signaling pathway, which reduces the synthesis and deposition of extracellular matrix components such as collagen and fibronectin.
• This makes it uniquely effective in mitigating fibrosis in chronic inflammatory and ischemic diseases, including post-myocardial infarction fibrosis.

1. Anti-Inflammatory Properties:

• Ac-SDKP has been shown to decrease chronic inflammatory responses by dampening cytokine release and immune cell infiltration [25].
• It modulates the polarization of macrophages, favoring a shift from a pro-inflammatory M1 state to a reparative M2 profile.
• It also suppresses inflammatory cytokines, such as IL-6 and TNF-α, which are associated with chronic disease progression [24, 25].

2. Cardiovascular Protection:

• Ac-SDKP promotes vascular remodeling by inhibiting fibrosis and thickening of the vascular walls. This is particularly important in diseases such as hypertension, coronary artery restenosis, and post-stent repair environments [7, 25].
• It is a well-known negative regulator of angiotensin II-mediated damage. Elevated levels of Ac-SDKP protect against angiotensin II-induced cardiac remodeling, thus reducing hypertrophy and fibrosis.

3. Immunological Role:

• Ac-SDKP diminishes leukocyte recruitment and activation in tissues undergoing chronic stress or damage. This helps attenuate the progression of inflammatory and degenerative diseases [25].
• Remarkably, it shows efficacy in autoimmune scenarios like lupus nephritis by downregulating pro-inflammatory mechanisms at the tissue level.

4. Limited Role in Angiogenesis:

• Unlike the LKKTET motif or full-length thymosin β4, the 1–4 fragment (Ac-SDKP) has minimal to no angiogenic activity. Its primary role in tissue protection comes from its anti-fibrotic and anti-inflammatory effects rather than endothelial cell migration or proliferation [27].
  […]

Specific Advantages and Distinctions of the 1–4 Fragment:

1. Ac-SDKP is highly specialized for fibrosis suppression, far outpacing the other fragments in this role.
2. Unlike the LKKTET motif, Ac-SDKP does not promote angiogenesis, cell migration, or cytoskeletal changes, making its effects distinct and specific.
3. It is uniquely potent in diseases where dysregulated TGF-β activity is central, such as organ scarring or hypertensive fibrosis.
4. However, Ac-SDKP alone lacks the multifaceted ability to promote direct tissue regeneration (e.g., vessel growth, cell migration), which TB-500 and the LKKTET motif excel at.

---

Conclusions on the Ac-SDKP Fragment

The 1–4 fragment (Ac-SDKP) represents a highly specialized and promising anti-fibrotic peptide derived from thymosin β4. Its effects, while narrower in scope compared to TB-500 or the full-length thymosin β4, make it especially powerful in regulating fibrosis (via TGF-β inhibition) and controlling inflammation. However, it has limited direct utility in angiogenesis, actin dynamics, or cellular migration, which are hallmarks of other thymosin β4 fragments like the LKKTET motif.

Thus, Ac-SDKP serves as a complement to other fragments in therapeutic applications, targeting fibrotic and inflammatory processes where other peptides might fall short.

[cl-user]

@Steve_Combi

TB500 (frag 17-23)

Continuing to go deeper on Thymosin β4 17–23 Fragment - LKKTET Motif (Actin-Binding Domain)
Looks like this one is the angiogenesis promoting one.
[EDIT: Added comparisons between the different fragments at the end]

@Undermind.ai

Functional Roles of the LKKTET Motif

The LKKTET sequence serves as the actin-binding domain of thymosin β4 and plays a pivotal role in cytoskeletal and cellular processes.

1. Actin Sequestration and Regulation:

• The LKKTET motif is essential for G-actin sequestration, where it binds to monomeric actin and prevents its polymerization into filamentous actin (F-actin) [11, 19].
• This regulation of actin dynamics allows cells to control their shape, motility, and intracellular transport processes, all of which are critical for tissue repair and immune responses.

