LE Magazine August 2002
Atherosclerosis
Plasma level of homocysteine is
inversely-associated with the development of collateral
circulation in patients with single-vessel coronary artery
disease.
Homocysteine induces endothelial injury and inhibits
endothelial cell proliferation, which is a key role in
angiogenesis. The purpose of this study was to investigate
whether the plasma level of homocysteine is associated with
the development of collaterals in patients with single-vessel
coronary artery disease (CAD). Among a series of 105 male
patients with angiographic estimation, 49 with single-vessel
CAD were intensively investigated. Development of collaterals
was classified by Rentrop’s method. Univariate and
multivariate analyses revealed that hyperhomocysteinemia
negatively affected the development of collaterals (p=0.0015
and 0.0011, odds ratio 0.69, 95% confidence interval
0.52-0.90), whereas the duration of angina and percent
stenosis evaluated by quantitative coronary angiography had a
positive affect. Moreover, the level of homocysteine in the
group with poorly developed collaterals (n=7, Rentrop class 0
and 1) was significantly higher than that in the group with
well-developed collaterals (n=12, Rentrop class 2 and 3) of
the patients with single-vessel disease showing total
occlusion (p=0.034). This study clearly demonstrates that the
plasma level of homocysteine is independently and inversely
associated with the development of collateral circulation in
CAD patients. Homocysteine might be a new undesirable aspect
of ischemic heart disease through its inhibition of collateral
development.
Circ J 2002 Feb;66(2):158-62
Risk factors for progression of aortic
atheroma in stroke and transient ischemic attack patients.
BACKGROUND AND PURPOSE: Aortic atheroma is an independent
risk factor for stroke and undergoes temporal progression.
Clinical and risk factor associations of such progression are
unknown. Hyperhomocysteinemia has been linked with
atherosclerosis, including that in the cerebral vasculature.
This study investigated associations between elevated
homocysteine levels and other stroke vascular risk factors and
the risk of aortic atheroma progression in patients with
cerebrovascular disease. METHODS: Fifty-seven stroke and 21
transient ischemic attack patients underwent multiplanar
transesophageal echocardiograms within one month of symptom
onset and again at nine months. Aortic atheroma was graded and
stratified by use of existing criteria. Stroke risk factors;
use of anticoagulant, antiplatelet and hypolipidemic drugs;
and clinical and etiological subtypes of stroke were recorded
and compared in patients stratified for the presence or
absence of aortic atheroma progression. RESULTS: Of the 78, 29
(37%) progressed, 32 (41%) remained unchanged, and 17 (22%)
regressed. Progression was most marked at the aortic arch
(P=0.005), followed by the ascending segment (P<0.04). In
nearly two-thirds of the patients in whom aortic atheroma
remained unchanged over nine months, no atheroma was evident
on baseline transesophageal echocardiogram. Only homocysteine
levels > or =14.0 micromol/L (P=0.02), total anterior
cerebral infarct (P=0.02), and large-artery atherosclerosis
(P=0.005) significantly correlated with progression.
CONCLUSIONS: Among vascular risk factors, elevated
homocysteine levels are associated with aortic atheroma
progression. Stroke and transient ischemic attack patients
with aortic atheroma should undergo assessment of homocysteine
levels, which, if elevated, may be treated with vitamins in an
effort to arrest aortic atheroma progression.
Stroke 2002 Apr;33(4):930-5
CLA/Weight Loss
Efficacy of dietary CLA and
CLA+Guarana (ADIPILL) on body adiposity, and adipocytes cell
number and size.
