X-Message-Number: 27843
Date: Thu, 13 Apr 2006 07:06:34 -0700 (PDT)
From: Doug Skrecky <>
Subject: some polyphenols can induce artery protective HO-1

[Caffeic acid phenethyl ester, carnosol (rosemary), curcumin (tumeric),
ethyl ferulate, M. pulchra var. microphylla, 3-O-caffeoyl-one-methylquinic
acid, piceatannol (grapes), S. formosanum can induce atherosclerosis
inhibiting heme oxygenase.]

Fitoterapia. 2006 Feb;77(2):109-15. Epub 2006 Jan 3.
Antioxidant and heme oxygenase-1 (HO-1)-induced effects of selected
Taiwanese plants.
  Recent studies have shown biological effects of heme oxygenase-1
(HO-1) induction and antioxidation in cardiovascular disorders. The
ethanol extracts of leaves of 12 selected indigenous Taiwanese plants
were investigated for their antioxidant activities, evaluated using
assays of 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl, and superoxide
radicals scavenging and reducing power activities as well as the
induction of heme oxygenase-1 (HO-1). Acer albopurpurascens, Cinnamomum
kanehirai, Diospyros discolor, Excoecaria kawakamii, Koelreuteria henryi,
and Syzygium formosanum showed better DPPH-scavenging activities than the
other plants. IC(50) values ranged from 1.7 to 8.7 microg/mL. Excepting
Millettia pulchra var. microphylla and Pittosporum moluccanum, the
extracts displayed hydroxyl-scavenging activities (IC(50) of 0.16-0.67
microg/mL). A. albopurpurascens, D. discolor, K. henryi, and S. formosanum
also showed good superoxide anion radical scavenging activities and
IC(50) values ranged from 12.9 to 28.5 microg/mL. D. discolor, K. henryi,
and S. formosanum showed potent reducing power and M. pulchra
var. microphylla and S. formosanum exhibited potent HO-1
induced activity. These active plant extracts also contained abundant
phenolic constituents. The present results provide candidates to isolate
the active constituents and develop natural antioxidants.


Antioxid Redox Signal. 2004 Oct;6(5):811-8.
Ethyl ferulate, a lipophilic polyphenol, induces HO-1 and protects rat
neurons against oxidative stress.
  In the CNS, the heme oxygenase (HO) system has been reported to be
active and to operate as a fundamental defensive mechanism for neurons
exposed to an oxidant challenge. We have recently shown that both
curcumin and caffeic acid phenethyl ester, two phenolic natural
compounds, potently induce HO-1 expression and activity in rat
astrocytes. We have extended our previous findings examining the effects
of two other plant-derived phenolic compounds, with analogous chemical
structures, in rat astrocytes and neurons. Ethyl ferulate (ethyl
4-hydroxy-3-methoxycinnamate) (EFE), the naturally occurring ester of
ferulic acid, was able to induce HO-1 protein expression. Maximal
expression of HO-1 mRNA and protein and a significant increase in HO
activity were detected after 6 h of incubation with 15 microM EFE in
astrocytes and 5 microM EFE in neurons. Higher concentrations of EFE (50
microM) caused a substantial cytotoxic effect with no change in HO-1
protein expression and activity. Exposure of astrocytes to resveratrol, a
phytoalexin derived from grapes, resulted in an increase of HO-1 mRNA,
but it was not able to induce HO-1 protein expression and
activity. Interestingly, preincubation (12 h) of neurons with EFE resulted
in an enhanced cellular resistance to glucose oxidase-mediated oxidative
damage; this cytoprotective effect was considerably attenuated by zinc
protoporphyrin IX, an inhibitor of HO activity. This study identifies a
novel natural compound that could be used for therapeutic purposes as a
potent inducer of HO-1 for the protection of brain cells against
oxidative and neurodegenerative conditions.