2. Angiogenesis:

• LKKTET plays a key role in angiogenesis by stimulating endothelial migration and tubulogenesis (formation of capillary-like structures) [7, 11].
• Thymosin β4 fragments containing the LKKTET sequence support vascular sprouting and new blood vessel growth in response to injury or ischemia.
• Studies suggest that the LKKTET-containing segment is sufficient for promoting angiogenic effects similar to those of full-length thymosin β4 [11].

3. Cell Migration and Wound Healing:

• The LKKTET motif is critical for cell migration by mediating actin polymerization at leading cell edges (lamellipodia and filopodia), processes necessary for wound healing and tissue regeneration [11, 19].
• Directly regulates the cytoskeletal dynamics underpinning cell motility in endothelial cells, fibroblasts, and immune cells [7].

4. Cytoskeletal Remodeling:

• Works in conjunction with integrin receptors (e.g., αvβ3 integrins) and focal adhesion complexes to reorganize the actin cytoskeleton.
• Enables cells to adhere, spread, and migrate, important for physiological processes like angiogenesis and pathological responses such as tissue repair [15, 21].

5. Regeneration After Ischemic Injury:

• Enhances endothelial progenitor cell (EPC) migration and survival, which are essential for repairing ischemic tissues, such as in myocardial infarction or hindlimb ischemia[8, 16].
• Both in vitro (tube formation assays) and in vivo models highlight its direct angiogenic and regenerative potential.
  […]

Key Strengths of LKKTET:

1. Core Actin Dynamics:

• The LKKTET region is indispensable for actin-related processes, driving cell migration and motility in nearly all thymosin β4 biological contexts.
• Without this region, thymosin β4 loses most of its cytoskeletal regulatory capacity [11].

2. Sufficient for Angiogenesis:

• Studies demonstrate that shorter fragments containing the LKKTET motif retain comparable angiogenic activity to full-length thymosin β4 [11, 7].

3. Minimized Complexity:

• Unlike full-length thymosin β4, which combines several motifs with broader roles (e.g., immune modulation, inflammation reduction), the LKKTET motif focuses specifically on angiogenesis, cell mobility, and cytoskeletal renovation, allowing for targeted applications.

Limitations of LKKTET:

1. Limited Anti-Inflammatory Action:

• While it drives migration of wound-healing immune cells like macrophages, its direct involvement in anti-inflammatory and anti-fibrotic signaling (e.g., TGF-β inhibition) is minimal compared to other fragments like Ac-SDKP.

2. Receptor Independence:

• Lacks strong receptor-specific signaling effects unless combined with ancillary sequences or cofactors. Full-length thymosin β4 (or modified versions like TB-500) engages multiple receptor-mediated pathways more effectively.

---

Applications of the 17–23 Fragment (LKKTET Motif)

1. Wound Healing:

• Facilitates epithelial and endothelial cell migration at injury sites, promoting rapid tissue closure and vascular repair.

2. Angiogenesis Therapies:

• Could be used independently to promote blood vessel formation in ischemic tissues (e.g., myocardial infarction, peripheral artery disease) [8, 28].

3. High-Purity Cytoskeletal Studies:

• Serves as a model fragment for probing actin-sequestration dynamics in cellular and molecular research contexts [19].

4. Regenerative Medicine:

• Particularly effective in settings requiring vascular regeneration or migration of progenitor cells, such as in cardiac, cerebral, or dermal repair therapies [13, 16].

To conclude that TB4 topic here are the comparisons between the different fragments.
Looks like 1-4 + 17-23 would get the most benefits.