We have compared in mice the effect of a dietary
supplementation with either conjugated linoleic acids (CLA) or
CLA and guarana (CLA-G) on adiposity. After six weeks, mice
were sacrified and all fat pads were removed and adipocytes
number and size were measured in subcutaneous (SCAT) and
gonadal (GAT) fat pad. CLA as well as CLA-G supplementation
induced a strong lipoatrophy, fat mass showing a three-fold
decrease in both groups. This effect was more pronouced in
gonadal than in subcutaneous site, GAT being reduced 10 times
and SCAT four times. Plasma leptin was decreased in CLA and
CLA-G treated mice by 40% and 55% respectively. In the CLA
group, the decreased fat mass was due to dramatic reduction in
adipocyte size without change in cell number. In the CLA-G
group, both adipocyte size and number were reduced (-50%).
These results demonstrate that dietary CLA are able to
decrease adiposity by reducing its capacity to store lipids
without affecting adipocyte differentiation. When guarana is
added to CLA, an additional effect of cell number is induced.
The mechanisms underlying this effect (cell
differentiation/apoptosis) and its potential in preventing
body fat accretion in the long-term remain to be
investigated.
Experimental Biology Meeting, New
Orleans. April 20-24, 2002.
The efficacy of conjugated linoleic
acid in mammary cancer prevention is independent of the level
or type of fat in the diet.
The objective of the present study was to investigate
whether the anticarcinogenic activity of conjugated linoleic
acid (CLA) is affected by the amount and composition of
dietary fat consumed by the host. Because the anticancer agent
of interest is a fatty acid, this approach may provide some
insight into its mechanism of action, depending on the outcome
of these fat feeding experiments. For the fat level
experiment, a custom formulated fat blend was used that
simulates the fatty acid composition of the U.S. diet. This
fat blend was present at 10, 13.3, 16.7 or 20% by weight in
the diet. For the fat type experiment, a 20% (w/w) fat diet
containing either corn oil (exclusively) or lard
(predominantly) was used. Mammary cancer prevention by CLA was
evaluated using the rat dimethylbenz[a]anthracene model. The
results indicated that the magnitude of tumor inhibition by 1%
CLA was not influenced by the level or type of fat in the
diet. It should be noted that these fat diets varied markedly
in their content of linoleate. Fatty acid analysis showed that
CLA was incorporated predominantly in mammary tissue neutral
lipids, while the increase in CLA in mammary tissue
phospholipids was minimal. Furthermore, there was no evidence
that CLA supplementation perturbed the distribution of
linoleate or other fatty acids in the phospholipid fraction.
Collectively these carcinogenesis and biochemical data suggest
that the cancer preventive activity of CLA is unlikely to be
mediated by interference with the metabolic cascade involved
in converting linoleic acid to eicosanoids. The hypothesis
that CLA might act as an antioxidant was also examined.
Treatment with CLA resulted in lower levels of mammary tissue
malondialdehyde (an end product of lipid peroxidation), but
failed to change the levels of 8-hydroxydeoxyguanosine (a
marker of oxidatively damaged DNA). Thus, while CLA may have
some antioxidant function in vivo in suppressing lipid
peroxidation, its anticarcinogenic activity cannot be
accounted for by protecting the target cell DNA against
oxidative damage. The finding that the inhibitory effect of
CLA maximized at 1% (regardless of the availability of
linoleate in the diet) could conceivably point to a limiting
step in the capacity to metabolize CLA to some active
product(s) which is essential for cancer prevention.
Carcinogenesis 1996
May;17(5):1045-50
Protection of conjugated linoleic
acids against 2-amino-3-methylimidazo[4,5-f]quinoline-induced
colon carcinogenesis in the F344 rat: a study of inhibitory
mechanisms.
