Current Pharmaceutical Design - Volume 13, Issue 30, 2007

Ever since the first observations that certain endogenously produced cystein-rich peptides have significant antibacterial and antifungal activity, interest has grown and evidence has accumulated that they may play multiple roles in maintaining oral health. Oral epithelium is constantly exposed to microbial agents. It is clear that the oral epithelium is not only a physical barrier but also has chemical defense mechanisms containing antimicrobial peptides such as the defensins. Epithelial cells secrete interleukin-8 and other cytokines that attract neutrophils and other cell types, and also they produce antimicrobial peptides against microorganisms and their products. Therefore, antimicrobial peptides of the oral epithelium belong to the first line of host defense mechanisms against infections in epithelial tissue. As part of innate immune system, antimicrobial peptides helping keep the balance between health and disease in the complex environment of oral cavity are small cationic antimicrobial peptides and have broad spectrum antimicrobial and antifungal activity. Thus, epithelial cells are active participants in antimicrobial activity and in interacting with innate and acquired immune responses. This theme issue of Current Pharmaceutical Design focuses on antimicrobial peptides, mainly on defensins in oral cavity. We asked numerous questions to explore and understand the importance and role of defensins in oral health and disease, to create new insights to the pharmaceutical discovery field, and to find out new treatment strategies for oral diseases. We are delighted to have Michael E. Selsted's introductory manuscript to the defensin research field in this issue of Current Pharmaceutical Design. Defensin amino acid sequences and term defensin first published by M. Selsted, T. Ganz and R. Lehrer more than 20 years ago and Lehrer Laboratory in UCLA pioneered defensin research in the world. Dr. Selsted's introduction provides a fascinating historical review of the development of the field as a whole, shares his insights into some of the determining factors in the directions of research that have evolved and provides observations on the context for the contributions of this issue. Humans have defense mechanisms in the oral cavity including the natural defenses of saliva and the host innate immune responses as well as the ability to generate antibodies by acquired immune responses. Saliva contains a large number of protective proteins, such as lactoferrin, lysozome, peroxidases, immunoglobulins, agglutinin and mucins, and several types of antimicrobial peptides, including histatins, defensins and cathelicidin/LL-37 that have an important role in innate host defense. In this issue, Drs. Abiko and Saitoh from University of Hokkaido review salivary defensins and discuss their importance in oral health and disease. Salivary defensins which protect mucosal epithelium are possibly derived from salivary ductal cells, oral epithelial cells and some blood cells. The antimicrobial activity of defensins may be affected by the components of saliva, which in turn may poteniate the protective role of saliva. The authors suggest that salivary defensin levels can be altered in oral diseases and therefore their level may be a useful marker for risk assessment, salivary diagnosis and new therapeutic strategies. Dr. Chung et al. from University of Washington, in their review article, create a picture of the role played by various antimicrobial peptides that are expressed in periodontal tissues and how they function in periodontal health and periodontal diseases. They also provide an overview of the differential regulation of human beta defensin expression as a host innate immune response to commensal vs. pathogenic bacteria. Dr. Chung and co-authors suggest that understanding how the expression of antimicrobial peptides is regulated in oral epithelia will lead us to discover new therapeutic targets to prevent and treat periodontal diseases.......

Antimicrobial peptides are among the most ancient effectors of host defense. Intersecting lines of research demonstrate that life forms as diverse as plants, insects, and vertebrates employ antimicrobial peptides to kill or neutralize a wide variety of microbial species. Defensins, of which there are three structural sub-families, constitute a major category of host defense peptides in vertebrates. Presented here is a brief history of the emergence of the defensin field with an emphasis on the role of these peptides in mammalian innate immunity.

Saliva contributes significantly to the protective barrier of oral epithelium through its mechanical rinsing action and the unique peptides it contains. Saliva contains several types of antimicrobial peptides, including defensins, which may have an important role in innate host defense. Many types of human defensins have been discovered and characterized in the last decade. This review summarizes the recent literature on salivary defensins and discusses their importance in oral health and disease. Salivary defensins are possibly derived from salivary ductal cells, oral epithelial cells and some blood cells. The antimicrobial activity of defensins may be affected by the components of saliva. Salivary defensin levels can be altered in oral diseases, and therefore may be a useful marker for risk assessment, salivary diagnosis and therapeutic strategies.

Oral epithelium is a stratified squamous epithelium that functions as the barrier between the outside environment and the host. In the oral cavity, epithelial tissues are constantly exposed to a variety of bacteria, but most individuals maintain healthy homeostasis. Epithelial cells contribute to the innate host response, and antimicrobial peptide expression in all human epithelia, including oral epithelia, is an important part of this epithelial function. These antimicrobial peptides have a broad spectrum of activity against both Gramnegative and Gram-positive bacteria as well as against yeast and viruses. In humans these antimicrobial peptides include defensins and a cathelicidin family member LL-37 in skin and oral mucosa and other epithelia. The human defensins include the α-defensins of intestinal and neutrophil origin, and the β-defensins of skin and oral mucosa and other epithelia. Present studies have identified specific signaling routes that pathogens and commensals take in stimulating these innate immune responses, and this may open the way for development of new therapeutic agents for periodontal diseases.

