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Metabolism of sepsis and multiple organ
failure
Michie H.R.
North Western Injury Research Center, Manchester University,
Bolton Hospitals NHS Trust, Manchester United Kingdom
World Journal of Surgery (USA), 1996, 20/4
(460-464)
'Septic autocannabalism' been coined to describe the
metabolic response that follows severe sepsis in humans. The
normal protein- and energy- conserving mechanisms evoked
during simple starvation are not observed following the onset
of sepsis. The metabolic response to sepsis entails rapid
breakdown of the body's reserves of protein, carbohydrate, and
fat. Hyperglycemia with insulin resistance, profound negative
nitrogen balance, and diversion of protein from skeletal
muscle to splanchnic tissues are prominent features. These
responses are believed to be mediated in large part by
inflammatory cytokines such as tumor necrosis factor alpha
(TNFalpha), interleukin 1beta (IL-1beta), and IL-6. Secondary
induction of catecholamines, cortisol, and glucagon by
cytokines is likely to be another important effector
mechanism. Infection and inflammation elicit a complex network
of interwoven responses, and no single mediator alone accounts
for the responses observed. Sepsis also commonly involves
alterations in cardiovascular function with altered flow to
key metabolic sites, hypoxia, damage to the gut's mucosal
barrier, secondary organ failure, and alterations in capillary
permeability. These structural and functional alterations also
strongly influence the metabolic profile during infection. If
these catabolic responses persist for more than a few days,
severe malnutrition results and is likely to be an important
risk factor for mortality in these patients. The altered
metabolic milieu during sepsis prevents effective use of
exogeneously delivered glucose and protein; at best,
administration of these agents ameliorates but does not
prevent the persistence of catabolism. Delivery of agents that
antagonize cytokines and other moieties such as glutamine and
growth hormone may, in the future, help to restore nitrogen
balance during sepsis.
Fibronectin fragment mediated cartilage
chondrolysis. II. Reparative effects of anti-oxidants
Homandberg G.A.; Hui F.; Wen C.
Department of Biochemistry, Rush Medical College,
Rush-Presbyt.-St Luke Medical Center, 1653 West Congress
Parkway, Chicago, IL 60612-3864 USA
Biochimica et Biophysica Acta - Molecular Basis of Disease
(Netherlands), 1996, 1317/2 (143-148)
In an accompanying manuscript, it was shown that the
cartilage chondrolytic activities of fibronectin fragments
(Fn-f), which are mediated through catabolic cytokines such as
TNF-alpha, IL-1 and IL-6, could be suppressed by anti-oxidants
(AOs). The AOs neutralized reactive oxygen species (ROS) which
are known to mediate catabolic cytokine action. The objective
in this work was to test whether AOs would promote restoration
of proteoglycan (PG) in Fn-f treated cartilage, since under
normal culturing conditions, PG is, not restored after removal
of the Fn-f. Cartilage was first cultured with an
amino-terminal 29-kDa Fn-f to cause loss of about half of the
total PG and then treated with NAC (1 and 10 mM) or
glutathione (10 microM) or DMSO (0.1 or 1%). Treatment with
NAC and glutathione maximally caused restoration of PG within
14 days to normal or supernormal levels, while DMSO was less
effective. Catalase, but not superoxide dismutase, enhanced PG
content to a small but significant extent. The restoration of
PG in Fn-f treated cartilage occurred throughout the full
depth of the cartilage slices as shown by histochemical
analysis. However, removal of the AO allowed a subsequent
decrease in PG content suggesting that the AOs had not blocked
cytokine expression but had merely suppressed cytokine
activities. Addition of NAC to IL-1 treated cartilage promoted
a restoration of PG, while addition to chymopapain or trypsin
treated cartilage was not very effective, suggesting that the
effect of Aos requires a cytokine driven damage system. We
conclude that the AOs promote a restoration of PG in the Fn-f
treated cartilage by suppressing the effects of catabolic
cytokines. The data suggest a potential for AOs in reversing
tissue damage caused by cytokines.
Fibronectin fragment mediated cartilage
chondrolysis. I. Suppression by anti-oxidants
Homandberg G.A.; Hui F.; Wen C.
Department of Biochemistry, Rush Medical College,
Rush-Presbyt.-St Luke Medical Center, 1653 West Congress
Parkway, Chicago, IL 60612-3864 USA
Biochimica et Biophysica Acta - Molecular Basis of Disease
(Netherlands), 1996, 1317/2 (134-142)
Fibronectin fragments damage cartilage in vitro by greatly
enhancing metalloproteinases and suppressing proteoglycan (PG)
synthesis which results in severe cartilage PG depletion.
Since reactive oxygen species (ROS) have been implicated in
catabolic cytokine action and preliminary data suggested that
catabolic cytokines such as TNF-alpha, IL-1alpha, IL-1beta and
IL-6 are responsible for fibronectin fragment mediated damage,
selected anti-oxidants (Aos) were tested as inhibitors of
cytokine, ROS and fibronectin fragment activity. Damage was
measured by depletion of cartilage PG during tissue culture.
