In article
<21ef979c-6b82-420d-9065-95d9e5c667d8@[EMAIL PROTECTED]
>,
soowhatdouthink@[EMAIL PROTECTED]
wrote:
> To Kofi and others - some food (or actually CR) for your thought.
>
> arbor
> [Abstrat is below the news article.]
>
> Existing anti-obesity drugs may be effective against flu, hepatitis
> and HIV
> New field of metabolomics yields exciting antiviral treatment approach
> Viruses dramatically increase cellular metabolism, and existing anti-
> obesity drugs may represent a new way to block these metabolic changes
> and inhibit viral infection, according to a study published today in
> the journal Nature Biotechnology.
For the original article, see
<<http://www.eurekalert.org/pub_releases/2008-09/uorm-ead092608.php>.
> Many metabolic processes are essential to the survival of human cells,
> and so are not candidates for research efforts that would shut them
> down in the attempt to stop viral replication. For that reason, Munger
> and colleagues chose to look at whether interfering with glucose-to-
> fatty acid metabolism could stop viral replication, because fatty acid
> biosynthesis is not essential in adult humans. It does appear,
> however, to be essential to the ability of viruses to build their
> envelopes, reproduce and spread.
>
> Thus, the team next used drugs known to inhibit enzymes that build
> fatty acids, acetyl-CoA carboxylase (ACC) and fatty acid synthase
> (FAS), used in the treatment of obesity and high cholesterol, to
> determine whether HCMV-induced fatty acid production was necessary for
> enveloped viruses to make copies of themselves. Indeed, treatment (10
> mg ml-1) with 5-tetradecyloxy-2-furoic acid (TOFA), an ACC inhibitor,
> resulted in a more than thousand-fold reduction in HCMV replication.
> C75 (trans-4-carboxy-5-octyl-3-methylene-butyrolactone), an inhibitor
> of FAS, resulted in a more than 100-fold effect at the same dose.
This is a very interesting find. Thank you for bringing it to our
attention. I've kept data on FAS inhibitors and cholesterol metabolism
for a while now and a few things jumped out at me - particularly the
overlap with virus-associated diseases like colitis and chronic fatigue
and the dietary changes that help. It seems many of these nutritional
interventions might inhibit FAS and, according to this, inhibit viral
replication too. Low carb diets and high fat diets - particularly with
good fats like fish oils or olive oil - tend to inhibit FAS. It's also
interesting how so many people with virally-linked diseases like M.S.
re****t benefits from diets with a better n-3/n-6 ratio. FAS inhibitors
have also been studied in the treatment of cancer. Green tea extract
inhibits FAS. Gut bacteria also regulate FAS.
Here are my notes on the subject (check out IgM, the immunoglobulin
cranked out first when an infection is detected). Note the possible
fatty liver complications. In mice without FAS, they get fatty liver
disease if their dietary fat consumption drops. Once again, PPARalpha
pops up. Anybody know what PPARalpha agonists do to FAS? What about
vitamin D3, melatonin or magnesium?
