Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1871-5303
Endocrine, Metabolic &
Immune Disorders - Drug Targets
Volume 9, Number 4, December 2009
Contents
Immune Cell Entry to Central Nervous System – Current Understanding
and Prospective Therapeutic Targets Pp. 315-327
Catriona T. Prendergast and Stephen M. Anderton
[Abstract] [Full
Text Article]
[PMID:
20028334 PubMed - indexed for MEDLINE]
Dendritic Cells for Active Anti-Cancer Immunotherapy:
Targeting Activation Pathways Through Genetic Modification
Pp. 328-343
E. Mira and S. Mañes
[Abstract] [Full
Text Article] [PMID:
19857199 PubMed - indexed for MEDLINE]
MHC Class I TCR Engineered Anti-Tumor CD4 T Cells:
Implications For Cancer Immunotherapy Pp. 344-352
Arvind Chhabra
[Abstract] [Full
Text Article] [PMID:
19807670 PubMed - indexed for MEDLINE]
Interleukin-24: A Molecule with Potential Anti-Cancer
Activity and a Cytokine in Search of a Function Pp.
353-360
Ali Dalloul and Alexander Sainz-Perez
[Abstract] [Full
Text Article] [PMID:
19751196 PubMed - indexed for MEDLINE]
Synergistic Activation of Leukocytes by Bacterial
Chemoattractants: Potential Drug Targets Pp. 361-370
Ling-Yu Chen and Zhixing K. Pan
[Abstract] [Full
Text Article] [PMID:
19601917 PubMed - indexed for MEDLINE]
Future Developments in Osteoporosis Therapy Pp. 371-384
K.W. Ng
[Abstract] [Full
Text Article] [PMID:
19857200 PubMed - indexed for MEDLINE]
Pleiotropic Effects of Cathepsin D Pp. 385-391
Aruna Vashishta, Sujata Saraswat Ohri and
Vaclav Vetvicka
[Abstract] [Full
Text Article] [PMID:
19807669 PubMed - indexed for MEDLINE]
A Current Update on the Use of Alpha Lipoic Acid in the Management
of Type 2 Diabetes Mellitus Pp. 392-398
Z.X. Poh and K.P. Goh
[Abstract] [Full
Text Article] [PMID:
19601918 PubMed - indexed for MEDLINE]
Abstracts 
[Back to top] [PMID:
20028334 PubMed - indexed for MEDLINE]
Immune Cell Entry to Central Nervous System – Current Understanding
and Prospective Therapeutic Targets
Catriona T. Prendergast and
Stephen M. Anderton
[Full
Text Article]
Under normal physiological conditions there is minimal
entry of immune cells into the central nervous system (CNS)
for the purpose of immune surveillance. During inflammation,
however, extensive infiltration of immune cells can lead to
the induction of CNS autoimmune disease, for example multiple
sclerosis (MS) and its animal model experimental autoimmune
encephalomyelitis (EAE). The barriers that regulate cellular
entry are the blood-brain barrier (BBB) within the CNS parenchyma,
and the blood-cerebrospinal fluid (blood-CSF) barrier within
the choroid plexus. Understanding how these barriers function
to allow the passage of leukocytes from the periphery into
the CNS for normal immune surveillance, and under inflammatory
conditions, is vital for the development of novel therapeutics
targeting immune cell migration in CNS diseases. Contributions
from selectins, chemokines, integrins and matrix metalloproteinases
allow the migration of leukocytes across the BBB and into
the CNS parenchyma. In EAE and MS, the strict maintenance
of this process is lost and a large influx of cells is seen.
This review focuses on the role of these homing molecules,
chemokines and enzymes in the entry of leukocytes into the
CNS during inflammatory conditions. It concludes with a model
of immune cell entry of the CNS, summarising the current knowledge
in this area. Targeting specific molecules to prevent infiltration
of inflammatory cells into the CNS could allow disease inhibition
without compromising beneficial immune surveillance.
[Back to top] [PMID:
19857199 PubMed - indexed for MEDLINE]
Dendritic Cells for Active Anti-Cancer Immunotherapy: Targeting
Activation Pathways Through Genetic Modification
E. Mira and S. Mañes
[Full
Text Article]
Tumour immunotherapy has become a treatment modality
for cancer, harnessing the immune system to recognize and
eradicate tumour cells specifically. It is based on the expression
of tumour associated antigens (TAA) by the tumour cells and
aims at the induction of TAA-specific effector T cell responses,
whilst overruling various mechanisms that can hamper the anti-tumour
immune response, e.g. regulatory T cells (Treg). (Re-) activation
of effector T cells requires the completion of a carefully
orchestrated series of specific steps. Particularly important
is the provision of TAA presentation and strong stimulatory
signals, delivered by co-stimulatory surface molecules and
cytokines. These can only be delivered by professional antigen-presenting
cells, in particular dendritic cells (DC). Therefore, DC need
to be loaded with TAA and appropriately activated. It is not
surprising that an extensive part of DC research has focused
on the delivery of both TAA and activation signals to DC,
developing a one step approach to obtain potent stimulatory
DC. The simultaneous delivery of TAA and activation signals
is therefore the topic of this review, emphasizing the role
of DC in mediating T cell activation and how we can manipulate
DC for the pill-pose of enhancing tumour immunotherapy. As
we gain a better understanding of the molecular and cellular
mechanisms that mediate induction of TAA-specific T cells,
rational approaches for the activation of T cell responses
can be developed for the treatment of cancer.
