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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 16, 2007
Contents
Smoking, Oxidative Stress and Cardiovascular Diseases–Do
Anti Oxidative Therapies Fail? Pp. 1703-1712
D. Bernhard and X.L. Wang
[Abstract]
Future Contrast Agents for Molecular Imaging in Stroke
Pp. 1713-1728
Stefan Heckl
[Abstract]
Mechanistic Insights Into Diabetes Mellitus and Oxidative
Stress Pp. 1729-1738
Kenneth Maiese, Zhao Zhong Chong and Yan Chen Shang
[Abstract]
Brittle Type 1 Diabetes Mellitus Pp. 1739-1744
Federico Bertuzzi, Roberto Verzaro, Vincenzo Provenzano
and Camillo Ricordi
[Abstract]
Crucial Role of PDX-1 in Pancreas Development, β-Cell
Differentiation, and Induction of Surrogate β-Cells
Pp. 1745-1752
Hideaki Kaneto, Takeshi Miyatsuka, Toshihiko Shiraiwa,
Kaoru Yamamoto, Ken Kato, Yoshio Fujitani and Taka-aki Matsuoka
[Abstract]
Dynamic Regulation of Acid-Sensing Ion Channels by
Extracellular and Intracellular Modulators Pp. 1753-1763
Tian-Le Xu and Zhi-Gang Xiong
[Abstract]
Dyslipidemia as a Risk Factor for Erectile Dysfunction
Pp. 1765-1770
G.E. Vrentzos, K.I. Paraskevas and D.P. Mikhailidis
[Abstract]
Chlorination Products: Emerging Links with Allergic
Diseases Pp. 1771-1782
A. Bernard
[Abstract]
Molecular Approaches for Neuropathic Pain Treatment
Pp. 1783-1787
Dario Siniscalco, Francesco Rossi and Sabatino Maione
[Abstract]
Bis and Tris Indole Alkaloids from Marine Organisms:
New Leads for Drug Discovery Pp. 1789-1803
Leena Gupta, Archna Talwar and Prem M.S. Chauhan
[Abstract]
Abstracts
[Back to top]
Smoking, Oxidative Stress and Cardiovascular
Diseases–Do Anti Oxidative Therapies Fail?
Pp. 1703-1712
D. Bernhard and X.L. Wang
Oxidative reactions caused by cigarette smoke (CS) chemicals
have been shown to initiate crucial events in atherogenesis.
However, physicians and scientists are confronted with the
paradoxical situation that an antioxidative treatment of smokers
improves acute smoking effects but hardly has any impact on
long term outcome of cardiovascular diseases (CVD). In this
review we make an attempt to explain this paradox. First,
smoke-derived free radicals and oxidants are part of CS causing
a pro-oxidative state in the circulatory system. Further,
smoke chemicals down-regulate antioxidant defence enzymes
that would counteract the oxidative burden by cigarette smoke.
With the prolonged exposure to smoke, oxidation catalysing
metals accumulate in the vessel wall and mediate local oxidation
reactions. Therefore, pharmacological intervention relying
on non-selective antioxidants often appears to be ineffective.
Consequently a novel strategy for the prevention and treatment
of CVD caused by smoking is suggest, relying on a combined
application of antioxidants, substitution of factors important
for physiological oxidant defence, and metal-detoxifying agents.
[Back to top]
Future Contrast Agents for Molecular Imaging in Stroke
Stefan Heckl
The objective of this article is to illustrate both the potential
and the limitations of molecular imaging in stroke research.
By molecular imaging we mean the visual representation of
biological processes at the cellular and molecular level.
