Disruption of the skin by acne inflammation, infection, sun damage, disease, injury due to trauma, surgery, burns, accidents, or by chemical, dermabrasion or laser procedures used for skin renewal, generates a signal to the natural immune system and initiates responses that may or may not be effective in a) preventing an impending invasion from surrounding microbes and b) in triggering the regeneration of new healthy cells to replace those damaged.

Cutaneous defense mechanisms by antimicrobial peptides

Braff MH , Bardan A , Nizet V , Gallo RL . Department of Medicine, University of California San Diego, and VA San Diego Healthcare System, San Diego, California, USA.

Anti-microbial peptides are mainly minuscule cationic polypeptides that are classified together due to their capacity to impede the proliferation of microbes.

As effectors of innate immunity, antimicrobial peptides instantly kill a wide spectrum of bacteria, fungi, and viruses. In addition, these peptides alter the local inflammatory reaction and trigger mechanisms of cellular and adaptive immunity. Cathelicidins and defensins comprise the most important families of antimicrobial peptides in the dermis, although other cutaneous peptides, such as proteinase inhibitors, chemokines, and neuropeptides also express antimicrobial activity.

Together, these multifunctional antimicrobial peptides play a crucial role in skin immune defense and disease pathogenesis.

The review referenced at the link above discusses the biology and clinical relevance of antimicrobial peptides expressed in the skin. The importance of the epithelial contribution to host immunity is evident, as alterations in antimicrobial peptide expression have been associated with various pathologic processes.

Antimicrobial Peptides in the Skin: Biological Relevance

Antimicrobial peptides, which are synthesized in the dermis at sites of potential microbial entry, supply a soluble barrier that acts as an impediment to infection. In the case of infection or trauma, antimicrobial peptide expression in the dermis is upregulated due to increased synthesis by keratinocytes and deposition from degranulation of recruited neutrophils. Although antimicrobial peptides certainly demonstrate in vitro antimicrobial activity, studies have revealed that many such peptides, including cathelicidins and defensins, are inactivated by physiological salt concentrations (Goldman et al, 1997).

In fact, a recent study has revealed that mammalian dermis contains a fundamental antimicrobial-enhancing factor that renders bacteria susceptible to cathelicidin in vitro, despite the presence of physiological salt and serum (Dorschner et al, 2004). The in vivo relevance of antimicrobial peptides in the physiological environment is further accentuated by the laboratory animal models and human skin diseases that are exposed below.

Cathelicidins are defined by an N-terminal signal peptide, a highly preserved cathelin domain and a structurally mutable cationic antimicrobial peptide at the C-terminus. The cathelin domain operates as both a protease inhibitor and as an antimicrobial peptide in humans (Zaiou et al, 2003). Mature cathelicidin peptides show rapid, potent, and broad-spectrum antimicrobial activity and have been implicated in various immunomodulatory faculties(Koczulla et al, 2003).

Human cathelicidin, LL-37, assumes an a-helical structure in solutions with ion compositions similar to human plasma, interstitial fluid, or intracellular fluid. Processing of LL-37 from the cathelicidin precursor is essential for activation of its antimicrobial activity and is consumated by neutrophil proteases such as proteinase 3 (Sorensen et al, 2001).

LL-37 expression in squamous epithelia is differentially regulated in several inflammatory conditions (Frohm et al, 1997; Dorschner et al, 2001). LL-37 is produced in eccrine structures, where it is secreted and transformed in sweat, indicating a further barrier role against topical skin inflammation (Murakami et al, 2004).

In addition, LL-37 is produced by mast cells and recruits mast cells (Di Nardo et al, 2003), thereby participating in innate immunity both by direct antimicrobial activity and by recruitment of cellular human b-defensin defenses. LL-37 production is upregulated in neonatal skin, where it may adjust for the developmental immaturity of adaptive immune responses (Dorschner et al, 2003). A true immunomodulatory effector molecule, LL-37 has direct antimicrobial activity, acts synergistically with other antimicrobial peptides, functions as a chemoattractant for neutrophils, monocytes and T cells, and triggers endothelial cell proliferation by binding to formyl peptide receptor-like 1(FPRL-1) (Koczulla et al, 2003).

