The NAMPT inhibitor FK866 reverts the damage in spinal cord injury.
Esposito E, Impellizzeri D, Mazzon E, Fakhfouri G, Rahimian R, Travelli C, Tron
GC, Genazzani AA, Cuzzocrea S. J Neuroinflammation. 2012 Apr 10;9(1):66. [Epub ahead of print]
[Show abstractHide abstract]
ABSTRACT: BACKGROUND: Emerging data implicate nicotinamide phosphoribosyl
transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT
inhibitors have proven beneficial in inflammatory animal models of arthritis and
endotoxic shock as well as in autoimmune encephalitis. Given the role of
inflammatory responses in spinal cord injury (SCI), the effect of NAMPT
inhibitors was examined in this setting. METHODS: We investigated the effects of
the NAMPT inhibitor FK866 in an experimental compression model of SCI. RESULTS:
Twenty-four hr following induction of SCI, a significant functional deficit
accompanied widespread edema, demyelination, neuron loss and a substantial
increase in TNF-alpha, IL-1beta, PAR, NAMPT, Bax, MPO activity, NF-kappaB
activation, astrogliosis and microglial activation was observed. Meanwhile, the
expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased
significantly. Treatment with FK866 (10 mg/kg), the best known and characterized
NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved
perilesional gray and white matter, restored anti-apoptotic and neurotrophic
factors, prevented the activation of neutrophils, microglia and astrocytes and
inhibited the elevation of NAMPT, PAR, TNF-alpha, IL-1beta, Bax expression and
NF-kappaB activity. We show for the first time that FK866, a specific inhibitor
of NAMPT, administered after SCI, is capable of reducing the secondary
inflammatory injury and partly reduce permanent damage. We also show that NAMPT
protein levels are increased upon SCI in the perilesional area which can be
corrected by administration of FK866. CONCLUSIONS: Our findings suggest that the
inflammatory component associated to SCI is the primary target of these
inhibitors.
55
Calcium signaling in closely related protozoan groups (Alveolata): Non-parasitic
ciliates (Paramecium, Tetrahymena) vs. parasitic Apicomplexa (Plasmodium,
Toxoplasma).
Plattner H, Sehring IM, Mohamed IK, Miranda K, De Souza W, Billington R,
Genazzani A, Ladenburger EM. Cell Calcium. 2012 Mar 2. [Epub ahead of print]
[Show abstractHide abstract]
[Download PDF]
The importance of Ca(2+)-signaling for many subcellular processes is well
established in higher eukaryotes, whereas information about protozoa is
restricted. Recent genome analyses have stimulated such work also with
Alveolates, such as ciliates (Paramecium, Tetrahymena) and their pathogenic close
relatives, the Apicomplexa (Plasmodium, Toxoplasma). Here we compare Ca(2+)
signaling in the two closely related groups. Acidic Ca(2+) stores have been
characterized in detail in Apicomplexa, but hardly in ciliates. Two-pore channels
engaged in Ca(2+)-release from acidic stores in higher eukaryotes have not been
stingently characterized in either group. Both groups are endowed with plasma
membrane- and endoplasmic reticulum-type Ca(2+)-ATPases (PMCA, SERCA),
respectively. Only recently was it possible to identify in Paramecium a number of
homologs of ryanodine and inositol 1,3,4-trisphosphate receptors (RyR, IP(3)R)
and to localize them to widely different organelles participating in vesicle
trafficking. For Apicomplexa, physiological experiments suggest the presence of
related channels although their identity remains elusive. In Paramecium, IP(3)Rs
are constitutively active in the contractile vacuole complex; RyR-related
channels in alveolar sacs are activated during exocytosis stimulation, whereas in
the parasites the homologous structure (inner membrane complex) may no longer
function as a Ca(2+) store. Scrutinized comparison of the two closely related
protozoan phyla may stimulate further work and elucidate adaptation to parasitic
life. See also "Conclusions" section.
54
Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast
cancer patients receiving radiotherapy after breast conserving surgery.
PURPOSE: To evaluate the impact of functional polymorphisms in genes related to
DNA repair mechanisms (XRCC1, TP53, MSH2, MSH3, XPD), oxidative stress response
(GSTP1, GSTA1, eNOS, SOD2) and fibroblast proliferation (TGFβ1) on the risk of
acute skin toxicity in breast cancer patients receiving radiotherapy. MATERIAL
AND METHODS: Skin toxicity was scored according to the Radiation Therapy Oncology
Group criteria in 286 breast cancer patients who received radiotherapy after
breast conserving surgery. Genotyping was conducted by PCR-RFLP analysis and
real-time PCR allelic discrimination assay on genomic DNA extracted from
peripheral blood. RESULTS: In the multivariate analysis, nominally significant
associations, before multiple testing corrections, were found between XRCC1 T-77C
(T carriers vs. CC, OR: 2.240, 95% CI: 1.015-4.941, P=0.046), eNOS G894T
polymorphisms (TT vs. G carriers, OR: 2.473, 95% CI: 1.220-5.012, P=0.012),
breast diameter (OR: 1.138, 95% CI: 1.001-1.293, P=0.048), boost
dose-fractionation (3Gy vs. no boost, OR: 4.902, 95% CI: 1.458-16.483, P=0.010)
and ⩾grade 2 acute radiation skin toxicity in breast cancer patients.
CONCLUSIONS: As our exploratory study suggests that XRCC1 T-77C and eNOS G874T
may confer an increased risk of acute skin reactions to radiotherapy in breast
cancer patients, further confirmatory studies are warranted to determine the
clinical significance.
53
Identification of novel antitubulin agents by using a virtual screening approach
based on a 7-point pharmacophore model of the tubulin colchi-site.
Massarotti A, Theeramunkong S, Mesenzani O, Caldarelli A, Genazzani AA, Tron GC. Chem Biol Drug Des. 2011 Dec;78(6):913-22. doi: 10.1111/j.1747-0285.2011.01245.x.
Epub 2011 Oct 31.
[Show abstractHide abstract]
[Download PDF]
Tubulin inhibition represents an established target in the field of anticancer
research, and over the last 20 years, an intensive search for new antimicrotubule
agents has occurred. Indeed, in silico models have been presented that might aid
the discovery of novel agents. Among these, a 7-point pharmacophore model has
been recently proposed. As a formal proof of this model, we carried out a
ligand-based virtual screening on the colchicine-binding site. In vitro testing
demonstrated that two compounds displayed a cytotoxic profile on neuroblastoma
cancer cells (SH-SY5H) and one had an antitubulinic profile.
52
N-Arylbenzamides: extremely simple scaffolds for the development of novel
estrogen receptor agonists.
Caldarelli A, Minazzi P, Canonico PL, Genazzani AA, Giovenzana GB. J Enzyme Inhib Med Chem. 2011 Dec 14.
[Show abstractHide abstract]
The research of estrogen receptor (ER) ligands has benefited in the last decade
from the implementation of combinatorial chemistry. The general pharmacophore has
been identified and subsequently a multitude of compounds have been synthesized.
Surprisingly, up to now simple amides have not been taken into consideration.
Here we show that amides resulting from the condensation of hydroxybenzoic acids
with aminophenols result in compounds retaining the pharmacophore structure of an
ER ligand with a clear estrogenic activity.
