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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 18, 2009
Contents
The Impact of Microbiota and Cytokines
on Inflammatory Bowel Disease
Executive Editors: O. Kanauchi and
K. Mitsuyama
Editorial: Pp. 2049-2050
The Intestinal Environment in Health and Disease –
Recent Insights on the Potential of Intestinal Bacteria to
Influence Human Health Pp. 2051-2065
S. Possemiers, C. Grootaert, J. Vermeiren,
G. Gross, M. Marzorati, W. Verstraete and T. Van
de Wiele
[Abstract] [Purchase
Article]
[PMID: 19519443 PubMed - indexed for MEDLINE]
Recent Advances in Molecular Approaches
to Gut Microbiota in Inflammatory Bowel Disease Pp.
2066-2073
A. Andoh, Y. Benno, O. Kanauchi and
Y. Fujiyama
[Abstract] [Purchase
Article] [PMID: 19519444 PubMed - indexed for MEDLINE]
The Therapeutic Impact of Manipulating
Microbiota in Inflammatory Bowel Disease Pp.
2074-2086
O. Kanauchi, K. Mitsuyama and A.
Andoh
[Abstract] [Purchase
Article] [PMID: 19519445 PubMed - indexed for MEDLINE]
Curcumin has Bright Prospects for the
Treatment of Inflammatory Bowel Disease Pp. 2087-2094
H. Hanai and K. Sugimoto
[Abstract] [Purchase
Article] [PMID: 19519446 PubMed - indexed for MEDLINE]
Interleukin-6 Trans-Signaling and Colonic
Cancer Associated with Inflammatory Bowel Disease Pp.
2095-2103
S. Rose-John, K. Mitsuyama, S. Matsumoto,
W.M. Thaiss and J. Scheller
[Abstract] [Purchase
Article] [PMID: 19519447 PubMed - indexed for MEDLINE]
Overview of the Role of Macrophage Migration
Inhibitory Factor (MIF) in Inflammatory Bowel Disease
Pp. 2104-2109
J. Nishihira and K. Mitsuyama
[Abstract] [Purchase
Article] [PMID: 19519441 PubMed - indexed for MEDLINE]
Recent Understanding of Leukocytapheresis
(LCAP) for the Treatment of Inflammatory Bowel Disease
Pp. 2110-2119
K. Mitsuyama, H. Yamasaki, K. Kuwaki, H.
Takedatsu and M. Sata
[Abstract] [Purchase
Article] [PMID: 19519448 PubMed - indexed for MEDLINE]
General Articles
Developments of Indoles as Anti-HIV-1 Inhibitors Pp.
2120-2148
Hui Xu and Min Lv
[Abstract] [Purchase
Article] [PMID: 19519449 PubMed - indexed for MEDLINE]
HCN Pacemaker Channels and Pain: A Drug
Discovery Perspective Pp. 2149-2168
A.D. Wickenden, M.P. Maher and S.R.
Chaplan
[Abstract] [Purchase
Article] [PMID: 19519450 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: The Impact of Microbiota and Cytokines
on Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic relapsing
disorder associated with uncontrolled inflammation within
the gastrointestinal tract, which has been shown to predispose
patients to the development of colorectal cancer later in
life. The pathogenesis of IBD is complex, but the current
model favors a dysregulated cytokine network that is triggered
by intestinal microbiota in a genetically-susceptible host.
Interestingly, a germ free rodent model was reported not to
cause cytokine dysregulation and intestinal inflammation.
Therefore, microbiota and cytokines are both considered as
theoretical targets for therapeutic approaches in IBD.
This special issue of Current Pharmaceutical Design
focuses on the role of microbiota and cytokines in IBD. Furthermore,
therapeutic approaches targeting these two factors are also
discussed including functional food and the pharmacological
and non-pharmacological treatment modalities.
First of all, Possemiers S, et al. provided a brief
overview on the importance of the indigenous microbial community
and its enormous metabolic potential, microbe-microbe interactions,
mechanisms of host-bacterium cross-talk and discussed the
onset of obesity, a specific disease state in which intestinal
microbiota play a role [1].
Andoh A, et al. provided a review focusing on new
insights into the role of commensal microbiota in gut health
and disease, and presented recent advances in molecular approaches
to the imbalance of intestinal microbiota in IBD [2].
Kanauchi O, et al. introduced the therapeutic impact
of manipulating microbiota in IBD [3]. This review shows that
the administration of selected prebiotics, probiotics and
synbiotics may improve the clinical outcome of patients with
IBD as a target for new forms of functional food. In addition,
they describe the possibility of preventive treatment of IBD-associated
colon cancer by using special prebiotics because of their
physiologic characteristics and lack of obvious toxicity.
