Gene/Protein Disease Symptom Drug Enzyme Compound
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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among neurodegenerative diseases, Alzheimer's disease (AD) is a leading cause of death in elderly individuals. AD is characterized, among other clinical findings, by unexplained weight loss, cachexia and altered immune function. To explore whether any relationship between gender and circulating levels of several eating-controlling metabolites exist, we evaluated leptin, tumor necrosis factor (TNF)-alpha, triiodothyronine (T(3)), free (F) thyroxine (T(4)), TSH, PRL, insulin (INS), and cortisol in 15 AD-treated patients (age range 55-82 years): 9 postmenopausal females (without hormone replacement therapy) and 6 males. The results (mean +/- SEM) indicated that circulating leptin levels were significantly (p < 0.05) higher in female AD (40.34 +/- 11.1 ng/ml) than in male AD (6.07 +/- 1.39 ng/ml) patients. The difference found in circulating leptin levels was noticed regardless of BMI (26.75 +/- 1.77 and 24.55 +/- 1.93 kg/m(2), in females and males, respectively) and waist:hip ratios (0.91 +/- 0.03 and 0.94 +/- 0.02, in females and males, respectively). Moreover, serum TNF-alpha concentrations were also significantly (p < 0.02) higher in AD females (12.24 +/- 1.47 pg/ml) than in AD males (6.62 +/- 1.44 pg/ml), regardless of TNF-alpha:BMI ratios (0.50 +/- 0.09 and 0.28 +/- 0.08, in females and males, respectively; p > 0.05). Finally, no differences were observed between gender (in female and male AD patients, respectively) in circulating levels of T(3) (151.33 +/- 9.91 vs. 116 +/- 17.04 ng/dl), FT(4) (1.26 +/- 0.08 vs. 1.24 +/- 0.06 ng/dl), TSH (1.28 +/- 0.16 vs. 2.46 +/- 0.67 microIU/ml), PRL (10.53 +/- 2.47 vs. 12.61 +/- 2.37 ng/ml), INS (11.76 +/- 1.95 vs. 8.59 +/- 1.34 microIU/ml) and cortisol (15.71 +/- 1.23 vs. 12.63 +/- 1.47 microg/dl). These results indicate that our AD group of patients, with normal corticoadrenal and thyroid functions and normoprolactinemia, displayed a gender-related characteristic in the circulating levels of two very important anorectic signals, leptin and TNF-alpha, being both higher in female than in male AD patients, regardless of BMI. Our study suggests that increased circulating levels of both anorexigenic adipokines may contribute to the metabolic changes observed in AD females.
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PMID:Alzheimer's disease patients display gender dimorphism in circulating anorectic adipokines. 1290 42

Gammadelta T lymphocytes make up approximately 50% of lymphocytes in the intestine. These cells have been shown to prime macrophages for TNF-alpha production after burn. We previously showed that neutralizing anti-TNF-alpha antibodies reduce mucosal atrophy by decreasing gut epithelial apoptosis after severe burn. We hypothesized that burn-induced mucosal turnover is diminished in T cell receptor delta gene knockout (TCR delta-/-) mice through diminished TNF-alpha activity. Forty-two wild-type and 42 TCR delta-/- mice (C57-BL6) were randomly assigned to burn and sham burn groups. The burn group underwent a 25% total body surface area (TBSA) scald burn. The proximal small intestine was harvested at 2, 12, and 48 h. To assess mucosal atrophy, mucosal height and cell numbers in the villi and crypts were determined on hematoxylin and eosin-stained tissue sections. Apoptotic gut epithelium was identified by terminal deoxyuridine nick-end labeling (TUNEL) staining, and cell proliferation was detected by immunostaining for proliferative cell nuclear antigen (PCNA). TNF-alpha mRNA expression was measured by RT-PCR. Caspase-8 activity was measured by colorimetric assay. Statistical analysis was performed with two-way analysis of variance and t testing. Significance was accepted at P < 0.05. Data are expressed as means +/- SEM. TNF-alpha mRNA expression was significantly decreased in TCR delta-/- mice at 2 h after burn. Gut epithelial apoptosis and proliferation in both wild-type and TCR delta-/- mice were significantly increased after burn, but TCR delta-/- mice had a significantly lower levels of apoptosis (P < 0.01) and proliferation (P < 0.05) when compared with wild-type mice. Burn-induced mucosal atrophy was identified in groups by decreasing villus height, crypt depth, and villus and crypt cell number (P < 0.001) compared with sham, but no difference was found between wild-type and TCR delta-/- mice. Caspase-8 activity was significantly diminished in TCR delta-/- mice compared with wild-type mice. Gammadelta T cells are associated with increased TNF-alpha expression and gut epithelial turnover in the small bowel after severe burn. However, absence of delta T cell receptor did not inhibit mucosal atrophy after severe burn. This study suggests that gut mucosal atrophy after severe burn is a multifactorial process associated with increased TNF-alpha activity.
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PMID:Burn-induced gut mucosal homeostasis in TCR delta receptor-deficient mice. 1467 84