____ Notes ____
old fat stored in peripheral tissues - thigh, abdomen, etc - canšt be
burned efficiently unless new fat is eaten or manufactured in the liver;
mice lacking fatty acid synthase (which converts glucose into fat) in
the liver canšt maintain normal sugar fat and cholesterol metabolism
unless they take in dietary fat; the mice developed fatty liver disease
when placed on a low fat diet; old fat stores mobilized into the liver
but couldnšt be burned and just ac***ulated; also blood sugar dropped;
effects were reversed with dietary fat or by activating PPARalpha; new
fat in the liver may initiate the PPARalpha pathway; fish oils and other
dietary fats might more effectively activate PPARalpha for people with
insulin resistance
<http://www.sciencedaily.com/releases/2005/05/050509173826.htm>
(see
infomation on LTB4, PPARalpha and antiviral responses)
rodents fed fish oils are less obese and have lower triglycerides; fish
oil consumption in people is protective against cardiovascular disease;
fish oils inhibit lipogenesis by decreasing SREBP-1 and stimulate fatty
acid oxidation by PPARalpha in the liver; in a high fat fish oil diet
vs. high fat safflower oil diet, antioxidant genes were upregulated
(glutathione transferases, uncoupling protein 2 (UCP2) and Mn-SOD) as
were lipid catabolism-related genes and CPT-II but cholesterol and fatty
acid synthesis-related genes were downregulated (fatty acid synthase,
LDL receptor, SREBP-1c. etc.) as were genes responsible for the
production of endogenous PPARalpha ligands (17-alpha hydroxylase/C17-20
lyase and sulfotransferases) and reactive oxygen species; upregulation
of antioxidant genes and downregulation of sulfotransferases were also
observed in mice receiving fenofibrate, which was mediated via PPARalpha
activation; a fish oil diet downregulated the endogenous PPARalpha
activaton system and increased antioxidant genes; worries about EPA and
DHA being easily oxidized to form lipid peroxide are unwarranted; fish
oils and fibrate, both PPARalpha agonists, trigger higher levels of
H2O2-generating peroxisomal fatty acyl CoA oxidase, first enzyme of the
peroxisomal fatty acid beta-oxidation system, and microsomal CYP4A1 and
CYP4A3 genes; dispro****tionate increases in H2O2-generating enzymes and
H2O2-degrading enzyme catalase and reductions in glutathione peroxidase
activity by peroxisome proliferators does lead to enhanced oxidative
stress in the liver; however the overall net effect of fish oils may
enhance antioxidant defense in the liver; tissue TBARS increases were
slight; fish oils also upregulated testosterone 17-alpha hydroxylase
related to steroid degradation; also increased: alpha 2 type IV collagen
beta-tubulin, IGFBP-2, biglycan, various immunoglobulin genes (IgM),
gelsolin (phagocytosis), leukocyte elastase inhibitor (which inactivates
enzymes related to immune reaction); gelsolin and IgM didnšt jump after
one week of fish oils but did after six months; the antioxidant
upregulation occured quickly and was due to PPARalpha agonism; fish oil
decreased Sir2 (whereas safflower oil increased it); life-extension from
calorie restriction requires Sir2 in yeast; fish oils downregulate genes
associated with the endogenous activation of PPARalpha as part of
negative feedback to prevent elevated PPARalpha levels (enzymes which
convert DHEAs from DHEA and DHEA from pregnenolone; DHEAs is a PPARalpha
agonist) <http://ajpgi.physiology.org/cgi/content/full/282/2/G338>
EGCG protects against hepatic steatosis (fatty liver disease) by
inhibiting fatty acid synthase; palmitic acid and linoleic acid levels
dropped in EGCG-treated animals, ATP levels increased, UCP2 dropped and
glutathione (GSH) increased; EGCG protects the liver after
ischemia/reperfusion injury by reducing hepatic fat content, increasing
energy status and via antioxidant protection [PMID 15719408]
J Pineal Res. 2008 May;44(4):373-8.
Regression of herpes viral infection symptoms using melatonin and SB-73:
comparison with Acyclovir.
Nunes Oda S, Pereira Rde S.
Universidade Federal de Sao Carlos, Departamento de Fisioterapia, Dr.
Nivaldo's laboratory, Rod. Wa****ngton Luis, Sao Carlos, SP, Brazil.
Infection with Herpes simplex virus type 1 (HSV-1) typically causes
lesions of the mouth, face, skin, esophagus, or brain. Herpes simplex
virus type 2 (HSV-2) usually causes infections of the genitals, rectum,
skin, hands, or meninges. The herpes viruses are a major cause of
blindness from keratitis. The usual drugs used for herpes are
Vidarabine, Acyclovir, Penciclovir and Ganciclovir; they are associated
with several complications. The aim of this study was to investigate if
a formulation containing 2.5 mg melatonin and 100 mg SB-73 would help
patients with herpes, and to compare the preparation with 200 mg
Acyclovir. SB-73 is a mixture of magnesium, phosphate, fatty acids
extracted from Aspergillus sp. which has anti-herpes virus properties. A
single blind randomized study was performed in which 70 patients
underwent treatment using the supplement cited above (group A) and 75
received treatment of 200 mg Acyclovir (group B). Sixty-seven patients
of the group A (95.7%) re****ted a complete regression of symptoms after
7 days of treatment. By comparison, 64 subjects (85.3%) of the Acyclovir
re****ted regression of symptoms in the same period. There was
statistically significant difference between the groups (P < 0.05).
