Peptide Sciences Blog

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How does ARA-290 protect and repair an inflammatory nervous system?

By Nemo 2 days ago

ARA-290 is derived from EPO, preserving its healing effects without creating red blood cells.

“Erythropoietin (EPO) is a cytokine that regulates hematopoiesis mediated by its binding to the erythropoietin receptor (EPOR), that is present also in non-erythroid tissues, including pancreatic islets. In addition to its hematopoietic action, EPO has been shown to exert anti-inflammatory, anti-apoptotic and cytoprotective effects in a wide variety of cell types by binding to the innate repair receptor (IRR) which is a heteromer of EPOR and CD131, the β common receptor. EPO treatment has been shown to protect against diabetes development in streptozotocin-induced and db/db mouse models of type 1 and type 2 diabetes, respectively, while exerting anti-apoptotic, anti-inflammatory, proliferative and angiogenic effects within the islets.” (4)

“Since prolonged treatment with EPO can increase the hematocrit and provoke thrombosis, we have studied an EPO analogue, ARA290. This 11 amino acid peptide lacks hematopoietic action, binds to the IRR and protects a number of tissues in response to injury. A recent phase 2 clinical trial evaluating ARA290 in patients with type 2 diabetes and painful neuropathy showed that ARA290 significantly reduced HbA1c levels as well as neuropathic symptoms.” (4)


Regenerates Myelin (The Protective Sheeth Around Nerves) and Reduces Inflammation of Nerve in Neuritis Disease.

“ARA 290 intervention suppressed demyelination and promoted remyelination of sciatic nerves” (12)

“ARA 290 exerted direct proliferation promotion and anti-inflammatory effects on Schwann cells.” (12)


Innate repair receptor (IRR) required for regenerative effects of ARA-290 on neuropathy

”The innate repair receptor (IRR) is a heteromer of the erythropoietin receptor and the b-common (CD131) receptor, which simultaneously activates anti-inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a b-common receptor knockout phenotype.” (5)

Forty-eight T2D patients with moderate to severe SFN-induced chronic pain were treated with daily subcutaneous injections of ARA290 4 mg or placebo for 28 days. The results of the trial were similar to those obtained earlier in sarcoidosis patients with improvements in neuropathic symptoms, an increase in CNFD in patients with an initial reduction in CNFD.”

“Despite a large reduction of allodynia maintained during the intensive treatment period, a slow trend toward an increase in pain behavior was observed during the weekly ARA 290 dosing paradigm. This observation could suggest that because of the biologic half-life of ARA290 of less than 1 week, more frequent dosing could prevent the trend for increased pain. An alternative explanation could be that noninflammatory processes slowly develop to foster proallodynic responses and gain in importance over time or that the inflammatory response becomes more resilient. If true, this suggests that treatment of neuropathic pain caused by nerve injury should be aimed at targeting multiple processes, of which suppression of the immune response is one that requires early (and continuous) treatment. It is not likely that decreasing the interval between nerve injury and the initiation of treatment or using ARA290 as a preemptive measure results in a more effective relief of neuropathic pain because the EPOR-cR complex is being up-regulated secondary to tissue damage. Alternatively, more intense treatment during the initial phase (e.g., higher doses or injections at a 1-day interval) may be more effective in neutralizing the initial hit induced by the peripheral nerve injury.” (7)

3“Innate repair receptor activation reduces mechanical allodynia after spared nerve injury (SNI) in the rat. Animals were sham operated (blue) or received SNI and vehicle (grey) or SNI and 60 mg/kg ARA290 (red), both administered on days 1, 3, 6, 8, and 10 postsurgery...” (5)

”In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis.” (5) “The results of the NERVARA trial indicate a significant increase in corneal nerve fiber area by 14% within the 4-week treatment period (relative to a small decrease after placebo treatment) without affecting proximal and distal limb intraepidermal nerve fiber densities.16 These data are important for 2 reasons. First, ARA290 initiates a rapid regrowth of small nerve fibers in the cornea, which is a sign of tissue healing and restoration as earlier observed in experimental studies… the corneal nerve fibers seem to be more sensitive to regeneration than skin fibers, and consequently, the cornea is the more appropriate location to assess not only the state of small fiber pathology but also assess the effect of treatment."

