Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 5, No. 3, 2005
Contents
Hormonal Contraception in Men Pp.249-257
Melanie Walton and
Richard A. Anderson
Signaling Processes in Tumoral Neuroendocrine
Pituitary Cells as Potential Targets for Therapeutic Drugs Pp.259-267
Marcelo Paez-Pereda,
Damiana Giacomini, Carlos Echenique, Gunter K. Stalla, Florian Holsboer,
Eduardo Arzt
Caspases as Drug Targets in Ischemic Organ
Injury Pp.269-287
S. Faubel and C. L.
Edelstein
Role of FXR in Regulating Bile Acid Homeostasis
and Relevance for Human Diseases Pp.289-303
Giovanni Rizzo,
Barbara Renga, Andrea Mencarelli, Roberto Pellicciari and Stefano Fiorucci
Estrogen Receptor Signalling: Bases for Drug
Actions Pp.305-314
Maria Marino, Filippo
Acconcia and Paolo Ascenzi
Therapeutic Potential of Glycolipid Ligands for
Natural Killer (NK) T Cells in the Suppression of Autoimmune Diseases Pp.315-322
Sachiko Miyake and
Takashi Yamamura
From Molecular Footprints of Disease to New
Therapeutic Interventions in Diabetic Nephropathy: A Detective Story Pp.323-329
Toshio Miyata, Kiyoshi
Kurokawa and Charles van Ypersele de Strihou
Functional Foods: Salient Features and
Clinical Applications
Pp.331-337
Giuseppe Riezzo,
Marisa Chiloiro and Francesco Russo
Drug Targets in Colonoscopic Polypectomy: Biological
Sealants with Special Reference to Fibrin-Glue (Tissucol) Pp.339-345
P. Venezia
Advances in Osteoclast Differentiation and
Function Pp.347-355
Yousef Abu-Amer
Abstracts
[Back
to top] Hormonal Contraception in Men
Melanie Walton and
Richard A. Anderson
All major advances in the development of hormonal
methods of contraception over the past 40 years have been exclusively female
orientated with male hormonal contraception forever “just around the corner”.
Despite this, the last few years have seen a significant increase in the pace
of research and increased involvement from the pharmaceutical industry. This is
essential if the progress derived from the public sector is to be translated
into a real product for widespread use. Current male methods of contraception,
condoms and vasectomy, are relied on by 30% of couples throughout the world but
there have been no new male contraceptive methods introduced in the last
century. There is currently an increasing emphasis on male involvement in
family planning, and evidence both that some men would be keen to shoulder this
responsibility and that their partners would trust them to do so. There are
several potential novel approaches to male contraception, but the hormonal one
is the only one at the stage of clinical research. This method is based on the
normal regulation of spermatogenesis by the pituitary gonadotrophins:
suppression of gonadotrophin secretion results in a reduction in the rate of
spermatogenesis, and azoospermia, the absence of sperm from the ejaculate, can
be achieved. Current approaches are now getting close to the ideal of inducing
azoospermia in all men. This approach also results in suppression of testicular
testosterone production, thus androgen ‘add-back’ is an essential component of
a contraceptive regime. Many different steroids and delivery methods -oral,
buccal, transdermal, subcutaneous implants- are under exploration at present,
each with their own advantages and drawbacks. The use of synthetic androgens is
also starting to be explored: these have the potential advantage of offering
tissue-specific actions.