The use of molecular imaging for stroke diagnosis is still
at a very preliminary stage and many of these procedures have
only been tested in animals. In rats, stroke therapy using
stem cells can be monitored by magnetic resonance imaging
(MRI), green fluorescent protein (GFP) or luciferase (LUC)
imaging. The migration of macrophages, which take up intravenously
administered iron-based contrast agents and then migrate to
the area of infarction, can already be observed in stroke
patients. With MRI, the new agent Gd-DTPA-sLexA
that binds to E- and P-selectin can specifically visualize
selectin-mediated early endothelial activation after transient
focal ischemia “in vivo”. Decreased glial
fibrillary acidic protein (GFAP) gene expression can be imaged
in vivo by scintigraphy 24 hours after cerebral ischemia
using a peptide nucleic acid antisense conjugate labeled with
111In and that hybridizes to the rat GFAP mRNA. Technetium-99m
hydrazine nicotinamide-labeled HYNIC-annexin V SPECT can not
only detect sites of neuronal injury in stroke patients but
also can monitor the effects of neuroprotective therapy with
a monoclonal antibody raised against FasLigand (FasL) in rats.
Finally, information about cell metabolism in the infarct
region can be gained using certain intracellular tracers [e.g.
18F-fluoromisonidazole (FMISO)]. Imaging benzodiazepine receptors
with 11C-flumazenil (FMZ) can distinguish between irreversibly
damaged and viable penumbra tissue early after stroke.
[Back to top]
Mechanistic Insights Into Diabetes Mellitus and Oxidative
Stress
Kenneth Maiese, Zhao Zhong Chong and Yan Chen Shang
Diabetes mellitus (DM) is a significant healthcare concern
worldwide that affects more than 165 million individuals leading
to cardiovascular disease, nephropathy, retinopathy, and widespread
disease of both the peripheral and central nervous systems.
The incidence of undiagnosed diabetes, impaired glucose tolerance,
and impaired fasting glucose levels raises future concerns
in regards to the financial and patient care resources that
will be necessary to care for patients with DM. Interestingly,
disease of the nervous system can become one of the most debilitating
complications and affect sensitive cognitive regions of the
brain, such as the hippocampus that modulates memory function,
resulting in significant functional impairment and dementia.
Oxidative stress forms the foundation for the induction of
multiple cellular pathways that can ultimately lead to both
the onset and subsequent complications of DM. In particular,
novel pathways that involve metabotropic receptor signaling,
protein-tyrosine phosphatases, Wnt proteins, Akt, GSK-3β,
and forkhead transcription factors may be responsible for
the onset and progression of complications form DM. Further
knowledge acquired in understanding the complexity of DM and
its ability to impair cellular systems throughout the body
will foster new strategies for the treatment of DM and its
complications.
[Back to top]
Brittle Type 1 Diabetes Mellitus
Federico Bertuzzi, Roberto Verzaro, Vincenzo Provenzano
and Camillo Ricordi
A small group of patients affected by type 1 diabetes mellitus
is characterized by a severe instability of glycemic values
with frequent and unpredictable hypoglycemic and/or ketoacidosis
episodes which cannot be explained by errors of patients or
diabetologists. The quality of life of these patients is dramatically
compromised in particular because of the frequency of acute
events, hospital recoveries and precocious appearance of chronic
complications. This clinical condition has been defined as
“brittle diabetes”. A precise quantification of
these patients is difficult because diagnostic criteria are
still not well defined and it is often difficult to verify
errors of patients in terms of inappropriate conduct with
the pathology. Even more than the other kinds of diabetes,
therapy is based on education, glycemic control, intensive
therapy and strict interaction between physicians and patients.
The introduction of insulin analogous, with either ultra-fast
and ultra-slow action and the use of subcutaneous insulin
pumps have significantly increased the possibility of treating
the most of these cases. However, there is a minority of patients
resistant to the therapy. In similar cases, pancreas or islet
transplantation represents an effective therapeutic option
entailing good expected outcomes. The main limiting factor
of beta cell function replacement by transplantation is so
far represented by the potentially severe side effects of
the immunosuppression therapy necessary to avoid graft rejection
and recurrence of autoimmunity.
