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FRANK BERGER
Tucker
JM, Murphy JT, Kisiel N, Diegelman P, Barbour KW, Davis C,
Medda M, Alhonen L, Janne J, Kramer DL, Porter CW, Berger FG.
Potent modulation of intestinal tumorigenesis in Apcmin/+
mice by the polyamine catabolic enzyme spermidine/spermine
N1-acetyltransferase.. Cancer Res. 2005 Jun
15;65(12):5390-8.
Intracellular polyamine pools are
homeostatically maintained by processes involving
biosynthesis, catabolism, and transport. Although most
polyamine-based anticancer strategies target biosynthesis,
we recently showed that activation of polyamine catabolism
at the level of spermidine/spermine N(1)-acetyltransferase-1
(SSAT) suppresses tumor outgrowth in a mouse prostate cancer
model. Herein, we examined the effects of differential SSAT
expression on intestinal tumorigenesis in the Apc(Min/+)
(MIN) mouse. When MIN mice were crossed with SSAT-overproducing
transgenic mice, they developed 3- and 6-fold more adenomas
in the small intestine and colon, respectively, than normal
MIN mice. Despite accumulation of the SSAT product,
N(1)-acetylspermidine, spermidine and spermine pools were
only slightly decreased due to a huge compensatory increase
in polyamine biosynthetic enzyme activities that gave rise
to enhanced metabolic flux. When MIN mice were crossed with
SSAT knock-out mice, they developed 75% fewer adenomas in
the small intestine, suggesting that under basal conditions,
SSAT contributes significantly to the MIN phenotype. Despite
the loss in catabolic capability, tumor spermidine and
spermine pools failed to increase significantly due to a
compensatory decrease in biosynthetic enzyme activity giving
rise to a reduced metabolic flux. Loss of heterozygosity at
the Apc locus was observed in tumors from both SSAT-transgenic
and -deficient MIN mice, indicating that loss of
heterozygosity remained the predominant oncogenic mechanism.
Based on these data, we propose a model in which SSAT
expression alters flux through the polyamine pathway giving
rise to metabolic events that promote tumorigenesis. The
finding that deletion of SSAT reduces tumorigenesis suggests
that small-molecule inhibition of the enzyme may represent a
nontoxic prevention and/or treatment strategy for
gastrointestinal cancers.
Mehl KA, Davis JM, Clements JM, Berger
FG, Pena MM, Carson JA.
Decreased intestinal polyp multiplicity is related to
exercise mode and gender in ApcMin/+ mice. J Appl Physiol.
2005 Jun;98(6):2219-25.
Moderate-intensity treadmill running can
alter male Apc(Min/+) mouse polyp formation. This purpose of
this study was to examine whether exercise mode
differentially affects Apc(Min/+) mouse intestinal polyp
development in male and female mice. Male and female Apc(Min/+)
mice were randomly assigned to control, treadmill (18 m/min;
60 min/day; 6 days/wk), or voluntary wheel running (24-h
access) groups. Nine weeks of training decreased total
intestinal polyps by 29% in male treadmill runners (66 +/-
9; P = 0.038) compared with male controls (93 +/- 7). The
number of large polyps (>/=1-mm diameter) were also reduced
by 38% in male treadmill runners (49 +/- 6; P = 0.005)
compared with male controls (79 +/- 6). Treadmill running in
female Apc(Min/+) mice and wheel running in both genders did
not affect polyp number or size. Spleen weight decreased in
male treadmill runners (91 +/- 9 mg; P = 0.011) and wheel
runners (75 +/- 6 mg; P = 0.004) compared with controls (141
+/- 13 mg). Plasma IL-6 was reduced by 96% in male treadmill
runners (1.2 +/- 0.6 pg/ml) and 78% in male wheel runners
(6.6 +/- 3.3 pg/ml) compared with control mice (27.9 +/- 2.8
pg/ml; P < 0.05). Female mice responded similarly with an
86% decrease in plasma IL-6 with treadmill running (3.2 +/-
1.2 pg/ml) and 90% decrease with wheel running (2.9 +/- 2.0
pg/ml) compared with control mice (21.1 +/- 5.3 pg/ml; P <
0.05). The crypt depth-to-villus height ratio in the
intestine, an indirect marker of intestinal inflammation,
decreased by 21 (P = 0.024) and 24% (P = 0.029),
respectively, in male and female treadmill runners but not
wheel runners. Physical activity-induced attenuation of
intestinal polyp number and size is dependent on exercise
mode and differs between genders. The modulation of systemic
and intestinal inflammation may also depend on exercise
mode.
Miller-Lotan R, Herskowitz Y,
Kalet-Litman S, Nakhoul F, Aronson D, Zoabi R, Asaf R, Ben-Izhak
O, Sabo E, Lim SK, Baumann H, Berger FG, Levy AP. Increased
renal hypertrophy in diabetic mice genetically modified at
the haptoglobin locus. Diabetes Metab Res Rev. 2005.
BACKGROUND: The human haptoglobin (Hp)
gene is polymorphic with two functional classes of alleles,
denoted 1 and 2. We have demonstrated in three longitudinal
studies and several cross-sectional studies that the Hp
genotype is an independent risk factor for diabetic vascular
disease. These studies have presented a compelling argument
that diabetic individuals homozygous for the Hp 1 allele are
at decreased risk of vascular complications as compared to
diabetic individuals with the Hp 2 allele. METHODS: The
naturally occurring (wild type) mouse Hp is a class 1 Hp
allele. We examined renal hypertrophy in wild-type mice, Hp
knockout mice (Hp 0), and in mice with the Hp 2 allele (Hp
2) with and without diabetes. RESULTS: In the absence of
diabetes, we found that renal hypertrophy was significantly
increased in Hp 0 mice and that this could be prevented with
vitamin E. There was no difference between wild type and Hp
2 mice with regard to renal hypertrophy in the absence of
diabetes. However, in the presence of diabetes, Hp 2 mice
demonstrated a significant increase in renal hypertrophy as
compared to wild-type mice. CONCLUSIONS: These results
support a direct linkage between diabetic vascular disease
and the Hp genotype. These Hp-modified mice may serve as a
platform on which to test a variety of pharmacological
agents in order to decrease diabetic vascular disease.
Copyright (c) 2005 John Wiley & Sons, Ltd.
Arredouani MS, Kasran A, Vanoirbeek
JA, Berger FG, Baumann H, Ceuppens JL. Haptoglobin dampens
endotoxin-induced inflammatory effects both in vitro and in
vivo. Immunology. 2005 Feb;114(2):263-71
We report that haptoglobin, an
acute-phase protein produced by liver cells in response to
interleukin-6 (IL-6), can modulate the inflammatory response
induced by endotoxins. We provide evidence that haptoglobin
has the ability to selectively antagonize lipopolysaccharide
(LPS) effects in vitro by suppressing monocyte production of
tumour necrosis factor-alpha, IL-10 and IL-12, while it
fails to inhibit the production of IL-6, IL-8 and IL-1
receptor antagonist. In two animal models of LPS-induced
bronchopulmonary hyperreactivity and endotoxic shock,
haptoglobin knockout mice were more sensitive to LPS effects
compared to their wild-type counterparts. The present data
suggest that haptoglobin regulates monocyte activation
following LPS stimulation. The increase in haptoglobin
levels during an acute-phase reaction may generate a
feedback effect which dampens the severity of cytokine
release and protects against endotoxin-induced effects.
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