[Back
to top] Signaling Processes in Tumoral Neuroendocrine Pituitary Cells as
Potential Targets for Therapeutic Drugs
Marcelo Paez-Pereda,
Damiana Giacomini, Carlos Echenique, Gunter K. Stalla, Florian Holsboer,
Eduardo Arzt
Pituitary adenomas are neuroendocrine tumors that
produce different endocrine and metabolic alterations, including
hyperprolactinemia, acromegaly and Cushing's disease. These different clinical
features of pituitary tumors are the result of the overproduction of hormones
produced by the different pituitary cell types. Recent advances in the
understanding of the signaling pathways that control hormone production in
pituitary cells provide a source of potential therapeutic targets. In
ACTH-secreting cells, the mechanisms that control hormone biosynthesis have
been clarified to a great extent, indicating a number of protein kinases and
ligand-activated nuclear receptors as targets for experimental drugs. ACTH
production requires the activation of signal transduction through the PKA, the
MAPK and the CamK pathways. These pathways activate nuclear receptors,
including Nur and PPAR gamma. The inhibition of these kinases and nuclear
receptors has been shown to produce therapeutic effects in mouse models of
Cushing's syndrome. On the other hand, the signaling pathways that control
prolactin and growth hormone production also have potential targets. It has
been recently shown that SMAD proteins activated by growth factors of the TGF
beta and BMP family interact with estrogen receptors to stimulate the
proliferation of prolactin and growth hormone-secreting cells. Cytokines that
bind to the membrane protein gp130 also stimulate the proliferation of these
cells. The inhibition of both of these pathways results in the decrease of
tumor growth in animal models of prolactinoma. Therefore, the study of
signaling pathways that control hormone production and proliferation is a good
source of candidate targets in pituitary tumors.
[Back
to top] Caspases as Drug Targets in Ischemic Organ Injury
S.
Faubel and C. L. Edelstein
Caspases are intracellular cysteine proteases
that mediate cell death and inflammation.
Caspase-3 is a major mediator of both apoptotic and necrotic cell death.
Caspase-1 mediates inflammation though the activation of the cytokines
interleukin-1b (IL-1b) and interleukin-18 (IL-18). Increases in both
caspase-1 and -3 have been described in ischemic injury to various organs
including brain, heart and kidney. Both pharmacological inhibitors and genetic
approaches have been used to inhibit caspases in vivo. Pancaspase
inhibitors protect against ischemic injury in brain, heart and kidney.
Pancaspase inhibition also reduces cold preservation injury due to apoptosis in
liver endothelial cells and prolongs animal survival after orthotopic liver
transplantation. Caspase-1 inhibition or caspase-1 deficiency protects against
ischemic injury in brain, heart and kidney models of ischemia. Specifically,
impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute
renal failure. This review focuses on studies of caspase-1 and pancaspase
inhibition in ischemic injury to brain, heart and kidney. In addition, the
studies of pancaspase inhibition in cold ischemic injury and organ preservation
will be reviewed. The therapeutic potential of caspase inhibition in ischemic
injury will be discussed.
[Back
to top] Role of FXR in Regulating Bile Acid Homeostasis and Relevance for Human
Diseases
Giovanni Rizzo, Barbara
Renga, Andrea Mencarelli, Roberto Pellicciari and Stefano Fiorucci
Recent studies reveal that bile acids are
signalling molecules that activate several nuclear receptors and regulate many
physiological pathways and processes to maintain bile acid and cholesterol
homeostasis. Analysis of orphan receptor expression patterns in enterohepatic
tissues identified bile acids as ligands for farnesoid X receptor (FXR). The
primary bile acid chenodeoxycholic acid (CDCA) was shown to be the most potent
FXR ligand in vitro at an EC50 of 10–50 mM. FXR can also be activated by the secondary
bile acids lithocholic acid (LCA) and deoxycholic acid (DCA). Upon activation
FXR heterodimerises with 9-cis retinoic X receptor (RXR) and regulates a
cohort of genes involved in cholesterol catabolism and bile acids biosynthesis.
Thus bile acid-activated FXR directly induces expression of Small Heterodimer
Partner (SHP), a nuclear receptor that suppresses bile acid biosynthesis
down-regulates the Na+ taurocholate cotransport peptide (NTCP), a
pump depicted to transport bile acids from the lumen into hepatocyte, and
induces expression of bile salt export pump (BSEP), the principal bile acid
efflux transporter in the liver. As demonstrated by the Fxr null mice, FXR
defends the liver against cholestasis. The 6-ethyl derivative of CDCA (6-ECDCA)
is »100 fold more potent than CDCA in activating FXR in vitro. In vivo
administration of 6-ECDCA protects against cholestasis induced by estrogen and
LCA in rats providing evidence that development of potent FXR agonists might
represent a new approach for the treatment of cholestastic disorders.