@undermind.ai

Direct Comparison: LKKTET vs Ac-SDKP

Feature	LKKTET Motif (17–23)	Ac-SDKP (1–4)
Primary Function	Actin dynamics and angiogenesis	Anti-fibrotic and anti-inflammatory
Key Pathway	Cytoskeletal regulation (actin/G-actin)	TGF-β inhibition
Role in Wound Healing	Enhances vascular endothelial migration	Reduces fibroblast-driven scarring
Angiogenesis	Potent	Minimal
Fibrosis Control	Limited	Potent
Immune Modulation	Indirect (macrophage migration)	Strong anti-inflammatory outcomes

Differences Between the 17–23 Fragment (LKKTET Motif) and Other Fragments

Fragment	Primary Role	Key Mechanistic Focus	Unique Strengths	Limitations
Full-Length Tβ4	General tissue repair	Combines actin, immune modulation, and VEGF activation	Multidimensional effects	Low stability and high systemic clearance
1–4 Fragment (Ac-SDKP)	Anti-inflammatory and anti-fibrotic	TGF-β inhibition, cytokine suppression	Potent fibrosis control	No significant angiogenic or actin-migration effects
17–23 Fragment (LKKTET)	Actin regulation, angiogenesis	G-actin binding, PI3K/Akt activation	Cytoskeletal control, endothelial migration	Limited anti-inflammatory and anti-fibrotic effects

[Steve_Combi]

@undermind.ai

|TB-500|Combined regenerative effects|VEGF signaling, NF-κB suppression|Balanced angiogenesis and anti-inflammatory effects|Lacks full-length receptor context

TB500 is either (1-4) or (17-23) or even (43aa) it is not all 3 at once. TB500 is like a generic term for Tβ4 bits and pieces in the peptide community. If you are buying direct from a peptide mfg, the first thing they will ask is what version you want.

I’m going to split a hair here

Not sure where TB500 came from, to be more technically correct one would call all these variations;
Tβ4(43aa),
Tβ4(1-4) or
Tβ4(17-23)

Regardless of my split hairs, TB500 (1-4) works for me and I use it in combination with BPC157 Have not tried (17-23) yet.

If TB500 (1-4) is VEGF signalling and BPC157 is the VEGF receptor enhancer it may explain the synergy people find in using “wolverine blood” as this combo is often called on the interwebs

[Davin8r]

@ChatGPT o1

n the current peptide marketplace, most references to “TB-500” are either the 17–23 fragment or a synthetic Tβ4 analog

I don’t know of any peptide manufacturers/retailers selling actual TB500 (the frag) except for one that had the 17-23 frag briefly. I’ve literally never seen TB500 (1-4) for sale. It’s all TB-4, i.e. the full 43 aa peptide.

[cl-user]

@Steve_Combi

If TB500 (1-4) is VEGF signalling and BPC157 is the VEGF receptor enhancer it may explain the synergy people find in using “wolverine blood” as this combo is often called on the interwebs

Apparently the VEGF signaling is the 17-23 fragment so maybe that’s why the 1-4 + BPC157 is such a good combination as BPC will bring the VEGF activation part that is missing from the 1-4 fragment making it a more complete package.

[desertshores]

Of the companies I buy from, I find BPC-157 / Thymosin Beta 4 Fragment 17-23 only on one site, and it appears to be a nasal spray.
Have you known anyone who used TB500 as a nasal spray?
Apparently, TB-500 has some memory benefits. (If these references have been posted before, I apologize.)

Buy Thymosin Beta 4 Fragment 17-23 (TB-500) | Made in USA

Peptide fragment of thymosin β4 increases hippocampal neurogenesis and...

Thymosin β4 overexpression regulates neuron production and spatial...

[cl-user]

I think @Steve_Combi uses the BPC-157 + TB4 1-4 combo. I’m going to try that too.

The second paper you reference is about TB4 17-23 but the first one is about TB4 1-4.

[Steve_Combi]

Nasal sprays are pretty easy DIY projects, only caveat is pH… Keep it between 5.5-6.5 and it’s all good.

I made a NAC nasal spray before I was aware of this issue (had made a skin lotion with NAC and no issues)… it was like FIRE! took 3 days to completely resolve LoL!

Turns out NAC is quite acidic

When I got the pH right the NAC nasal spray was pretty interesting. Shared it with a few people with TBI and they indicated it was like turning the lights on.

[Steve_Spencer]

I went to their website, but they seem to be out of business. Do you know of any other reputable suppliers? Thanks.