[Back to top] [PMID:
19807670 PubMed - indexed for MEDLINE]
MHC Class I TCR Engineered Anti-Tumor CD4 T Cells: Implications
For Cancer Immunotherapy
Arvind Chhabra
[Full
Text Article]
T cell immunity is critical for a protective immune response
against cancers. Traditionally, this function has been ascribed
to CD8 T lymphocytes with cytotoxic activity, which are restricted
by MHC class I molecules. The lack of direct cytolytic effector
function on part of CD4 T cells, which are MHC class II restricted,
coupled with the MHC class II negative nature of most human
cancers have been the main reasons for CD8 centered cancer
immunotherapy approaches, so far. However, recent findings
showing that CD4 T cells play an essential role towards the
generation of a productive CD8 response and that the CD4 T
cells can also play a direct role in anti-tumor immunity have
resulted in growing enthusiasm towards engaging CD4 T cells
in cancer immunotherapy. We here discuss the current approaches
used for immune based cancer therapy, role of natural MHC
class II-restricted CD4 T cells in tumor immunity, factors
limiting the engagement of natural CD4 T cells in cancer immunotherapy
protocols alongside CD8 T cells, and recent advances in TCR
engineering approach to address these limitations. We will
also discuss the significance of the MHC class I directed
anti-tumor CD4 T cells in tumor immunity.
[Back to top]
[PMID:
19751196 PubMed - indexed for MEDLINE]
Interleukin-24: A Molecule with Potential Anti-Cancer
Activity and a Cytokine in Search of a Function
Ali Dalloul and Alexander Sainz-Perez
[Full
Text Article]
The gene encoding Melanoma-differentiation antigen-7
(MDA-7) was discovered more than 10 years ago. Its potential
anti-cancer activity was surmised because its expression is
inversely correlated with the cell proliferation status. Indeed
adenoviral delivery of this gene proved to be efficient in
killing several cancer cell lines and great strides have been
made concerning its molecular ways of action. Later it was
shown that mda7 encoded a secreted cytokine which belongs
to the IL-10, class-II family of cytokines. We recently found
that this molecule exerted apoptotic activity on stimulating
but not on resting lymphocytes from a B cell leukaemia. This
activity is distinct from that of intracellular MDA-7, and
may pave the way for using the cytokine in cancers provided
that they express the IL-24 Receptors; in this respect, melanomas
are insensitive to the recombinant cytokine due to the lack
of IL-24 receptors at their surface. In contrast to its anti-cancer
activity, the immunological role of IL-24 is still unclear,
with differences between mice and human. If however it is
demonstrated that IL-24 can inhibit the function of STAT3
in normal lymphocytes as it is the case in leukemic cells,
and given that STAT3 is needed for the differentiation of
several lymphocyte subsets, this will give us hints as to
the potential role of this cytokine in the immune system.
[Back to top] [PMID:
19601917 PubMed - indexed for MEDLINE]
Synergistic Activation of Leukocytes by Bacterial Chemoattractants:
Potential Drug Targets
Ling-Yu Chen and Zhixing K. Pan
[Full
Text Article]
Accumulating evidence demonstrates that bacterial chemoattractants
not only attract leukocytes (chemotaxis) but also contribute
directly to inflammation by activation of leukocytes to produce
a variety of pro-inflammatory cytokines. Recent studies have
shown that mixtures of the bacterial chemoattractant fMLP
(N-formyl-Met-Leu-Phe) and other bacterial products/components
such as LPS (lipopolysaccharide) behave synergistically in
activating leukocytes. These results suggest that inflammatory
responses are induced by multiple inducers that operate synergistically
through multiple signaling pathways. This synergy is likely
to play a significant role in the induction of host defense
to bacterial infections and in the pathogenesis of inflammatory
disorders. These results also demonstrate that the control
of inflammation is likely best understood at the level of
synergistic regulation of intracellular signaling. The use
of pharmacological inhibitors to modulate synergistic molecules
is therefore an attractive possibility for the treatment of
inflammatory disease. In this review, we will provide a brief
summary of recent studies on the regulation of leukocyte functioning
by bacterial chemoattractants.