Antimicrobial peptides play an important role in the human innate immune defense system. In the oral cavity, a number of antimicrobial peptides, including defensins and LL37, are produced from various tissues such as salivary glands, gingival epithelium, tongue and buccal mucosa. These peptides are believed to function as a host defense system by controlling the activities of commensal bacteria and thus preventing the colonization and growth of pathogenic bacteria in oral cavity. Two major oral diseases, dental caries and periodontitis are known as infectious diseases. Therefore, it is of great interest to elucidate the mechanisms underlying the onset and progression of these diseases by investigating the interaction between cariogenic, or periodontopathogenic bacteria and antimicrobial peptides. Since these peptides have a broad antimicrobial spectrum, they are implicated as possible therapeutic agents. Therefore, in this review, we first focus on the susceptibility of oral bacteria, especially cariogenic and periodontopathogenic bacteria, to antimicrobial peptides, and then we discuss their potential diagnostic and clinical therapeutic uses.

Defensins are small, β-sheet-rich, cationic peptides found in many organisms. All defensins have amphiphilic properties, which are central for antimicrobial activities of the proteins. The human genome encodes many defensin-line molecules, of which 10 have been characterized. Molecules of all known human defensins are stabilized by three intramolecular disulfide bonds arranged in a conserved pattern. To date, studies of human defensins indicate that these proteins are involved in various biological processes associated primarily with defensive and regulatory responses to infections by pathological agents. A comprehensive understanding of the multiple roles played by defensins within the immune system is greatly increased by reviewing the results of detailed structural studies. Emerging structural data, derived by the X-ray crystallography and the NMR spectroscopy in solution combined with functional studies; allow a rational understanding of the different activities of defensins and the mechanisms controlling these activities. Due to their well-established antimicrobial properties, defensins are also being investigated for their potential as therapeutics agents. Recently, increased effort has been focused on studies of the immunoregulatory properties of defensins, associated with their ability to bind and activate the Gi-proteincoupled seven-transmembrane receptors. Comprehensive studies of defensins require development of simple, efficient, and inexpensive methods to generate these proteins and their derivatives in correctly folded form. This review highlights the current status of the sample generation methods, structural studies, and the structure-function relationships for human defensins.

There is increasing evidence that antimicrobial peptides (AMPs) are differentially regulated in cancers such as oral squamous cell carcinomas (OSCC). Data showing that AMPs influence the growth of tumor cells, exhibit direct cytotoxic activity towards cancer cells, function as a tumor suppressor gene or activate the adaptive immunity suggest that a dysregulation of AMPs may be associated with the development of cancer. There is no question that, with increasing resistance against conventional chemotherapy, novel anticancer agents are needed. It is interesting to speculate that natural AMP or synthetic derivatives can be used to develop novel strategies to fight cancer diseases and may represent a novel family of anticancer agents. However, future research is needed to employ the role of AMPs in cancer and to investigate their role as potential anticancer drugs.

Defensins are endogenous, small, cysteine-rich antimicrobial peptides that are produced by leukocytes and epithelial cells. Substantial evidence accumulated in recent years indicates that mammalian defensins are multifunctional and, by interacting with host cell receptor(s), participate in both the innate and adaptive antimicrobial immunity of the host. A better understanding of the function of defensins in immunity has implications for the development of potential clinical therapeutics for the treatment of infection or cancer. Here we will briefly outline the classification, genes, expression, and structure of mammalian defensins and focus on their roles in innate and adaptive immune response of the host.

Based on the mode of action of antibacterial drugs currently used, targets can be defined as distinct cellular constituents such as enzymes, enzyme substrates, RNA, DNA, and membranes which exhibit very specific binding sites at the surface of these components or at the interface of macromolecular complexes assembled in the cell. Intriguingly, growth inhibition or even complete loss of bacterial viability is often the result of a cascade of events elicited upon treatment with an antibacterial agent. In addition, their mode of action frequently involves more than one single target. A comprehensive description of the targets exploited so far by commercialized antibacterial agents, including anti-mycobacterial agents, is given. The number of targets exploited so far by commercial antibacterial agents is estimated to be about 40. The most important biosynthetic pathways and cellular structures affected by antibacterial drugs are the cell wall biosynthesis, protein biosynthesis, DNA per se, replication, RNA per se, transcription and the folate biosynthetic pathway. The disillusionment with the genomics driven antibacterial drug discovery is a result of the restrictive definition of targets as products of essential and conserved genes. Emphasis is made to not only focus on proteins as potential drug targets, but increase efforts and devise screening technologies to discover new agents interacting with different RNA species, DNA, new protein families or macromolecular complexes of these constituents.

Dithiocarbamates and their complexes with transition metals have been used as common pesticides, vulcanizing or analytical agents for decades. These compounds are one of the most reported inhibitors of nuclear factor-κB (NF-κB) signaling cascade. Recently, it has been found that dithiocarbamates are very potent inhibitors of proteasome. NF-κB plays a central role in the immune system and is described as a major actor in many of human cancers mainly because of its protective effects against apoptosis. Molecular mechanisms involved in regulation and function of NF-κB pathway have been elucidated recently. In particular, pivotal zinc containing proteins that alter NF-κB signal transduction were recognized. Additionally, proteasome system was found to be a key player in NF-κB pathway and is an attractive target for anticancer drug development. Collectively, the capability of dithiocarbamates to inhibit NF-κB and proteasome makes these compounds promising anticancer agents. This review focuses on the biological activity of dithiocarbamate coordination compounds with regard to their possible molecular targets in NF-κB signaling and proteasome (JAMM domain proteins). Future research should aim to find the most suitable dithiocarbamate coordination compounds for treatment of cancer and other diseases.