Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1871-5303
Endocrine, Metabolic &
Immune Disorders - Drug Targets
Volume 8, Number 1, March 2008
Contents
Possible Roles of Reg Family Proteins in Pancreatic
Islet Cell Growth Pp. 1-10
Jun-Li Liu, Wei Cui, Bing Li and Yarong Lu
[Abstract] [Purchase
Article]
The Use of Mycophenolate Mofetil for the Treatment
of Systemic Sclerosis Pp. 11-14
Max Shenin, Manisha Naik and Chris T. Derk
[Abstract] [Purchase
Article]
Host-Pathogen Interactions in Latent Mycobacterium
tuberculosis Infection: Identification of New Targets
for Tuberculosis Intervention Pp. 15-29
May Young Lin and Tom H.M. Ottenhoff
[Abstract] [Purchase
Article]
The HIV-1 Rev Binding Family of Proteins: The
Dog Proteins as a Study Model Pp. 30-46
Maria A. Panaro, Vincenzo Mitolo, Antonia Cianciulli,
Pasqua Cavallo, Carlo I. Mitolo and Angela Acquafredda
[Abstract] [Purchase
Article]
Distinct Functions of Retinoic Acid Receptor Beta
Isoforms: Implications for Targeted Therapy Pp. 47-50
Catherine B. Swift, John L. Hays and W. Jeffrey Petty
[Abstract] [Purchase
Article]
G Protein Coupled Receptors as Drug Targets: The Role
of β-Arrestins Pp. 51-61
Jasmin R. Dromey and Kevin D.G. Pfleger
[Abstract] [Purchase
Article]
Monoclonal Antibodies: New Therapeutic Agents for
Autoimmune Hemolytic Anemia? Pp. 62-68
Giovanni D’Arena, Ronald P. Taylor, Nicola Cascavilla and Margaret A. Lindorfer
[Abstract] [Purchase
Article]
Epithelial-Mesenchymal Transition as a Therapeutic
Target for Prevention of Ocular Tissue Fibrosis Pp.
69-76
Shizuya Saika, Osamu Yamanaka, Kathleen C. Flanders,
Yuka Okada, Takeshi Miyamoto, Takayoshi Sumioka,
Kumi Shirai, Ai Kitano,Ken-ichi Miyazaki, Sai-ichi Tanaka and Kazuo Ikeda
[Abstract] [Purchase
Article]
Abstracts
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Possible Roles of Reg Family Proteins in Pancreatic
Islet Cell Growth
Jun-Li Liu, Wei Cui, Bing Li and Yarong Lu
Reg proteins constitute a conserved family in human and
rodents;their production in the pancreas (including the islets
of Langerhans) is induced upon β-cell
damage. While some members of the family (Reg1 and islet neogenesis-associated
protein, i.e. INGAP) have been implicated in β
-cell replication and/or neogenesis, including from
in vivo studies using transgenic and knockout mice;
the roles of the other five members have yet to be characterized.
Among them, Reg2 was recently proposed to serve as an autoantigen
on β
-cells that elicits T-cell attack in type 1 diabetes mellitus.
Elucidation of their actions and identification of their molecular
targets should provide insight into the biology of these proteins
and lead to the design and development of novel strategies
aimed at promoting the survival and function of the pancreatic
islets. As the current terminology used for mammalian Reg
genes/proteins is very confusing, we also proposed a uniformed
classification in human and rodents through sequence alignments.
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The Use of Mycophenolate Mofetil for the Treatment
of Systemic Sclerosis
Max Shenin, Manisha Naik and Chris T. Derk
Mycophenolate mofetil (MMF) is an inosine monophosphate
dehydrogenase inhibitor, that inhibits the de novo pathway
of guanosine nucleotide synthesis, the proliferative responses
of T and B lymphocytes as well as antibody production by B
lymphocytes. It is indicated for the prophylaxis of organ
rejection after allogeneic cardiac, hepatic and renal transplants
. It has recently also been used with good success in patients
with lupus nephritis . Based on these actions, MMF appears
to be a novel agent for the treatment of systemic sclerosis,
especially during early disease where an inflammatory infiltrate
preceeds the development of fibrosis. Disease modification
early on during the inflammatory stage of systemic sclerosis
may lead to an overall decrease in fibrotic complications
both in relation to cutaneous and internal organ involvement.