Hanai H, et al. summarized the effects of curcumin,
polyphenolic compound used as savory food-additives on IBD
patients [4]. Although curcumin is unstable in the gut and
is rapidly degraded or conjugated through glucuronidation,
it is known to be a non-specific NF-κB
inhibitor with potent anti-inflammatory action. In this review,
they outline the clinical efficacy of curcumin in IBD as well
as that in rodent colitis models.
Interleukin-6 (IL-6) is a pleiotropic cytokine that plays
a crucial role in inflammation, immune regulation, and oncogenesis.
There is growing evidence that an IL-6 signaling pathway plays
a crucial role in the uncontrolled intestinal inflammatory
process of IBD. Rose-John S, et al. have reviewed
the properties of IL-6 in IBD as well as IBD-associated colon
cancer and summarized the consequences of these new results
for the prospects of IL-6-targeted therapeutic strategies
for the treatment of these diseases [5].
Macrophage migration inhibitory factor (MIF) is one of the
first cytokines discovered in the early 60’s with a
broad range of functions including induction of proinflammatory
mediators and has demonstrated roles in both innate and adaptive
immunity, which also plays an important role in the development
of inflammatory and malignant diseases. Nishihira J, et
al. overviewed the pathophysiological function of MIF,
particularly in IBD, and introduced new MIF-targeted therapeutic
approaches [6].
Finally, IBD is frequently associated with the mucosal infiltration
of a large number of leukocytes that release large quantities
of proinflammatory cytokines. Therefore, the removal of circulating
leukocytes may be an attractive non-pharmacological approach
for IBD. Mitsuyama K, et al. have provided an overview
of the current knowledge on the mechanisms of action, available
clinical data, and possible future perspectives for the use
of this leukocytapheresis in the management of IBD; and on
the utility and current practice of metabolite identification
and profiling that will assist in drug design [7].
References
[1] Possemiers S, Grootaert C, Vermeiren J Gross G, Marzorati1
M, Verstraete1 W, et al. The intestinal environment
in health and disease – Recent insights on the potential
of intestinal bacteria to influence human health. Curr Pham
Des 2009; 15(18): 2051-2065.
[2] Andoh A, Benno Y, Kanauchi O, Fujiyama Y. Recent advances
in molecular approaches to gut microbiota in inflammatory
bowel disease. Curr Pham Des 2009; 15(18): 2066-2073.
[3] Kanauchi O, Mitsuyama K, Andoh A. The therapeutic impact
of manipulating microbiota in inflammatory bowel disease.
Curr Pham Des 2009; 15(18): 2074-2086.
[4] Hanai H, Sugimoto K. Curcumin has bright prospects for
the treatment of inflammatory bowel disease. Curr Pham Des
2009; 15(18): 2087-2094.
[5] Rose-John S, Mitsuyama K, Matsumoto S, Thaiss WM, Scheller
J. Interleukin-6 trans-signaling and colonic cancer associated
with inflammatory bowel disease. 2009; 15(18): 2095-2103.
[6] Nishihira J, Mitsuyama K. Overview of the role of macrophage
migration inhibitory factor (MIF) in inflammatory bowel disease.
Curr Pham Des 2009; 15(18): 2104-2109
[7] Mitsuyama K, Yamasaki H, Kuwaki K, Takedatsu H, Sata M.
Recent understanding of leukocytapheresis (LCAP) for the treatment
of inflammatory bowel disease. Curr Pham Des 2009; 15(18):
2110-2119.
Osamu Kanauchi
Central Laboratories for Frontier Technology
Kirin Holdings Co. Ltd., 1-13-5
Fukuura, Kanazawa-ku,
Yokohama, 236-0004,
Japan
E-mail: kanauchio@kirin.co.jp
Keiichi Mitsuyama
Division of Gastroenterology
Department of Medicine
Kurume University School of Medicine
Asahi-machi 67, Kurume 830-0011
Japan
E-mail: ibd@med.kurume-u.ac.jp
[Back to top]
[Purchase
Article] [PMID: 19519443 PubMed - indexed for MEDLINE]
The Intestinal Environment in Health and Disease –
Recent Insights on the Potential of Intestinal Bacteria to
Influence Human Health
S. Possemiers, C. Grootaert, J. Vermeiren,
G. Gross, M. Marzorati, W. Verstraete and T. Van
de Wiele
The human intestine is colonized by a complex microbial
ecosystem, which could be considered as a separate organ within
the human host, having a coding capacity which exceeds the
liver by a factor 100. On the one hand, this extensive microbiome
is closely involved in the first-pass metabolism and bioavailability
of food and drug compounds. Understanding to which extent
each individual’s gut microbiota affects the bioavailability
and response to orally administered drugs is therefore a first
important challenge towards novel drug development strategies.