The AO, N-acetylcysteine (NAC), decreased the extent of
cartilage PG depletion caused by TNF-alpha and IL-1alpha and
by the ROS, hydrogen peroxide and superoxide anion, confirming
that the cytokines operate through ROS and that ROS can
initiate cartilage PG depletion. NAC at 0.1 and 1 mM, totally
suppressed PG depletion caused by a highly potent
amino-terminal 29-kDa fibronectin fragment (Fn-f) for 14 days
in culture. NAC at 10 mM totally blocked Fn-f mediated PG
depletion for 21 days and increased the cartilage PG content
by 30% above normal levels, Glutathione (10 microM) and DMSO
(1%) were also totally effective while catalase and superoxide
decreased Fn-f mediated damage only during the first week and
superoxide dismutase alone caused damage after 1 wk. The AOs
caused protection by reducing the major catabolic activities
of the Fn-f: enhanced release of stromelysin-1 (MMP-3) and
suppression of PG and protein synthesis. NAC also decreased
normal rates of PG degradation and increased the half-lives of
labeled PG in both control and Fn-f treated cartilage. We
conclude that the Fn-f mediates cartilage chondrolysis through
ROS, consistent with the involvement of catabolic cytokines in
the Fn-f mechanism, and that AOs greatly reduce Fn-fmediated
cartilage chondrolysis. In an accompanying manuscript we also
report that AOs promote reparative responses in Fn-f and
cytokine treated cartilage.
Could L-carnitine be an acute energy inducer in
catabolic conditions?
Keskin S; Seven A; Mert M; Akalp F; Yurdakul F; Candan
G
Pediatrics Department, Cerrahpasa University, Istanbul,
Turkey.
Dev Med Child Neurol (England) Mar 1997, 39 (3)
p174-7
Serum free carnitine levels in five children (aged between
2.5 months and 4 years) with the findings of septic shock
without disseminated intravascular coagulopathy and seven
children (aged between 1.5 and 6.5 years) with the first
attack of idiopathic status epilepticus were compared with
those of eight healthy children (aged between 2.5 months and 5
years). Serum free carnitine levels showed a statistically
significant decrease in the sepsis (mean 51.5 +/- 19 mg/L) and
status epilepticus groups (mean 4.1 +/- 12.4 mg/L) (P = 0.006
and P = 0.001, respectively) when compared with the controls
(mean 90.8 +/- 17.2 mg/L).
Bacterial carnitine metabolism.
Kleber HP
Institut fur Biochemie, Fakultat fur Biowissenschaften,
Pharmazie und Psychologie, Universitat Leipzig, Germany
kleber@rz.uni-leipzig.de
FEMS Microbiol Lett (Netherlands) Feb 1 1997, 147 (1)
p1-9
L-(-)-Carnitine is a ubiquitously occurring substance,
essential for the transport of long-chain fatty acids through
the inner mitochondrial membrane. Bacteria are able to
metabolize this trimethylammonium compound in three different
ways. Some, especially Pseudomonas species, assimilate
L-(-)-carnitine as sole source of carbon and nitrogen. The
first catabolic step is catalysed by the L-(-)-carnitine
dehydrogenase. Others, for instance, Acinetobacter species,
degrade only the carbon backbone, with formation of
trimethylamine. Finally, various members of the
Enterobacteriaceae are able to convert carnitine, via
crotonobetaine, to gamma-butyrobetaine in the presence of C
and N sources and under anaerobic conditions. This two-step
pathway, including a L-(-)-carnitine dehydratase and the
crotonobetaine reductase, was demonstrated in Escherichia
coli. The DNA sequence encompassing the cai genes of E. coli,
which encode the carnitine pathway, has been determined. Some
bacteria are also able to metabolize the non-physiological
D-(+)-carnitine, which results as a waste product in some
chemical procedures for L-(-)-carnitine production based on
the resolution of racemic carnitine.
Release of ischemia in paced rat Langendorff hearts
by supply of L-carnitine: role of endogenous long-chain
acylcarnitine.
Hulsmann WC; Peschechera A; Serafini F; Ferrari LE
Thorax Center, Erasmus University, Rotterdam, The
Netherlands.
Mol Cell Biochem (Netherlands) Mar 9 1996, 156 (1)
p87-91
Rat Langendorff hearts perfused with media that do not
contain erythrocytes or fluorocarbon as oxygen carriers are
borderline aerobic during 5 Hz pacing. This follows from the
release of catabolic products measured: lactate, urate and
Iysophosphatidyl-choline (IysoPC). Addition of L-carnitine to
the perfusion medium reduced the level of these compounds,
while the release of long-chain acylcarnitine (LCAC)
increased. Previously, we found (Biochim Biophys Acta
847:62-66,1985) that micromolar LCAC protects membranes during
reperfusion after ischemia. Therefore, the observed inverse
relation between LCAC and the other compounds measured
suggests that LCAC is the basis of an acute relief of imminent
ischemia by carnitine addition. LCAC may be released from
various cell types, including vascular endothelium, as
demonstrated. The cationic amphiphilic nature of LCAC is
responsible for protection of membrane functions in imminent
ischemia.
Prevalence of essential fatty acid deficiency in
patients with chronic gastrointestinal disorders.
Siguel EN; Lerman RH
Clinical Nutrition Unit, Evans Memorial Department of
Clinical Research, Boston University Medical Center Hospital,
MA, USA.