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Host-Pathogen Interactions in Latent Mycobacterium
tuberculosis Infection: Identification of New Targets
for Tuberculosis Intervention
May Young Lin and Tom H.M. Ottenhoff
Mycobacterium tuberculosis (M. tuberculosis)
is one of the worlds’most successful and sophisticated
pathogens. It is estimated that over 2 billion people today
harbour latent M. tuberculosis infection
without any clinical symptoms. Since most new cases of active
tuberculosis (TB) arise from this (growing) number of latently
infected individuals, urgent measures to control TB reactivation
are required, including more effective drugs and new TB vaccines.
The currently widely used BCG vaccines, as well as most new
generation TB-vaccines that are being developed are designed
as prophylactic or as BCG-booster vaccines.Unfortunately,
many of these vaccines are unlikely to be effective in individuals
already latently infected with M. tuberculosis.
Here we argue that detailed analysis of M. tuberculosis
genes that are switched on predominantly during the latent
stage of infection may lead to the identification of new M.
tuberculosis tar-gets for drug and vaccine development.
First, we will describe essential host-pathogen interactions
in TB with particular emphasis on TB latency and persistent
infection. Subsequently, we will focus on a novel group of
late-stage specific genes, encoded by the M.tuberculosis
dormancy (dosR) regulon, and summarize recent studies
describing human T-cell recognition of these dormancy antigens
in relation to (latent) M.tuberculosis infection.
We will discuss the possible relevance of these new classes
of antigens for new TB intervention strategies.
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The HIV-1 Rev Binding Family of Proteins:
The Dog Proteins as a Study Model
Maria A. Panaro, Vincenzo Mitolo, Antonia Cianciulli,
Pasqua Cavallo, Carlo I. Mitolo and Angela Acquafredda
Various proteins that are required for the building of
new complete human immunodeficiency type 1 virions (HIV-1)
are coded by unspliced or partly spliced virus-derived mRNAs.
HIV-1 has developed special strategies for moving these mRNAs
to the cytoplasm to be translated. In the nucleus of the infected
cell the virus-derived protein Regulator of expression of
viral proteins (Rev) can bind both the viral intron-containing
mRNAs and the cellular co-factor HIV-1 Rev binding protein
(HRB) and this complex may be shuttled through the nuclear
pores. HRB gene have been relatively well conserved during
evolution, from Drosophila to humans. However, as a consequence
of reading-frame shifts due to nt insertions/deletions, the
protein products generated may differ considerably from the
prototypal HRB protein, which comprises one Arf-GAP zinc finger
domain, several Phenylalanine-Glycine (FG) motifs and four
Asparagine-Proline-Phenylalanine (NPF) motifs. This variability
is best exemplified by four HRB proteins of the dog, which
are discussed here in more detail. The hypothesis is advanced
that atypical HRB proteins may not be able to bind Rev and
possibly have other, still undetermined, functions. Since
the cellular co-factor HRB is essential for viral replication
and spread but is not required for cell viability and main
bodily functions, it might be an attractive candidate for
anti-HIV-1 drug targeting
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Distinct Functions of Retinoic Acid Receptor Beta
Isoforms: Implications for Targeted Therapy
Catherine B. Swift, John L. Hays and W. Jeffrey Petty
Vitamin A is essential for development and differentiation
of multiple tissues. Its derivatives, the retinoids, are potent
drugs used to treat and prevent a variety of diseases. Retinoid
effects are mediated by retinoic acid receptors (RARs) and
retinoid X receptors (RXRs). There are three known RARs (α
, β
, and γ),and
multiple isoforms of each receptor exist. Many of the therapeutic
effects of retinoids including cancer chemoprevention and
treatment of dermatologic disorders are mediated through RARβ.
In humans, five isoforms of this gene have been described.
Specific isoforms of RARβ
exert distinct and sometimes opposing functions by altering
patterns of target gene induction. Functional isoforms that
activate distinct cassettes of target genes with differing
biologic consequences include RARβ1'
and RARβ2.
Dominant negative isoforms of this gene that inhibit target
gene activation include RARβ
4 and RARβ
5. RARβ
1 is poorly understood although this may function as an oncogene
in certain cancers. Chromatin modifying drugs have been shown
to trigger isoform-specific changes in the RARβ
gene. This review focuses on the structure and function of
RARβ
isoforms as well as recent work in the epigenetic targeting
of specific RARβ
isoforms.Discerning isoform-specific functions will be critical
for exploiting the full potential of retinoid-based therapy
including rational approaches to combining retinoids with
chromatin modifying drugs.