Free Radic Biol Med. 2004 Jan 1;36(1):40-52.
Cytoprotective effects of heme oxygenase-1 induction by
3-O-caffeoyl-1-methylquinic acid.
  The novel antioxidant 3-O-caffeoyl-one-methylquinic acid (MCGA3) is a
methyl chlorogenic acid derivative isolated from bamboo leaves. MCGA3
scavenges reactive oxygen species (ROS) and inhibits lipid peroxidation
and xanthine oxidase in vitro. In this study, we evaluated the
cytoprotective effect of MCGA3, which occurs via heme oxygenase-1
(HO-1) induction in bovine vascular endothelial cells exposed to
tert-butylhydroperoxide (tBHP). Cells treated with 1 mM tBHP (6-18
h) generated substantial ROS and concomitantly lost most intracellular
lactate dehydrogenase (LDH), which then caused necrotic cell death. Of the
several MCGA antioxidants and structurally related phenolic acids
examined in this study, MCGA3 (0.01-0.15 mM) was found to completely
block this necrosis and generation of ROS by tBHP. Surprisingly, MCGA3 by
itself was found to be a potent inducer of HO-1. We observed
the time- and dose-dependent induction of HO-1 mRNA and protein, which
was closely associated with decreased intracellular ROS and necrosis
against tBHP. Deesterified or Al-chelated MCGA3 or co-treatment with
MCGA3 and actinomycin D abolished HO-1 induction and the antinecrotic
effect of MCGA3. Zinc protoporphyrin IX and cycloheximide attenuated the
cytoprotection afforded by MCGA3, but did not reduce HO-1
mRNA. Interestingly, N-acetylcysteine (1 mM) enhanced the HO-1 induction
of MCGA3, but N-acetylcysteine itself did not induce HO-1. These results
suggested that not only ortho-dihydroxyl groups but also aromatic ester
and methoxyl ester moieties are necessary for full HO-1 induction and
cytoprotection against toxic tBHP-derived ROS. Ferritin mRNA was also
upregulated during all HO-1 induction by MCGA3, which might decrease iron
and lower ROS levels. Consequently, the combined action
of HO-1 and ferritin may protect cells from toxic tBHP-mediated necrosis.

Mol Pharmacol. 2002 Mar;61(3):554-61.
Erratum in:
Mol Pharmacol 2002 May;61(5):1264.
Caffeic acid phenethyl ester and curcumin: a novel class of heme
oxygenase-1 inducers.
  Heme oxygenase-1 (HO-1) is a redox-sensitive inducible protein that
provides efficient cytoprotection against oxidative stress. Curcumin, a
polyphenolic natural compound that possesses anti-tumor and
anti-inflammatory properties, has been reported recently to induce
potently HO-1 expression in vascular endothelial cells (Free Rad Biol Med
28:1303-1312, 2000). Here, we extend our previous findings by showing
that caffeic acid phenethyl ester (CAPE), another plant-derived phenolic
agent, markedly increases heme oxygenase activity and HO-1 protein in
astrocytes. The effect seems to be related to the peculiar chemical
structures of curcumin and CAPE, because analogous antioxidants
containing only portions of these two molecules were totally
ineffective. At a final concentration of 30 microM, both curcumin and
CAPE maximally up-regulated heme oxygenase activity while promoting
marked cytotoxicity at higher concentrations (50-100 microM). Similar
results were obtained with Curcumin-95, a mixture of curcuminoids
commonly used as a dietary supplement. Incubation of astrocytes with
curcumin or CAPE at concentrations that promoted maximal heme oxygenase
activity resulted in an early increase in reduced glutathione followed by
a significant elevation in oxidized glutathione contents. A
curcumin-mediated increase in heme oxygenase activity was not affected by
the glutathione precursor and thiol donor N-acetyl-L-cysteine. These data
suggest that regulation of HO-1 expression by polyphenolic compounds is
evoked by a distinctive mechanism which is not necessarily linked to
changes in glutathione but might depend on redox signals sustained by
specific and targeted sulfydryl groups. This study identifies a novel
class of natural substances that could be used for therapeutic
purposes as potent inducers of HO-1 in the protection of tissues against
inflammatory and neurodegenerative conditions.

