Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 30, 2007
Contents
Antimicrobial Peptides, Mainly Defensins in Oral Cavity
Executive Editors: S. Vardar-Sengul and D. Mercola
Editorial Pp. 3059-3060
A Pocket Guide to Explorations of the Defensin Field
Pp. 3061-3064
M.E. Selsted
[Abstract]
Salivary Defensins and Their Importance in Oral Health
and Disease Pp. 3065-3072
Y. Abiko and M. Saitoh
[Abstract]
Expression of Defensins in Gingiva and Their Role
in Periodontal Health and Disease Pp. 3073-3083
W.O. Chung, H. Dommisch, L. Yin and B.A. Dale
[Abstract]
Susceptibility of Periodontopathogenic and Cariogenic
Bacteria to Defensins and Potential Therapeutic Use of Defensins
in Oral Diseases Pp. 3084-3095
H. Komatsuzawa, K. Ouhara, T. Kawai, S. Yamada, T. Fujiwara,
H. Shiba, H. Kurihara, M.A. Taubman and M. Sugai
[Abstract]
Human Defensins: Synthesis and Structural Properties
Pp. 3096-3118
M. Pazgier, X. Li, W. Lu and J. Lubkowski
[Abstract]
Antimicrobial Peptides in Oral Cancer Pp.
3119-3130
J.E. Meyer and J. Harder
[Abstract]
Defensin Participation in Innate and Adaptive Immunity
Pp. 3131-3139
D. Yang, Z.-h. Liu, P. Tewary, Q. Chen, G. de la Rosa
and J.J. Oppenheim
[Abstract]
General Articles
The Targets of Currently Used Antibacterial Agents: Lessons
for Drug Discovery Pp. 3140-3154
R.P. Lange, H.H. Locher, P.C. Wyss and R.L. Then
[Abstract]
Targeting of Nuclear Factor-κB
and Proteasome by Dithiocarbamate Complexes with Metals
Pp. 3155-3167
B. Cvek and Z. Dvorak
[Abstract]
Abstracts
[Back to top]
Editorial: Antimicrobial Peptides,
Mainly Defensins in Oral Cavity
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.
Dr. Komatsuzawa et al. from Hiroshima University
review the susceptibility of oral bacteria, mainly cariogenic
and periodontopathogenic bacteria, to antimicrobial peptides,
and they discuss their potential use in diagnostic and therapeutic
purposes. It is of great interest to elucidate the mechanisms
underlying the onset and progression of dental caries and
periodontitis by investigating the interaction between cariogenic
or periodontopathogenic bacteria and antimicrobial peptides.
Dr. Pazgier et al. from National Cancer Institute
at Frederick and University of Maryland highlight the current
status of the sample generation methods, structural studies,
and the structure-function relationships for human defensins.
Defensins are being investigated for their potential as therapeutic
agents because of their antimicrobial activities. Recently,
increased effort has been focused on the studies of the immunoregulatory
properties of defensins that are associated with their ability
to bind and activate the Gi-protein-coupled seven-transmembrane
receptors. The authors conclude that comprehensive studies
of defensins require development of simple, efficient, and
inexpensive methods to generate defensins and their derivatives
in correctly folded form.
Drs. Meyer and Harder from University of Luebeck and University
of Kiel provide an overview on how antimicrobial peptides
play a role in tumor biology. Interestingly, antimicrobial
peptides exhibit direct cytotoxic activity towards cancer
cells, influence the growth of tumor cells, function as a
tumor suppressor gene, or activate the adaptive immunity.
They also discussed anticancer potential of antimicrobial
peptides in oral cancer. The authors state that a dysregulation
of antimicrobial peptides may be associated with the development
of cancer. Future research on antimicrobial peptides in relation
to cancer biology may inspire the development of new strategies
for cancer treatment.
Dr. Yang et al. from National Cancer Institute at
Frederick outlined the known and potential mechanisms of defensin
participation in innate and adaptive immunity.