Read More Posted in: ARA-290

How does Epitalon enhance sleep while protecting DNA and Telomeres?

By Nemo 1 month ago


Epithalon Peptide Induces Telomerase Activity and Telomere Elongation in Human Somatic Cells and Overcomes the Hayflick Limit

Each cell contains DNA as an instruction manual for how to divide and grow. The DNA inside of each cell is shielded by proteins called telomeres. During cellular division, a new cell must take some telomeres from its originating cell to shield the DNA of the new cell. The telomeres shorten after every cell division because the new cell can only take a portion of the telomeres from the previous cell, else the previous cell’s DNA will become completely unprotected.

Once there are no left over telomeres to take, the cell stops dividing. This happens after a single cell divides and grows about 64 other cells, which is known as the Hayflick limit. This limit exists because cells without shield material are more vulnerable DNA damage. If the DNA of a cell becomes damaged, the cell will follow broken instructions. If the instructions within the DNA of the cell are damaged, then the cell may not be able to eliminate itself through the process of apoptosis like it is supposed to.

"The telomere length is increased by approximately 33% in epitalon treated cells [by increasing the telomerase enzyme that strengthens telomeres]." (10)

“Telomerase is a reverse transcriptase that has two distinct functions, to replicate pre-existing chromosome ends (telomeres) and to heal broken chromosomes by de novo addition of telomeric sequences directly on to non-telomeric DNA.” (11)

"Addition of Epithalon to aging cells in culture induced elongation of telomeres to the size comparable to their length during early passages. Peptide-treated cells with elongated telomeres made 10 extra divisions (44 passages) in comparison with the control and continued dividing. Hence, Epithalon prolonged the vital cycle of normal human cells due to overcoming the Hayflick limit." (12)

How does Semax enhance memory and protect the brain during injury?

By Nemo 2 months ago

Semax Stimulates Neurogenesis.

"Here, we found that a single application of Semax (50 μg/kg body weight) results in a maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosporylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively, in the rat hippocampus. Semax-treated animals showed a distinct increase in the number of conditioned avoidance reactions. We suggest that Semax affects cognitive brain functions by modulating the expression and the activation of the hippocampal BDNF/trkB system." (18)

Semax, an analog of ACTH(4–10) with cognitive effects, regulates ...

Semax, an analog of ACTH(4–10) with cognitive effects, regulates ...

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LL-37 blocks an enzyme required by the original coronavirus and may eliminate damaged cells without inflammation.

By Nemo 2 months ago

LL-37 selectively inhibits the Cathepsin L protease involved in SARS-CoV activation while partially enhancing proteases Cathepsins S and K.

LL-37 inhibits cathepsin L at a concentration of 150 nM. (15) Cathepsin L primes (helps activate) the SARS-CoV RNA virus when it is entering the cell. (16)

Read More Posted in: LL-37

How can Thymosin Beta4 (TB500) improve recovery, inflammation, neuropathies, fibrosis, telomerase and senescent cell removal?

By Nemo 3 months ago

Thymosin B4 Reduces Inflammation by Upregulating MicroRNA-146a and Promotes Myelin

"Tissue inflammation results from neurological injury, and regulation of the inflammatory response is vital for neurological recovery. The innate immune response system, which includes the Toll-like receptor (TLR) proinflammatory signaling pathway, regulates tissue injury... TB4-mediated oligodendrogenesis results from [up-regulating] miR-146a [causing the] suppression [of] the TLR proinflammatory pathway and modulation of the p38 MAPK pathway." (8)

"By targeting IRAK1 and TRAF6, miR-146 inhibits NF-κB activation. We therefore hypothesized that TB4 regulates the TLR proinflammatory signaling pathway by specifically regulating miR-146a to promote differentiation of OPCs [oligodendrocyte progenitor cells] to mature myelin basic protein (MBP)-expressing OLs [oligodendrocytes]... transfection with anti-miR-146a inhibitor nucleotides significantly inhibited the expression of MBP and phosphorylation of p38 MAPK." (8)

How does PNC-27 selectively target certain types of cancer cells?