On the other hand, as our microbiota is directly or indirectly
involved in the onset of a number of disease states, a new
generation of therapeutics may be developed that affect the
structure and functioning of the intestinal microbiota and
interfere with their specific cross-talk with the human host.
Ultimately, the intestinal microbiota may even be used as
a biomarker for impending diseases inside or outside the gastrointestinal
tract and for the evaluation of responses to specific therapeutic
interventions. This review will therefore highlight the importance
of the indigenous microbial community and its enormous metabolic
potential, microbe-microbe interactions, mechanisms of host-bacterium
cross-talk and will discuss the onset of obesity, a specific
disease state in which the role of intestinal bacteria becomes
more and more apparent. Understanding the importance of the
intestinal ecosystem in these phenomena may open the door
for new strategies which target the management of the intestinal
microbiome into the desired direction and therefore to a completely
new type of nutrition research and pharmaceutical design.
[Back to top]
[Purchase
Article][PMID: 19519444 PubMed - indexed for MEDLINE]
Recent Advances in Molecular Approaches to Gut Microbiota
in Inflammatory Bowel Disease
A. Andoh, Y. Benno, O. Kanauchi and
Y. Fujiyama
Inflammatory bowel diseases [IBD], ulcerative colitis
[UC] and Crohn’s disease [CD], are chronic intestinal
disorders of unknown etiology. UC and CD are heterogeneous
diseases characterized by various genetic abnormalities that
lead to overly aggressive T-cell responses to a subset of
commensal enteric bacteria in genetically susceptible individuals.
As one of critical factors involved in pathogenesis of IBD,
relative imbalance of aggressive and protective bacterial
species, termed dysbiosis, has been reported by various literatures.
Since early days of microbiology, representatives of microbial
species [over 400 species] have been isolated from human gastrointestinal
tract, and analyses of dysbiosis in IBD were mainly dependent
on culture techniques. However, recent molecular ecological
studies based on ribosomal RNA [rRNA] sequences have revealed
that cultivation has been able only to access a small fraction
of the microbial diversity within the gastrointestinal tract.
These techniques enable characterization and quantification
of the microbiota. Clone libraries enable identification of
the composition of the microbiota. Microbial community structure
can be analyzed via fingerprinting techniques, and
dot blot hybridization or fluorescent in situ hybridization
can analyze abundance of particular taxa. Recent report shows
a systematic framework of the microbial diversity in the human
gut of more than 1000 different species-level phylogenetic
types [phylotypes]. This review focuses on recent advances
in the molecular ecological approaches for studying the gut
microbiota in IBD.
[Back to top]
[Purchase
Article][PMID: 19519445 PubMed - indexed for MEDLINE]
The Therapeutic Impact of Manipulating Microbiota
in Inflammatory Bowel Disease
O. Kanauchi, K. Mitsuyama and A.
Andoh
It is well established that intestinal microbiota play
an important role in the pathogenesis of inflammatory bowel
disease (IBD), including ulcerative colitis and Crohn's disease.
Various methods of altering the composition of intestinal
microbiota have been examined. Recent evidence suggests that
the administration of select prebiotics, probiotics and synbiotics
may improve the clinical outcome of patients with IBD. In
addition, IBD patients are well known to carry a higher risk
of developing colorectal cancer due to chronic inflammation.
Therefore, probiotics and/or prebiotics may be appropriate
treatments for prophylactic use due to their physiologic characteristics
and lack of obvious toxicity. This review summarizes the current
experimental and clinical knowledge about the role of intestinal
microbiota in IBD, the prevention of carcinogenesis related
to IBD, and its importance as a target for new forms of neutraceutical
therapy.
[Back to top] [Purchase
Article] [PMID: 19519446 PubMed - indexed for MEDLINE]
Curcumin has Bright Prospects for the Treatment of Inflammatory
Bowel Disease
H. Hanai and K. Sugimoto
Inflammatory bowel disease (IBD) is a chronic relapsing-remitting
condition that afflicts millions of people throughout the
world and impairs their daily functions and quality of life.
While the aetiology of IBD is not understood well, it appears
to be driven by inflammatory cytokines such as tumor necrosis
factor (TNF)-α.