Publication Types:
* Randomized Controlled Trial
* Research Sup****t, Non-U.S. Gov't
PMID: 18410585
mice grown without gut bacteria gain a great deal of weight when that
bacteria is reintroduced even though they eat less; their leptin levels
go up; insulin sensitivity drops and they develop hyperglycemia; the
reintroduced microbiota triggered liver enzymes to produce more
triglycerides, upregulating acetyl-CoA carboxylase (ACC-1) and fatty
acid synthase (FAS) in the liver - both of which are targets of SREBP-1
(Sterol response element binding protein 1) and ChREBP; both ChREBP and
SREBP-1 are upregulated by the microbiota too; this promotes increased
monosaccharide uptake from the gut; the microbiota promote storage in
fat pads through the suppression of intestinal expression of a
circulating LPL (lipoprotein lipase) inhibitor; LPL (which can be
reduced by fasting) causes ac***ulation of fat; Fiaf (angiopoietin-like
protein 4) is produced by white/brown fat and the intestine and inhibits
LPL; Fiaf expression was very low in the microbiota mice; the problem
seems to do with how microbiota expand after the transition from
lipid/lactose-rich motheršs milk to the low-fat/polysaccharide-rich chow
and how microbiota react with metabolic changes; this implies that
antibiotic use and insulin resistance are interrelated phenomena
<http://www.pnas.org/cgi/content/full/101/44/15718>
Int J Mol Med. 2008 Oct;22(4):433-9.
Analyzing effects of extra-virgin olive oil polyphenols on breast
cancer-associated fatty acid synthase protein expression using
reverse-phase protein microarrays.
Menendez JA, Vazquez-Martin A, Oliveras-Ferraros C, Garcia-Villalba R,
Carrasco-Pancorbo A, Fernandez-Gutierrez A, Segura-Carretero A.
Catalan Institute of Oncology-Girona (ICO-Girona), Girona Biomedical
Research Institute (IdIBGi), Medical Oncology, Dr. Josep Trueta
University Hospital of Girona, E-17007 Girona, Catalonia, Spain.
Inhibitors of fatty acid synthase (FASN), a key enzyme involved in the
anabolic conversion of dietary carbohydrates to fat in mammals, are
receiving increasingly more attention as they may provide therapeutic
moieties for the treatment of human malignancies. Natural compounds,
such as the green tea polyphenol epigallocatechin-3-gallate, have been
shown to induce anti-cancer effects by suppressing FASN, which may
account for the epidemiologically observed inverse correlation between
green-tea drinking and cancer risk in Oriental populations. Since
extra-virgin olive oil (EVOO)-derived phenolics have been suggested to
possess biological activities that may explain the health-promoting
effects of the 'Mediterranean diet', we evaluated their effects on the
expression of FASN protein in human breast epithelial cell lines. First,
we developed a reverse phase protein microspot array (RPPA) capable of
rapidly *****sing the relative amount of FASN protein in whole lysates
from cultured human cells. Then we tested the effects of phenolic
fractions from EVOO and its main constituents including single phenols
(i.e. tyrosol, hydroxytyrosol, vanillin), phenolic acids (i.e. caffeic
acid, p-coumaric acid, vanillic acid, ferulic acid, elenolic acid),
lignans (i.e. 1-[+]-pinoresinol, 1-[+]-acetoxy-pinoresinol), flavonoids
(i.e. apigenin, luteolin), or secoiridoids (i.e. deacetoxyoleuropein
aglycone, ligstroside aglycone, oleuropein glycoside, oleuropein
aglycone) on FASN protein expression. EVOO polyphenols lignans,
flavonoids and secoiridoids were found to drastically suppress FASN
protein expression in HER2 gene-amplified SKBR3 breast cancer cells.