By Nemo 3 months ago

How does PNC-27 target cancer cells without relying on the master regulator of apoptosis p53?

“The results strongly suggest, that PNC-27 (and by inference PNC-28) is inserted in the plasma membrane of cancer cells upon binding to HDM2, where, by random movement, the HDM2-PNC-27 complexes assemble into oligomers and eventually into membrane pores. Influx of free PNC-27 molecules through the newly formed membrane pores into the cells... cytoplasm leads to the assembly of pores in mitochondrial membranes and rapid cell death.” (5)

“PNC-27 induces cancer cell membrane lysis by acting as the whole peptide, not fragments.” (4)

Fig. 4 Confocal microscopy results for MCF-10-2A cells treated with double-Xuorescentlabeled PNC-27 as described in the legend to Fig. 3. As in Fig. 3, the time frames proceed from top to bottom, the 30-min time frame occurring at the top of the Wgure and the 48 time frame at the bottom, as labeled on the left of the Wgure. For each time frame, red, green and combined (yellow) Xuorescence is shown from left to right, respectively

Read More Posted in: PNC-27

How does BPC-157 help balance dopamine, cardiovascular function, and healing?

By Nemo 3 months ago

Multi-Organ Membrane Repair and Dopamine Balancing.

"Pentadecapeptide BPC 157 antagonises the incidence of a series of gastrointestinal lesions, it has a positive impact on the healing processes of various wounds, a proven angiogenic effect, protective effect on endothelium and it modulates synthesis of NO." (1)

"Apart from the effects on various gastrointestinal lesions, the potentially beneficial effect on pancreas, liver injuries, endothelium and heart damage, i.e. dysrhythmias following reoxygenation, and blood pressure, along with effect on experimental acute/chronic inflammation, wound and fracture (pseudoarthrosis) healing are described. It appears that these beneficial effects all together provide a particular network reflecting activity of a special peptidergic defence system." (4)

"In support of this concept, it appears that there are interactions of this pentadecapeptide with many important systems (namely, dopamine-, NO-, prostaglandin-, somatosensory neurone-systems), that could provide a basis for the observed protective effects. Moreover, since disturbance of these systems' functions (i.e. dopamine-, NO-, somatosensory neuronal-system) which manifest either over-activity or as inhibition, may contribute to the multiple lesions in different organs. The reported evidence that this pentadecapeptide is able to counteract both their over-action, and their inhibition, may suggest this pentadecapeptide as a new, but most probably essential physiological defence system and that should be further investigated." (4)

File:Gastric Ulcer.png

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Can viral replication be reduced with MOTS-c and FOXO4-DRI by killing zombie (senescent) cells?

By Nemo 3 months ago

Senescent cells increase replication of a DNA virus in vitro.

“A significant increase in viral replication efficiency was detected by replicative senescence during IFV and VZV infection. ... As one of possible mechanisms for the increase in viral replication in senescent cells, a reduction in interferon (IFN) response after viral infection may account for it.” (2)

The concentration of this DNA virus in senescent cells is 300% more infected than non-senescent cells.

300% increase of viral infection in senescent cells

"Similarly, Andrew et al. showed that by increasing SASP phenotype, MOTS-c could make senescent cells more easily detected and then cleaned by the immune system, thus protecting normal cells."

How does Thymosin Alpha 1 improve anti-viral immune responses?

By Nemo 3 months ago

Antigen, Antibody, and Lymphocytic White Blood Cell Recruitment.