This study examined the hypothesis that nicotinamide could attenuate endotoxin-induced inflammatory responses in humans as indicated by levels of cytokines and nitric oxide. Ten healthy male volunteers participated in a randomised, double-blind, cross-over design with regard to the effects of nicotinamide. The volunteers received orally 4 g nicotinamide or placebo at 14 h and at 2 h preceding the experiment (total dose of 8 g). Endotoxin (E. coli, 2 ng/kg), was administered intravenously. Blood samples and haemodynamic data were collected prior to and up to 6 h after the endotoxin infusion. Orally exhaled NO was measured hourly. Following endotoxin, body temperature increased from baseline 36.3 +/- 0.09 degrees C to a maximum of 38.0 +/- 0.1 degrees C for all (mean +/- SEM, P < 0.001) and heart rate increased from 59 +/- 1.9 to 87.0 +/- 2.6 beats/min after 3 h (mean +/- SEM, P < 0.001). Endotoxin challenge also markedly elevated the TNF-alpha, IL-6, IL-8 and IL-10 concentrations (P < 0.001 versus baseline for all) during the study period. Orally exhaled NO also increased (P < 0.01) compared to baseline. Nicotinamide treatment did not influence the patterns of cytokine and NO response to endotoxin. In conclusion, there was no effect on the inflammatory parameters by oral nicotinamide at a dose of 8 g, limiting the potential use of this agent for anti-inflammatory purpose in man.
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PMID:Nicotinamide does not influence cytokines or exhaled NO in human experimental endotoxaemia. 1467 71

Sepsis and its sequela remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Many models of neonatal sepsis have been developed for investigating the pathophysiology of this disease and application of therapy, and a model with an infectious focus is closer to clinical reality. To establish an animal model that mimics the clinical characteristics of neonatal sepsis, the cecal devascularization and perforation procedure was implemented on 15 mixed-strain newborn piglets, which produced an infectious focus that acted as a continuous source of microorganisms to the peritoneal cavity. The mean survival time in animals with sepsis was 10.4 h (range 5.5-17.9 h), whereas all of the sham-operated control animals survived more than 24 h. Animals with sepsis showed a gradual significant decrease in the mean systemic blood pressure (mSBP; 71 +/- 3 mmHg in sepsis vs. 64 +/- 3 mmHg in control at 3 h, 38 +/- 7 mmHg in sepsis vs. 59 +/- 4 mmHg in control at 6 h, mean +/- SEM). They also showed an increase of serum levels of endotoxin (5.6 x 10 +/- 4.5 x 10 pg/mL in sepsis vs. 6.0 x 10 +/- 3.8 x 10 pg/mL in control at 6 h). Serum levels of TNF-alpha in the animals with sepsis became significantly higher than the control animals at 0 h (96 +/- 31 pg/mL in sepsis vs. 12 +/- 1 pg/mL in control) and remained significantly higher than all through the experiment. Serum levels of IL-6 in animals with sepsis showed a gradual increase (484 +/- 231 pg/mL in sepsis in its peak at 6 h vs. 24 +/- 5 pg/mL in control), however, there were no significant differences in serum IL-10 levels between the groups. Microorganisms detected in the blood of animals with sepsis were gram-negative enteric and anaerobic organisms. These results suggested that this model mimics the clinical state of neonatal sepsis and hence may have significant implications for the treatment of sepsis, including its use as a model in further investigations.
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PMID:Development and characterization of a novel porcine model of neonatal sepsis. 1517 33