Metabolism (United States) Jan 1996, 45 (1)
p12-23
Patients with chronic intestinal disorders causing
malabsorption, nutritional losses through diarrhea, or
catabolic illness would be expected to have essential fatty
acid (EFA) deficiency (EFAD), but such deficiency has not been
demonstrated in patients treated in accordance with the
prevailing standard of care. We studied plasma fatty acid
patterns of 56 reference or control subjects and 47 patients
with chronic intestinal disorders (mostly Crohn's disease)
using high-resolution capillary column gas-liquid
chromatography. Patients exhibited a shift in fatty acid
metabolism similar to that previously shown to be associated
with EFAD. Compared with control subjects, patients had (1)
decreased polyunsaturated fatty acid (PUFA) levels (43.7% v
50.4%, P < .0001), (2) increased monounsaturated fatty acid
(MUFA) levels (25.8% v 22.0%, P < .0001), (3) higher ratios
of mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid
(0.020 v 0.013, P < .04), and (4) lower concentrations of
total (214 v 284 mg/dL, P < .01), saturated ([SFA] 63 v 75
mg/dL, P < .001), MUFA (56 v 63 mg/dL, P < .001), and
PUFA (93 v 143 mg/dL, P < .001). Patients had metabolic
shifts toward increased production of MUFA and an increased
ratio of derivatives to precursors of omega 6 fatty acids,
shifts that occur when cells are EFA-deficient. More than 25%
of the patients had biochemical evidence of EFAD according to
at least one criterion. Optimal diagnosis requires a
concurrent evaluation of concentrations of fatty acids in
plasma and in lipoproteins (percent fatty acids). On indices
of EFA status that depend on percents, ratios, or
concentrations of fatty acids or on the production of abnormal
fatty acids, the patients were between patients with severe
whole-body EFAD and healthy subjects, a state referred to as
absolute EFA insufficiency. Patients with chronic intestinal
disease should be evaluated for likely EFA deficiencies and
imbalances, and treated with substantial amounts of
supplements rich in EFAs, such as oral vegetable and fish
oils, or intravenous lipids if necessary.
Induction of muscle glutamine synthetase gene
expression during endotoxemia is adrenal gland
dependent.
Lukaszewicz GC; Souba WW; Abcouwer SF
Division of Surgical Oncology, Massachusetts General
Hospital, Harvard Medical School, Boston 02114, USA.
Shock (United States) May 1997, 7 (5) p332-8
Skeletal muscle plays a crucial role in maintaining
nitrogen homeostasis during health and critical illness by
exporting glutamine, the most abundant amino acid in the
blood. We hypothesized that induction of glutamine synthetase
(GS) expression, the principal enzyme of de novo glutamine
biosynthesis, in skeletal muscle after endotoxin
administration was adrenal gland dependent. We studied the
expression of GS in normal and adrenalectomized rats after
intraperitoneal administration of Escherichia coli
lipopolysaccharide (LPS). Treatment of normal rats with LPS
resulted in a marked increase in GS mRNA that was dose and
time dependent, and preceded the increase in GS protein and
specific activity. The increase in muscle GS mRNA observed in
normal rats in response to LPS was abrogated in
adrenalectomized rats at 3 h after high dose LPS treatment and
markedly attenuated at 5.5 h after low dose LPS treatment.
These and other studies implicate glucocorticoid hormones as a
key, but not exclusive, regulator of skeletal muscle GS
expression after a catabolic insult.
Gut endotoxin restriction prevents catabolic
changes in glutamine metabolism after surgery in the bile
duct-ligated rat.
Houdijk AP; Teerlink T; Bloemers FW; Wesdorp RI; van Leeuwen
PA
Department of Surgery, Free University Hospital, Amsterdam,
The Netherlands.
Ann Surg (United States) Apr 1997, 225 (4)
p391-400
OBJECTIVE: The objective of this study was to investigate
the role of gut-derived endotoxemia in postoperative glutamine
(GLN) metabolism of bile duct-ligated rats.
SUMMARY BACKGROUND DATA: Postoperative complications in
patients with obstructive jaundice are associated with
gut-derived endotoxemia. In experimental endotoxemia,
catabolic changes in GLN metabolism have been reported.
Glutamine balance is considered important in preventing
postsurgical complications.
METHODS: Male Wistar rats were treated orally with the
endotoxin binder cholestyramine (n = 24, 150 mg/day) or saline
(n = 24). On day 7, groups received a SHAM operation or a bile
duct ligation (BDL). On day 21, all rats were subjected to a
laparotomy followed 24 hours later by blood flow measurements
and blood sampling. Glutamine organ handling was determined
for the gut, liver, and one hindlimb. Intracellular GLN muscle
concentrations were determined.
RESULTS: Compared to the SHAM groups, BDL rats showed lower
gut uptake of GLN (28%, p < 0.05); a reversal of liver GLN
release to an uptake (p < 0.05); higher GLN release from
the hindlimb (p < 0.05); and lower intracellular muscle GLN
concentration (32%, p < 0.05). Cholestyramine treatment in
BDL rats maintained GLN organ handling and muscle GLN
concentrations at SHAM levels.
CONCLUSIONS: Disturbances in postoperative GLN metabolism
in BDL rats can be prevented by gut endotoxin restriction.
Gut-derived endotoxemia after surgery in obstructive jaundice
dictates GLN metabolism.
Glucocorticoid-dependent induction of interleukin-6
receptor expression in human hepatocytes facilitates
interleukin-6 stimulation of amino acid transport
Fischer C.P.; Bode B.P.; Takahashi K.; Tanabe K.K.; Souba
W.W.; Evers B.M.; Beauchamp R.D.; Norton J.A.; Fischer
J.E.
Cox Building, Massachusetts General Hospital, 100 Blossom
St., Boston, MA 02114 USA
Annals of Surgery (USA), 1996, 223/5 (610-619)
OBJECTIVE: The authors studied the effects of interleukin-6
(IL-6) and tumor necrosis factor-alpha (TNF-alpha) on
glutamine and alanine transport in isolated human hepatocytes.
