Eccipienti, coloranti e conservanti
ho acquistato seppioline penscate nell'oceano indiano surgelate.
Hanno acido citrico e citrato di sodio. Che roba sono? Sono dannosi per la salute?
Ovvio che non li ricomprerò!
Sì, sarebbe meglio evitare i citrati, perché interferiscono con dei meccanismi regolatori nelle cellule. Tra l'altro l'acido citrico industriale e quello "naturale" sono diversi nel senso che tramite analisi possono notarsi le differenze. In alcuni casi, a detta di Ray Peat, possono indirizzare le cellule verso pattern caratteristici del cancro.
Tra l'altro avevo aperto un thread proprio su questo ultimamente:
"If extra citrate enters the cytoplasm of cells from the blood, there could be chronic disturbance of pyruvate dehydrogenase and fatty acid metabolism (in the direction characteristic of cancer)."
Vopr Med Khim. 1981 Jan-Feb;27(1):68-72.
[Features of pyruvate and lactate metabolism in tumor-bearing rats following
[Article in Russian]
Velichko MG, Trebukhina RV, Ostrovskiĭ IuM.
Everyday administration of citrate (250 mg/kg of body mass) into healthy rats
within 4 days inhibited activities of pyruvate kinase, pyruvate dehydrogenase,
alanine transaminase and of reverse lactate dehydrogenase in liver tissue but not
in sceletal muscles. Within the longer period of citrate administration (8 or 12
days) activities of pyruvate dehydrogenase and alanine transaminase continued to
decrease in liver tissue, at the same time, content of pyruvate proceeded to
increase in sceletal muscles. More distinct inhibitory effect of citrate on the
pyruvate dehydrogenase activity was observed not only in liver tissue but and in
sceletal muscles of tumor-bearing animals. Alanine transaminase, which was
inactivated in liver tissue of healthy animals after citrate treatment, was
markedly activated in tumor-bearing rats in the same conditions. The data
obtained suggest that some regulatory functions of citrate were qualitatively
transformed in tumor-bearing animals, mainly, in relation to turnover of
glucogenic amino acids.
Mol Cancer Ther. 2012 Sep;11(9):1925-35.
ATP citrate lyase knockdown induces growth arrest and apoptosis through different
cell- and environment-dependent mechanisms.
Zaidi N (1), Royaux I, Swinnen JV, Smans K.
(1)Department of Oncology, Janssen Research and Development, Division of Janssen
Pharmaceutica NV, Beerse, Belgium.
ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of
acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and
isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its
inhibition induces proliferation arrest in certain cancer cells. As ACLY is
involved in several pathways, its downregulation may affect multiple processes.
Here, we have shown that short hairpin RNA-mediated ACLY silencing in cell lines
derived from different types of cancers induces proliferation, cell-cycle arrest,
and apoptosis. However, this antiproliferative effect of ACLY knockdown was
observed only when cells were cultivated under lipid-reduced growth conditions.
Proliferation arrest induced by ACLY silencing was partially rescued by
supplementing the media with fatty acids and/or cholesterol. This indicates that
the ACLY knockdown-mediated growth arrest might be the result of either fatty
acid or cholesterol starvation or both. In the absence of ACLY, the cancer cells
displayed elevated expression of sterol regulatory element binding
protein-regulated downstream genes involved in de novo fatty acid and cholesterol
biosynthesis. Furthermore, ACLY suppression resulted in elevated expression of
acyl-CoA synthetase short-chain family member 2 (ACSS2), an enzyme that also
produces acetyl-CoA using acetate as a substrate. Acetate supplementation
partially rescued the cancer cells from ACLY suppression-induced proliferation
arrest. We also observed that the absence of ACLY enhanced ACSS2-dependent lipid
synthesis. These findings provide new insights into the role of ACLY in cancer
cell growth and give critical information about the effects of ACLY silencing on
different pathways. This information is crucial in understanding the possible
application of ACLY inhibition in cancer therapeutics.
Biochem J. 2011 Sep 15;438(3):e5-6.
