LL37 Peptide for Sale here for the fantastic price of $95.00! You will find our website stocks the best quality Peptide Sciences products. We have pages of research products, including LL-37 5 mg, for all your research needs. The research peptide LL37 is a synthetic version of the human form of cathelicidin LL-37.
The human cathelicidin LL-37 plays a big part in the innate immune system. This peptide defends against bacterial infections in the body. LL-37 works with the cell wall molecules. With this, it perforates membranes, which results in cell death. LL-37 will act as a defense to controlling infection and inflammation. LL-37 can eradicate specific pathogens such as bacteria, fungi, parasites, and viruses.
What is Cathelicidin LL-37?
The research peptide LL-37 is antimicrobial and the only known member of the cathelicidin family of peptides expressed in humans. LL-37 is a multifunctional host defense molecule. It provides normal immune responses to infection and tissue injury. LL-37 peptide is a potent killer of different microorganisms. This peptide prevents immunostimulatory effects of bacterial wall molecules such as lipopolysaccharide. It can protect against lethal endotoxemia. The main actions of LL-37 include:
- Chemoattractant function
- Inhibition of neutrophil apoptosis
- Stimulation of angiogenesis
- Tissue regeneration
- Cytokine release
Cellular production from LL-37 is affected by many factors. These include bacterial products, host cytokines, oxygen availability, and sun exposure from the activation of CAP-18 gene expression by vitamin D. At infection sites, the function of LL-37 is by charge-driven interactions with DNA and F-actin released from dead neutrophils and other cell lyses due to inflammation. A better understanding of LL-37’s biological properties is necessary for its possible therapeutic application for immunomodulatory purposes and treating bacterial infection.
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Where is LL-37 Found?
LL-37, a peptide originating from its precursor hCAP-18, has a chain of 37 amino acids. It is found in the secondary granules of neutrophils and macrophages, and it is secreted by epithelial cells, monocytes, macrophages, T lymphocytes, and mast cells when in contact with PAMPs.
LL-37 also exhibits chemotactic activity, mainly on neutrophils and CD4 T lymphocytes. Likewise, LL-37 has both pro-inflammatory and anti-inflammatory properties. For example, differentiation of monocytes to macrophages in the presence of LL-37 promotes a pro-inflammatory response. This results in down-regulation of IL- 10 and the positive regulation of IL-12p40.
Furthermore, LL-37 exposure increases IL-1ß production through the activation of P2X7R 11. However, various studies indicate that more than a direct effect, they present interesting immunomodulatory effects in the field of tissue regeneration, specifically in the area of wound healing as described next…
Why is LL-37 used?
Healing and angiogenic activities of antimicrobial peptides
The proper healing of cutaneous wounds depends on dynamic, complex, and orderly phenomena in which blood cells, components of the extracellular matrix, and parenchymal cells interact. In this sense, MPAs have substantial implications.
The HBD-2 is found in the stratum corneum and stored in lamellar bodies of the keratinocytes of the spinous layer. Its expression induces the migration and proliferation of keratinocytes by activating the epidermal growth factor receptor (EGFR), STAT1 / STAT3). 12,13 Likewise, another report describes that HBD-3 shows anti-inflammatory activity in vitro and in vivo by inhibiting TLR signaling pathways in immune cells, suggesting its possible participation in the resolution of the inflammatory process in the early stages of healing.
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Key roles of LL-37
Similarly, LL-37 plays a key role in recovery, contributing to cell re-epithelialization and the secretion of cytokines (IL-6, IL-8, IL-10, IL-18, and IP-10) and chemokines (MCP-1, MIP-3a, and RANTES) that allow the arrival of immune cells to the injury site, thus avoiding the formation of bacterial biofilms in the injured skin.
Interestingly, CRAMP-deficient mice were more susceptible to group A streptococcal skin infections than wild-type mice. 16In addition, LL-37 can protect keratinocytes from apoptosis by activating the cyclooxygenase 2 (COX-2) / prostaglandin (PGE2) pathway. 17 Furthermore, it has been reported that LL-37 can induce angiogenesis, as demonstrated in an in vitro and in vivo model, by activating the FPRL1 receptor expressed in endothelial cells, resulting in more significant proliferation and formation of similar structures to the blood vessels. Likewise, other experts suggest that the angiogenic effect of LL-37 is due to the release of PGE2 dependent on the activation of the COX-1 pathway.
