X-Message-Number: 28001
Date: Sun, 28 May 2006 20:48:18 -0700 (PDT)
From: Doug Skrecky <>
Subject: modulating HO-1 & TNF-a may boost human longevity II

[The main weapons against atherosclerosis include neither medications to
lower cholesterol nor lower blood pressure. Although a lot of good
research has been done promoting statins and ACE inhibitors for example,
typical reductions in human mortality found in intervention trails
testing these medications are quite modest. The reason for this is because
the main driver of atherosclerosis is aging, and not cholesterol
or blood pressure. Indeed, even the modest benefit of statins has been
attributed largely to non-cholesterol mediated mechanisms. Prescription
medications can slow the deterioration of measurements of atherosclerosis
such as intima-media thickness (IMT), but they generally can not halt,
much less reverse it. To obtain large reductions in human mortality an
actual reduction in IMT is an absolute requirement. This has been achieved
in humans (below) by pomegranate juice for example, which lowers neither
cholesterol nor (initially) blood pressure.]

[A class of flavonoid called anthocyanidins was found to be
associated with a reduced risk of a heart attack. Within the range of
(low) normal dietary intake these food pigments reduced risk by over
half. Notable sources include red cabbage, red & black rice, berrys,
grapes, plums - and pomegranates.]

Public Health Nutr. 2006 May;9(3):369-374.
Intake of specific flavonoids and risk of acute myocardial infarction in Italy.
  Objective: As intake of flavonoids has been associated with reduced
risk of coronary heart disease but data on the relation with specific
classes of flavonoids are scarce, we assessed the relation between
dietary intake of specific classes of flavonoids and the risk of acute
myocardial infarction (AMI) in an Italian population.Design: Case-control
study. Dietary information was collected by interviewers on a
questionnaire tested for validity and reproducibility. Adjusted odds
ratios (OR) and 95% confidence intervals (CI) were obtained by multiple
logistic regression models including terms for energy and alcohol intake,
as well as sociodemographic factors, tobacco and other major recognised
risk factors for AMI.Setting: Milan, Italy, between 1995 and
2003.Subjects: Cases were 760 patients, below age 79 years, with a first
episode of non-fatal AMI, and controls were 682 patients
admitted to hospital for acute conditions unrelated to diet. Results: A
reduced risk of AMI was found for increasing intake of anthocyanidins
(OR=0.45, 95% CI 0.26-0.78 for the highest vs. the lowest quintile,
Ptrend=0.003) and flavonols (OR=0.65, 95% CI 0.41-1.02, Ptrend=0.02). A
tendency towards reduced risks, although not significant, was observed for
flavan-3-ols (OR=0.73, 95% CI 0.48-1.10) and total flavonoids (OR=0.74,
95% CI 0.49-1.14). No meaningful heterogeneity was found between the
sexes. No association emerged for other flavonoids, including
isoflavones, flavanones and flavones.Conclusions: High intake of
anthocyanidins reduced the risk of AMI even after allowance for alcohol,
fruit and vegetables, supporting a real inverse association between this
class of flavonoids and AMI risk.

[Although numerous animal trials have detected reductions in
atherosclerosis with dietary derived anthocyanidins, these are not the
only items of interest. Below a combination of policosanol and red yeast
extract offered only a modest 33% reduction in atherosclerosis. The
addition of astaxanthin boosted this reduction to a remarkable 92%.]

Arzneimittelforschung. 2005;55(6):312-7.
Antiatherosclerotic efficacy of policosanol, red yeast rice extract and
astaxanthin in the rabbit.
  The effects of policosanol (P), of extract of red yeast rice (rice
fermented with Monascus purpureus) (RYE) and of astaxanthin
(A) (constituents of Armolipid) were investigated in a model of
experimental atherosclerosis provoked in the rabbit by atherogenic
cholesterol-enriched feed (ACEF). P and RYE and their combination were
able to lower the increase of serum total cholesterol and of LDL
cholesterol elicited by 3-month feeding with ACEF. They also were able to
reduce the increase of blood malondialdehyde (MDA), a tracer of lipid
peroxidation by the free radicals released by ACEF. When
combined, the substances developed either additive or potentiated
effects, supporting the rationale of their combination. Remarkable was
the protective effect on lipid infiltration in the aortic wall provoked
by ACEF, which was reduced by P and by RYE and almost completely
prevented by the addition of A to the P-RYE combination. The results
support the rationale of a combination of P, RYE and A as a useful food
supplement in hyperlipemic patients.

[Not all antioxidant combinations offer synergism. N-acetylcysteine
antagonises the protective HO-1 inducing effect of piceatannol.]

