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1: Mol Cell Biochem. 1995 Jul 5;148(1):9-15.
Lipopolysaccharide (LPS) increases the in vivo oxidation of branched-chain amino acids in the rat: a cytokine-mediated effect.

* Garcia-Martinez C, * Llovera M, * Lopez-Soriano FJ, * del Santo B, * Argiles JM.

Departament de Bioquimica i Fisiologia, Universitat de Barcelona, Spain.

Septic rats (as induced by cecal puncture and ligation) showed an increased rate of in vivo leucine oxidation as measured from the formation of 14CO2 from an intravenously injected [1-14C]leucine tracer dose. Acute lipopolysaccharide (LPS) administration (1 mg/kg) to rats caused a similar effect on the rate of in vivo leucine oxidation. Additionally, both tumour necrosis factor-alpha (TNF) and interleukin-1-alpha (IL-1), in an acute dose of 100 micrograms/kg, also increased the rate of the oxidation of the amino acid, although only IL-1 caused a similar increase to that observed following LPS. The observed increased leucine oxidation was related to lower leucine concentrations both in LPS- and cytokine-treated rats. Important decreases were also observed in the other branched-chain amino acids (valine and isoleucine) in the LPS- and IL-1-treated animals. Isolated incubated muscles from TNF- and IL-1-treated rats did not show any changes in the rate of leucine utilization, thus suggesting that the mechanism by which the cytokines stimulate whole-body leucine oxidation is not based on an increase in the activity of the enzymatic machinery responsible for leucine oxidation. Additionally, glucocorticoids do not seem to mediate the enhanced in vivo oxidation of the amino acid since, although they are increased by both LPS and cytokines, treatment of the animals with RU486 (a glucocorticoid antagonist) was not able to suppress the effects of the cytokine on in vivo leucine oxidation.

PMID: 7476939 [PubMed - indexed for MEDLINE]

* Zhu Y,
* Carvey PM,
* Ling Z.

Department of Pharmacology, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA; Fujian Institute of Geriatrics, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, China.

We previously reported that injection of bacterial lipopolysaccharide (LPS) into gravid female rats at embryonic day 10.5 resulted in a birth of offspring with fewer than normal dopamine (DA) neurons along with innate immunity dysfunction and many characteristics seen in Parkinson's disease (PD) patients. The LPS-exposed animals were also more susceptible to secondary toxin exposure as indicated by an accelerated DA neuron loss. Glutathione (GSH) is an important antioxidant in the brain. A disturbance in glutathione homeostasis has been proposed for the pathogenesis of PD. In this study, animals prenatally exposed to LPS were studied along with an acute intranigral LPS injection model for the status of glutathione homeostasis, lipid peroxidation, and related enzyme activities. Both prenatal LPS exposure and acute LPS injection produced a significant GSH reduction and increase in oxidized GSH (GSSG) and lipid peroxide (LPO) production. Activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, was up-regulated in acute supranigral LPS model but was reduced in the prenatal LPS model. The GCS light subunit protein expression was also down-regulated in prenatal LPS model. GSH redox recycling enzyme activities (glutathione peroxidase, GPx and glutathione reducdase, GR) and glutathione-S-transferase (GST), gamma-glutamyl transpeptidase (gamma-GT) activities were all increased in prenatal LPS model. Prenatal LPS exposure and aging synergized in GSH level and GSH-related enzyme activities except for those (GR, GST, and gamma-GT) with significant regional variations. Additionally, prenatal LPS exposure produced a reduction of DA neuron count in the substantia nigra (SN). These results suggest that prenatal LPS exposure may cause glutathione homeostasis disturbance in offspring brain and render DA neurons susceptible to the secondary neurotoxin insult.

PMID: 17291629 [PubMed - in process]

Hyperalgesia is an extreme sensitivity to pain

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1: Pain. 1996 May-Jun;65(2-3):211-9. Hyperalgesia in rats following intracerebroventricular administration of endotoxin: effect of bradykinin B1 and B2 receptor antagonist treatment.

