X-Message-Number: 27740
Date: Tue, 21 Mar 2006 08:09:19 -0800 (PST)
From: Doug Skrecky <>
Subject: luteolin or apigenin are bioavailable TNF-alpha inhibitors

[Since TNF-alpha is known to be one of the primary drivers of mortality
in aged humans, there exists reason to suppose that the
administration of luteolin or apigenin to aged humans would
significantly lower human mortality rates. One of the most potent
dietary sources of these flavonoids is artichoke.]

Biosci Biotechnol Biochem. 2004 Jan;68(1):119-25.
A hydroxyl group of flavonoids affects oral anti-inflammatory
activity and inhibition of systemic tumor necrosis factor-alpha
production.
  We previously reported that oral administration of luteolin can
inhibit serum tumor necrosis factor (TNF)-alpha production and
several inflammatory and allergic models. We investigated here
the effect of various flavonoids which resemble luteolin in
structure. Lipopolysaccharide (LPS)-induced TNF-alpha production
from macrophages was inhibited by treatment with flavone
(luteolin, apigenin, and chrysin), flavonol (quercetin and
myricetin), flavanonol (taxifolin), and anthocyanidin (cyanidin
chloride) in vitro. Most of these, however, did not affect mice
when administered orally. Serum TNF-alpha production was
inhibited only by luteolin or apigenin, and only luteolin or
quercetin inhibited 12-O-tetradecanoylphorbol-13-acetate
(TPA)-induced ear edema. These results suggest that the structure
of luteolin: 3',4',5,7-tetrahydroxyflavone, is most suitable for
the oral anti-inflammatory activity and that existence or
disappearance of a hydroxy group may cause a loss of efficiency.

Am J Respir Crit Care Med. 2002 Mar 15;165(6):818-23.
Luteolin reduces lipopolysaccharide-induced lethal toxicity and
expression of proinflammatory molecules in mice.
  Luteolin is a flavonoid that has been shown to reduce
proinflammatory molecule expression in vitro. In the present study,
we have tested the ability of luteolin to inhibit lipopolysaccharide
(LPS)- induced lethal toxicity and proinflammatory molecule
expression in vivo. Mice receiving LPS (Salmonella enteriditis LPS,
32 mg/kg, intraperitoneally) exhibited high mortality with only
4.1% of the animals surviving seven days after the LPS challenge.
On the contrary, mice that had received luteolin (0.2 mg/kg,
intraperitoneally) before LPS showed an increased survival rate
with 48% remaining alive on Day 7. To investigate the mechanism by
which luteolin affords protection against LPS toxicity we measured
intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis
factor-alpha (TNF-alpha) production in response to LPS in the
presence or absence of luteolin pretreatment. Treatment of animals
with LPS increased serum TNF-alpha levels in a time-dependent
manner. The increase in peak serum TNF-alpha levels was sensitive
to luteolin pretreatment. Luteolin pretreatment also reduced
LPS-stimulated ICAM-1 expression in the liver and abolished
leukocyte infiltration in the liver and lung. We conclude that
luteolin protects against LPS-induced lethal toxicity, possibly by
inhibiting proinflammatory molecule (TNF-alpha, ICAM-1) expression
in vivo and reducing leukocyte infiltration in tissues.

Microcirculation. 1996 Sep;3(3):279-86.
Apigenin inhibits tumor necrosis factor-induced intercellular
adhesion molecule-1 upregulation in vivo.
  OBJECTIVE: Apigenin is a flavonoid that effectively blocks
intercellular adhesion molecule-1 (ICAM-1) upregulation and
leukocyte adhesion in response to cytokines in vitro. In the
present study, we characterized the effects of tumor necrosis
factor (TNF) on ICAM-1 expression in different tissues of the rat.
We then assessed whether apigenin alters this response. METHODS:
ICAM-1 expression was measured under baseline conditions or 5 h
after treatment with rTNF. We used 125I-labeled anti-rat ICAM-1
monoclonal antibody (mAb) and an isotype-matched control mAb
labeled with 131I to correct for nonspecific accumulation of the
binding mAb. Animals were pretreated with either placebo, apigenin,
narigenin (a flavonoid without inhibitory effect in vitro), or
vehicle. Additional groups of animals were treated with either
allopurinol, glutathione, dimethyl-thiourea, or an anti-CD18
monoclonal antibody in order to assess possible actions of
flavonoids that were mediated via free radical scavenging or
through interference with neutrophil function. RESULTS: Treatment
with rTNF resulted in a marked increase in ICAM-1 expression in
all organs studied. The magnitude of the response varied in
different organs and increases ranged from onefold (lung) to
threefold (muscle). Treatment with apigenin blocked ICAM-1
upregulation in organs with low to intermediate responses to rTNF
and it significantly attenuated the increased ICAM-1 expression
in organs that normally exhibit more marked upregulation.
Treatment with narigenin or vehicle did not affect rTNF-induced
ICAM-1 upregulation in all tissues studied. Pretreatment with
either allopurinol, free radical scavengers, or anti-CD18
monoclonal antibody did not affect the ICAM-1 upregulatory
response to rTNF. CONCLUSIONS: TNF-induced ICAM-1 upregulation
in vivo effectively is blocked by apigenin through a mechanism
that is unrelated to free radical scavenging or leukocyte function.