They also evaluated the role of dexamethasone in modulating
this response and its effects on the expression of the plasma
membrane high-affinity IL-6 receptor.
SUMMARY BACKGROUND DATA: Animal studies indicate that
cytokines are important mediators of the increased hepatic
amino acid uptake that occurs during cancer and sepsis, but
studies in human tissues are lacking. The control of transport
by cytokines and cytokine receptor expression in the liver may
provide a mechanism by which hepatocytes can modulate amino
acid availability during catabolic disease states.
METHODS: Human hepatocytes were isolated from wedge biopsy
specimens and plated in 24-well trays. Interleukin-6 and
TNF-alpha, in combination with the synthetic glucocorticoid
dexamethasone, were added to hepatocytes in culture, and the
transport of radiolabeled glutamine and alanine was measured.
Fluorescent-activated cell sorter (FACS) analysis was used to
study the effects of dexamethasone on IL-6 receptor number in
the well-differentiated human hepatoma HepG2.
RESULTS: Both IL-6 and TNF-alpha exerted a small
stimulatory effect on alanine and glutamine transport.
Dexamethasone alone did not alter transport rates, but
pretreatment of cells augmented the effects of both cytokines
on carrier-mediated amino acid uptake. Dexamethasone
pretreatment and a combination of IL-6 and TNF-alpha resulted
in a greater than twofold increase in transport activity.
Fluorescent-activated cell sorter analysis demonstrated that
dexamethasone induced a threefold increase in the expression
of high-affinity IL-6 receptors.
CONCLUSIONS: Interleukin-6 and TNF-alpha work coordinately
with glucocorticoids to stimulate amino acid uptake in human
hepatocytes. Dexamethasone exerts a permissive effect on
cytokine-mediated increases in transport by increasing IL-6
receptor expression on the cell surface. It is likely that
this upregulation of IL-6 receptors "primes" human liver cells
for subsequent stimulation by cytokines. The resulting
increase in hepatic amino acid transport provides the liver
with substrate to support key metabolic pathways during
catabolic states.
Feeding conjugated linoleic acid to animals
partially overcomes catabolic responses due to endotoxin
injection.
Miller CC, Park Y, Pariza MW, Cook ME
Poultry Science Dept., U.W. Madison 53706.
Biochem Biophys Res Commun 1994 Feb
15;198(3):1107-12
The ability of conjugated linoleic acid to prevent
endotoxin-induced growth suppression was examined. Mice fed a
basal diet or diet with 0.5% fish oil lost twice as much body
weight after endotoxin injection than mice fed conjugated
linoleic acid. By 72 hours post injection, mice fed conjugated
linoleic acid had body weights similar to vehicle injected
controls; however, body weights of basal and fish oil fed mice
injected with endotoxin were reduced. Conjugated linoleic acid
prevented anorexia from endotoxin injection. Splenocyte
blastogenesis was increased by conjugated linoleic acid.
The effect of polyunsaturated fatty acids on the
progress of cachexia in patients with pancreatic cancer
Wigmore SJ, Ross JA, Falconer JS, Plester CE, Tisdale MJ,
Carter DC, Fearon KC
University Department of Surgery, Royal Infirmary of
Edinburgh, UK.
Nutrition 1996 Jan;12(1 Suppl):S27-30
Cachexia is common in patients with pancreatic cancer and
has been associated with persistent activation of the hepatic
acute phase response and increased energy expenditure. Fatty
acids have been shown to have anticachectic effects in animal
models and to reduce inflammatory mediators in healthy
subjects and patients with chronic inflammatory disease.
Eighteen patients with unresectable pancreatic cancer received
dietary supplementation orally with fish oil capsules (1 g
each) containing eicosapentaenoic acid 18% and docosahexaenoic
acid 12%. Anthropometric measurement, body composition
analysis, and measurement of resting energy expenditure and
serum C-reactive protein were performed before and after
supplementation with a median of 12 g/day of fish oil.
Patients had a median weight loss of 2.9 kg/month (IQR 2- 4.6)
prior to supplementation. At a median of 3 months after
commencement of fish oil supplementation, patients had a
median weight gain of 0.3 kg/month (IQR 0.-0.5) (p <
0.002). Changes in weight were accompanied by a temporary but
significant reduction in acute phase protein production (p
< 0.002) and by stabilisation of resting energy
expenditure. This study suggests a component fish oil, perhaps
EPA, merits further investigation in the treatment of cancer
cachexia.
Comparison of the effectiveness of eicosapentaenoic
acid administered as either the free acid or ethyl ester as an
anticachectic and antitumour agent
Hudson EA, Tisdale MJ
CRC Nutritional Biochemistry Research Group, Aston
University, Birmingham, UK.
Prostaglandins Leukot Essent Fatty Acids 1994
Aug;51(2):141-5
A comparison has been made of the effectiveness of
eicosapentaenoic (EPA) acid administered as either the free
acid or the ethyl ester as an anticachectic and antitumour
agent in mice bearing an experimental cachexia-inducing tumour
(MAC16 colon adenocarcinoma). While the free acid of EPA was
effective in reversing host body weight loss and inhibiting
tumour growth the ethyl ester was ineffective in either
respect at the same dose level, even when administered with a
high fat diet. The lack of effectiveness of the ethyl ester
correlated with the inability to reach effective plasma and
tumour concentrations of EPA over the initial time period.