Grilled ground beef contains a number of heterocyclic amine
carcinogens, such as 2-amino-3-methylimidazo[4,5-f] quinoline
(IQ), as well as anticarcinogenic conjugated linoleic acids
(CLA). In the present study, CLA was administered to male F344
rats by gavage on alternating days in weeks 1-4, while IQ was
given by gavage every other day in weeks 3 and 4 (100 mg/kg
body wt). Rats were killed 6 h after the final carcinogen dose
16 in order to score colonic aberrant crypt foci (ACF). In the
ACF study, CLA had no effect on the size of the foci, but
inhibited significantly (P < 0.05) the number of ACF/colon,
from 4.3 +/- 2.4 in controls to 1.1 +/- 1.3 in CLA-treated
rats (mean +/- SD, n = 10). Rats given CLA also had
significantly lower IQ-DNA adducts in the colon as determined
by 32P-postlabeling analysis; relative adduct labeling levels
(RAL x 10(7) for the major adduct were 9.13 +/- 2.6 in
controls versus 5.42 +/- 1.8 in CLA-treated animals (P <
0.05). Mechanism studies indicated that CLA and other fatty
acids interact with certain heterocyclic amines in a manner
consistent with substrate-ligand binding. However, no such
interaction occurred with IQ, and CLA failed to inhibit
significantly the mutagenicity of N-hydroxy-IQ in the
Salmonella assay. Liver microsomes from CLA-treated rats
exhibited lower activities for dealkylation of
7-ethoxyresorufin and methoxyresorufin and activated IQ to DNA
binding species less effectively than microsomes from control
animals. Direct addition of CLA to the in vitro incubation
inhibited IQ-DNA binding and was associated with increased
recovery of unmetabolized parent compound. In the Salmonella
assay, CLA inhibited the mutagenic activity of IQ in the
presence of S9 or ram seminal vesicle microsomes.
Collectively, these results support a mechanism involving
inhibition of carcinogen activation by CLA, as opposed to
direct interaction with the procarcinogen, scavenging of
electrophiles or selective induction of phase I detoxification
pathways.
Carcinogenesis 1995
Dec;16(12):3037-43
Conjugated dienoic linoleate: a
polyunsaturated fatty acid with unique chemoprotective
properties.
Conjugated dienoic linoleate (CLA), a linoleic acid
derivative, has received considerable attention as a
chemoprotective agent in the past few years because it has
been shown experimentally to inhibit rat mammary
tumorigenesis, mouse forestomach neoplasia and mouse skin
carcinogenesis. CLA has several unique structural and
functional properties resulting in chemical and physiological
effects that are different from those of all-cis,
nonconjugated polyunsaturated fatty acids. In turn, these
unique qualities appear to modulate cellular processes
involved in carcinogenesis. This review will introduce the
chemical background of conjugated dienoic linoleate, examine
findings describing its chemoprotective qualities, present
possible mechanisms of chemoprotection, and correlate the
possible significance of dietary CLA modulation to
carcinogenesis to humans.
Nutr Rev 1995 Apr;53(4 Pt 1):83-9
Dietary conjugated linoleic acid
normalizes impaired glucose tolerance in the Zucker diabetic
fatty fa/fa rat.
Conjugated linoleic acid (CLA) is a naturally occurring
fatty acid which has anti-carcinogenic and anti-atherogenic
properties. CLA activates PPAR alpha in liver, and shares
functional similarities to ligands of PPAR gamma, the
thiazolidinediones, which are potent insulin sensitizers. We
provide the first evidence that CLA is able to normalize
impaired glucose tolerance and improve hyperinsulinemia in the
pre-diabetic ZDF rat. Additionally, dietary CLA increased
steady state levels of aP2 mRNA in adipose tissue of fatty ZDF
rats compared to controls, consistent with activation of PPAR
gamma. The insulin sensitizing effects of CLA are due, at
least in part, to activation of PPAR gamma since increasing
levels of CLA induced a dose-dependent transactivation of PPAR
gamma in CV-1 cells cotransfected with PPAR gamma and PPRE X
3-luciferase reporter construct. CLA effects on glucose
tolerance and glucose homeostasis indicate that dietary CLA
may prove to be an important therapy for the prevention and
treatment of non-insulin-dependent diabetes mellitus
(NIDDM).
Biochem Biophys Res Commun 1998 Mar
27;244(3):678-82
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