S100B protein (S100B) has been described as a marker of brain injury. Various cytokines also increase in the cerebrospinal fluid (CSF) of patients with severe traumatic brain injury (TBI). Thus, we investigated early changes in the concentrations of CSF S100B and various cytokines after TBI and evaluated the relations of both S100B and cytokines to intracranial pressure (ICP) and prognosis. Twenty-three patients with severe TBI and a Glasgow Coma Scale score of 8 or less on admission were included in this study. CSF and serum samples were obtained on admission and at 6, 12, 24, 48, 72, and 96 h after injury. CSF concentrations of S100B and CSF and serum concentrations of five cytokines (IL-1beta, TNF-alpha, IL-6, IL-8, and IL-10) were measured and compared. The CSF S100B concentration was increased for 6 h after injury and decreased thereafter. The CSF concentrations of IL-6 and IL-8 peaked within 6 h after injury; other cytokines (IL-1beta, TNF-alpha, and IL-10) were elevated for 24 h after injury and gradually decreased thereafter. Peak CSF S100B concentrations correlated significantly with ICP determined at the time CSF samples were taken (r = 0.729, P < 0.0001). For the cytokines investigated, only the peak CSF IL-1beta concentration correlated significantly and positively with the peak CSF S100B concentration (r = 0.397, P < 0.005). Peak CSF concentrations of S100B (1649 +/- 415 microg/L, mean +/- SEM) and IL-1beta (16.5 +/- 3.3 pg/mL) in the 6 patients with high ICP were significantly higher than those (233 +/- 67 microg/L, 7.6 +/- 1.7 pg/mL, respectively) in the 17 patients with low ICP (P < 0.05). The CSF S100B concentration (1231 +/- 378 microg/L) in eight patients with an unfavorable outcome was significantly higher than that (267 +/- 108 microg/L) in 15 patients with a favorable outcome (P < 0.05). The CSF IL-1beta concentration (14.8 +/- 3.4 pg/mL) in eight patients with an unfavorable outcome tended to be higher than that (7.3 +/- 1.5 pg/mL) in 15 patients with a favorable outcome (P = 0.057). CSF concentrations of S100B and cytokines peak within 24 h after severe TBI and decrease gradually thereafter. CSF S100B and IL-1beta may be useful as predictors of outcome in cases of severe TBI.
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PMID:Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. 1525 81

Activated myelin-specific T cells are thought to mediate inflammatory tissue damage in multiple sclerosis (MS). Applying a large panel of myelin antigens, we demonstrate the direct ex vivo detection of viable IFN-gamma/TNF-alpha producing CD4+/CD69+ T cells 6 hours after antigenic challenge, by intracellular flow cytometry in 3/33 MS patients and 2/26 healthy controls with calculated frequencies of (mean +/- SEM): 0.031% +/- 0.002% versus 0.037% +/- 0.029%. By comparison, the recently developed IL-7 modified proliferation assay revealed i) a higher number of individuals showing myelin reactivity (17/37 MS patients and 12/24 healthy individuals) and ii) a significant difference in the response to myelin basic protein (MBP) between the two groups in a longitudinal analysis, indicating a higher activity of myelin-specific T cells in MS patients. Our data provide new perspectives in detecting pathogenetically relevant T cells, but clearly demonstrate the different conclusions which must be drawn from various approaches concerning the quantification of autoreactive T cells.
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PMID:Cross-sectional and longitudinal analysis of myelin-reactive T cells in patients with multiple sclerosis. 1537 55

In vitro studies suggest that extracellular nucleotides and nucleosides may be important regulators of inflammatory and immune responses. Most studies with adenosine 5'-triphosphate (ATP) have been performed in cell lines, which are remote from the human situation. The purpose of the present study was to determine the effects of ATP on TNF-alpha, IL-6 and IL-10 release in stimulated whole blood. Blood samples were drawn from healthy volunteers and incubated with ATP and lipopolysaccharide (LPS) + phytohemagglutinin (PHA) for 24 h. Contrary to expectations, ATP at 100 microM and 300 microM induced a reduction in TNF-alpha secretion by 32+/-8% (mean +/- SEM) and 65+/-4%, respectively. Furthermore, these ATP concentrations induced an increase in IL-10 secretion by 48+/-5% and 62+/-7% in whole blood. The ATP analogue adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S) and adenosine 5'-diphosphate (ADP) also inhibited TNF-alpha release, but only ADP showed a stimulatory effect on IL-10. Co-treatment with adenosine deaminase did not reverse the ATP effect on TNF-alpha and IL-10. These results show, for the first time, that ATP inhibits the inflammatory response in stimulated whole blood as indicated by inhibition of TNF-alpha and stimulation of IL-10 release and that this effect is predominantly mediated by ATP and not by adenosine.
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PMID:Immunoregulatory effects of adenosine 5'-triphosphate on cytokine release from stimulated whole blood. 1571 72

