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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 4, Number 3, October 2008
Contents
Potential Lithium and Fluoride Interactions in Studies
of Glycogen Synthase Kinase-3 Pp. 93-99
Anna Strunecka and Jiri Patocka
[Abstract]
Fatty Acid Synthase: A Target for the
Reversal of Liver Steatosis Pp. 100-108
Zachary P. Evans, Justin D. Ellett and
Kenneth D. Chavin
[Abstract]
The NPC1L1 Inhibitor Ezetimibe in the
Treatment of the Dyslipidemia in Patients Affected by the
Metabolic Syndrome: Evidences and Perspectives Pp.
109-120
Giovanni Anfossi, Chiara Frascaroli, Katia
Bonomo, Massimo Chirio, Chiara Giordanino and Mariella
Trovati
[Abstract]
Recent Findings on the Multifaceted Functionality
of Enzyme Inhibition by Natural Compounds: A Review Pp.
121-152
John Paul Délano-Frier, José
Luis Castro-Guillén and Alejandro Blanco-Labra
[Abstract]
Aurora B Kinase and Passenger Proteins
as Targets for Cancer Therapy Pp. 153-159
Thi My Nhung Hoang, Marlène Delacour-Larose
and Annie Molla
[Abstract
Abstracts
[Back to top]
Potential Lithium and Fluoride Interactions in Studies
of Glycogen Synthase Kinase-3
Anna Strunecka and Jiri Patocka
The discoveries of the pluripotent role of glycogen synthase
kinase-3 (GSK-3) are pointing to GSK-3 as a potential target
for therapy of neurodegenerative disorders and type 2 diabetes.
GSK-3 is a constitutively active protein kinase that is inhibited
in response to various extracellular signals. Lithium has
been found to be an important inhibitor of GSK-3 activity
and its use as a laboratory tool has contributed to the understanding
of the role of GSK-3. Fluoride has been often used in study
designs on GSK-3 as the inhibitor of protein phosphatases.
Potential interactions of fluoride with the observed lithium
effects are discussed.
[Back to top]
Fatty Acid Synthase: A Target for the Reversal of Liver Steatosis
Zachary P. Evans, Justin D. Ellett and
Kenneth D. Chavin
Liver steatosis, or fatty liver, is characterized by
the excess accumulation of triglycerides and fatty acids within
hepatocytes. This accumulation is marked by an imbalance between
the import/synthesis and export/degradation of fat in the
liver. Liver steatosis is typically a benign condition, but
is associated with severe complications following major liver
surgery, as well as the progression of the liver to fibrosis,
cirrhosis, and hepatocellular carcinoma. The hallmark of treatment
has traditionally been the use of behavioral modification
leading to long-term phenotypic reversal. However, the rapid
reversal of liver steatosis is essential, especially prior
to surgeries including hepatic resection or transplantation.
The liver is a primary lipogenic tissue, making the enzyme
fatty acid synthase (FAS, EC 2.3.1.85) a logical target for
the treatment of steatosis. For steatosis of alcoholic or
nonalcoholic etiology, fat accumulation is linked to the de
novo synthesis of fatty acids through FAS. Recent reports
have shown success using FAS inhibitors to reduce the amount
of liver steatosis, and to reduce ischemia/reperfusion injury
in those livers. Thus, FAS emerges as a key target for the
reversal of hepatic steatosis, both for the preconditioning
of livers prior to surgery.
[Back to top]
The NPC1L1 Inhibitor Ezetimibe in the Treatment of the Dyslipidemia
in Patients Affected by the Metabolic Syndrome: Evidences
and Perspectives
Giovanni Anfossi, Chiara Frascaroli, Katia
Bonomo, Massimo Chirio, Chiara Giordanino and Mariella
Trovati
Ezetimibe is the first lipid-lowering drug which selectively
inhibits the intestinal uptake of dietary and biliary cholesterol
by binding to the cholesterol transporter protein Niemann-Pick
C1 Like 1 (NPC1L1). This drug is an effective new tool for
cholesterol lowering and allows to better investigate the
mechanisms involved in cholesterol absorption by small intestine.
Ezetimibe is rapidly absorbed after oral administration and
extensively metabolized (>80%)
to the pharmacologically active ezetimibe-glucuronide compound;
furthermore, it shows a favourable drug-drug interaction profile
due to the absence of clinically relevant interactions with
a variety of drugs commonly used in patients with hypercholesterolemia
(in particular, statins, fibrates and nicotinic acid). In
primary hypercholesterolemia, ezetimibe alone reduces low
density lipoprotein (LDL) cholesterol by about 18% and induces
an additional 25% reduction when added to on-going statins.
The combination therapy of ezetimibe with statins or fibrates
is effective and safe also in patients affected by the Metabolic
Syndrome, which is characterized by complex lipid alterations,
including increased triglyceride levels, low high density
lipoprotein (HDL) cholesterol concentrations, preponderance
of small dense LDL particles and post-prandial hyperlipidemia.
In this review, we considered the main studies evaluating
the rationale and the efficacy of therapy with ezetimibe alone
or in combination with other lipid-lowering drugs, in order
to provide clinical indications.
[Back to top]
Recent Findings on the Multifaceted Functionality of Enzyme
Inhibition by Natural Compounds: A Review
John Paul Délano-Frier, José
Luis Castro-Guillén and Alejandro Blanco-Labra
Enzyme inhibition is a fundamental process to preserve
the orderly sequence of events required for life, from seed
germination to apoptosis. This review will verse on recent
findings showing the various ways in which enzyme inhibition
has been incorporated into the arsenal of many organisms,
either as an effective defensive weapon or as a factor needed
for the establishment of infection, parasitism and/or symbiotic
associations, and how this diverse functionality can be exploited
for therapeutic uses. It will describe several non-proteinaceous
enzyme inhibitors isolated from natural sources or synthesized
on the basis of structural or functional similarity to biosynthetic
enzymes that have been employed for effective treatment against
infections and/or aggresive diseases, such as cancer and AIDS,
given their ability to disrupt critical functions of the target
organisms or malignant cells. A relation of novel plant proteinase
inhibitors (PPIs) with multiple and/or novel functions or
engineered to have a highly selectivity on their target enzymes
in order to avoid delete-rious effects in a multi-trophic
level that negatively affect insect pollinators or predators,
is included too. This development could eliminate or reduce
one of the most pressing concerns about the use of PIs as
transgenes in many important crops. Finally, an account of
the highly specific inhibition of enzymatic activity by biotechnological
(e.g. gene silencing) or biochemical means, which have proven
to be powerful tools to reveal novel functions for a variety
of enzymes will be made in the context of defense, development,
senescence and programmed cell death in plants.
[Back to top]
Aurora B Kinase and Passenger Proteins as Targets for Cancer
Therapy
Thi My Nhung Hoang, Marlène Delacour-Larose
and Annie Molla
The chromosome passenger complex (CPC) is composed of
five proteins: Aurora B kinase, Borealin, INCENP, Survivin
and TD-60. CPC functions as an oligo-enzyme, each member activating
the catalytic subunit, Aurora B kinase.
CPC controls chromosome congression, bidirectional tension
on kinetochores and spindle checkpoint signalling as well
as cytokinesis completion. CPC is thus a key regulator during
mitosis; CPC proteins are exclusively expressed during mitosis
and are up-regulated in many tumours. Their overexpression
correlates with the level of genomic instability within tumours.
Altogether, this leads to the proposal of passenger proteins
as potential targets for cancer therapy.
This review describes the chromosomal passenger complex and
its involvement in mitosis and the different strategies developed
towards its inactivation.
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