[Back to top]
Crucial Role of PDX-1 in Pancreas Development, β-Cell
Differentiation, and Induction of Surrogate β-Cells
Hideaki Kaneto, Takeshi Miyatsuka, Toshihiko Shiraiwa,
Kaoru Yamamoto, Ken Kato, Yoshio Fujitani and Taka-aki Matsuoka
Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a
crucial role in pancreas development, β-cell
differentiation, and maintaining mature β-cell
function. At an early stage of embryonic development, PDX-1
is initially expressed in the gut region when the foregut
endoderm becomes committed to common pancreatic precursor
cells. During pancreas development, PDX-1 expression is maintained
in precursor cells, and later it becomes restricted to β-cells.
In mature β-cells,
PDX-1 transactivates the insulin gene and other genes involved
in glucose sensing and metabolism, such as GLUT2 and glucokinase.
MafA is a recently isolated β-cell-specific
transcription factor which functions as a potent activator
of insulin gene transcription. During pancreas development,
MafA expression is first detected at the beginning of the
principal phase of insulin-producing cell production. Furthermore,
these transcription factors play a crucial role in inducing
surrogate β-cells
from non-β-cells
and thus could be therapeutic targets for diabetes.
[Back to top]
Dynamic Regulation of Acid-Sensing Ion Channels by
Extracellular and Intracellular Modulators
Tian-Le Xu and Zhi-Gang Xiong
Changes of extracellular pH values can have profound
effects on neuronal function. For example, the low pH (also
called acidosis) generated in brain ischemia causes acute
neuronal injury. For years the receptors that detect pH variations
surrounding neurons and their physiological/pathological importance
remain uncertain. The recent finding that acidosis activates
a distinct family of membrane ion channels, the acid-sensing
ion channels (ASICs) in both peripheral and central neurons
has dramatically changed the view of acidosis-associated signaling
and provided a new strategy for therapeutic inventions. Although
proton is the only known agonist for the activation of ASICs,
a variety of extracellular and intracellular signaling molecules
can modulate the activities of ASICs and have profound influence
on the functions of these channels in both physiological and
pathological processes. The goal of this article is therefore
to provide a comprehensive review of the modulators of ASICs
that adapt ASIC activity to changes of extracellular and intracellular
environments.
[Back to top]
Dyslipidemia as a Risk Factor for Erectile Dysfunction
G.E. Vrentzos, K.I. Paraskevas and D.P. Mikhailidis
Erectile dysfunction (ED) is a common condition with a significant
effect on quality of life. The prevalence of ED increases
with age and other risk factors (hypertension, diabetes, smoking,
coronary heart disease, dyslipidemia and depression). Nitric
oxide (NO) activity is adversely affected, in penile and vascular
tissue, by these risk factors. Endothelial dysfunction and
a reduced generation or bioavailability of NO have emerged
as major pathophysiological mechanisms in ED.
Hyperlipidemia may impair erectile function by affecting endothelial
and smooth muscle cells of the penis. Oxidized low-density
lipoprotein is a causative factor for the impaired relaxation
response of the corpus cavernosum. Elevated serum cholesterol
and reduced high density lipoprotein cholesterol levels are
associated with an increased risk of ED. It follows that treating
dyslipidemia could have a beneficial effect on ED.
Phosphodiesterase type 5 inhibitors are now considered as
first line treatment for ED. There is evidence that statins
improve responses to these drugs.
ED is considered as a warning sign of silent or early vascular
disease. The use of statins may be beneficial in these patients.