Equivalent results were observed in MCF-7 cells engineered to
overexpress the HER2 tyrosine kinase receptor, a well-characterized
up-regulator of FASN expression in aggressive sub-types of cancer cells.
EVOO-derived lignans, flavonoids and secoiridoids were significantly
more effective than the mono-HER2 inhibitor trastuzumab ( approximately
50% reduction) and as effective as the dual HER1/HER2 tyrosine kinase
inhibitor lapatinib (>/=95% reduction) at suppressing high-levels of
FASN protein in HER2-overexpressing SKBR3 and MCF-7/HER2 cells. EVOO
single phenols and phenolic acids failed to modulate FASN expression in
SKBR3 and MCF-7/HER2 cells. These findings reveal for the first time
that phenolic fractions, directly extracted from EVOO, may induce
anti-cancer effects by suppressing the expression of the lipogenic
enzyme FASN in HER2-overexpressing breast carcinoma cells, thus offering
a previously unrecognized mechanism for EVOO-related cancer preventive
effects.
PMID: 18813848
Acta Vet Hung. 2007 Jun;55(2):229-39.
Veterinary aspects and perspectives of nutrigenomics: a critical review.
Fekete SG, Brown DL.
Institute of Animal Breeding, Nutrition and Laboratory Animal Science,
Faculty of Veterinary Science, Szent Istvan University, H-1400 Budapest,
P.O. Box 2, Hungary.
Nutrigenomics examines nutrient-gene interactions on a genome-wide
scale. Increased dietary fat or higher non-esterified fatty acids (NEFA)
from starvation-induced mobilisation may enhance hepatic oxidation and
decrease esterification of fatty acids by reducing the expression of the
fatty acid synthase gene. The key factors are the peroxisome
proliferator-activated receptors (PPARs). Dietary carbohydrates--both
independently and through insulin effect--influence the transcription of
the fatty acid synthase gene. Oleic acid or n-3 fatty acids downregulate
the expression of leptin, fatty acid synthase and lipoprotein lipase in
retroperitoneal adipose tissue. Protein-rich diets entail a shortage of
mRNA necessary for expression of the fatty acid synthase gene in the
adipocytes. Conjugated linoleic acids (CLAs) are activators of PPAR and
also induce apoptosis in adipocytes. Altered rumen microflora produces
CLAs that are efficient inhibitors of milk fat synthesis in the mammary
gland ('biohydrogenation theory'). Oral zinc or cadmium application
enhances transcription rate in the metallothionein gene. Supplemental
CLA in pig diets was found to decrease feed intake and body fat by
activating PPARgamma-responsive genes in the adipose tissue. To prevent
obesity and type II diabetes, the direct modulation of gene expression
by nutrients is also possible. Nutrigenomics may help in the early
diagnosis of genetically determined metabolic disorders and in designing
individualised diets for companion animals.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
* Review
PMID: 17555288
Curr Pharm Biotechnol. 2006 Dec;7(6):495-502.
Mediterranean dietary traditions for the molecular treatment of human
cancer: anti-oncogenic actions of the main olive oil's monounsaturated
fatty acid oleic acid (18:1n-9).
Menendez JA, Lupu R.
Fundacio d'Investigacio Biomedica de Girona Dr. Josep Trueta (IdIBGi),
Girona, Catalonia, Spain.
The final proof about the specific mechanisms by which the different
components of olive oil, the principal source of fat in a typical
"Mediterranean diet", exert their potential protective effects on the
promotion and progression of several human cancers requires further
investigations. A recent discovery that dietary fatty acids can interact
with the human genome by regulating the amount and/or activity of
transcription factors has opened a whole new line of research aimed to
molecularly corroborate the ant-cancer benefits of the olive oil-based
Mediterranean diet and the underlying mechanisms. Our most recent
findings reveal that oleic acid (OA; 18:1n-9), the main olive oil's
monounsaturated fatty acid, can suppress the overexpression of HER2
(erbB-2), a well-characterized oncogene playing a key role in the
etiology, invasive progression and metastasis in several human cancers.