Hence, there is a strong interest in agents that can block
the generation or actions of inflammatory cytokines. Curcumin
is a bioactive substance present in the rhizomes of the herb
“Curcuma longa” which has been used for centuries
in Asia, both in traditional medicine and in cooking as turmeric
which gives food an exotic natural yellow color. Further,
in recent years, a large number of research papers have reported
intriguing pharmacologic effects associated with curcumin.
These include inhibitory effects on cyclooxygenases 1, 2 (COX-1,
COX-2), lipoxygenase (LOX), TNF-α,
interferon γ
(IFN-γ),
inducible nitric oxide synthase (iNOS), and the transcriptional
nuclear factor kappa B (NF-κB),
in addition to a strong anti-oxidant effect. NF-κB
is a key factor in the upregulation of inflammatory cytokines
that have a high profile in inflammatory diseases, suggesting
that curcumin could be a novel therapeutic agent for patients
with IBD. Therefore, in recent years, the efficacy of curcumin
has been investigated in several experimental models of IBD.
The results indicate striking suppression of induced IBD colitis
and changes in cytokine profiles, from the pro-inflammatory
Th1 to the anti-inflammatory Th2 type. In human IBD, up to
now, only one open study has achieved encouraging results.
In this study, patients were given curcumin (360mg/dose) 3
or 4 times/day for three months. Further, curcumin significantly
reduced clinical relapse in patients with quiescent IBD. The
inhibitory effects of curcumin on major inflammatory mechanisms
like COX-2, LOX, TNF-α,
IFN-γ,
NF-κB
and its unrivalled safety profile suggest that it has bright
prospects in the treatment of IBD. However, randomized controlled
clinical investigations in large cohorts of patients are needed
to fully evaluate the clinical potential of curcumin.
[Back to top]
[Purchase
Article] [PMID: 19519447 PubMed - indexed for MEDLINE]
Interleukin-6 Trans-Signaling and Colonic Cancer Associated
with Inflammatory Bowel Disease
S. Rose-John, K. Mitsuyama, S. Matsumoto,
W.M. Thaiss and J. Scheller
The complex pathogenesis of inflammatory bowel disease
(IBD) and inflammation induced colon cancer involves a wide
range of mediators including cytokines. Recent investigations
underline the fundamental role of interleukin-6 (IL-6) signaling
in the development and maintenance of IBD and for the progression
of this inflammation to colon cancer. The molecular mechanisms
of this pathway, the source of the cytokine and the identity
of target cells in the intestine are incompletely understood.
It is known that the circulating and intestinal levels of
IL-6 as well as the soluble IL-6 receptor (sIL-6R) are increased
in patients with IBD. Remarkably, mucosal T cells of IBD patients
are extremely resistant to apoptosis and a large fraction
of these cells express membrane-bound gp130 but not the IL-6R.
Increasing evidence suggests that the development and perpetuation
of IBD relies on IL-6 synthesized by T-cells and myeloid cells
and on increased formation of IL-6/sIL-6R complexes interacting
with membrane-bound gp130 on T-cells, a process called IL-6
trans-signaling. Recent investigations suggested a protective
role of IL-6 mediated STAT3 signaling in intestinal epithelial
cells. Here we review these pro- and anti-inflammatory properties
of IL-6 in IBD and inflammation induced colon cancer and we
will summarize the consequences of these new results for the
prospects of IL-6 targeted therapeutic strategies for the
treatment of chronic inflammatory diseases such as IBD.
[Back to top]
[Purchase Article] [PMID: 19519441 PubMed - indexed for MEDLINE]
Overview of the Role of Macrophage Migration Inhibitory Factor
(MIF) in Inflammatory Bowel Disease
J. Nishihira and K. Mitsuyama
An array of investigations has revealed that macrophage
migration inhibitory factor (MIF) plays an important role
in the exacerbation of a wide range of inflammatory diseases.
For the past two decades, we have extensively studied MIF’s
pathophysiological roles in human diseases, and have accumulated
evidence elucidating its molecular mechanisms in the pathogenesis
of immune disorders and inflammatory diseases, such as rheumatoid
arthritis and inflammatory bowel diseases (IBD). In a study
of IBD, we demonstrated for the first time that anti-MIF antibody
suppressed the degree of dextran-sulfate sodium (DSS)-induced
colitis, indicating its potential therapeutic use for IBD
patients. Following that report, a number of researchers,
including us, clarified that MIF was profoundly involved in
various gastrointestinal disorders, such as hepatitis and
pancreatitis. We recently revealed that a MIF-deficient mouse
was resistant to a challenge of DSS, and showed few clinical
and pathological signs. Currently, we are developing new therapeutic
approaches targeting MIF in inflammatory disorders, particularly
IBD. We here overview MIF’s pathophysiological function,
mainly in IBD, and introduce two therapeutic approaches, anti-MIF
antibody treatment and MIF-antisense therapy, via
a drug delivery system using 1,3-β
glucan.