[Back
to top] Estrogen Receptor Signalling: Bases for Drug Actions
Maria Marino, Filippo
Acconcia and Paolo Ascenzi
Estrogen receptors (ERa and ERb) mediate
the effects of 17b-estradiol (E2) and account for E2 role on
growth, development, and homeostasis maintenance in different tissues and
organs. ERa and ERb function as
ligand-dependent transcription factors which directly bind to specific estrogen
responsive element (ERE) present into DNA and, in turn, regulate the
transcription of E2-sensitive genes. In addition, ERa and ERb, without
direct binding to DNA, regulate transcription indirectly by binding to other
transcription factors activating or inactivating the transcription of
E2-dependent-ERE-devoid genes. Along with these two E2 mechanisms, it has been
recently uncovered that a third signalling pathway, involving cytoplasmic
proteins and rapid membrane-initiated responses, serves largely for mitogenic
E2-induced effects. The commitment of ERb in these
rapid E2-induced effects is openly debated. This review will focus and
summarize the latest findings regarding the multiple E2 molecular mechanisms
and underlines the development of our understanding of anti-cancer drugs acting
as ER signalling modulators.
[Back
to top] Therapeutic Potential of Glycolipid Ligands for Natural Killer (NK) T
Cells in the Suppression of Autoimmune Diseases
Sachiko Miyake and Takashi Yamamura
NKT cells emerge as important regulatory cells in
autoimmune responses. Abnormalities in the numbers and functions of natural
killer T (NKT) cells have been observed in patients with autoimmune diseases as
well as in a variety of mouse strains that are genetically predisposed for
development of autoimmune diseases. Unlike conventional T cells that recognize
peptides in association with major histocompatibility complex (MHC), NKT cells
recognize glycolipid antigens presented by the non-polymorphic MHC class I-like
protein, CD1d. Recently, we and other groups have demonstrated that
administration of glycolipid ligands such as a-galactosylceramide
(a-GC ) or its sphingosine truncated derivative,
OCH suppressed autoimmune diseases such as experimental autoimmune
encephalomyelitis (EAE), diabetes in NOD mice and collagen-induced arthritis
(CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. OCH is a unique
ligand to stimulate NKT cells to selectively produce Th2 cytokines whereas a-GC induces both interleukin (IL)-4 and
interferon (IFN)-g, and is more beneficial for treatment of a wide
variety of Th1-mediated autoimmune diseases. The lack of polymorphism of CD1d
and cross-reactive responses of mouse and human NKT cells to the same ligand
indicates that targeting NKT cells with this ligand may be an attractive means
for intervening in human autoimmune diseases such as type I diabetes (T1D),
multiple sclerosis (MS) and rheumatoid arthritis (RA).
The present review will focus on the potential
roles of NKT cells in the pathogenesis of autoimmune diseases and the recent
advances in glycolipid therapy for autoimmune disease models. The molecular
mechanism of OCH-induced Th2-selective cytokine secretion will also be discussed.
[Back
to top] From Molecular Footprints of Disease to New Therapeutic Interventions
in Diabetic Nephropathy: A Detective Story
Toshio Miyata, Kiyoshi
Kurokawa and Charles van Ypersele de Strihou
Oxidative tissue damage in vivo is a
complex phenomenon involving many factors and pathways. Proteins are
particularly attractive targets for oxidative products analysis in order to
understand better the physiopathology of human diseases. Protein modifications
serve as footprints of biochemical processes. They also help ascertain the
mechanism of anti-oxidative action of medical drugs and further search for
novel agents that inhibit efficiently oxidative protein damage. Several drugs
already used clinically interfere with oxidative protein damage through
different mechanisms characteristic of their chemical structure. This review
delineates the oxidative protein modifications existing in diabetic nephropathy
and their regression in association with renoprotective anti-hypertensive
agents. Our hypothetical approach will require further testing. Nevertheless,
the insights gained on the biochemistry of protein modifications open new
avenues towards the development of new classes of renoprotective agents for diabetic
nephropathy.