Whereas effective plasma concentrations of EPA were achieved
within 24 h after administration of the free acid, a time
lapse of 96 h was required with the ethyl ester, even when
combined with a high fat diet. Due to the acuteness of the
MAC16 model this time is too long for a therapeutic benefit to
be realized.
Kinetics of the inhibition of tumour growth in mice
by eicosapentaenoic acid-reversal by linoleic acid
Hudson EA, Beck SA, Tisdale MJ
Pharmaceutical Sciences Institute, Aston University,
Birmingham, U.K.
Biochem Pharmacol 1993 Jun 9;45(11):2189-94
Oral administration of eicosapentaenoic acid (EPA) (2.0
g/kg) by gavage to female NMRI mice bearing the MAC16 colon
adenocarcinoma and with weight loss, prevented further loss in
body weight and produced a delay in the growth of the tumour.
Cell production and loss were determined by the
(125I)5-iodo-2'-deoxyuridine method during the stationary and
growth phase of the tumour in animals treated with EPA. Tumour
stasis appeared to arise from an increase in the rate of cell
loss from 38 to 71% without a significant change in the
potential doubling time. During the subsequent growth phase
the cell loss factor was reduced to 52% and this was combined
with a reduced potential doubling time from 32 to 26 hr. The
antiproliferative, but not the anticachectic effect of EPA
could be reversed by oral administration of pure linoleic acid
(LA), (1.9 g/kg) which acted to increase tumour growth by
reducing the cell loss factor to 45%. Despite this reversal,
incorporation of EpA into tumour cell lipids was not
significantly different in animals administered with either
EpA alone or combined with LA. This suggests that the
antiproliferative effect of EPA in this system may arise from
an indirect effect through the blocking of the catabolic
effect of the tumour on host adipose tissue, which normally
supplies fatty acids essential for tumour growth. This
suggests that LA may be required by some tumours to prevent
cell loss and that the catabolism of adipose tissue, which
accompanies cancer cachexia effectively supplies this fatty
acid to the tumour.
Anticachectic and antitumor effect of
eicosapentaenoic acid and its effect on protein turnover
Beck SA, Smith KL, Tisdale MJ
Cancer Research Campaign Experimental Chemotherapy Group,
Aston University, Birmingham, United Kingdom.
Cancer Res 1991 Nov 15;51(22):6089-93
The effect of the polyunsaturated fatty acids
eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) on
host body weight loss and tumor growth has been investigated
in mice bearing a cachexia-inducing colon adenocarcinoma, the
MAC16. EPA effectively inhibited both host weight loss and
tumor growth rate in a dose-related manner with optimal
effects being observed at a dose level of 1.25 to 2.5 g/kg. At
these concentrations host body weight was effectively
maintained, and there was a delay in the progression of growth
of the tumor, such that overall survival was approximately
doubled in EPA- treated animals, using the criteria dictated
by the United Kingdom Coordinating Committee for the welfare
of animals with neoplasms. Even when tumor growth resumed,
weight loss did not occur. Animals bearing the MAC16 tumor
showed a decreased protein synthesis and an increased
degradation in skeletal muscle. Treatment with EPA
significantly reduced protein degradation without an effect on
protein synthesis. The effect of GLA on both host body weight
loss and tumor growth was much less pronounced than that of
EPA, with an effect only being seen at a dose of 5 g/kg, at
which some toxicity was observed. In vitro studies showed that
while EPA was effective in inhibiting tumor-induced lipolysis,
GLA was ineffective in this respect. However, prostaglandin
E1, which is formed from GLA in vivo, showed partial reversal
of tumor-induced lipolysis and probably accounted for the
anticachectic effect of GLA. These results suggest that EPA as
the pure fatty acid should be considered for clinical
investigation as both an anticachectic and antitumor agent,
since prior work has shown that the other major component of
fish oil docosahexaenoic acid is without pharmacological
activity in this system.
Muscle wasting and dedifferentiation induced by
oxidative stress in a murine model of cachexia is prevented by
inhibitors of nitric oxide synthesis and antioxidants
Buck M, Chojkier M
Department of Medicine, Veterans Affairs Medical Center, San
Diego, CA, USA.
EMBO J 1996 Apr 15;15(8):1753-65
Muscle wasting is a critical feature of patients afflicted
by AIDS or cancer. In a murine model of muscle wasting, tumor
necrosis factor alpha (TNFalpha) induces oxidative stress and
nitric oxide synthase (NOS) in skeletal muscle, leading to
decreased myosin creatinine phosphokinase (MCK) expression and
binding activities. The impaired MCK-E box binding activities
resulted from abnormal myogenin-Jun-D complexes, and were
normalized by the addition of Jun-D, dithiothreitol or Ref-1,
a nuclear redox protein. Treatment of skeletal muscle cells
with a phorbol ester, a superoxide-generating system, an NO
donor or a Jun-D antisense oligonucleotide decreased Jun-D
activity and transcription from the MCK-E box, which were
prevented by antioxidants, a scavenger of reducing
equivalents, a NOS inhibitor and/or overexpression of Jun-D.
The decreased body weight, muscle wasting and skeletal muscle
molecular abnormalities of cachexia were prevented by
treatment of TNFalpha mice with the antioxidants
D-alpha-tocopherol or BW755c, or the NOS inhibitor
nitro-L-arginine.