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[Purchase
Article] [PMID: 19519448 PubMed - indexed for MEDLINE]
Recent Understanding of Leukocytapheresis (LCAP) for the Treatment
of Inflammatory Bowel Disease
K. Mitsuyama, H. Yamasaki, K. Kuwaki, H.
Takedatsu and M. Sata
Inflammatory bowel disease (IBD) is frequently associated
with the infiltration of a large number of leukocytes into
the bowel mucosa. Therefore, the removal of circulating leukocytes
may be an attractive approach for the treatment of IBD. Leukocytapheresis
with Cellsorba, a column of polyethylenephtarate fibers that
captures monocytes, granulocytes, and lymphocytes, has been
used to treat IBD, particularly ulcerative colitis, in Japan.
The objective of this paper is to provide an overview of current
knowledge regarding the mechanisms of action, available clinical
data, and possible future perspectives for the use of LCAP
with Cellsorba in the management of IBD. Leukocytapheresis
appears to remove or inactivate inflammatory cells, to reset
immunity by modulating immune system components like cytokines,
and to repair the intestinal mucosa by mobilizing mesenchymal
progenitors. Although the majority of clinical studies had
an open-label design and enrolled only a small number of patients,
leukocytapheresis has been demonstrated to exert clinical
efficacy with an excellent safety profile. Although leukocytapheresis
with Cellsorba appears very promising, its future in the treatment
of IBD requires further evaluation.
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Article] [PMID: 19519449 PubMed - indexed for MEDLINE]
Developments of Indoles as Anti-HIV-1 Inhibitors
Hui Xu and Min Lv
Since the first case of acquired immunodeficiency syndrome
(AIDS) was reported in 1981, AIDS has always been a global
health threat and the leading cause of deaths due to the rapid
emergence of drug-resistance and unwanted metabolic side effects.
Every day in 2007 an estimated 6850 people were newly infected
with human immunodeficiency virus (HIV). Over the past 28
years the rapid worldwide spread of AIDS has prompted an intense
research effort to discover compounds that could effectively
inhibit HIV. The development of new, selective and safe inhibitors
for the treatment of HIV, therefore, still remains a high
priority for medical research. To the best of our knowledge,
the indole derivatives have been considered as one class of
promising HIV-1 inhibitors, such as delavirdine approved by
the Food and Drug Administration (FDA) in 1997 for use in
combination with other antiretrovirals in adults with HIV
infection. In this review we focus on the synthesis and anti-HIV-1
activity of indole derivatives, in the meantime, the structure–activity
relationship (SAR) for some derivatives are also surveyed.
It will pave the way for the design of indole derivatives
as anti-HIV-1 drugs in the future.
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Article] [PMID: 19519450 PubMed - indexed for MEDLINE]
HCN Pacemaker Channels and Pain: A Drug Discovery
Perspective
A.D. Wickenden, M.P. Maher and S.R.
Chaplan
This article reviews evidence that hyperpolarization-activated,
cation nonselective (HCN) channels, the molecular basis of
the Ih current, potentially
represent valid targets for novel analgesic agents. Ih
is a prominent current in many peripheral sensory nerves,
with highest current density typically found in large diameter
neurons. Recent data suggest that Ih
may represent a valid target for the treatment of spontaneous
pain and allodynia associated with nerve injury. The majority
of available electrophysiological and molecular evidence suggests
that fast activating, weakly cyclic adenosine monophosphate
(cAMP) sensitive HCN1-based channels may make a significant
contribution to Ih, especially
in large diameter, mechanosensitive fibers, where the Ih
current appears to support abnormal spontaneous firing after
nerve injury. In contrast, HCN4 channels seem to play the
predominant role in cardiac pacemaker tissue. These observations
raise the possibility that HCN1 selective blockers may inhibit
pain associated with nerve injury without dramatic effects
on heart rate. Development of novel HCN blocking analgesics
presents a number of significant technical challenges. Although
a number of HCN blockers are available, such as ZD-7288, ivabradine,
and others, these drugs inhibit all HCN isoforms with the
same potency. As a result, these compounds have powerful effects
on heart rate, severely limiting their utility for non-cardiac
indications such as pain. Selectivity challenges, mechanisms
of compound interaction with the channel, and assay methods
are described in detail.
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