[Back
to top] Functional Foods: Salient Features and Clinical Applications
Giuseppe
Riezzo, Marisa Chiloiro and Francesco Russo
The term “functional food” refers to foods or
ingredients of foods providing an additional physiological benefit beyond their
basic nutritional needs. Health benefits are best obtained through a varied
diet containing fruits, vegetables, grains, legumes and seeds. However,
fortified foods and dietary supplements have been marketed and food industry
have made functional food one of their current leading trends. Recently, the
number of functional foods that have a potential benefit on health has hugely
grown and scientific evidence is supporting the role of functional foods in
prevention and treatment of several diseases. Cancer, diabetes, heart disease
and hypertension are the most important diseases that can be treated or
prevented by functional foods; other diseases are osteoporosis, abnormal bowel
motility, and arthritis. It has been estimated that 80% of cancer in USA have a
nutrition/diet component suggesting a great impact of functional food and foods
components on incidence and treatment of cancer. Numerous factors complicate
the evaluation of scientific evidence such as the complexity of food substance,
effect on food, metabolic changes associated to dietary changes, the lack of
biological markers of disease development. This paper reviews the scientific
evidence supporting this area regarding only those foods and ingredients in
which a clear experimental and clinical evidence exists for their
chemopreventive and therapeutic effects.
[Back
to top] Drug
Targets in Colonoscopic Polypectomy: Biological Sealants with Special Reference
to Fibrin-Glue (Tissucol)
P. Venezia
The increasing outpatient use of colonoscopy in
the diagnostic study and prophylaxis of colon diseases has allowed early
identification of polypoid neoformations, thus indicating their increased
incidence during the asymptomatic phase. In this respect, the application of
biological sealants immediately before the polypectomy has represented a novel
therapeutic strategy in the treatment of these preneoplastic lesions. The
injection of biological sealants with needle under the polyp peduncle or
sub-mucosa has demonstrated a protective action on the electrocoagulated area,
an anti-haemorrhagic effect owing to the strengthened seal of the eschar that
is formed, and a facilitated tissue regeneration, respectively. The author
report his experience acquired over the past five years with regard to the use
of biological sealant in colonoscopic polypectomy and conclude that biological
sealants, a human fibrin glue, which utilises components of the human plasma,
may allow a more generous removal of neoformations, the absence of
post-polypectomy complications and, consequently, the dramatic reduction of
time of patient’s admission in the hospital. In fact, all patients were
discharged after two hours from polypectomy, thus implying a better quality of
life for patients, in the absence of post-operative complications and a
reduction of non-medical costs.
[Back
to top] Advances
in Osteoclast Differentiation and Function
Yousef Abu-Amer
Osteoclasts are the sole bone resorbing cells.
These cells are essential for skeletal development and remodeling throughout
the life of animal and man. Deficiency of osteoclasts leads to osteopetrosis, a
diseases manifested by increased non-remodeled bone mass, which ultimately
leads to bone deformities and functional failure of other body systems. On the
other hand, increased number and activity of osteoclasts under certain
pathologic conditions causes accelerated bone resorption and may lead to
osteoporosis and osteolytic diseases. To better understand the mechanisms
underlying osteoclast-based diseases and design relevant therapies, one should
unveil the molecular basis of osteoclast differentiation and function and
regulatory mechanisms of osteoclast signaling. This review will outline
up-to-date information regarding osteoclast differentiation and activation.
Molecular mechanisms underlying osteoclast signaling pathways in inflammatory
osteolysis and arthritis will be discussed. In addition, stimulators and
inhibitors of osteoclasts, as well as current therapies for osteoclast activity
will be addressed.