Antimicrobial Apoptosis

Recently, the activities of host defense peptides related to the resolution of infection have been suggested to result in part from nondirect antimicrobial activities. It has been postulated that immunomodulation may represent the primary action of these peptides in vivo as the immunomodulatory activities are retained under physiological conditions in contrast to the direct antimicrobial activities of most natural mammalian host defense peptides. These immunomodulatory activities include, but are not limited to, direct chemotactic activity, induction of chemokines and other immune mediators, stimulation of leukocyte degranulation and other microbicidal activities, effects on leukocyte and epithelial cell survival and apoptosis, stimulation of epithelial and endothelial cell proliferation, promotion of wound healing and angiogenesis, antiendotoxic and anti-inflammatory activities, and adjuvant fiinctions. These will be described in detail in the following sections and a summary is found in Table 1. 

In contrast, Snyder has demonstrated that an RI derivative ofp53 can restore endogenous p53 activity the RI derivative induced apoptosis by activation of endogenous p53 and by restoration of function to several p53 DNA contact mutants. Rl-modified peptides have also been investigated as potential alternatives for bost defense peptides. Indeed, a RI derivative of indolicidin retained tbe antimicrobial and antiendotoxic acitivities of the natural peptide. As the antiendotoxin activities of the Rl-derivative were conserved these results might indicate the conservation of multiple immunomodulatory activities upon retro-inversion, highlighting the potential of this modification for therapeutic applications. 

Many skin disorders are associated with at least one of the characteristics of inflammation, oxidative stress, hyperproliferation, hypodifferentiation, infection, apoptosis, and autoimmune reactions. GTPs are uniquely positioned to antagonize these conditions with anti-inflammatory, antioxidant, antimicrobial, prodifferentiation, anti-apoptosis, and inhibition of autoantigen properties. Thus, many skin conditions, including autoimmune-induced lupus and psoriasis, wounds created by trauma or infections, damage induced by environmental factors such as UVB, and seborrheic dermatitis (dandruff), could be treated or managed by topical application of GTPs. 

Lapachol (95, from the lapacho tree, genus Tabebuia, family of the catalpa trees, Bignoniaceae) and its analogues show very broad therapeutic capabilities , including activity against cancer which results in apoptosis and inhibition in metastasis, antimicrobial, antifungal, antimalarial and other activities . However, clinical application of lapachol is limited by its high toxicity. Lapachol forms complexes with many metal ions. 

Cathelicidins may also control tissue damage and inflammation, inhibiting the production of reactive oxygen species (proline-arginine-rich porcine cathelicidin, PR-39) or inducing apoptosis in activated lymphocytes (bovine antimicrobial peptide-28) [9]. 

A peptide (DPI), comprised of a protein transduction domain fused to an antimicrobial peptide (AMP) KLAKLAKKLAKLAK, triggered apoptosis in murine fibrosarcoma (MCA205) and human head and neck tumor cell lines in vitro. It also induced tumor apoptosis and reduction of tumor volume (MCA205) by direct intratumor injection [245]. 

PBDs have shown different biological properties but, probably the three most important are the cytoprotection against HIV-1 in vitro of guttiferones [3-4], antimicrobial properties [5-11] and cytotoxic activity found in diverse nucleus [12-16]. Interesting bioactivity such as antibacterial activity against methicillin-resistant Straphylococcus aureus [6-8], antioxidant activity [44,59,60] and cytotoxic activity due to induction of apoptosis in human leukemia cells have been reported [61,62],... 

Rankovic B, Misic M, Sukdolak S (2008) The antimicrobial activity of substances derived from the lichens Physcia aipolia, Umbilicaria polyphylla, Parmelia caperata and Hypogymnia physodes. World J Microbiol Biotechnol 24 1239-1242 Russo A, Piovano M, Lombardo L et al (2008) Lichen metabolites prevent UV light and nitric oxide-mediated plasmid DNA damage and induce apoptosis in human melanoma cells. Life Sci 83 468-474... 

Fabiani, R. et al.. Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Fur. J. Cancer Prev., 11, 351, 2002. Fumeri, P.M. et al., Antimycoplasmal activity of hydroxytyiDsol, Antimicrobial agents and chemotherapy, 48, 4892, 2004. 

---