Changes in the expression of antimicrobial peptides during type 2 diabetes mellitus and its consequences
In conclusion, the information collected shows that AMPs are essential for wound repair. It will be interesting to study them under hyperglycemic conditions and investigate their behavior under a therapeutic scheme. It is to explore their expression under the influence of insulin, metformin, or glibenclamide.
DBT2 is a public health problem increasing in recent decades and has strongly associated with various comorbidities such as cancer, 19viral infections (e.g.: HIV), and bacterial (tuberculosis), among others. A common denominator is found, partial or total suppression of the immune response, due to hyperglycemia per se. DBT2 patients have been reported to have an abnormal immune response. These include:
- Failures in humoral immunity
- Defects in phagocytosis
- Defects in inflammatory cell extravasation
- Neutrophil dysfunction
- T cell-mediated immune response
However, despite the advances in the knowledge of the immune response in individuals with DBT2, very little is known about the changes in AMP expression during this disease and what consequences they could bring. The group reported that the AMP levels: LL-37, HBD-2, HBD-3, and HBD-4 are decreased at the serum level in people with DBT2, with or without tuberculosis.
This suggests that the deficiency in the production of these AMPs in individuals with DBT2 makes them more susceptible to pulmonary tuberculosis. Later, increasing glucose concentrations were shown to correlate with a low expression of LL-37 in uninfected macrophages.
Whereas in macrophages infected by Mycobacterium tuberculosis, the expression of LL-37 increased at high glucose concentrations. The mycobacterium was not eliminated. So this could be attributed to the immunomodulatory effect of cathelicidin. However, more studies are needed to determine the role of cathelicidin in DBT2 during infection by M. tuberculosis. Other studies have shown the importance of the part of vitamin D. This is for the induction of AMP in healthy individuals or DBT2.
Some patients with DBT2 have lower expression of the vitamin D receptor (VDR). This activity translates into lower production of HBD-2 and LL-37. In addition, increasing the dose of vitamin D induces an increase in VDR, which leads to a rise in both HBD-2 and LL-37, thus eliminating intracellular bacteria.
Other groups found similar results in finding a decrease in vitamin D concentration and cathelicidin in patients with DBT2. There is an association with the production of IFN- ?, IL-4 and IL-17.
Antimicrobial Peptides in Diabetic Foot Ulcers
As mentioned previously, UPDs are one of the main complications of DBT2. These are characterized by low angiogenesis, scarce healing, neuropathy, and infections. Among the main characteristics of AMP, it corresponds to its recovery and angiogenic capacity. As its name indicates, it also has antimicrobial properties. These characteristics led to the study of MPAs in UPDs.
Our group has described that most of the biopsies from UPD had a null gene expression of LL-37 in the affected area, consistent with the lack of healing since this peptide is known for its solid angiogenic activity and induction keratinocyte migration.
Compared to healthy skin samples, increased peptides HNP-1, HBD-2, HBD-3, and HBD-4 were found. However, by making primary cultures from the ulcers and stimulating those with S. aureus primary cultures from UPDs produced fewer defenses than healthy skin under the same conditions, which suggests that, although ulcers respond to infections with AMP production, this production is not sufficient to control infection and induce scarring.
In subsequent studies, it was determined that the RNAse7 peptide is also decreased in UPD and that, furthermore, its expression cannot be induced with vitamin D, sodium butyrate, or isoleucine L (Rivas-Santiago et al., Unpublished data). These results suggest that there is a decrease in AMP production in UPDs.
The origin of this decrease is still unknown. It may be due to the alteration in the signaling pathways caused by hyperglycemia or by reducing circulating levels of vitamin D. However, more studies are needed to determine the causes of this decrease. It is also necessary to investigate the effect of the main hypoglycemic agents in the production of AMP since, on the one hand, they could induce them and this could benefit to prevent diabetic ulcerations, and on the other hand, they could inhibit production. In this sense, it is necessary to carry out epidemiological studies and basic research to determine the role of these hypoglycemic agents in AMP production.