Modulation of immune function and weight loss by
L-arginine in obstructive jaundice in the rat
Kennedy JA, Kirk SJ, McCrory DC, Halliday MI, Barclay GR,
Rowlands BJ
Department of Surgery, Queen's University of Belfast,
UK.
Br J Surg 1994 Aug;81(8):1199-201
Jaundiced surgical patients have a high incidence of
postoperative complications. Many causative factors have been
identified including cachexia and immune suppression. The
amino acid L-arginine has anabolic and immunostimulatory
properties. It was hypothesized that dietary supplementation
with L-arginine would diminish the weight loss and immune
suppression of obstructive jaundice. Sixteen male Wistar rats
rendered jaundiced by bile duct ligation were allocated to two
groups. The test group (n = 8) received drinking water
supplemented with 1.8 per cent L-arginine ad libitum and the
control group (n = 8) received a solution of isonitrogenous
glycine. Both groups had free access to standard chow.
Body-weight, and fluid and food intake were recorded. After 21
days, delayed-type hypersensitivity to
2,4-dinitrofluorobenzene was assessed. Animals receiving
L-arginine consumed more food than controls (mean(s.e.m.)
414(16) versus 360(13) g, P < 0.05) and lost less weight
(mean(s.e.m.) proportion of initial body-weight lost 7.8(1.2)
versus 14.8(1.4) per cent, P < 0.05). The delayed-type
hypersensitivity response was significantly greater in rats
receiving L-arginine (mean(s.e.m.) increase in ear thickness
23.9(2.7) versus 9.4(2.1) per cent, P < 0.05). In this
animal model of obstructive jaundice dietary supplementation
with L-arginine diminished both weight loss and immune
suppression.
Effects of L-carnitine on serum triglyceride and
cytokine levels in rat models of cachexia and septic
shock
Winter BK, Fiskum G, Gallo LL
Department of Biochemistry and Molecular Biology, George
Washington University Medical Center, Washington, DC 20037,
USA.
Br J Cancer 1995 Nov;72(5):1173-9
Inappropriate hepatic lipogenesis, hypertriglyceridaemia,
decreased fatty acid oxidation and muscle protein wasting are
common in patients with sepsis, cancer or AIDS. Given
carnitine's role in the oxidation of fatty acids (FAs), we
anticipated that carnitine might promote FA oxidation, thus
ameliorating metabolic disturbances in lipopolysaccharide
(LPS)- and methylcholanthrene-induced sarcoma models of
wasting in rats. In the LPS model, rats were injected with LPS
(24 mg kg-1 i.p.), and treated with carnitine (100 mg kg-1
i.p.) at- 16, - 8, 0 and 8 h post LPS. Rat health was
observed, and plasma inflammatory cytokines and triglycerides
(TG) were measured before and 3 h post LPS. In the sarcoma
model, rats were implanted subcutaneously with tumour, and
treated continuously with carnitine (200 mg kg-1 day-1 i.p.)
via implanted osmotic pumps. Tumour burden, TG and cytokines
were measured weekly for 4 weeks. Carnitine treatment
significantly lowered the tumour-induced rise in TG (% rise)
in the sarcoma model (700 plus or minus 204 vs 251 plus or
minus 51, P<0.03) in control and carnitine groups
respectively. Levels of interleukin-1beta (IL-1beta),
interleukin-6 (IL-6) and tumour necrosis factor-cc (TNF-alpha)
(pg ml-1) were also lowered by carnitine in both LPS
(IL-1beta: 536 plus or minus 65 vs 378 plus or minus 44: IL-6:
271 plus or minus 29 vs 222 plus or minus 32; TNF-alpha: 618
plus or minus 86 vs 367 plus or minus 54, P less than or equal
to 0.02) and sarcoma models (IL-1beta: 423 plus or minus 33 vs
221 plus or minus 60; IL-6: 222 plus or minus 18 vs 139 plus
or minus 38; TNF-alpha: 617 plus or minus 69 vs 280 plus or
minus 77, P less than or equal to 0.05) for control and
carnitine groups respectively. We conclude that carnitine has
a therapeutic effect on morbidity and lipid metabolism in
these disease models, and that these effects could be the
result of down-regulation of cytokine production and/or
increased clearance of cytokines.
L-carnitine deficiency in AIDS patients
De Simone C, Tzantzoglou S, Jirillo E, Marzo A, Vullo V,
Martelli EA
Dipartimento di Medicina Sperimentale, Universita dell'
Aquila, Italy.
AIDS 1992 Feb;6(2):203-5
Objective: To evaluate carnitine
(3-hydroxy-4-N-trimethyl-ammoniobutanoat e) deficiency in AIDS
patients by measuring serum total, free and short-chain
carnitine concentrations.
Design: We conducted an open study.
Setting: All patients were seen at the Infectious Diseases
Clinic, Universita 'La Sapienza', Rome, Italy.
Patients, participants: Twenty-nine AIDS patients, aged
27-41 years, with a previous history of drug use; and 14
healthy age- and sex-matched controls were studied.
Interventions: Study subjects were administered 500-800 mg
zidovudine daily for 2 to 28 months (8 plus or minus 6
months). Main outcome measures: Carnitine deficiency was
suspected in study participants prior to data collection
because of previously reported cardiac symptoms, muscle
weakness, hypometabolism and/or cachexia.
Results: A marked decrease in total and free carnitine was
observed in 21 (72%) subjects Nine of these patients also had
low levels of short-chain carnitine.