[Back to top]
Chlorination Products: Emerging Links with Allergic
Diseases
A. Bernard
Exposure of the human population to chlorination products
has considerably increased during the 20th
century especially after the 1960s with the development of
public and leisure pools. The present article summarizes current
knowledge regarding the human exposure to chlorination products
and reviews studies suggesting that these chemicals might
be involved in the development or exacerbation of allergic
diseases. Populations regularly in contact with chlorination
products such as swimmers, lifeguards or workers using chlorine
as cleaning or bleaching agent show increased risks of allergic
diseases or of respiratory disorders frequently associated
with allergy. Experimental evidence suggests that chlorination
products promote allergic sensitization by compromising the
permeability or the immunoregulatory function of epithelial
barriers. These findings led to the chlorine hypothesis proposing
that the rise of allergic diseases could result less from
the declining exposure to microbial agents (the hygiene hypothesis)
than from the increasing and largely uncontrolled exposure
to products of chlorination, the most widely used method to
achieve hygiene in the developed world. Giving the increasing
popularity of water recreational areas, there is an obvious
need to assess the effects of chlorine-based oxidants on human
health and their possible implication in the epidemic of allergic
diseases.
[Back to top]
Molecular Approaches for Neuropathic Pain Treatment
Dario Siniscalco, Francesco Rossi and Sabatino Maione
Neuropathic pain is initiated or caused by a primary lesion
or dysfunction in the nervous system.
It is estimated that 75–150 million people in the United
States have a chronic pain disorder. Neuropathic pain has
a great impact on the quality of life. It is debilitating
and often has an associated degree of depression that contributes
to decreasing human wellbeing. Moreover, the management of
chronic pain is costly to the health care system. The United
States Congress has declared the present decade (2001-2010)
as the “Decade of Pain Control and Research”,
making pain a national healthcare priority.
In Europe, statistics provided by the International Association
on the Study of Pain (IASP) and the European Federation of
the IASP Chapters (EFIC) indicate that one in five people
suffer from moderate to severe chronic pain, and that one
in three are unable or less able to maintain an independent
lifestyle due to their pain. Between one-half and two-thirds
of people with chronic pain are less able or unable to exercise,
enjoy normal sleep, perform household chores, attend social
activities, drive a car, walk or have sexual relations. The
effect of pain means that one in four reports that relationships
with family and friends are strained or broken, according
to the IASP/EFIC data.
Neuropathic pain treatment is extremely difficult. Neuropathic
pain is a very complex disease, involving several molecular
pathways. Excitatory or inhibitory pathways controlling neuropathic
pain development show altered gene expression, caused by peripheral
nerve injury. Current available drugs are usually not acting
on the several mechanisms underlying the generation and propagation
of pain.
Nowadays, pain research is directing on new molecular methods,
such as gene therapy, stem cell therapy and viral vectors
for delivery of biologic antinociceptive molecules. These
methods could provide a new therapeutic approach to neuropathic
pain relief.
[Back to top]
Bis and Tris Indole Alkaloids from Marine Organisms:
New Leads for Drug Discovery
Leena Gupta, Archna Talwar and Prem M.S. Chauhan
The marine organisms are a rich source of varied natural products
with unique functionality. Marine natural products chemistry
has undergone an explosive growth during the past three decades.
A variety of natural products of new molecular structures
with diverse biological activities have been reported from
marine flora and fauna, thus ensuring motivation in the search
of newer natural products. The bis and trisindole alkaloids
are a class of marine natural products that show unique promise
in the development of new drug leads. 3-hydroxy staurosporine
51, an indolo carbazole having powerful antiproliferative
activity. Hamacanthin A 1 and B 2,
pyrazinone alkaloids have significant antimicrobial activity.
Coscinamides 60-62 and Chondriamides 63-65
an indolic enamides which have anti-HIV and cytotoxic activity
respectively. Gelluisine A 66 and B 67,
trisindole alkaloids have strong anti-serotonin activity and
strong affinity with somatostatin and neuropeptide Y receptors
in receptor-binding assays. This report reviews the literature
on these alkaloids of marine origin and highlights the isolation,
structure, latest synthesis and specific biological activities
including cytotoxicity, antiviral, antiparasitic, serotonin
antagonism and other pharmacological activities of sixty-nine
bis and trisindole alkaloids.
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