[bookofjoe]

Histatins: antimicrobial peptides with therapeutic potential

ABSTRACT

Histatins are a group of antimicrobial peptides, found in the saliva of man and some higher primates, which possess antifungal properties. Histatins bind to a receptor on the fungal cell membrane and enter the cytoplasm where they target the mitochondrion. They induce the non-lytic loss of ATP from actively respiring cells, which can induce cell death. In addition, they have been shown to disrupt the cell cycle and lead to the generation of reactive oxygen species. Their mode of action is distinct from those exhibited by the conventional azole and polyene drugs, hence histatins may have applications in controlling drug-resistant fungal infections. The possibility of utilising histatins for the control of fungal infections of the oral cavity is being actively pursued with the antifungal properties of topical histatin preparations and histatin-impregnated denture acrylic being evaluated. Initial clinical studies are encouraging, having demonstrated the safety and efficacy of histatin preparations in blocking the adherence of the yeast Candida albicans to denture acrylic, retarding plaque formation and reducing the severity of gingivitis. Histatins may represent a new generation of antimicrobial compounds for the treatment of oral fungal infections and have the advantage, compared with conventional antifungal agents, of being a normal component of human saliva with no apparent adverse effects on host tissues and having a mode of action distinct to azole and polyene antifungals.

Kavanagh, Kevin and Dowd, Susan (2004) Histatins: antimicrobial peptides with therapeutic potential. Journal of Pharmacy and Pharmacology, 56.

http://eprints.maynoothuniversity.ie/354/1/R03014.pdf

[bookofjoe]

Histatins are the major wound-closure stimulating factors in human saliva as identified in a cell culture assay

ABSTRACT

Wounds in the oral cavity heal much faster than skin lesions. Among other factors, saliva is generally assumed to be of relevance to this feature. Rodent saliva contains large amounts of growth factors such as epidermal growth factor (EGF) and nerve growth factor (NGF). In humans, however, the identity of the involved compounds has remained elusive, especially since EGF and NGF concentrations are ∼100,000 times lower than those in rodent saliva. Using an in vitro model for wound closure, we examined the properties of human saliva and the fractions that were obtained from saliva by high-performance liquid chromotography (HPLC) separation. We identified histatin 1 (Hst1) and histatin 2 (Hst2) as major wound-closing factors in human saliva. In contrast, the d-enantiomer of Hst2 did not induce wound closure, indicating stereospecific activation. Furthermore, histatins were actively internalized by epithelial cells and specifically used the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, thereby enhancing epithelial migration. This study demonstrates that members of the histatin family, which up to now were implicated in the antifungal weaponry of saliva, exert a novel function that likely is relevant for oral wound healing.

Oudhoff, M. J., Bolscher, J. G. M., Nazmi, K., Kalay, H., van 't Hof, W., Nieuw Amerongen, A. V., Veerman, E. C. I.

http://www.fasebj.org/doi/pdf/10.1096/fj.08-112003

[euler_]

Thanks for the information! After reading the abstracts, I still have two question.

1. It sounds like the mechanism for killing cells is very general. Why do histatins not attack somatic cells?

2. Do mouth wounds simply heal faster because the mouth is cleaner?

[bookofjoe]

I'm an anesthesiologist by specialty, with experience as a GP/Family practitioner; the answer to your first question is above my medical pay grade.

In regard to the second, I can say this: in the ER, a human bite is considered FAR more dangerous than a dog bite, because the human mouth has more — and more dangerous — pathogens. The mouth is much dirtier (not cleaner) than skin.

[sndean]

> 1. It sounds like the mechanism for killing cells is very general. Why do histatins not attack somatic cells?

They semi-specifically target a receptor on C. albicans and other pathogens. They're also cationic [1], so they bind anionic lipids in bacteria and mitochondria that aren't found (in large quantities) on the mammalian cell surface.

> 2. Do mouth wounds simply heal faster because the mouth is cleaner?

From that second abstract:

"..histatins were actively internalized by epithelial cells and specifically used the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, thereby enhancing epithelial migration."

It's a relatively simple assay: Just grow a lawn of the skin cells, scrape a line down the middle, and see how quickly the line is filled in (with or without exogenous histatin).

So those peptides tend to do both: kill bacteria and lead to wounds healing faster.

[1] http://aps.unmc.edu/AP/database/query_output.php?ID=00505

[IntronExon]

The cells lining the entire upper GI are exposed to digestive enzymes, and are perforce replaced rapidly and constantly. Until bicarbonate rich bile is added to the mixture in the duodenum, those enzymes (and acids) eat your own cells too. Chemotherapy plays havoc with your GI tract because it selectively kills cells which rapidly divide.

As for histamines, mast cells are designed to respond to them and rupture as part of your inflammatory cycle. They release more cytokines, recruiting neutrophils and in general telling your immune system to attack.

[classichasclass]

Histatins, not histamines.

[IntronExon]

Oops, thanks for the correction!