Conclusions: AIDS patients may become carnitine-depleted
and therefore at risk for alterations in fatty-acid oxidation
and energy supply.
The enzymatic activities of branched-chain amino
acid catabolism in tumour-bearing rats
Argiles JM, Lopez-Soriano FJ
Departament de Bioquimica i Fisiologia, Facultat de Biologia,
Universitat de Barcelona, Spain.
Cancer Lett 1992 Jan 31;61(3):239-42
Rats bearing the Walker-256 carcinosarcoma showed
significant changes in branched-chain amino acid metabolism as
compared with their non-tumour-bearing controls. In vitro
measurement of branched-chain amino acid transaminase and
branched-chain 2-oxo acid dehydrogenase showed significant
increases in the skeletal muscle of tumour-bearing animals. In
addition, the circulating concentration of leucine was
increased in the tumour-bearing group. It can be concluded
that the metabolism of branched-chain amino acids in the host
is profoundly altered by the presence of a tumour and this may
well be one of the main factors contributing to the so-called
cancer cachexia.
Branched chain amino acids as the protein component
of parenteral nutrition in cancer cachexia
Hunter DC, Weintraub M, Blackburn GL, Bistrian BR
Laboratory of Nutrition and Infection, New England Deaconess
Hospital, Harvard Medical School, Boston, Massachusetts
02215.
Br J Surg 1989 Feb;76(2):149-53
A prospective randomized trial was conducted to determine
the effects of branched chain amino acids (BCAA) as the
protein component of total parenteral nutrition (TPN) on
protein kinetics in patients with intraabdominal
adenocarcinoma. Nine malnourished patients were given both
conventional TPN containing 19 per cent BCAA (AA) and
isocaloric, isonitrogenous TPN containing 50 per cent BCAA
(BCAA-TPN), in random order. Both (13C)leucine and
(14C)tyrosine were employed as tracers to avoid the potential
bias due to the different amino acid composition of the two
TPN solutions. With BCAA-TPN, leucine and tyrosine flux
increased significantly from (meanplus or minuss.d.) 158.0plus
or minus37.2 to 243.5plus or minus75.8 micromol kg-1h-1
(P<0.025) and from 35.0plus or minus8.4 to 42.6plus or
minus11.0 micromol kg-1h-1 (P<0.05) respectively. Leucine
oxidation was significantly higher on BCAA-TPN (24.1plus or
minus6.3 on AA versus 68.3plus or minus37.1 micromol kg-1h-1,
P<0.025) while tyrosine oxidation was significantly lower
(3.7plus or minus1.8 micromol kg-1h-1 on AA versus 2.5plus or
minus2.0 micromol kg-1h-1 on BCAA-TPN, P<0.05). Whole body
protein synthesis and breakdown was significantly higher on
BCAA-TPN by the tyrosine (31.3plus or minus7.3 on AA versus
40.1plus or minus9.3 micromol kg-1h-1, P<0.025 and 33.0plus
or minus8.4 on AA versus 41.3plus or minus11.1 micromol
kg-1h-1, P<0.05) respectively. Using the leucine tracers
both synthesis and breakdown were increased, but not
significantly, from 133.8plus or minus40.0 to 175.3plus or
minus65.1 micromol kg-1h-1 and from 127.9plus or minus33.6 to
167.7plus or minus71.2 micromol kg-1h-1 respectively. The
fractional albumin synthetic rate increased significantly on
BCAA-TPN from 4.3plus or minus2.9 on AA to 8.0plus or minus5.1
per cent per day (P<0.05). The reduction in tyrosine
oxidation, suggesting improved protein utilization, coupled
with an increase in protein and albumin synthesis, strongly
support a positive benefit from BCAA-TPN in cancer
cachexia.
Zinc in different tissues: Relation to age and
local concentrations in cachexia, liver cirrhosis and
long-term intensive care
Brandt G, Schenck J
Infusionsther Klin Ernahr 1979 Aug;6(4):225-9
Zinc concentrations in autopsy material of human heart
muscle, skeletal muscle, iliac crest, pancreas and liver were
analyzed by atomic absorption spectrophotometry. Age dependent
differences of zinc concentrations are seen in the liver. High
values show liver of premature infants, a minimum is measured
in childhood which is followed by an increase in adult and old
patients. The other organs show no significant changes.
Different diseases like diabetes or liver cirrhosis do not
influence the zinc concentration in skeletal muscle and iliac
crest. Long-term intensive care patients show a marked
decrease in zinc concentration of the heart muscle. In the
cirrhotic liver the zinc pool is depleted. In diabetes
mellitus zinc concentration of the whole pancreas is normal,
in cachexia it is critically decreased.
The role of serum protein in congestive heart
failure
Nambu S.; Masuda I.; Waki M.; Kasamatsu K.; Kurata M.; Koh
H.; Itoh A.; Hiramori K.
Clinical Research Institute, Cardiovascular Center, National
Zentsuji Hospital, Kagawa Japan
Nutritional support in organ failure: proceedings of the
International Symposium. ICS836 1990, (45-52)
We searched to elucidate the influence of hypoalbuminemia
upon congestive heart failure (CHF) by experimental aortic
regurgitation (AR) in dogs and by a follow-up study of
patients with CHF (NYHA classes III, IV). We found that (1) In
the dog with AR the incorporation of 14C-labeled glycine into
myocardial actomyosin was decreased in the condition of
hypoproteinemia produced by the combination of plasmapheresis
with a low protein diet. But this phenomenon was improved by
daily injection of vitamin B12 for 10 days. (2) In the study
on protein metabolism using 15N-labeled glycine in humans,
over 70 g day of protein intake (28% of total calorie intake)
was necessary to prevent a decrease in the active protein pool
produced by low calorie intake. (3) In the follow-up study on
patients with CHF, we found that the mortality rate from CHF
was worse in the patients with both low body mass index and
hypoalbuminemia. In conclusion, maintaining both serum albumin
and body weight on normal levels may be an important factor in
the management of CHF and the prevention of cachexia.