First, exogenous supplementation with physiological concentrations of OA
significantly down-regulates HER2-coded p185(Her-2/neu) oncoprotein in
human cancer cells naturally harboring amplification of the HER gene.
Second, OA exposure specifically represses the transcriptional activity
of the human HER2 gene promoter in tumor-derived cell lines naturally
exhibiting HER2 gene amplification and p185(Her-2/neu) protein
overexpression but not in cancer cells expressing physiological levels
of HER2. Third, OA treatment induces the up-regulation of the Ets
protein PEA3 (a transcriptional repressor of the HER2 gene promoter)
solely in cancer cells naturally displaying HER2 gene amplification.
Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot
be negatively regulated by OA, while treatment with OA fails to repress
the expression of a human full-length HER2 cDNA controlled by a SV40
viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity
does not occur if HER2 gene-amplified cancer cells do no concomitantly
exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen-519)
as specific depletion of FASN, which itself similarly suppresses HER2
overexpression by inducing PEA3-dependent repression of HER2 gene
promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene
promoter activity. Considering that OA treatment efficiently blocks FASN
activity and down-regulates FASN protein expression, it is reasonable to
suggest that an ac***ulation of supra-physiological concentrations of
the FASN substrate malonyl-CoA, due to its reduced utilization by FASN
in the presence of exogenous OA, appears to act as an indicator of "cell
fuel" availability capable to suppress HER2 expression via formation of
inhibitory "PEA3 protein-PEA3 DNA binding site" complexes on the
endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically
decreases HER2 promoter activity, while OA or malonyl-CoA similarly
up-regulates PEA3 gene promoter activity. This previously unrecognized
ability of OA to directly affect the expression of a cluster of
interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open
a new line of research aimed to explore the anti-cancer effects of OA.
Certainly, an appropriate dietary intervention reproducing this
prominent anti-oncogenic feature of the "Mediterranean diet" must be
carried out in animal models and human pilot studies in the future. Only
then we will know whether the old "Mediterranean dietary traditions"
will become a new molecular approach in the management of cancer disease.
Publication Types:
* Research Sup****t, N.I.H., Extramural
* Research Sup****t, Non-U.S. Gov't
* Review
PMID: 17168666
J Nutr. 2006 Jul;136(7):1779-85.
Reduced fat mass in rats fed a high oleic acid-rich safflower oil diet
is associated with changes in expression of hepatic PPARalpha and
adipose SREBP-1c-regulated genes.
Hsu SC, Huang CJ.
Division of Nutritional Science, Institute of Microbiology and
Biochemistry, National Taiwan University, Taipei, Taiwan.
PPARs and sterol regulatory element-binding protein-1c (SREPB-1c) are
fatty acid-regulated transcription factors that control lipid metabolism
at the level of gene expression. This study compared a high oleic
acid-rich safflower oil (ORSO) diet and a high-butter diet for their
effect on adipose mass and expressions of genes regulated by PPAR and
SREPB-1c in rats. Four groups of Wistar rats were fed 30S (30% ORSO), 5S
(5% ORSO), 30B (29% butter + 1% ORSO), or 5B (4% butter plus 1% ORSO)
diets for 15 wk. Compared with the 30B group, the 30S group had less
retroperitoneal white adipose tissue (RWAT) mass and lower mRNA
expressions of lipoprotein lipase, adipocyte fatty acid-binding protein,
fatty acid synthase, acetyl CoA carboxylase, and SREBP-1c in the RWAT,
higher mRNA expressions of acyl CoA oxidase, carnitine
palmitoyl-transferase 1A, fatty acid binding protein, and mitochondrial
3-hydroxy-3-methylglutaryl-CoA synthase in the liver (P < 0.05). The
18:2(n-6) and 20:4(n-6) contents in the liver and RWAT of the 30S group
were >2 fold those of the 30B group (P < 0.05). These results suggested
that the smaller RWAT mass in rats fed the high-ORSO diet might be
related to the higher tissue 18:2(n-6) and 20:4(n-6). This in turn could
upregulate the expressions of fatty acid catabolic genes through the
activation of PPARalpha in the liver and downregulate the expressions of
lipid storage and lipogenic gene through the suppression of SREBP-1c in
the RWAT.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 16772437
J Lipid Res. 2003 Jun;44(6):1199-208. Epub 2003 Mar 16.