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G Protein Coupled Receptors as Drug Targets: The Role
of β
-Arrestins
Jasmin R. Dromey and Kevin D.G. Pfleger
G protein coupled receptors (GPCRs) are extremely important
drug targets and the β-arrestin
intracellular scaffolding and adaptor proteins regulate major
aspects of their pharmacology. β-arrestin
binding to activated, GPCR kinase (GRK)phosphorylated receptors
has the capacity to terminate G protein coupling, internalize
the receptors into clathrin-coated vesicles and establish
a secondary signaling complex independent of Gprotein signaling.
These events appear to be differentially regulated by GRK
phosphorylation, ubiquitination and potentially β-arrestin
oligomerization, which are likely to be highly receptor and
cell-type dependent. The role of β-arrestins
in switching from G-protein dependent to independent signaling
places them in apivotal position to dictate the downstream
effects of ligand binding. Consequently, we must appreciate
the functioning of these molecules as we strive to discover
and optimize new GPCR drug therapies for endocrine, metabolic
and immune disorders.
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Monoclonal Antibodies: New Therapeutic Agents for
Autoimmune Hemolytic Anemia?
Giovanni D’Arena, Ronald P. Taylor, Nicola Cascavilla and Margaret A. Lindorfer
Conventional treatment of autoimmune hemolytic anemia (AIHA)comprises
corticosteroids and splenectomy and / or other immunosuppressive
drugs for refractory/relapsed patients.Monoclonal antibodies
(MoAbs) rituximab and alemtuzumab have gained widespread acceptance
in the management of B-cell malignancies. More recently, they
have been used to treat a number of autoantibody-mediated
diseases, such as both idiopathic and secondary AIHA, with
encouraging results. Herein we report an overview of the medical
literature on the use of MoAbs to treat AIHA. The therapeutic
mechanism of action of rituximab in the treatment of autoimmune
diseases such as rheumatoid arthritis and lupus is currently
a subject of considerable investigation. We have proposed
that cell associated IgG immune complexes, generated by the
binding of rituximab to CD20 on B cells, may serve as decoys
that attract FcγR-expressing
effector cells and downregulate effector cell pathogenic action,
thus reducing inflammation and tissue destruction in these
diseases. We briefly review evidence that suggests that this
immune complex decoy hypothesis plays a role in the therapeutic
action of rituximab in AIHA, and we propose new measurements
that should allow for a more complete evaluation of the importance
of this mechanism in AIHA.
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Epithelial-Mesenchymal Transition as a Therapeutic
Target for Prevention of Ocular Tissue Fibrosis
Shizuya Saika, Osamu Yamanaka, Kathleen C. Flanders,
Yuka Okada, Takeshi Miyamoto, Takayoshi Sumioka, Kumi Shirai,
Ai Kitano,Ken-ichi Miyazaki, Sai-ichi Tanaka and Kazuo Ikeda
Fibrotic diseases are characterized by the appearance
of myofibroblasts, the key cell type involved in the fibrogenic
reaction, and by excess accumulation of extracellular matrix
with resultant tissue contraction and impaired function. Myofiborblasts
are generated by fibroblast-myofibrobalst conversion, and
in certain tissues through epithelial-mesenchymal transition
(EMT),a process through which an epithelial cell changes its
phenotype to become more like a mesenchymal cell. Although
inflammatory/fibrogenic growth factors/cytokines produced
by injured tissues orchestrate the process of EMT, transforming
growth factor β
(TGFβ)
is believed to play a central role in the process. Unlike
fibrotic lesions in kidney or other tissues where myofibroblasts
are generated from both fibroblasts and epithelial cells,
fibrotic le-sions in the eye crystalline lens are derived
only from lens epithelial cells without contamination of fibroblast
derived myofibroblasts. Thus, this tissue is suitable to investigate
detailed mechanisms of EMT and subsequent tissue fibrosis.
EMT in retinal pigment epithelium is involved in the development
of another ocular fibrotic disease, proliferative vitreo-retinopathy,fibrosis
in the retina. EMT-related signal transduction cascades, i.e.,
TGFβ/Smad,
are a target to prevent or treat unfavorable ocular tissue
fibrosis, e. g., fibrotic diseases in the crystalline
lens or retina, as well as possibly in other organs.
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