[The primary determinant of cardiovascular disease related
mortality is not cholesterol or blood pressure, but instead is
simple chronological age. Artichoke can rejuvenate aged arteries,
and so may be able to help block age-associated increases in mortality.]

J Agric Food Chem. 2005 Dec 28;53(26):10291-6.
Wild artichoke prevents the age-associated loss of vasomotor
function.
  Endothelial dysfunction, which is more often observed in conduit
arteries such as the aorta, carotid, femoral, and brachial arteries,
is largely due to alterations in cellular signal transduction
initiated by an escalating cycle of damage triggered by oxidative
stress. This phenomenon is exacerbated in the elderly, where a
progressive loss of vascular endothelial function and concurrent
loss of vasomotor control is frequent. In a previous study, we
demonstrated that the wild artichoke (Cynara cardunculus) is able
to increase the production of the vasorelaxant factor nitric oxide
by cultured aortic endothelial cells. We now extended that study
to verify (1) the vasorelaxant potential of C. cardunculus on
isolated rat aortic rings and (2) whether the vasomodulating
properties of C. cardunculus are maintained in vivo, after
administration to aged rats. The results demonstrate that the wild
artichoke and its main components, namely, luteolin and apigenin,
improve aortic relaxation when added to the incubation bath.
Moreover, the feeding of wild artichoke [10 mg (kg of polyphenols)
(-1) day(-1)] to aged rats significantly restores proper vasomotion,
to a degree similar to that observed in young animals. This study
provides further justification to the advice to consume wild greens
as part of a balanced diet and suggests that close attention should
be paid to the diet of the elderly, because it can effectively
modulate important parameters of cardiovascular risk.

[TNF-alpha looks to be a primary driver of mortality in centenarians.]

Am J Med. 2003 Sep;115(4):278-83.
Elevated levels of tumor necrosis factor alpha and mortality in
centenarians.
  BACKGROUND: Aging is accompanied by low-grade inflammation. Tumor
necrosis factor (TNF) alpha initiates the cytokine cascade, and high
levels are associated with dementia and atherosclerosis in persons
aged 100 years. We hypothesized that TNF-alpha was also a prognostic
marker for all-cause mortality in these persons. METHODS: We enrolled
126 subjects at or around the time of their 100th birthday. Plasma
levels of TNF-alpha, interleukin (IL)-6, IL-8, and C-reactive protein
were measured at baseline, and we determined the associations between
the markers of inflammation and mortality during the subsequent
5 years. RESULTS: Only 9 subjects were alive after 5 years. Elevated
levels of TNF-alpha were associated with mortality in both men and
women (hazard ratio = 1.34 per SD of 2.81 pg/mL; 95% confidence
interval: 1.12 to 1.60, P = 0.001). Levels of IL-6 and IL-8 did not
affect survival; levels of C-reactive protein were not associated with
mortality when levels of TNF-alpha were included in the analysis.
Dementia and cardiovascular diseases represented the major causes of
comorbid conditions at baseline. TNF-alpha was still associated with
mortality in multivariate models that included these parameters as
confounders. CONCLUSION: TNF-alpha was an independent prognostic
marker for mortality in persons aged 100 years, suggesting that it
has specific biological effects and is a marker of frailty in the
very elderly.

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