X-Message-Number: 28044
Date: Fri, 16 Jun 2006 11:38:03 -0700 (PDT)
From: Doug Skrecky <>
Subject: perilla leaf extract inhibits TNF-a

[For a variety of reasons, confidence is high that inhibitors of
tumour necrosis alpha (TNF-a) can offer a significant reduction in human
age associated mortality increases. Luteolin and the structurally related
apigenin are two flavones that are responsible for the TNF-a inhibitory
effect of a variety of orally administered food materials. Quercetin is
another flavone which fails to inhibit TNF-a orally. The difference
appears to be due to the higher molecular weight of quercetin reducing
its cellular uptake, and thus reducing bioavailability intercellularly.]

[The anti-inflammitory effect of oral perilla leaf is due solely to
luteolin.]

Biol Pharm Bull. 2002 Sep;25(9):1197-202.
Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla
frutescens.
  Oral administration of the perilla leaf extract (PLE) to mice inhibits
inflammation, allergic response, and tumor necrosis factor-alpha
production. We also found that PLE suppressed the tumor necrosis
factor-alpha (TNF-alpha) production in vitro. Using the inhibitory
activity of TNF-alpha production in vitro as the index for isolation, we
searched the active constituents from PLE and isolated luteolin,
rosmarinic acid and caffeic acid as active components. Among the isolated
compounds, only luteolin showed in vivo activity: inhibition of serum
tumor necrosis factor-alpha production, inhibition of arachidonic
acid-induced ear edema, inhibition of
12-O-tetradecanoylphorbol-13-acetate-induced ear edema and inhibition of
oxazolone-induced allergic edema. These results suggest that luteolin is
a genuinely active constituent which is accountable for the oral effects
of perilla.

[Only luteolin and apigenin are only orally effective TNF-a
inhibitors.]

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.

[Luteolin dramatically boosts survival from septic shock from 4.1% to
48%.]

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.

[Although luteolin and apigenin are both antioxidants, their TNF-a
inhibitory ability does not derive from free radical scavenging. Although
the free-radical theory of aging might be false, some antioxidents might
antagonise aging associated mortality by other means.]

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.

[TNF-a is involved in the death of heart failure patients.]

Circulation. 2005 Feb 22;111(7):863-70. Epub 2005 Feb 7.
Tumor necrosis factor-alpha receptor 1 is a major predictor of mortality
and new-onset heart failure in patients with acute myocardial
infarction: the Cytokine-Activation and Long-Term Prognosis in Myocardial
Infarction (C-ALPHA) study.
  BACKGROUND: Tumor necrosis factor alpha-alpha (TNF-alpha) activation is
an independent prognostic indicator of mortality in patients with heart
failure (HF). Despite the recognition that several TNF family cytokines
are elevated during myocardial infarction, their role in predicting
subsequent prognosis in these setting remains poorly understood. METHODS
AND RESULTS: We performed a systematic evaluation of TNF-alpha and its
type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1
receptor antagonist, and IL-10, in 184 patients (132 men; mean age,
64+/-12) consecutively admitted for myocardial infarction. We correlated
their values to short- and long-term incidence of death and HF (primary
outcome). In 10 patients, we also studied the presence of transcardiac
gradients for TNF-alpha and its soluble receptors. The control group
comprised 45 healthy subjects who were sex and age matched (33 men; mean
age, 65+/-6 years) to the patients. All tested cytokines were increased
in patients, and no transcardiac or systemic AV difference was
found. After a median follow-up of 406 days (range, 346 to 696 days), 24
patients died and 32 developed HF. Univariate analysis showed that all
cytokines were related to outcome, whereas after adjustment for baseline
and clinical characteristics, sTNFR-1 remained the only independent
predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile
1 versus 3), together with left ventricular ejection fraction, Killip
class, and creatine kinase-MB at peak. CONCLUSIONS: sTNFR-1 is a major
short- and long-term predictor of mortality and HF in patients with acute
myocardial infarction.

[Although TNF-a increases with age, centenarians avoid these increases in
lymphocytes. Extreme human longevity appears to require some avoidance of
TNF-a in critical subsystems. Humans which do not possess this attribute
appear to have no chance at all of reaching 100 years of age.]