Fatty acid flux suppresses fatty acid synthesis in hamster intestine
independently of SREBP-1 expression.
Field FJ, Born E, Mathur SN.
Department of Veterans Affairs and Department of Internal Medicine,
University of Iowa, Iowa City, IA 52242, USA.
Hamsters were fed a control diet or diets containing palm, olive,
safflower, or fish oil for 2 weeks. In villus cell populations from
duodenum, jejunum, and ileum, rates of intestinal fatty acid and
cholesterol synthesis were estimated, as were sterol regulatory
element-binding protein (SREBP)-1a, SREBP-1c, SREBP-2, HMG-CoA synthase,
fatty acid synthase, ATP citrate lyase, acetyl-CoA carboxylase mRNA
levels, and SREBP-1 and SREBP-2 mass. Plasma cholesterol and
triacylglcerol levels were increased in animals ingesting palm oil and
decreased in animals ingesting fish oil. Fatty acid synthesis and fatty
acid synthase activity were decreased in the proximal intestine of
animals ingesting all the fat-containing diets. Intestinal cholesterol
synthesis was unaltered. In animals fed fat, SREBP-1c gene expression
was modestly increased in the duodenum of hamsters fed palm oil or olive
oil, and decreased in animals ingesting safflower oil or fish oil. Fatty
acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, SREBP-2, and
HMG-CoA synthase mRNA levels were not altered, nor were SREBP-1 or
SREBP-2 mass. In the intestine, dietary polyunsaturated fatty acids
suppress SREBP-1c mRNA without altering expression of its target genes,
fatty acid synthase, acetyl-CoA carboxylase, or ATP citrate lyase. Fatty
acid influx decreases intestinal fatty acid synthesis by a
posttranscriptional mechanism independent of the SREBP pathway.
Publication Types:
* Research Sup****t, U.S. Gov't, Non-P.H.S.
PMID: 12639972
Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation that
possesses antiviral activities and it drives the defense against in
vitro cytomegalovirus (CMV) infection of human leukocytes via the
high-affinity LTB4 receptor (BLT1) and neutrophil degranulation;
treatment of CMV-infected peripheral blood leukocytes with LTB4 (10 nM)
leads to a significant reduction in viral titers via neutrophil
activation through the BLT1 receptor, because no reduction in viral
titers was observed after neutrophil depletion from cellular preparation
or when leukocytes were pretreated with the BLT1 antagonist U75,302;
direct stimulation of neutrophils with LTB4 (in the presence or absence
of CMV) leads to the release of myeloperoxidase, alpha-defensins,
eosinophil-derived neurotoxin, and the human cathelicidin LL-37 in a
BLT1-dependent manner; LTB4 does not act exclusively on the secretion of
preformed antimicrobial peptides, but also acts on the synthesis of
selected peptides as reflected by the increase in transcriptional levels
of eosinophil-derived neurotoxin (EDN) and LL-37 in LTB4-treated
neutrophils; treatment of cell cultures with neutralizing antibodies
directed against alpha-defensins, EDN, and LL-37 significantly reduces
the antiviral effect of LTB(4), suggesting that LTB4 may act through the
release of antimicrobial peptides; ex vivo experiments using
LTB4-treated neutrophils from peritoneal wa****ng of wild-type and BLT1
knockout mice further sup****ted the role played by antimicrobial
peptides in LTB4-mediated antiviral activity toward CMV; LTB4 induces
host defense against viral infection [PMID 17931111]; because of the
im****tance of LTB4, substances which block LTB4 are contraindicated -
certain anti-allergy drugs (singulair?), theophylline, lyprinol and also
vitamin E; pollen-associated lipid mediators contain LTB4 ligands,
perhaps accounting for the antiviral properties of honey; LTB4 binds to
PPARalpha and triggers downstream transcription elements involved in
oxidation of fats (which might boost carnitine uptake and butyrate
metabolism)
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