The multilayered expression and multifunctionality of cathelicidin in the skin present a formidable innate defense system against infection.

Cathelicidins Cathelicidins are strategically expressed and contribute multiple functions to skin defense. The human cathelicidin precursor protein hCAP18 is expressed by several cell types in the skin including keratinocytes, neutrophils, eccrine ducts, and mast cells. Cathelicidins are processed to active peptides such as LL-37 in neutrophils and more potent peptides in sweat.

These peptides have been best characterized as natural antibiotics, killing a variety of bacterial, fungal, and viral pathogens. Other functions include chemotactic and angiogenic behaviors, and an ability to modify fibroblast proteoglycan synthesis. The N-terminal cathelin-like domain of the hCAP18 precursor protein contains both antimicrobial and proteinase inhibitor activity.

Defensins Defensins have six cysteine residues that form characteristic disulfide bridges. Disulfide bridge alignment and molecular structure divide this fundamental antimicrobial peptide family into a-, b-, and y-defensins. Mammalian defensins exhibit antimicrobial activity against bacteria, fungi and enveloped viruses. á-Defensins have three disulfide bridges in a 1–6, 2–4, 3–5 alignment. Human neutrophils express four á-defensins, which are also referred to as human neutrophil peptides 1 through 4 (HNP-1 to -4) (Harwig et al, 1994). Human defensins 5 and 6 (HD-5 and -6) are substantially expressed as propeptides in Paneth cells of small intestinal crypts and in epithelial cells of the female urogenital tract.

In humans, defensins are accumulated in azurophil granules of neutrophils as fully processed, mature peptides. Like cathelicidins, á -defensins alter both microbes and the host. For example, HNP-1, -2, and -3 upregulate tumor necrosis factor alpha (TNF- á) and IL-1 in human monocytes that have been stimulated by bacteria; these peptides also diminish the expression of the adhesion molecule VCAM-1 in endothelial cells stimulated by TNF-a (Chaly et al, 2000).

b-Defensins have three disulfide bridges that are spaced in a 1–5, 2–4, 3–6 pattern. The four best-known human b-defensins, hBD-1 to -4, have been identified in various cell types, including epithelial and peripheral blood mononuclear cells (Harder et al, 2001; Fang et al, 2003; Liu et al, 2003). hBD-1 is constitutively expressed in epithelia, whereas hBD-2 is highly upregulated in inflamed skin. hBD- 3, which was sterilized from human psoriatic scales and calluses (Harder et al, 2001), is inducible in a variety of tissues. b-Defensins have broad-spectrum antimicrobial activity and additional immune-related cellular functions.

For example, hBD-2 binds to CCR6 and is chemotactic for immature dendritic cells and memory T cells (Yang et al, 1999). hBD-2 also stimulates histamine release and prostaglandin D2 production in mast cells, indicating a probable immunotherapeutic role as a vaccine adjuvant to improve antibody production (Befus et al, 1999). hBD-2 is practically absent in normal skin and its expression in human keratinocytes needs activation by cytokines or bacteria (Liu et al, 2003). The upregulation of hBD-2 by keratinocytes demonstrates the important role that defensins play in host defense against cutaneous pathogens.

Interestingly, the stability of the antimicrobial activity of these peptides on their primarly described function modifies, and no clear trend is noted. For example, the antimicrobial activity of ECP/RNase 3 does not need ribonuclease activity, which is essential for the antiviral activity of both ECP/RNase 3 and EDN/RNase 2 (Domachowske et al, 1998a, b). P-cystatin a inhibits bacterial proteinase activity as a mechanism of microbial growth inhibition (Takahashi et al, 1994), whereas cystatin C antimicrobial activity does not depend on its ability to inhibit bacterial proteinases (Blankenvoorde et al, 1998). The antiviral activity of cystatin C, however, appearsto remain in the proteinase-binding domain. Calprotectin contains zinc-binding sites and inhibits microbial growth through competition for metals (Sohnle et al, 2000), whereas NGAL interferes with bacterial iron acquisition (Goetz et al, 2002).

Antimicrobial Peptides in the Skin: Clinical Relevance

Differential expression of antimicrobial peptides appears to play a role in the vulnerability of patients with constant inflammatory skin diseases to infectious complications.