Gerontology. 2003 May-Jun;49(3):155-60.
High circulating levels of tumor necrosis factor-alpha in centenarians
are not associated with increased production in T lymphocytes.
  BACKGROUND: Aging is characterized by increased inflammatory activity
reflected by increased plasma levels of proinflammatory cytokines,
concomitant with an altered cytokine profile of T lymphocytes. High
plasma levels of tumor necrosis factor (TNF)-alpha are strongly
associated with morbidity and mortality in elderly humans. However, the
cellular source and mechanisms for the increased circulating TNF-alpha
levels are unknown. OBJECTIVE: The aim of the present study was to
investigate if high plasma levels of TNF-alpha are associated with
increased production of TNF-alpha by T lymphocytes in elderly
humans. METHODS: TNF-alpha production by CD4+ and CD8+ T lymphocytes was
measured by flow cytometry following stimulation with phorbol
12-myristate 13-acetate and ionomycin in 28 young controls, 14,
81-year-olds and 25 centenarians. RESULTS: Plasma levels of TNF-alpha
increased with increasing age. An increased percentage and number of T
lymphocytes from the 81 year olds expressed TNF-alpha, whereas
centenarians did not show this altered TNF-alpha secretion
profile. CONCLUSION: T cells may contribute to the elevated levels of
plasma TNF-alpha in healthy elderly subjects, whereas other mechanisms are
responsible in very old individuals.

[TNF-a is highly variable, and has restricted plasma access. Interleukin-6
levels are increased by TNF-a, and appear to offer a more reliable
biomarker for TNF-a than a single measurement of TNF-a itself.]

Clin Exp Immunol. 2003 Apr;132(1):24-31.
Predicting death from tumour necrosis factor-alpha and interleukin-6 in
80-year-old people.
  Ageing is associated with low-grade inflammation and markers such as
IL-6 possess prognostic value. Tumour necrosis-alpha
(TNF-alpha) initiates the inflammatory cascade and has been linked to
several age-associated disorders. It remains, however, unknown if
TNF-alpha is associated with mortality in old populations. The aim of the
present study was to investigate if serum levels of TNF-alpha were
associated with all-cause mortality independently of interleukin (IL)-6
in a prospective study of 333 relatively healthy 80-year-old people. A
Cox regression model was used to explore effects of TNF-alpha and IL-6 on
survival in the following 6 years. A total of 133 participants died
during this follow-up period. TNF-alpha was associated with mortality in
men, but not in women, whereas low-grade elevations in IL-6 were
associated strongly with mortality in both sexes. TNF-alpha explained
only 7% of the variability in IL-6 and effects of the two cytokines were
independent of each other as well as of other traditional risk factors
for death [smoking, blood pressure, physical exercise, total cholesterol,
co-morbidity, body mass index (BMI) and intake of anti-inflammatory
drugs]. These findings indicate that at least in old populations chronic

elevated levels of TNF-alpha and IL-6 have different biological functions that 
trigger age-associated pathology and cause mortality.

[Back to perilla leaf. To no great surprise the powerful anticancer effect
of perilla leaf has been attributed to luteolin. Please note that
artichoke leaf is also a good source of luteolin.]

Biol Pharm Bull. 2003 Apr;26(4):560-3.
Inhibitory effect of Perilla leaf extract and luteolin on mouse skin
tumor promotion.
  In the present study, the effects of perilla leaf extract (PLE) and
luteolin on 7,12-dimethylbenz[a]anthracene (DMBA)- and
12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin papillomas in
mice were investigated. Topical application of PLE prior to TPA treatment
in DMBA-initiated mouse skin resulted in a significant reduction in tumor
incidence and multiplicity. An even more potent preventive effect was
observed with topical application of luteolin, which we previously
identified as an antiinflammatory constituent. PLE was dissolved in
drinking water at a 0.05% dose and mice ingested it ad libitum; no
significant difference was observed in tumor incidence or multiplicity
but there was a significant reduction in tumor volume between the
PLE-treated and untreated groups. These results suggest that PLE has
potent antipromotion activity and ingesting it as a daily food may
provide a beneficial chemopreventive effect.

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