Walker K, Dray A, Perkins M.

Sandoz Institute for Medical Research, London, UK.

The present study investigated the development of thermal and mechanical hyperalgesia following intracerebroventricular (i.c.v.) injections of E. coli lipopolysaccharide (LPS). Hind paw withdrawal to von Frey filament stimulation and thermal withdrawal latencies were measured before and up to 24 or 48 h following an i.c.v. injection of LPS (dose range: 0.02--200 micrograms). Thermal and mechanical hyperalgesia were evident by 6 h after LPS injection. LPS-induced hyperalgesia was reversed by the B2 receptor antagonist, HOE 140 (10--30 pmol), when administered i.c.v. but not systemically (0.01--1 mmol/kg, i.v.). Central co-administration of the B1 receptor antagonists, des-Arg9-Leu8 Bk (0.1--1 nmol) or des-Arg10 HOE 140 (0.1--1 nmol) had no effect on thermal or mechanical hyperalgesia. LPS-induced hyperalgesia was also inhibited by indomethacin administered either i.c.v. (10 nmol) or i.v. (1 mumol/kg). These results indicate that administration of endotoxin to the CNS induces the development of hyperalgesia and that this response involves the activity of kinins, via the stimulation of centrally located B2 receptors, and the formation of prostanoids.

PMID: 8826509 [PubMed - indexed for MEDLINE]

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1: J Infect Dis. 1995 Jun;171(6):1539-44.
Mortality of Candida albicans-infected mice is facilitated by superinfection of Escherichia coli or administration of its lipopolysaccharide.

* Akagawa G, * Abe S, * Yamaguchi H.

Department of Microbiology and Immunology, Teikyo University School of Medicine, Tokyo, Japan.

Pathogenesis of complex infection with Candida albicans and gram-negative bacteria was studied by determining the influence of infection with Escherichia coli or injection of E. coli lipopolysaccharide (LPS) on mortality of C. albicans-infected mice. Mice were infected intravenously with lethal doses of C. albicans, then treated intravenously at various times with viable E. coli or E. coli LPS, which individually were not lethal. Treatments 3 h after C. albicans infection clearly facilitated the death of the mice. Corresponding to this facilitated death, production of tumor necrosis factor (TNF) in sera was augmented 2 h after LPS injection into the infected mice. Similar increased production of TNF was also observed in mice treated with a nonlethal combination of heat-killed C. albicans and LPS. The number of viable C. albicans in kidneys of the infected mice was increased by LPS treatment, which was assumed to be the main cause of the greater mortality rate.

PMID: 7769289 [PubMed - indexed for MEDLINE]

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1: Hepatology. 1997 May;25(5):1184-91.
Endotoxin impairs biliary glutathione and HCO3- excretion and blocks the choleretic effect of nitric oxide in rat liver.

* Trauner M, * Nathanson MH, * Rydberg SA, * Koeppel TA, * Gartung C, * Sessa WC, * Boyer JL.

Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520-8019, USA.

Cholestasis in patients with sepsis has been attributed to the effects of endotoxin (lipopolysaccharides, LPS) and LPS-induced cytokines, which are also potent stimulators of systemic and hepatic nitric oxide (NO) synthesis. NO donors stimulate bile acid-independent bile flow in normal rat liver, but the effects of LPS-induced NO on bile formation remain unclear. To address this question we examined the effects of NO and its mediator guanosine 3',5'-cyclic monophosphate (cGMP) on bile flow and biliary HCO3- and glutathione excretion in isolated perfused rat livers (IPRL) from LPS-treated rats. Portal and systemic NO2- + NO3- plasma levels were increased 47-fold in LPS-treated rats and were also elevated in perfusate (6-fold) and bile (9-fold) after isolating and perfusing livers from these animals. Bile flow, HCO3-, and glutathione output were decreased by 33%, 25%, and 81% in these IPRL, respectively. Stimulation of NO synthesis with L-arginine or inhibition of inducible NO synthesis with aminoguanidine did not change bile flow, although pretreatment with aminoguanidine inhibited NO production by 85%. Moreover, the choleretic effects of infusions of the NO donors sodium nitroprusside (SNP) and S-nitroso-acetyl-penicillamine were markedly reduced in endotoxemic IPRL compared with normal controls, and SNP-induced HCO3- and glutathione excretion were reduced by 61% and 86%, respectively. SNP-induced cyclic GMP production was 2.3-fold lower than in normals, but the choleretic effect of dibutyryl cGMP was only slightly reduced in endotoxemic livers. These findings indicate that LPS reduces bile acid-independent bile flow primarily by inhibiting biliary excretion of glutathione and to a lesser extent HCO3-, whereas LPS-induced NO does not modulate bile formation in endotoxemia. Thus, impairment of the major determinants of bile acid-independent bile flow by LPS may contribute significantly to the pathogenesis of the cholestasis of sepsis.