Clinical rise of a combination containing
phosphocreatinine as adjuvant to physiokinesiotherapy
Riabilitazione (Italy), 1976, 9/2 (51-62)
The authors make a clinical contribution to the therapeutic
use of phosphocreatinine, both alone and in combination with
vitamin B12, folic acid, vitamin B6 and fructose 1-6
diphosphate. The study was carried out on 24 adult patients of
both sexes, suffering from neuromyolesions (paraplegia,
hemiparesis, tetraparesis, neuraxitis, myopathy,
radiculoneuritis) and presenting, as therapeutic indications,
conditions of organic wasting, marked asthenia, cachexia, or
the requirement of physical performance and intense muscular
effort in connection with the use of kinesitherapy techniques.
An analysis of the collected data showed that both
phosphocreatinine preparations (the simple form and combined
with vitaminic coenzymes) induced significant improvements in
the initial symptomatology; no statistically significant
difference was observed between the 2 treatments. Particular
interest is placed on the finding with regard to the effect on
motor re education; in fact, the 2 preparations considered
phosphocreatinine influenced this parameter favourably in over
half the cases investigated. The drug was excellently
tolerated in all the cases studied, from both the clinical
point of view and the blood chemistry standpoint. In
conclusion, the results obtained make the therapeutic use of
phosphocreatinine undoubtedly useful as a valid factor in
association with physiokinesitherapy.
Myopathy and HIV infection
Chariot P, Gherardi R
Groupe de Recherche en Pathologie Neuromusculaire, Hopital
Henri Mondor, Creteil, France.
Curr Opin Rheumatol 1995 Nov;7(6):497-502
Skeletal muscle involvement may occur at all stages of HIV
infection. The most simple classification of muscular
disorders in HIV-infected patients is
1) HIV-associated myopathies,
2) zidovudine myopathy,
3) HIV wasting syndrome, and
4) opportunistic infections and tumoral infiltrations of
muscle.
Immunohistology for major histocompatibility complex class
1 antigen and histochemical reaction for cytochrome c oxidase
are helpful in correctly classifying a myopathy as HIV
polymyositis or zidovudine myopathy. Studies of cytokine
expression in HIV-infected patients and of supplementation
with compounds such as carnitine or micronutrients such as
selenium might yield new insights into the pathogenesis and
treatment of the various AIDS- associated muscular
disorders.
Effects of L-carnitine on serum triglyceride and
cytokine levels in rat models of cachexia and septic
shock
Winter BK, Fiskum G, Gallo LL
Department of Biochemistry and Molecular Biology, George
Washington University Medical Center, Washington, DC 20037,
USA.
Br J Cancer 1995 Nov;72(5):1173-9
Inappropriate hepatic lipogenesis, hypertriglyceridaemia,
decreased fatty acid oxidation and muscle protein wasting are
common in patients with sepsis, cancer or AIDS. Given
carnitine's role in the oxidation of fatty acids (FAs), we
anticipated that carnitine might promote FA oxidation, thus
ameliorating metabolic disturbances in lipopolysaccharide
(LPS)- and methylcholanthrene-induced sarcoma models of
wasting in rats. In the LPS model, rats were injected with LPS
(24 mg kg-1 i.p.), and treated with carnitine (100 mg kg-1
i.p.) at- 16, - 8, 0 and 8 h post LPS. Rat health was
observed, and plasma inflammatory cytokines and triglycerides
(TG) were measured before and 3 h post LPS. In the sarcoma
model, rats were implanted subcutaneously with tumour, and
treated continuously with carnitine (200 mg kg-1 day-1 i.p.)
via implanted osmotic pumps. Tumour burden, TG and cytokines
were measured weekly for 4 weeks. Carnitine treatment
significantly lowered the tumour-induced rise in TG (% rise)
in the sarcoma model (700 plus or minus 204 vs 251 plus or
minus 51, P<0.03) in control and carnitine groups
respectively. Levels of interleukin-1beta (IL-1beta),
interleukin-6 (IL-6) and tumour necrosis factor-cc (TNF-alpha)
(pg ml-1) were also lowered by carnitine in both LPS
(IL-1beta: 536 plus or minus 65 vs 378 plus or minus 44: IL-6:
271 plus or minus 29 vs 222 plus or minus 32; TNF-alpha: 618
plus or minus 86 vs 367 plus or minus 54, P less than or equal
to 0.02) and sarcoma models (IL-1beta: 423 plus or minus 33 vs
221 plus or minus 60; IL-6: 222 plus or minus 18 vs 139 plus
or minus 38; TNF-alpha: 617 plus or minus 69 vs 280 plus or
minus 77, P less than or equal to 0.05) for control and
carnitine groups respectively. We conclude that carnitine has
a therapeutic effect on morbidity and lipid metabolism in
these disease models, and that these effects could be the
result of down-regulation of cytokine production and/or
increased clearance of cytokines.
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