For example, LL-37 is stimulated in human keratinocytes during psoriasis, lupus erythematosus and contact dermatitis (Frohm et al, 1997). hBD-2 and hBD-3 are also upregulated in keratinocytes of inflamed psoriatic lesions (Harder et al, 2001; Nomura et al, 2003).

The magnified expression of antimicrobial peptides in psoriasis correlates with a low rate of secondary infection. In contrast, the expression of LL-37 and hBD-2 is not upregulated in individuals with atopic dermatitis, who are highly vulnerable to viral and bacterial infections (Ong et al, 2002). The differences in antimicrobial peptide expression between these two disorders achieve immunological relevance in light of the antimicrobial activity of LL-37 against S. pyogenes (Dorschner et al, 2001) and its synergistic activity with b-defensins against S. aureus (Ong et al, 2002), a leading agent of human skin infections.

LL-37 expression is upregulated in inflammatory skin lesions of erythema toxicum neonatorum and immunolocalizes within CD15-expressing neutrophils, EG-2-expressing eosinophils, and CD1a-expressing dendritic cells (Marchini et al, 2002). LL-37 is also stimulated within the epidermis during development of verruca vulgaris and condyloma accuminata, indicating that it represents a element of the innate immune reaction to papillomavirus infection (Conner et al, 2002).

Both hBD-1 and hBD-2 are upregulated in the lesions of acne vulgaris and may therefore be included in the pathogenesis or resolution of this condition (Philpott, 2003).

In addition, hBD-2 and the HNP are abundant in lesions of superficial folliculitis, a typical skin disease distinguished by inflammation of the hair follicle and infection with S. aureus (Oono et al, 2003). These studies demonstrate potential roles for antimicrobial peptides in host immune defense against skin infection.

Cathelicidin is produced at high levels in the skin after wounding (Dorschner et al, 2001) and is strongly expressed in healing skin epithelium (Heilborn et al, 2003). After cutaneous wounding, growth factors stimulate tissue regeneration until the physical barrier protecting the skin from microbial infections has been re-established.

Growth factors crucial in skin wound healing, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-a (TGF-a, induce the expression of cathelicidins and defensins in human keratinocytes (Sorensen et al, 2003). LL-37 antibodies impede post-wounding re-epithelialization in a concentration-dependent manner and cathelicidin expression is low or absent in chronic ulcers (Heilborn et al, 2003).

The ability of LL-37 to induce angiogenesis further highlights the relevance of cathelicidin in wound healing and tissue repair (Koczulla et al, 2003). Moreover, the expression of hBD-2 is dramatically decreased in burn wounds and blister fluid from partial thickness burns (Ortega et al,2000), providing evidence that innate immune defects may contribute to the risk of burn wound infection and sepsis.

Conclusion Natural immune defense function is greatly improved by a soluble antimicrobial peptide barrier that is activated when physical barriers fail to avoid microbial entry.

The skin not only acts as a physical barrier against microorganisms, it also produces peptides which tend to display broad-spectrum antimicrobial activity. The skin also produces growth factors, inhibitors of tumors and proteins. Following skin injury or wounds, growth factors are produced to stimulate the regeneration of tissue and to induce the creation of antimicrobial peptides. The growth factor response ceases after regeneration of the tissue, when the physical barrier protecting against microbial infections is re-established.

The body's response to acne, skin infection or injuries may or may not be impaired due to a malfunction of the immune system but when those occur we tend to address the problem with antibiotics and medicines that may have undesired side effects. Our product is an alternative and natural product made with the same biocid and skin regenerating substance a little creature with a skin similar to human skin uses to repair his own body when it has been damaged and is attacked by opportunistic bacteria and microbes.

Clears Skin Infections in Days
Skin infection can also be addressed with BIOSKINCARE CREAM instead of using antibiotics that create bacterial resistance.

The current situation of antibiotic resistant bacteria is creating alarm throughout the medical community. The over-prescription of antibiotics and people not taking the full recommended dosage, has created some super bacteria that are quite deadly because they are resistant to antibiotics. A good example is the new form of pneumonia that usually ends with infected people being placed in an Intensive Care Unit.