PMID: 9141437 [PubMed - indexed for MEDLINE]

Difficulties with Light Stimulation.

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1: Neuroimmunomodulation. 1996 Nov-Dec;3(6):352-7.
Effects of bacterial endotoxin on the glucocorticoid feedback regulation of adrenocortical response to stress.

* Weidenfeld J, * Yirmiya R.

Department of Neurology, Hadassah University Hospital, Jerusalem, Israel.

Previous studies have shown that LPS and cytokines modulate the binding of glucocorticoids (GCs) in the CNS, and therefore may affect the negative feedback exerted by GCs. In this study, we investigated the effect of lipopolysaccharide (LPS) on the inhibitory action of GCs upon the adrenocortical response to a neural stressful stimulus.

Male rats were treated with either LPS (50 micrograms/kg) or saline for 5 consecutive days. Two days later, the LPS- and saline-treated rats were injected intraperitoneally with either dexamethasone (20 micrograms/kg) or saline and sacrificed 3.5 h later, after exposure to acute stressful photic stimulation. In saline-pretreated rats, photic stimulation caused a 5-fold increase in serum corticosterone levels compared to basal levels, and pretreatment with dexamethasone completely abolished this response. In LPS-pretreated rats, corticosterone levels following photic stimulation increased 20-fold, and dexamethasone was ineffective.

Additional experiments were conducted to examine whether the impairment in the negative feedback was specific to the prolonged LPS treatment, rather than to LPS-induced hypersecretion of GCs. In groups of rats which were exposed to either daily acoustic stress or daily administration of corticosterone (5 mg, twice daily) for 5 days, the pattern of corticosterone secretion mimicked the corticosterone secretion induced by LPS. In these groups, the adrenocortical response to acute photic stimulation and the effect of dexamethasone were similar to saline-pretreated controls. These results suggest that LPS impairs the negative feedback of either endogenous or exogenous GC upon the adrenocortical response to stress. This finding may be relevant to the enhanced adrenocortical activity associated with sepsis and major depression.

PMID: 9266546 [PubMed - indexed for MEDLINE]

Many children with ASD show a decrease in zinc and an increase in copper. Some children with autism also show abnormal iron levels.

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1: Am J Vet Res. 2007 May;68(5):529-34.
Effects of intravenous infusion of lipopolysaccharide on plasma micromineral, magnesium, and cytokine concentrations and serum cortisol concentrations in lactating goats.

* Wang J, * Jiao L, * Ma J, * Wu C, * Wang K, * Wang M.

College of Veterinary Medicine, China Agricultural University, Beijing 100094, People's Republic of China.