Biochem Biophys Res Commun. 2003 Sep 5;308(4):950-5.
Changes in temperature modulate heme oxygenase-1 induction by curcumin in
renal epithelial cells.
  The stress protein heme oxygenase-1 (HO-1) plays an essential role in
the prevention of transplant-associated organ injury and rejection. Prior
to transplantation, organs are normally subjected to variable periods of
cold storage in appropriate preservation solutions. Here, we examined
whether curcumin, a phenolic plant extract which strongly induces HO-1 in
many cell types, could up-regulate HO-1 protein in cultured renal
epithelial cells at temperatures lower than the physiological 37 degrees
C. We found that stimulation of HO-1 following incubation of cells with
curcumin for 6h was dramatically reduced by decreasing the temperature
from 37 to 10 degrees C. Interestingly, renal cells displayed high HO-1
expression and heme oxygenase activity when exposed to a programmed
change in temperature that consisted of 3h at 37 degrees C followed by
1.5h at 20 degrees C and 1.5h at 10 degrees C. Increased HO-1 levels were
observed also after incubation of cells with curcumin during the
programmed change in temperature under hypoxia, another feature typical
of cold storage procedures. Upon challenge with an oxidant-generating
system, cells pretreated with curcumin at 37 degrees C or during the
programmed change in temperature exhibited increased resistance to
oxidative stress-mediated injury. These findings highlight the
feasibility of modulating HO-1 expression during hypothermic storage to
confer tissues a better protection to counteract the damage
characteristic of organ transplantation.

Transplantation. 2005 Dec 15;80(11):1556-9.
Beneficial effects of the bioflavonoids curcumin and quercetin on early
function in cadaveric renal transplantation: a randomized placebo
controlled trial.
  BACKGROUND: The bioflavonoids quercetin and curcumin are renoprotective
natural antioxidants. We wished to examine their effects on early graft
function (EF). METHODS: Between September 2002 and August 2004, 43
dialysis dependent cadaveric kidney recipients were enrolled into a study
using Oxy-Q which contains 480 mg of curcumin and 20 mg of quercetin,
started after surgery and taken for 1 month. They were randomized into
three groups: control (placebo), low dose (one capsule, one placebo) and
high dose (two capsules). Delayed graft function (DGF) was defined as
first week dialysis need and slow function (SGF) as Cr >2.5 mg/dl by day
10. Category variables were compared by chi squared and continuous
variables by Kruskal-Wallis. RESULTS: There were four withdrawals: one by
patient choice and three for urine leak. The control group had 2/14
patients with DGF vs. none in either treatment group. Incidence of EF was
control 43%, low dose 71% and high dose 93% (P=0.013). Serum creatinine
was significantly lower at 2 days (control 7.6+/-2.1, low 5.4+/-0.6, high
3.96+/-.35 P=0.0001) and 30 days (control 1.82+/-.16, low 1.65+/-.09,
high 1.33 +/-.1, P=0.03). Acute rejection incidence within 6 months was
control 14.3%, low dose 14.3% and high dose 0%. Tremor was detected in
13% of high dose patients vs. 46% of others. Urinary HO-1 was higher in
bioflavonoid groups. CONCLUSION: Bioflavonoid therapy improved early
graft function. Acute rejection and neurotoxicity were lowest in the
high dose group. These bioflavonoids improve early outcomes in cadaveric
renal transplantation, possibly through HO-1 induction.

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 inhibito 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.

Planta Med. 2005 Oct;71(10):973-6.
Two new antioxidant stilbene dimers, parthenostilbenins A and B from
Parthenocissus tricuspidata.
  The ethyl acetate fraction of an aqueous alcoholic extract from the
stem of Parthenocissus tricuspidata yielded 11 known compounds (1-11) and
two new stilbene dimers parthenostilbenins A (12) and B (13) upon
purification either by preparative TLC or reversed phase HPLC. The
structures of the new isolates were identified using a combination of
FAB-MS and NMR. These compounds were assessed for antioxidant activities
in three different bioassay systems. Among them, piceatannol showed the
strongest inhibitory activity in these assay systems. Two new compounds,
parthenostilbenins A (12) and B (13) inhibited lipid peroxidation (IC
(50) = 20.35 +/- 1.22 and 18.68 +/- 0.51 microg/mL, respectively) in a
rat liver homogenate.