So what do we do now? One thing we can do is to look at how humans and other organisms ward off infections. The answer for many of humans infectious problems may lie with antimicrobial peptide antibiotics which have been found to be produced by all living animals tested to date.

Antibacterial activity of snail mucus mucin

Sanae M. M. Iguchi, Takashi Aikawa and Juichiro J. Matsumoto

Department of Chemistry, Faculty of Science and Technology, Sophia University, 7-1, Kioi-cho, Chiyoda-ku, Tokyo 102, Japan

Received 13 November 1981. Available online 21 March 2003.

Abstract

1. 1. An antibacterial activity was found in the mucin obtained from the body surface mucus of the African giant snail, Achatina fulica Férussac.

2. 2. The water soluble fraction (WSF) and the mucin fraction (MF) of the mucus exhibited positive antibacterial activity both for the Gram positive bacteria, Bacillus subtilis and Stuphylococcus aureus, and for the Gram negative bacteria, Escherichia coli and Pseudomonas aeruginosa, when assayed by the paper-disc method.

3. 3. When MF was digested with a proteinase (Pronase), the activity was lost, while no changes in the activity was found on treatment with glycosidase. Thus, the antibacterial activity was ascribed to the protein moiety of the snail mucus mucin.

This includes frogs (Journal of Peptide Research - Amphibians, The antibiotic and anticancer active aurein peptides from the Australian Bell Frogs) cows, fish ( Characterization of a Fish Antimicrobial Peptide), pigs Natural antibiotics help aid swine health and food safety, insects Antimicrobial peptides in insects), snails (Antimicrobial peptides in the secretion of land snails ) , snakes, birds and plants. And they are produced by many different tissues and organs of the body, including our skin.

These peptides are thought to punch holes in the membranes of bacteria much like the complement proteins do in our immune system. But what is really exciting about these antimicrobial peptide antibiotic substances is that the target bacterium may not be able to mutate and defend itself against this antibiotic action.

Bacteria have survived for millions of years by developing resistance to new stressors including natural antibiotics like penicillin. What simply happens is that the bacteria, with a high rate of mutation, ends up modifying one or more of its enzymes that are used to break the link between a target protein and the antibiotic. As a result, the antibiotic does not work.

But to adapt to a peptide antibiotic that punches a hole in the cell membrane is a different story. To protect itself, the bacterium would have to change the entire composition of the cell membrane. And to change the composition of a membrane would mean changing many of the enzymes that are responsible for making the complex membrane in the first place.

Peptide antibiotics respond within minutes. Part of the reason for this rapid response is how the peptide acts on the cell membrane. But to destroy a cell, the peptide must also quickly find the bacterial membrane. How does this happen? The answer lies in the construction of the cell membrane.

The plasma membrane of eukaryotic cells is much different than the membrane of a prokaryotic cell. Eukaryotic cell membranes are constructed of a phospholipid bilayer and cholesterol. Consequently, these membranes have a low negative electrical charge. On the other hand, a bacterial membrane is made up of fats and sugars. This difference in construction means that bacteria have a high negative electrical charge that quickly attracts the peptide antibiotics.

Peptide antibiotics are effective. In one clinical trial for the treatment of meningitis, a disease that affects 3,000 children a year, a peptide antibiotic not only killed the bacterium which produces the toxin, but it also bound to the toxin preventing the damage the endotoxin produces. This is a promising new venue for research ... and creating effective drugs...

But bringing a drug to clinical trial is time consuming and expensive. It takes $300 million to bring a drug to market. This cost covers every thing from discovery, identification, synthesis and clinical trials. This process may also take 10 or more years to accomplish.

Fortunately we do not have to wait to get the benefits of antimicrobial peptides when fighting acne or skin injuries, for they can be addressed with the peptides and proteins contained in the mucin of certain species of land snails, the same they use to repair their own body and calcium shell whenever damaged.

The natural biocid action of the snail's mucin is very effective against skin infections and acne inflammation, and without the pitfalls of pharmaceutical antibiotics or the side effects of harsh chemicals. The mucin also helps to get rid of the chemical inflammatory promoters (i.e. interleukin-6, hydrogen peroxide, histamines, bacterial toxins) that are significantly increased by acne infection.

Forget about chemicals, now you can take care of your skin with nature's gift for healthy skin.

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