A critical role for citrate metabolism in LPS signalling.
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
email [email protected]
Biochem J. 2011 Sep 15;438(3):433-6.
Macrophage activation is a key event in the inflammatory process, since these
cells produce a range of pro-inflammatory molecules, including ROS (reactive
oxygen species), prostaglandins, cytokines and nitric oxide. These factors
promote inflammation by causing vasodilation and recruitment of neutrophils,
monocytes and lymphocytes, which ultimately clear infection and repair damaged
tissue. One of the most potent macrophage activators is the Gram-negative-derived
bacterial cell wall component LPS (lipopolysaccharide). LPS is sensed by TLR4
(Toll-like receptor 4) and triggers highly complex signalling pathways that
culminate in activation of transcription factors such as NF-κB (nuclear factor
κB), which in turn increases transcription of genes encoding proteins such as
COX2 (cyclo-oxygenase 2, a key enzyme in prostaglandin biosynthesis), nitric
oxide synthase and cytokines such as TNF (tumour necrosis factor). Recently, a
role for metabolic pathways in the regulation of LPS signalling has become a
focus of research in inflammation. A notable example is LPS promoting the
so-called Warburg effect - aerobic glycolysis. This allows for an up-regulation
in ATP production, and also for the production of biosynthetic intermediates to
meet the demands of the activated macrophages. In this issue of the Biochemical
Journal, Infantino et al. add a new finding to the role of metabolism in LPS
action. They demonstrate a requirement for the mitochondrial citrate carrier in
the induction of ROS, nitric oxide and prostaglandins by LPS. The knockdown of
the carrier with siRNA (small interfering RNA), or the use of an inhibitor BTA
(benzene-1,2,3-tricarboxylate), abolishes these responses. Although no mechanism
is provided, the authors speculate that acetyl-CoA is synthesized from citrate in
the cytosol. The acetyl-CoA generated could be required for phospholipid
biosynthesis, the phospholipids being the source of arachidonic acid for
prostaglandin production. Another product of citrate metabolism, oxaloacetate,
will indirectly generate nitric oxide and ROS. This finding places citrate,
transported from the mitochondria, as a key player in LPS signalling, at least
for ROS, nitric oxide and prostaglandin production. This somewhat unexpected role
for citrate in LPS action adds to a growing literature on the role for metabolism
in the regulation of signalling in inflammation.
Recent Pat Anticancer Drug Discov. 2012 May 1;7(2):154-67.
ATP citrate lyase inhibitors as novel cancer therapeutic agents.
Zu XY, Zhang QH, Liu JH, Cao RX, Zhong J, Yi GH, Quan ZH, Pizzorno G.
Clinical Research Institution, the First Affiliated Hospital, and School of
Medicine, University of South China, Hengyang, Hunan, PR China.
ATP citrate lyase (ACL or ACLY) is an extra-mitochondrial enzyme widely
distributed in various human and animal tissues. ACL links glucose and lipid
metabolism by catalyzing the formation of acetyl-CoA and oxaloacetate from
citrate produced by glycolysis in the presence of ATP and CoA. ACL is aberrantly
expressed in many immortalized cells and tumors, such as breast, liver, colon,
lung and prostate cancers, and is correlated reversely with tumor stage and
differentiation, serving as a negative prognostic marker. ACL is an upstream
enzyme of the long chain fatty acid synthesis, providing acetyl-CoA as an
essential component of the fatty acid synthesis. Therefore, ACL is a key enzyme
of cellular lipogenesis and potent target for cancer therapy. As a hypolipidemic
strategy of metabolic syndrome and cancer treatment, many small chemicals
targeting ACL have been designed and developed. This review article provides an
update for the research and development of ACL inhibitors with a focus on their
patent status, offering a new insight into their potential application.
Nature. 2011 Nov 20;481(7381):380-4.
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.
Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM,
Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O,
Department of Chemical Engineering, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, USA.
Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid
synthesis and protein acetylation. In the conventional view of mammalian cell
metabolism, AcCoA is primarily generated from glucose-derived pyruvate through
the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating
cells that exhibit aerobic glycolysis and those exposed to hypoxia convert
glucose to lactate at near-stoichiometric levels, directing glucose carbon away
from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is
consumed at levels exceeding that required for nitrogen biosynthesis, the
regulation and use of glutamine metabolism in hypoxic cells is not well
understood. Here we show that human cells use reductive metabolism of
α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate
dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under
normal culture conditions, but cells grown under hypoxia rely almost exclusively
on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo
lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau
tumour suppressor protein preferentially use reductive glutamine metabolism for
lipid biosynthesis even at normal oxygen levels. These results identify a
critical role for oxygen in regulating carbon use to produce AcCoA and support
lipid synthesis in mammalian cells.
TIIE Joumar. oz BIOLOGICAL CHEMISTRY
Vol. 248, No. 12, Issue of June 25, PP. 4318-4326, 1973
Printed in U.S.A.
Regulation of Fatty Acid Synthesis in Isolated Hepatocytes
EVIDENCE FOR A PHYSIOLOGICAL ROLE FOR LONG CHAIN FATTY ACYL COENZYME A AND CITRATE *
ALAN G. GOODRIDGE
From the Bantina and Best Department of Medical Research, University of Toronto, Toronto, On,tario, Canada
In isolated hepatocytes prepared from unfed neonatal
chicks, stimulation of fatty acid synthesis by fructose or di-
hydroxyacetone required acetate or octanoate in the medium,
suggesting that the stimulatory effect of these compounds
required the enhanced production of intramitochondrial
acetyl coenzyme A. Stimulation of fatty acid synthesis by
lactate or pyruvate did not require a supplementary substrate.
Distribution of acetyl-CoA synthetase was 80% intramito-
chondrial and 20% cytosolic. However, sufficient acetate
could be activated in the cytosol to accommodate the most
rapid rates of fatty acid synthesis observed in isolated cells.
This was shown experimentally by an undiminished rate of
incorporation of [lJ4C]acetate plus [W]lactate or [Y]fruc-
tose into fatty acids when ATP-citrate lyase was inhibited by
The citrate content of the isolated cells was positively cor-
related with fatty acid synthesis under all incubation condi-
tions. The ATP content of the cells did not correlate with
fatty acid synthesis. Fatty acyl-CoA and cu-glycerophos-
phate levels only partially correlated with fatty acid synthesis.
Hence, citrate appears to be an important determinant in the
regulation of fatty acid synthesis in intact liver cells, probably
via its ability to activate acetyl-CoA carboxylase.
Inhibition of fatty acid synthesis by free fatty acids was
reversible, did not increase with time of incubation, and was
not relieved by simultaneous incubation with the inhibitor
of fatty acid oxidation, (+)-decanoylcarnitine. Thus, the
active inhibitor was not a stable product of the esterification
of fatty acids nor a product of the oxidation of fatty acids.
Inhibition of fatty acid synthesis by medium free fatty acids
was accompanied by an increase in the fatty acyl-CoA level.
Fatty acyl-CoA may inhibit fatty acid synthesis by directly
inhibiting acetyl-CoA carboxylase or by inhibiting the mito-
chondrial citrate carrier and, thereby, reducing the activation
of acetyl-CoA carboxylase caused by citrate.
Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo
Carl Grunfeld: Jennifer A. Verdier: Richard Neese,t Arthur H. Moser: and
Kenneth R. Feingold*
Metabolism Section' and Cardiology Section,t Department of Medicine, University of California,
San Francisco, and the Veterans Administration Medical Center, San Francisco, CA 94121
Abstract We have previously shown that bolus intravenous ad-
ministration of tumor necrosis factor (TNF) to normal rats
results in a rapid (within 90 min) stimulation of hepatic fatty
acid synthesis, which is sustained for 17 hr. We now demonstrate
that TNF stimulates fatty acid synthesis by several mechanisms.