Objective-To assess the effects of various doses of lipopolysaccharide (LPS) administered IV on plasma microminerals, magnesium, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 concentrations and serum cortisol concentrations in lactating goats. Animals-6 lactating goats. Procedures-Goats were allotted to 3 LPS-treatment groups: control (0 mug/kg), low LPS (10 mug/kg), and high LPS (50 mug/kg). Rectal temperatures and behaviors of goats were recorded immediately before a 10-minute IV infusion of LPS and at 0.5, 1, 2, 4, 6, 8, and 24 hours after infusion. Blood samples were obtained before IV infusion and at 0.5, 1, 2, 4, 6, 8, and 24 hours after infusion. Plasma zinc, copper, iron, and magnesium concentrations were determined by atomic absorption spectrometry; plasma TNF-alpha and IL-6 concentrations were measured by use of an ELISA; and serum cortisol concentrations were determined by use of a radioimmunoassay. Results-A monophasic fever developed in low-LPS and high-LPS groups. In the low-LPS and high-LPS group, plasma zinc concentrations decreased at 6 hours after infusion; compared with control groups. Plasma iron concentrations were lower at 24 hours after infusion in low-LPS and high-LPS groups than in the control group. Plasma TNF-alpha and IL-6 concentrations were higher in low-LPS and high-LPS groups than in the control group at 1, 2, and 4 hours after infusion. In low-LPS and high-LPS groups, serum cortisol concentrations increased from 0.5 hours onward and peaked at 1 (high-LPS group) and 2 (low-LPS group) hours after infusion. Conclusions and Clinical Relevance-Following IV infusion of LPS, the immune system is activated, which might affect micromineral homeostatic regulation and, subsequently, the metabolic health of lactating goats.

PMID: 17472454 [PubMed - in process]

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Biochem. J. (1996) 314 (793�797) (Printed in Great Britain)

Trace metal, acute phase and metabolic response to endotoxin in metallothionein-null mice
Allan M. ROFE*, Jeffrey C. PHILCOX and Peter COYLE

Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000, Australia

Accumulation of hepatic zinc via metallothionein (MT) induction during infection/inflammation is postulated to benefit a range of metabolic processes. The metabolic consequences of two doses of endotoxin (LPS) (1 and 5 mg/kg, intraperitoneally) were examined in normal (MT+/+) and MT-null (MT-/-) mice (all results means�S.E.M., n = 6). At 16 h after 1 mg/kg LPS, hypozincaemia was pronounced in the MT+/+ mice (4.4�0.2 mM), concomitant with a 36% increase in hepatic Zn and a > 10-fold increase in hepatic MT. Plasma Zn (16.6�0.7 mM) and total hepatic Zn were unchanged in MT-/- mice, confirming the importance of MT in altering plasma and hepatic Zn during inflammation. Plasma iron was lower in LPS-treated MT-/- mice, whereas plasma copper increased to a similar extent in both groups of mice. Plasma fibrinogen more than doubled, and was similar in both groups of mice, which questions the importance of MT in acute-phase protein synthesis. Blood and liver glucose concentrations were not significantly different between groups before or after LPS, whereas blood and liver lactate concentrations were significantly lower (31% and 24% respectively) in MT-/- mice after LPS. At 16 h after 5 mg/kg LPS, plasma Zn was decreased even further in MT+/+ mice (2.6�0.3 mM), but remained unchanged in MT-/- mice at concentrations significantly above those in 16 h-fasted MT-/- mice (15.8�0.5 versus 11.3�0.3 mM). Total liver Zn was 17% lower than fasting values in MT-/- mice, in contrast with 32% higher in MT+/+ mice. Synthesis of MT (in MT+/+ mice) and fibrinogen in all mice was not further enhanced by the higher LPS dose. Blood glucose was significantly decreased by 18% in MT+/+ mice and by 38% in MT-/- mice after 5 mg/kg LPS. There was a marked 44% decrease in liver glucose in MT-/- mice; that in MT+/+ mice was unchanged from fasting levels, implying a deficit in hepatic gluconeogenesis in LPS-treated MT-/- mice. In the absence of any indication of major hepatotoxicity, the results of this study indicate that energy production, and not acute-phase protein synthesis, may be most influenced by Zn supply during endotoxaemia, suggesting that MT has a role in maintaining hepatic and blood glucose in this metabolic setting.

Abbreviations used: MT, metallothionein; LPS, endotoxin (lipopolysaccharide); LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PEPCK, phosphoenolpyruvate carboxykinase.

* To whom correspondence should be addressed.