[Back to top]
[PMID:
19857200 PubMed - indexed for MEDLINE]
Future Developments in Osteoporosis Therapy
K.W. Ng
[Full
Text Article]
Anti-resorptives that prevent osteoclasts from resorbing
bone are the mainstay of treatment for osteoporosis, while
parathyroid hormone is the only agent available that stimulates
osteoblasts to form bone. Advances in knowledge about metabolic
pathways in bone cell biology have identified specific points
of intervention whereby formation and function of osteoclasts
and osteoblasts can be inhibited or stimulated. The next generation
of therapies for osteoporosis may include molecules that antagonize
integrin or inhibit Src tyrosine kinase, vacuolar H+-ATPase,
chloride channel or cathepsin K, thus preventing osteoclasts
from attaching to bone, form a ruffled border, acidify resorption
lacunae or digest organic bone matrix. At least some of these
may form a novel class of anti-resorptives capable of inhibiting
bone resorption without being coupled to inhibition of bone
formation. Human and mouse genetics studies demonstrating
the pivotal role of the Wnt signaling pathway in bone metabolism
have led to the development of strategies to disrupt Wnt signaling
in order to increase bone formation. Selective androgen receptor
modulators that produce an anabolic effect on muscle and bone
without undesirable androgenic side effects can potentially
be used to treat osteoporosis, aged-related frailty, muscle
wasting disorders and glucocorticoid-induced osteoporosis.
Studies involving these molecules are still in either preclinical
or early investigational stage, without fracture data. Nonetheless,
preliminary results hold the promise that at least some of
these new therapies may develop into effective means of treating
and preventing osteoporosis. Any new therapy for osteoporosis
must take into consideration its safety, efficacy, affordability
and specificity of action.
[Back to top] [PMID:
19807669 PubMed - indexed for MEDLINE]
Pleiotropic Effects of Cathepsin D
Aruna Vashishta, Sujata Saraswat Ohri and
Vaclav Vetvicka
[Full
Text Article]
Over the past decades, the paradigm that lysosomal enzymes
participate only in non-specific protein degradation during
cell death has changed. Studies conducted both in cell cultures
and in animals defined the role of these enzymes that includes
cathepsin D (CD). Knockout mice revealed the role of CD in
postnatal tissue homeostasis and remodeling. Mutations that
abolish the CD enzymatic activity have been implicated in
neural ceroid lipofuscinosis. Recent studies suggested a differential
role of CD in regulation of apoptosis. The zymogen of CD,
procathepsin D (pCD), is secreted by various cancer cells.
Extensive studies showed that it acts as a mitogen on both
cancer and stromal cells by stimulating their invasive and
metastatic properties. Additional studies suggested that procathepsin
D/CD is an independent prognostic factor in various cancers,
leading to the investigations of pCD/CD as a potential target
for designing anti-cancer therapy. In this review, we described
the various forms of CD and their implications in numerous
physiological as well as pathological conditions.
[Back to top] [PMID:
19601918 PubMed - indexed for MEDLINE]
A Current Update on the Use of Alpha Lipoic Acid in the Management
of Type 2 Diabetes Mellitus
Z.X. Poh and K.P. Goh
[Full
Text Article]
Type 2 Diabetes Mellitus (T2DM) which is characterised
by insulin resistance, is closely linked to the triad of glucolipotoxicity,
inflammation and oxidative stress. Increased adiposity, leading
to increased free fatty acids (FFAs), contributes to insulin
resistance by disrupting the signal transduction pathway of
insulin mediated glucose disposal, and causes impaired insulin
secretion. Hyperglycaemia and dyslipidaemia driven oxidative
stress resulting from enhanced free-radical formation and/or
defects in antioxidant defence is implicated in the pathogenesis
of diabetic neuropathy (DN). This and other inflammatory pathways
account for a complex network of interacting metabolic factors
responsible for causing diabetes and her complications. There
is growing evidence that Alpha Lipoic Acid (ALA) has beneficial
effects on the treatment of T2DM and some of its complications.
It represents an attractive pharmacological target in the
treatment of T2DM by modulating the signal transduction pathways
in insulin resistance and antagonizing the oxidative and inflammatory
stresses, which are major players in the pathogenesis of this
disorder. A potent anti-oxidant and free radical scavenger,
ALA also targets cellular signal transduction pathways which
increases glucose uptake and utilization, thus providing specific
targeted therapy in the treatment of insulin resistance and
diabetic neuropathy. Apart from the rare risk of Insulin Autoimmune
Syndrome (IAS), ALA has shown to be relatively safe, even
in patients with renal and liver failure. This review focuses
and summarises the molecular mechanisms of T2DM, and underlines
the therapeutic value of ALA in this globally significant
disease.
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