J Mol Endocrinol. 2005 Oct;35(2):269-81.
The red wine phenolics piceatannol and myricetin act as agonists for
estrogen receptor alpha in human breast cancer cells.
  Previous epidemiological reports have suggested that red wine intake is
associated with beneficial health effects due to the ability of certain
phytochemical components to exert estrogen-like activity. It has been
also documented that estrogens induce the proliferation of
hormone-dependent breast cancer cells by binding to and transactivating
estrogen receptor (ER) alpha, which in turn interacts with responsive DNA
sequences located within the promoter region of target genes. In order to
provide further insight into the positive association between wine
consumption and the incidence of breast carcinoma in postmenopausal women,
we have evaluated the estrogenic properties of two abundant wine-derived
compounds, named piceatannol (PIC) and myricetin (MYR), using as model
systems the hormone-sensitive MCF7 and the endocrine-independent SKBR3
breast cancer cells. On the basis of our experimental evidence PIC and MYR
may contribute to the estrogenicity of red wine since: (1) they
transactivate endogenous ER alpha; (2) they activate the
agonist-dependent activation function (AF) 2 of ER alpha and ER beta in
the context of the Gal4 chimeric proteins; (3) they rapidly induce the
nuclear immunodetection of ER alpha; (4) they regulate the expression of
diverse estrogen target genes; (5) they compete with 17beta-estradiol for
binding to ER alpha and ER beta; and--as a biological counterpart of the
aforementioned abilities--(6) they exert stimulatory effects on the
proliferation of MCF7 cells. Hence, the estrogenic activity of PIC and
MYR might be considered at least as a potential factor in the association
of red wine intake and breast tumors, particularly in postmenopausal
women.

J Biol Chem. 2004 Mar 5;279(10):8919-29. Epub 2003 Dec 19.
Regulation of heme oxygenase-1 expression through the
phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription
factor in response to the antioxidant phytochemical carnosol.
  The phosphatidylinositol 3-kinase (PI3K)/Akt pathway elicits a survival
signal against multiple apoptotic insults. In addition, phase II enzymes
such as heme oxygenase-1 (HO-1) protect cells against diverse toxins and
oxidative stress. In this work, we describe a link between these defense
systems at the level of transcriptional regulation of the antioxidant
enzyme HO-1. The herb-derived phenol carnosol induced HO-1 expression at
both mRNA and protein levels. Luciferase reporter assays indicated that
carnosol targeted the mouse ho1 promoter at two enhancer regions
comprising the antioxidant response elements (AREs). Moreover, carnosol
increased the nuclear levels of Nrf2, a transcription factor governing
AREs. Electrophoretic mobility shift assays and luciferase reporter
assays with a dominant-negative Nrf2 mutant indicated that carnosol
increased the binding of Nrf2 to ARE and induced Nrf2-dependent activation
of the ho1 promoter. While investigating the signaling pathways
responsible for HO-1 induction, we observed that carnosol activated the
ERK, p38, and JNK pathways as well as the survival pathway driven by
PI3K. Inhibition of PI3K reduced the increase in Nrf2 protein levels
and activation of the ho1 promoter. Expression of active PI3K-CAAX (where
A is aliphatic amino acid) was sufficient to activate AREs. The use of
dominant-negative mutants of protein kinase Czeta and Akt1, two kinases
downstream from PI3K, demonstrated a requirement for active Akt1, but not
protein kinase Czeta. Moreover, the long-term antioxidant effect of
carnosol was partially blocked by PI3K or HO-1 inhibitors, further
demonstrating that carnosol attenuates oxidative stress through a pathway
that involves PI3K and HO-1.

J Agric Food Chem. 2006 Mar 22;54(6):2064-8.
Radioprotective-antimutagenic effects of rosemary phenolics against
chromosomal damage induced in human lymphocytes by gamma-rays.
  The radioprotective effects of carnosic acid (CA), carnosol (COL), and
rosmarinic acid (RO) against chromosomal damage induced by gamma-rays,
compared with those of L-ascorbic acid (AA) and the S-containing compound
dimethyl sulfoxide (DMSO), were determined by use of the micronucleus
test for antimutagenic activity, evaluating the reduction in the frequency
of micronuclei (MN) in cytokinesis-blocked cells of human lymphocytes
before and after gamma-ray irradiation. With treatment before
gamma-irradiation, the most effective compounds were, in order, CA > RO >
or = COL > AA > DMSO. The radioprotective effects (antimutagenic) with
treatment after gamma-irradiation were lower, and the most effective
compounds were CA and COL. RO and AA presented small radioprotective
activity, and the sulfur-containing compound DMSO lacked gamma-ray
radioprotection capacity. Therefore, CA and COL are the only compounds
that showed a significant antimutagenic activity both before and after
gamma-irradiation treatments. These results are closely related to those
reported by other authors on the antioxidant activity of the same
compounds, and the degree of effectiveness depends on their
structure. Furthermore, the results for treatments before and after
gamma-ray irradiation suggest the existence of different radioprotective
mechanisms in each case.

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