Pharmacol Res. 2006 Feb;53(2):113-22. Epub 2005 Oct 21.
Piceatannol upregulates endothelial heme oxygenase-1 expression via novel
protein kinase C and tyrosine kinase pathways.
  Piceatannol is an anti-inflammatory and anti-proliferative
plant-derived stilbene. Heme oxygenase-1 (HO-1) is a cytoprotective
enzyme to activate by various phytochemicals. In this study, we examined
the ability of piceatannol to upregulate HO-1 expression in endothelial
cells. We found piceatannol at micromolar (10-50 microM) concentrations
dramatically increased HO-1 protein levels in a time-dependent
manner. Piceatannol was similarly potent in the induction of HO-1 as
hemin, arsenate, and 15d-PGJ2, and was more potent than some other
phytochemicals including curcumin, EGCG, baicalein, and quercetin. In
contrast, the similar chemical structure compounds, trans-stilbene,
stilbene oxide, and resveratrol had no HO-1-inducing effects, suggesting
a critical role for the hydroxyl groups in HO-1 induction. No
cytotoxicity and superoxide production was observed after 10-50
microM piceatannol treatments. Piceatannol-mediated HO-1 induction was
abrogated in the presence of N-acetylcysteine and glutathione, but not by
other antioxidants. Induction of HO-1 by piceatannol was further enhanced
by using buthionine sulfoximine. In addition, we determined that tyrosine
kinase was involved in the induction of HO-1 by using tyrosine kinase
inhibitors, herbimycin A, erbstatin, and genistein; in contrast, no
significant changes in the pretreatment of PI3 kinase or MAP kinase
inhibitors was determined. HO-1 induction was blocked by the protein
kinase C inhibitors calphostin C, rottlerin, and long PMA pretreatment,
whereas conventional PKC inhibitors, Go6976, and Ca2+ chelator BAPTA/AM,
had no effect. Elevated HO-1 protein levels were associated with the
inhibition of tumor necrosis factor-alpha (TNFalpha)-induced
intercellular adhesion molecule-1 (ICAM-1) expression.
Treating ECs with zinc protoporphyrin, an HO-1 inhibitor blocked the
anti-inflammatory effect of piceatannol. In summary, this study
identified piceatannol as a novel phytochemical inducer of HO-1
expression and identified the mechanisms involved in this process.

[The report below has generated little discussion in medical
journals. However the fact that pomegranate juice actually reduced IMT by
30% in a year is a result beyond the capabilites of either statins or ACE
inhibitors. Indeed 60% of control subjects were taking these medications,
yet still experienced a progressive deterioration in this atherosclerosis
measurement. Pomegranate has no immediate effect on blood pressure, yet
over a year reduced systolic from 174 to 153 mm, probably as a side effect
of the reduction in atherosclerosis. Pomegranate juice contains
anthocyanidins, but the main active ingrediants are believed to be
tannins. Subjects drank a mere 50 ml of juice daily containing 1979 mg of
tannins, and 384 mg of anthocyanidins.]

Clin Nutr. 2004 Jun;23(3):423-33.
Pomegranate juice consumption for 3 years by patients with carotid artery
stenosis reduces common carotid intima-media thickness, blood pressure
and LDL oxidation.
  Dietary supplementation with polyphenolic antioxidants to animals was
shown to be associated with inhibition of LDL oxidation and macrophage
foam cell formation, and attenuation of atherosclerosis development. We
investigated the effects of pomegranate juice (PJ, which contains potent
tannins and anthocyanins) consumption by atherosclerotic patients with
carotid artery stenosis (CAS) on the progression of carotid lesions and
changes in oxidative stress and blood pressure. Ten patients were
supplemented with PJ for 1 year and five of them continued for up to 3
years. Blood samples were collected before treatment and during PJ
consumption. In the control group that did not consume PJ, common carotid
intima-media thickness (IMT) increased by 9% during 1 year, whereas, PJ
consumption resulted in a significant IMT reduction, by up to 30%, after
1 year. The patients' serum paraoxonase 1 (PON 1) activity was increased
by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to
copper ion-induced oxidation were both significantly reduced, by 90% and
59%, respectively, after 12 months of PJ consumption, compared to values
obtained before PJ consumption. Furthermore, serum levels of antibodies
against oxidized LDL were decreased by 19%, and in parallel serum total
antioxidant status (TAS) was increased by 130% after 1 year of PJ
consumption. Systolic blood pressure was reduced after 1 year of PJ
consumption by 21% and was not further reduced along 3 years of PJ
consumption. For all studied parameters, the maximal effects were
observed after 1 year of PJ consumption. Further consumption of PJ, for
up to 3 years, had no additional beneficial effects on IMT and serum PON1
activity, whereas serum lipid peroxidation was further reduced by up to
16% after 3 years of PJ consumption. The results of the present study thus
suggest that PJ consumption by patients with CAS decreases carotid IMT
and systolic blood pressure and these effects could be related to the
potent antioxidant characteristics of PJ polyphenols.

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