Immunology,
Endocrine & Metabolic Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Immunology, Endocrine
and Metabolic Agents')
ISSN: 1871-5222
OPEN ACCESS ARTICLES
Contents
Contribution of Recent Transgenic Models and Transcriptional
Profiling Studies to Our Understanding of the Mechanisms by
which Androgens Control Spermatogenesis, 2008, 8,
2-13
G. Verhoeven, E. Denolet, J.V. Swinnen, A. Willems, F.
Claessens, P.T.K. Saunders, R.M. Sharpe and K. De Gendt
[Abstract] [Full
text article]
“Unlocking” the Blood-Testis
Barrier and the Ectoplasmic Specialization by Cytokines During
Spermatogenesis: Emerging Targets for Male Contraception,
2008, 8, 20-27
M.W.M. Li, D.D. Mruk and C.Y. Cheng
[Abstract] [Full
text article]
Nitric Oxide-cGMP Signaling: Its
Role in Cell Junction Dynamics During Spermatogenesis,
2008, 8, 28-35
O. Sarkar, P.P. Mathur and D.D. Mruk
[Abstract] [Full
text article]
Dynamins, Spermatogenesis and Contraceptive
Development, 2008, 8, 51-58
P.P.Y. Lie, D.D. Mruk and C.Y. Cheng
[Abstract] [Full
text article]
Delivery of Contraceptives to Men:
Lesson from Other Therapeutic Drugs, 2008, 8, 91-94
E.W.P. Wong, D.D. Mruk and C.Y. Cheng
[Abstract] [Full
text article]
Abstracts
[Back to top]
Contribution of Recent Transgenic Models and Transcriptional
Profiling Studies to Our Understanding of the Mechanisms by
which Androgens Control Spermatogenesis
G. Verhoeven, E. Denolet, J.V. Swinnen, A. Willems, F.
Claessens, P.T.K. Saunders, R.M. Sharpe and K. De Gendt
[Full
text article]
Androgens play a key role in the control of spermatogenesis
and interference with their intratesticular secretion and
action is a critical element in many contraceptive strategies.
Nonetheless, the cellular and molecular mechanisms by which
androgens control germ cell development remain poorly understood.
Recent transgenic models in which the androgen receptor (AR)
is selectively ablated in Sertoli cells show unambiguously
that the Sertoli cell is the main target for androgen action
in the control of spermatogenesis. A number of additional
mouse models have been developed mimicking human diseases
in which mutations of the AR cause disturbed fertility without
affecting male development. Transcriptional profiling studies
in mice with Sertoli cell-selective AR ablation and in some
other experimental paradigms have tried to identify androgen-regulated
genes relevant to the control of spermatogenesis. The overlap
in genes identified in different studies is poor but this
may be due mainly to dissimilarities in experimental setup.
In all studies, relatively large numbers of genes rather than
a few key genes seem to be affected by androgen action. Genes
related to tubular restructuring, cell junction dynamics,
cytoskeleton, solute transportation and vitamin A metabolism
are prominently present. Although further work is obviously
needed, it may be anticipated that these studies will result
in the identification of subsets of genes that can be used
as diagnostic tools as well as in the identification of targets
for the development of novel contraceptives.
[Back to top]
“Unlocking” the Blood-Testis Barrier and
the Ectoplasmic Specialization by Cytokines During Spermatogenesis:
Emerging Targets for Male Contraception
M.W.M. Li, D.D. Mruk and C.Y. Cheng
[Full
text article]
Cytokines are known to regulate an array of physiological
functions in the testis, including cell differentiation, apoptosis,
ste-roidogenesis, and cell division. Recent studies have illustrated
that cytokines also take a crucial role in the regulation
of junction dynamics. These include the regulation of cell-cell
adhesion and tight junction permeability barriers in multiple
epithelia and endothelia, such as those found in the small
intestine, kidney, skin, and testis. In this review, we summarize
recent findings in this field with an emphasis on the role
of cytokines in junction restructuring events during spermatogenesis
in the seminiferous epithelium of testes. This review also
identifies several areas of research that functional studies
can be designed to unravel the physiological significance
of cytokines in junction restructuring at the Sertoli-Sertoli
or Sertoli-germ cell interface in the seminiferous epithelium.