We sought to determine if hypertonic saline (HTS) impacted alveolar macrophage (AM) activation and intracellular inflammatory gene signaling in a model of systemic inflammation. Rats received an intravenous administration of 4 mL/kg of 7.5% HTS or L-lactate lactated Ringer's (L-LR). They were simultaneously treated with an intraperitoneal injection of zymosan, which induces noninfectious systemic inflammation. AM were harvested by bronchoalveolar lavage 24 h after treatment. AM activation was analyzed by measurement of baseline and lipopolysaccharide (LPS)-induced TNF-alpha production. Intracellular signaling was analyzed for activation of the mitogen-activated protein kinases (MAPKs): ERK1/2, JNK, and p38. AM from HTS-treated rats produced less TNF-alpha than from L-LR-treated rats (927 +/- 335 pg/mL [SEM] vs. 3628 +/- 783 pg/mL [SEM], P = 0.001) and were also less responsive to LPS (4444 +/- 86 pg/mL [SEM] vs. 6666 +/- 91 pg/mL [SEM], P = 0.058). However, there was no difference in MAPK activation. In vivo HTS prevents excessive AM activation during systemic inflammation. This suppression is mediated through alternate pathways and does not induce the classic MAPK signaling cascade.
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PMID:Hypertonic saline modulates innate immunity in a model of systemic inflammation. 1583 13

Clinical experience suggests that the administration of fluids in human endotoxemia reduces symptoms. In the present study, the effects of a standardised fluid protocol on symptoms, inflammatory and hemodynamic parameters in human endotoxemia are determined. With approval of the local ethics committee, 16 healthy volunteers received 2 ng/kg of Escherichia coli endotoxin (O:113). After an overnight fast, nine subjects received 1.5 l of 2.5% glucose/0.45% NaCl the hour prior to the endotoxin administration and 150 ml/h during the course of the experiment ('prehydrated group'). Seven subjects only received a continuous infusion of 75 ml/h during the experiment ('non-prehydrated group'). The course of inflammatory parameters and symptoms were determined and mean arterial pressure, heart rate and forearm blood flow were measured. In the prehydrated group, TNF-alpha increased to 522 +/- 63 pg/ml (mean +/- SEM) while the maximum in the non-prehydrated group was 927 +/- 187 pg/ml (P < 0.04). IL-10 increased similarly in both groups (non-prehydrated 117 +/- 18 pg/ml and prehydrated 99 +/- 18 pg/ml; P = NS). The prehydrated group had a significantly lower (P < 0.004) symptom score and recovered sooner (P = 0.004). Endotoxin-induced changes in hemodynamics revealed no significant differences between groups. We demonstrate that prehydration in experimental human endotoxemia significantly shifts the cytokine balance towards a more anti-inflammatory pattern. This effect is associated with a reduction in symptoms, whereas the changes in hemodynamic parameters are not influenced by prehydration.
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PMID:Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia. 1626 1

The objective of this study was to investigate energy metabolism of the gut and liver as well as serum inflammatory cytokines following exploratory laparotomy at moderate hypothermia. Two groups of rats were studied, (n=6-8/group); laparotomy at normothermia for 120 min and laparotomy at hypothermia (32-33 degrees C) for 120 min. Study 1: Intestinal glucose, succinate, lactate, phosphocreatine, and ATP as well as hepatic glucose, succinate, lactate, and ATP were measured in terms of micromole per gram using magnetic resonance spectroscopy. Study 2: Serum levels of TNF-alpha, IL-1beta, LPS-inducible chemokine (LIX), and sICAM-1 were measured by ELISA. Histology of the gut and liver were interpreted. Data are expressed as mean and SEM. In Study 1, laparotomy at hypothermia caused an increase in intestinal glucose levels (0.78+/-0.03 vs. 1.29+/-0.11, P=0.0012) with a decrease in hepatic lactate levels (0.82+/-0.04 vs. 0.44+/-0.06, P<0.001). There were no differences in the other metabolites between the two groups. In Study 2, there were no differences in serum TNF-alpha, IL-1beta, LIX, or sICAM-1 between the two groups. Histological features of the gut and liver among groups were comparable. In conclusion, the intestine and liver react to hypothermia differently. However, levels of high-energy phosphates in both organs are not affected by hypothermia suggesting adequate energy for the organs. It is unlikely that hypothermia induces either systemic inflammatory response or hypoxic damage to the intestine and liver in this model.
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PMID:The effects of moderate hypothermia on energy metabolism and serum inflammatory markers during laparotomy. 1632 33


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