“Importantly, Ta1 acts without overstimulation of cytokine production and is generally well tolerated; it has an excellent safety profile and does not appear to induce the side effects and toxicities commonly associated with agents in this class such as interferon alpha and interleukin-2.” (1)

“Clinical trials using Ta1 in the treatment of patients with immunodeficiency or cancer indicate that this agent is nontoxic, enhances immune responsiveness and augments specific lymphocyte functions, including lymphoproliferative responses to mitogens, maturation of T-cells, antibody production, and T-cell-mediated cytotoxicity” (5)

• Increased Natural Killer (NK) activity

• A shift of T helper (Th or CD4) cells to the Th1 cell subset

• Increased expression of Th1 type cytokines such as Interleukin (IL) 2, and Interferon (IFN)-alpha

• Increased levels of Cytotoxic T (Tc1 or CD8) cells

Thymalin boosts immune system while mitigating fever and excess cell death induced by cytokine storms.

By Nemo 4 months ago

Immune Paralysis Following "cytokine storm" may be reversed by Thymalin.

"Uncontrolled development of the initial [cytokine storm] stage inevitably leads to immune imbalance, which increases the probability of secondary infections, such as pneumonia, and activation of latent herpes virus (including cytomegalovirus) infections." (2)

"Over the last decade, preclinical and clinical studies have definitively shown that sepsis leads not only to hyperinflammation, but also impaired immunity, including dysfunction of the adaptive immune system. Certain investigators and clinical practitioners believe that the main cause of the failure of sepsis therapy involves the development of severe immunodeficiency..." (2)

“Administration of Thymalin to old mice led to an increase of the titer of FTS in the blood, the restoration of disturbed circannual rhythm, the number of CD4+ cells in the bone marrow, and the concentration of corticosterone in the blood.” (4) “Both natural and synthetic pharmaceuticals activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced the changes in intracellular composition of cyclic nucleotides and cytokine [interleukin (IL-2), interferon (IFN)] excretion of blood lymphocytes.” (3)

"Adequate zinc is essential for T-cell division, maturation, and differentiation. Zinc itself is a cofactor for thymulin, a best known zinc-dependent thymic hormone crucial for T-cell formation and maturation which exists in two forms, a zinc-bound active one, and a zinc-free inactive form. What’s more, zinc may also prevent the programmed death (apoptosis) of precursor T-cell populations and mature CD4+T cells through various enzymatic mechanisms and through chronic production of glucocorticoids. Thymulin and thymopentin restore antibody avidity in aged or thymectomized animals, enhance antibody production in aging mice... Additionally, thymulin reduces induced hyperalgesia in rats and mice.” (7)


Thymulin: An Emerging Anti-Inflammatory Molecule

MOTS-c Vascular Calcification and Insulin Resensitization

By Nemo 4 months ago

AMPK Activation Targets Vascular Calcification and Metabolic Homeostasis

"Recently, MOTS-c, a novel bioactive mitochondrial-derived peptide, has been demonstrated to activate the AMPK pathway to promote metabolic homeostasis... Our findings provide evidence that MOTS-c may act as an inhibitor of VC [Vascular Calcification] by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors." (1)

"Angiotensin II type 1 (AT-1) and endothelin B (ET-B) have been found to be involved in the AMPK pathway by binding to the AT-1 and ET-B receptors, respectively. A decreased level of the AT-1 receptor plays roles in reducing oxidative stress and preventing the development of myocardial contractile dysfunction, while a high level of the AT-1 receptor induces myocardial fibrosis and cardiac dysfunction. AT-1 can induce the relocation and suppression of the AMPK pathway via the AT-1 receptor in the development of diabetic proteinuria. After treatment with metformin, AMPK signaling is activated and AT-1 levels are decreased in the kidney. In epithelial ovarian carcinoma, ET-1 plays a role in epithelial-mesenchymal transition. A decrease in ET-1 receptor activation is beneficial in attenuating biventricular remodeling, and the overexpression of ET-1 causes sustained blood pressure elevation and vascular and renal injury. The activation of the AMPK pathway can also upregulate the ET-B receptor to inhibit autophagy in vascular smooth muscle cells under high glucose conditions." (1)