It is expected that multiple cytokines, such as TGF-β3
and TNFα
, are working in concert with other yet-to-be identified molecules
to coordinate the intriguing events of junction restructuring
during different stages of the seminiferous epithelial cycle
in adult testes in mammals.
[Back to top]
Nitric Oxide-cGMP Signaling: Its Role in Cell Junction
Dynamics During Spermatogenesis
O. Sarkar, P.P. Mathur and D.D. Mruk
[Full
text article]
During spermatogenesis, development of spermatogonia into
elongated spermatids takes place in the seminiferous epithelium
of the adult mammalian testis. Specifically, post-meiotic
germ cell maturation occurs in a unique microenvironment sequestered
from the systemic circulation by the blood-testis barrier
(BTB), which is formed by adjacent Sertoli cells. Therefore,
an intact BTB, as well as stable Sertoli-germ cell adhesion,
are important criteria for successful spermatogenesis. To
date, numerous factors have been shown to influence spermatogenesis,
and among them is the well-studied nitric oxide (NO) /guanosine
3’,5’-cyclic monophosphate (cGMP) signaling cascade.
The enzymes of this pathway, namely nitric oxide synthase,
soluble guanylate cyclase and cGMP-dependent protein kinase,
have all been shown to regulate cell junctions in the testis.
Likewise, recent findings have shown that this signaling cascade
also plays a critical role in the regulation of Sertoli-germ
cell adhesion. In this mini-review, we briefly discuss the
regulatory role of each protein component of the NO/cGMP pathway
in the context of testicular junction dynamics, as well as
their importance in fertility and male contraception.
[Back to top]
Dynamins, Spermatogenesis and Contraceptive Development
P.P.Y. Lie, D.D. Mruk and C.Y. Cheng
[Full
text article]
Dynamins are large GTPases of ~100 kDa known to participate
in endocytosis and interact with the actin-based cytoskeletal
network in multiple tissues. Recent studies have shown that
dynamins play a critical role in the internalization of integral
membrane proteins via either clathrin-mediated or
clathrin-independent endocytosis. Furthermore, recent studies
have shown that dynamin II interacts with junctional complex
adaptors, namely ZO-1 and β-catenin,
at the blood-testis barrier in the seminiferous epithelium
of adult rat testes. This interaction may be responsible for
pulling away tight junction- and adherens junction-based protein
complexes, thereby facilitating blood-testis barrier opening
to permit preleptotene and leptotene spermatocyte migration,
which is a critical event in spermatogenesis occurring at
stage VIII of the seminiferous epithelial cycle. In this short
review, we highlight some of the latest findings on dynamins
in the field, and discuss how this information can be used
to further expand the functional studies to tackle the role
of dynamins in spermatogenesis. It is likely that dynamins
per se or their interacting protein partners can
become a target for male contraceptive research to compromise
spermatogenesis, leading to transient male infertility without
perturbing the hypothalamic-pituitary-testicular axis.
[Back to top]
Delivery of Contraceptives to Men: Lesson from Other Therapeutic
Drugs
E.W.P. Wong, D.D. Mruk and C.Y. Cheng
[Full
text article]
Besides hormonal-based male contraceptives, such as testosterone
undecanoate (a long-chain ester of testosterone) which can
be administered either orally as contraceptive pill or by
injection, some efforts have been made in the field to develop
non-hormonal contraceptives to suppress spermatogenesis. One
of the major goals for non-hormonal contraceptives is to avoid
a disruption of the hypothalamic-pituitary-testicular axis,
without affecting the systemic testosterone, LH and FSH levels,
hoping to minimize the side-effects since testosterone has
multiple target organs besides the testis. However, these
non-hormonal male contraceptives are often met with poor absorption
at the gastrointestinal tract and if they are peptide/protein
based, they are subjected to proteolytic cleavage following
oral administration. Thus, other non-oral routes are being
considered. In this short review, we highlighted some of the
latest development in the field regarding the administration
of other therapeutic drugs via non-parenteral and
non-oral routes. This information as briefly reviewed herein
should provide some insights for delivery of male contraceptives
in the future.
|