Fatty acid synthetase and acetyl-coA carboxylase (measured
after maximal stimulation by citrate) were not higher in livers
from animals that had been treated with TNF 90 min before
study compared to controls. In contrast, 16 hr after treatment
with TNF, fatty acid synthetase was slightly elevated (35%)
while acetyl-CoA carboxylase was increased by 58%. To explain
the early rise in the hepatic synthesis of fatty acids, we examined
the regulation of acetyl-coA carboxylase. The acute increase in
fatty acid synthesis was not due to activation of acetyl-coA car-
boxylase by change in its phosphorylation state (as calculated by
the ratio of activity in the absence and presence of 2 mM
citrate). However, hepatic levels of citrate, an allosteric activator
of acetyl-coA carboxylase, were significantly elevated (51 %)
within 90 min of TNF treatment. TNF also induces an acute in-
crease (within 90 min) in the plasma levels of free fatty acids.
However, hepatic levels of fatty acyl-CoA, which can inhibit
acetyl-coA carboxylase, did not rise 90 min following TNF
treatment and were 35% lower than in control livers by 16 hr
after TNF. IIp These data suggest that TNF acutely regulates
hepatic fatty acid synthesis in vivo by raising hepatic levels of
citrate. This is later followed by an increase in acetyl-coA car-
boxylase and fatty acid synthetase and a decrease in hepatic
fatty acyl CoA levels. - Grunfeld, C., J. A. Verdier, R. Neese,
A. H. Moser, and K. R. Feingold. Mechanisms by which
tumor necrosis factor stimulates hepatic fatty acid synthesis in
vivo. J. Lipid Res. 1988. 29: 1327-1335
Diabetes. 2002 Jul;51(7):2018-24.
Critical role for cataplerosis via citrate in glucose-regulated insulin release.
Flamez D(1), Berger V, Kruhøffer M, Orntoft T, Pipeleers D, Schuit FC.
(1)Molecular Pharmacology Unit, Diabetes Research Center, Faculty of Medicine, Vrije
Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.
The molecular mechanisms mediating acute regulation of insulin release by glucose
are partially known. The process involves at least two pathways that can be
discriminated on basis of their (in)dependence of closure of ATP-sensitive
potassium (K+(ATP)) channels. The mechanism of the K+(ATP) channel-independent
pathway was proposed to involve cataplerosis, the export of mitochondrial
intermediates into the cytosol and in the induction of fatty acid-derived
signaling molecules. In the present article, we have explored in
fluorescence-activated cell sorter (FACS)-purified rat beta-cells the molecular
steps involved in chronic glucose regulation of the insulin secretory response.
When compared with culture in 10 mmol/l glucose, 24 h culture in 3 mmol/l glucose
shifts the phenotype of the cells into a state with low further secretory
responsiveness to glucose, lower rates of glucose oxidation, and lower rates of
cataplerosis. Microarray mRNA analysis indicates that this shift can be
attributed to differences in expression of genes involved in the K+(ATP)
channel-dependent pathway, in cataplerosis and in fatty acid/cholesterol
biosynthesis. This response was paralleled by glucose upregulation of the
transcription factor sterol regulatory element binding protein 1c (SREBP1c)
(ADD1) and downregulation of peroxisome proliferator-activated receptor
(PPAR)-alpha and PPAR-beta (PPARdelta). The functional importance of cataplerosis
via citrate for glucose-induced insulin release was further supported by the
observation that two ATP-citrate lyase inhibitors, radicicol and
(-)-hydroxycitrate, block part of glucose-stimulated release in beta-cells. In
conclusion, chronic glucose regulation of the glucose-responsive secretory
phenotype is associated with coordinated changes in gene expression involved in
the K+(ATP) channel-dependent pathway, in cataplerosis via citrate and in acyl
In passato le compravo perché non c'erano quelle schifezze.
Ora non le comprerò più.
Lo so, purtroppo è un problema, ma che vuoi farci 🙁
Erano un buon prodotto in sè. Peccato. Non le ricomprerò più!