The use of antimicrobial peptides as adjuvants
The important pro-scarring characteristics of AMP and the lack of these in UPD processes have led to research on using these peptides to treat chronic wounds. In vivo studies using adenoviral transfer of LL-37 to wounds of diabetic ob/ob mice, showed a significant increase in the production of LL-37 in the skin of these mice, improving re-epithelialization and the formation of granular tissue, decreasing the time healing compared to untreated mice.
This was later confirmed in an independent study, where LL-37 was shown to promote both re-epithelialization and angiogenesis in both in vitro and in vivo models of chronic wounds.
Subsequently, using LL-37 and PDH IDR-1018, which is a synthetic derivative of bovine bactenecin, IDR-1018 was shown to be less toxic than LL-37 in vitro. Furthermore, it is shown that healing was accelerated in wounds infected by S. aureus in both murine and porcine models.
However, when using this peptide in murine models of diabetes, there was no difference between the two peptides in terms of epithelial regeneration time. It seems that the effect of hyperglycemia blocks the signaling of the receptors to which this peptide binds.
Or that there is glycation in the receptors that prevent the healing activity of peptides that need to be studied in the future. Further studies, using both keratinocytes and human endothelial cells, showed that IDR-1018 could induce VEGF-165, angiogenin, and TGF-B under hypoxic conditions with high glucose concentrations.
Various studies have suggested AMPs as solid candidates in the treatment of UPDs, but the microenvironment of UPDs must be taken into account. For example, a high concentration of metalloproteases (MMPs) has been reported in ulcers.
Therefore, the topical administration of LL-37 is unstable in the microenvironment of wounds and infections due to the action of these MMPs, which break down into smaller peptides, disabling the function of LL-37, 33 which could be avoided using peptides with disulfide bridges or replacing alpha-amino acids with the beta, accompanied by MMP inhibitors together with the application of AMP.
Studies with LL-37 Peptide
Similarly, other studies have proposed using LL-37 as an adjunct in treating chronic varicose ulcers, obtaining partially satisfactory results. That is, complete healing was achieved in none of the treated patients. The authors suggest that the results obtained are due to the limited time of treatment. In addition, it was also mentioned that the use of LL-37 for treatment would have a very high cost, to which many patients would not have access.
To avoid excessive costs in the treatment of diabetic ulcers using synthetic AMP, some research groups have chosen to induce peptides with exogenous molecules. There are many molecules capable of generating antimicrobial peptides in both blood and epithelial cells. The molecule identified with the most marked inducing effect is vitamin D.
The use of calcitriol and isoleucine L in cells from UPD has been reported to induce HBD-2 and LL-37. The supernatants from the stimulated cells were used to induce keratinocyte migration and proliferation, obtaining a remarkable result. The use of antibodies to block LL-37 and HBD-2 from the supernatants were related to healing and was abrogated.
The authors also demonstrated that the supernatants had antimicrobial activity against clinical isolates from UPD. However, many of these isolates had the gene for resistance to antimicrobial peptide activity (mprf). These data also suggest that broad-spectrum antibiotics should accompany the use of AMP or its inducers.
Later, the same group reported that calcitriol also affected the induction of critical pro-inflammatory molecules such as angiogenin and VEGF. It is interesting to note that calcitriol, in addition to inducing AMP in UPDs, decreases the expression of MMP-1 and MMP-10. However, the decrease in MMP-9 did not reach a statistically significant difference when compared to the control. Despite this last result, calcitriol continues to be the most promising inducer is used as an adjunct in the treatment of UPD. However, multicenter studies are needed in patients with UPD.
Future in research and therapy in diabetic foot ulcers
Research on the use of AMP as adjuvants in the treatment of PUs continues to advance in several lines of research, for example, the synthesis of peptides with specific angiogenic activities, the use of insect or amphibian, and synthetic peptides.
Some of these approaches have had highly suggestive results for clinical use; for example, pexiganan, a megainin-like antimicrobial peptide isolated from the skin of the African frog Xenopus leavis, showed effectiveness in treating UPD, even when compared to oral antibiotics.
Other studies have demonstrated the efficacy of peptides from frogs, which can efficiently promote angiogenesis and healing activities and regulate inflammatory processes in diabetic ulcers.
Another amphibian-derived peptide is esculetin 1, which induces migration in keratinocytes with even greater potency than LL-37. It highlights this peptide has an important antimicrobial activity against P. aeruginosa, suggesting its possible use as an antimicrobial agent in UPD.