Overall, this issue provides extensive and fascinating overview
of the scope and limitations of antimicrobial peptides, mainly
defensins as potential diagnostic and therapeutic agents in
oral diseases. The authors contributing to this issue are
well-known for their contributions to this field. As an Executive
Editor of Current Pharmaceutical Design, it is a
pleasure to thank the authors for their contributions and
making this issue happen for Current Pharmaceutical Design
readers. We believe this issue will be of great interest
for all interested in new insights of the antimicrobial peptides
as new class antibiotics and also for all discussion and research
on how to engineer epithelium to express these antimicrobial
peptides against infections.
References
[1] Selsted ME. A pocket guide to explorations of the defensin
field. Curr Pharm Des 2007; 13(30): 3061-3064.
[2] Abiko Y and Saitoh M. Salivary defensins and their importance
in oral health and disease. Curr Pharm Des 2007; 13(30): 3065-3072.
[3] Chung WO, Dommisch H, Yin L, Dale BA. Expression of defensins
in gingiva and their role in periodontal health and disease.
Curr Pharm Des 2007; 13(30): 3073-3083.
[4] Komatsuzawa H, Ouhara K, Kawai T, Yamada S, Fujiwara T,
Shiba H, et al. Susceptibility of periodontopathogenic
and cariogenic bacteria to defensins and potential therapeutic
use of defensins in oral diseases. Curr Pharm Des 2007; 13(30):
3084-3095.
[5] Pazgier M, Li X, Lu W, Lubkowski J. Human defensins: Synthesis
and structural properties. Curr Pharm Des 2007; 13(30): 3096-3118.
[6] Meyer JE, Harder J. Antimicrobial peptides in oral cancer.
Curr Pharm Des 2007; 13(30): 3119-3130.
[7] Yang D, Liu Z, Tewary P, Qian Chen Q, De la Rosa G, Oppenheim
JJ. Defensin participation in innate and adaptive immunity.
Curr Pharm Des 2007; 13(30): 3131-3139.
Saynur VARDAR-SENGUL, DDS, PhD.
University of California, Irvine
School of Medicine
Department of Pathology and Laboratory Medicine
Irvine, California-USA
Ege University
School of Dentistry
Department of Periodontology
Bornova, Izmir-TURKEY
Dan MERCOLA, MD, PhD.
University of California, Irvine
School of Medicine
Department of Pathology and Laboratory Medicine
Irvine, California-USA
[Back to top]
A Pocket Guide to Explorations of the Defensin Field
Pp. 3061-3064
M.E. Selsted
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.
[Back to top]
Salivary Defensins and Their Importance in Oral Health
and Disease
Y. Abiko and M. Saitoh
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.
[Back to top]
Expression of Defensins in Gingiva and Their Role
in Periodontal Health and Disease
W.O. Chung, H. Dommisch, L. Yin and B.A. Dale
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 Gram-negative
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.
[Back to top]
Susceptibility of Periodontopathogenic and Cariogenic
Bacteria to Defensins and Potential Therapeutic Use of Defensins
in Oral Diseases
H. Komatsuzawa, K. Ouhara, T. Kawai, S. Yamada, T. Fujiwara,
H. Shiba, H. Kurihara, M.A. Taubman and M. Sugai
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.
[Back to top]
Human Defensins: Synthesis and Structural Properties
M. Pazgier, X. Li, W. Lu and J. Lubkowski
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-protein-coupled
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.
[Back to top]
Antimicrobial Peptides in Oral Cancer
J.E. Meyer and J. Harder
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.
[Back to top]
Defensin Participation in Innate and Adaptive Immunity
D. Yang, Z.-h. Liu, P. Tewary, Q. Chen, G. de la Rosa
and J.J. Oppenheim
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.
[Back to top]
The Targets of Currently Used Antibacterial Agents: Lessons
for Drug Discovery
R.P. Lange, H.H. Locher, P.C. Wyss and R.L. Then
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 bio-synthetic 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.
[Back to top]
Targeting of Nuclear Factor-κB
and Proteasome by Dithiocarbamate Complexes with Metals
B. Cvek and Z. Dvorak
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.
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