"Previous reports have shown that MOTS-c can amplify glucose uptake, inhibit the folate cycle and de novo purine biosynthesis following metabolic stress, and regulate nuclear gene expression in an AMPK-dependent manner. MOTS-c treatment dramatically reduced the number of disordered elastic fibers and significantly improved vascular wall structure (Fig. 2c). Moreover, MOTS-c also significantly reduced VDN [Vitamin D3 plus Nicotine] induced calcium phosphate salt deposition in the calcified aortas, as detected by alizarin red S staining and von Kossa staining... Our results showed that MOTS-c reverses VDN-induced AMPK downregulation. In mice with hypoxia-induced pulmonary hypertension, the activation of the AMPK pathway can effectively improve right ventricular systolic pressure and right ventricular hypertrophy due to treatment with liraglutide." (1)

Read More Posted in: MOTS-c

Potential Synergy of MOTS-c or Humanin with Senolytics

By Nemo 4 months ago

FOXO4-DRI senescent cell remover is potentiated by SASP factors

"SASP factors as IL-6 may be the cause for the observed loss in renal function, and we wondered how FOXO4-DRI would function under such high SASP conditions. In vitro experiments showed FOXO4-DRI to be more potent against senescent cells in which SASP wastransiently boosted by recombinant IL1a/b or lipopolysaccharide (LPS), whereas an IL1 receptor antagonist or the general anti-inflammatory drug cortisol reduced its potency (Figures 6H and 6I). Thus, FOXO4-DRI actually is most effective against senescent cells expressing high levels of SASP and could as such be particularly effective against loss of renal function. Excitingly, while not substantially influencing total body nor kidney weight (Figure S6G), FOXO4-DRI treatment normalized the percentage of tubular cells lacking LMNB1 (Figure 6G), the tubular IL-6 elevation (Figure 6J), and the elevations in plasma urea levels (Figure 6K)." (4)

GHK affects the Gene Expression of COPD, Damaged Protein Clearing, and Nervous System

By Nemo 4 months ago
"GHK (glycyl-l-histidyl-l-lysine) is a human copper-binding peptide with biological actions that appear to counter aging-associated diseases and conditions. GHK, which declines with age, has health promoting effects on many tissues such as chondrocytes, liver cells and human fibroblasts, improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, boney tissue), increases collagen, decorin, angiogenesis, and nerve outgrowth, possesses anti-oxidant, anti-inflammatory, anti-pain and anti-anxiety effects, increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Studies using the Broad Institute Connectivity Map show that GHK peptide modulates expression of multiple genes, resetting pathological gene expression patterns back to health."
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Hexarelin research and the reduction of cardiac fibrosis

By Nemo 4 months ago

"MMPs, particularly MMP-9 and MMP-2 [collagen degrading enzymes], are involved in cardiac fibrosis. Activities of MMP-2 and MMP-9 in the heart did not show significant differences between SHRs and Wistar rats (Fig. 6). However, hexarelin treatment remarkably increased MMP-2 and MMP-9 activities in SHRs, especially MMP-9 activity, in a GHS-R-dependent manner, since blockade of GHS-R abolished the hexarelin-induced increase in MMP-2 and MMP-9 activities (Fig. 6A). mRNA expression of TIMP-1, the inhibitor of MMPs, was dramatically increased in SHRs compared with Wistar rats and was reduced by hexarelin in SHRs in a GHS-R-dependent manner (Fig. 6B)."

Hexarelin suppressed TIMP-1 mRNA and its inhibition of collagen degrading enzymes in the rat heart, thereby boosting the collagen degrading enzymes MMP-2 and MMP-9.

Humanin Mitochondrial Peptide Prevents Age-related Myocardial Fibrosis in mice

By Nemo 4 months ago

"Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart."

"HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. The percentage of other cell types did not change among these groups... Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation and attenuated transforming growth factor-β1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression. Myocardial apoptosis was inhibited in HNG-treated aged mice."

"Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3β pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice."

Read More Posted in: Humanin