4-hydroxy-2-nonenal and Acute-Disease

Muscle dysfunction is a major problem in chronic obstructive pulmonary disease (COPD), particularly after exacerbations. We thus asked whether neuromuscular electrostimulation (NMES) might be directly useful following an acute exacerbation and if such a therapy decreases muscular oxidative stress and/or alters muscle fibre distribution. A pilot randomised controlled study of NMES lasting 6 weeks was carried out in 15 in-patients (n=9 NMES; n=6 sham) following a COPD exacerbation. Stimulation was delivered to the quadriceps and hamstring muscles (35 Hz). Primary outcomes were quadriceps force and muscle oxidative stress. At the end of the study, quadriceps force improvement was statistically different between groups (p=0.02), with a significant increase only in the NMES group (median (interquartile range) 10 (4.7-11.5) kg; p=0.01). Changes in the 6-min walking distance were statistically different between groups (p=0.008), with a significant increase in the NMES group (165 (125-203) m; p=0.003). NMES did not lead to higher muscle oxidative stress, as indicated by the decrease in total protein carbonylation (p=0.02) and myosin heavy chain carbonylation (p=0.01) levels. Finally, we observed a significant increase in type I fibre proportion in the NMES group. Our study shows that following COPD exacerbation, NMES is effective in counteracting muscle dysfunction and decreases muscle oxidative stress.

Topics: Acute Disease; Aged; Aldehydes; Catalase; Electric Stimulation Therapy; Female; Glutathione Reductase; Humans; Lipid Peroxidation; Male; Middle Aged; Muscle Contraction; Muscle Fibers, Slow-Twitch; Muscular Diseases; Oxidative Stress; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Quadriceps Muscle; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Topics: Acute Disease; Acute Lung Injury; Aldehydes; Animals; Autophagy; Autophagy-Related Protein 5; Beclin-1; Down-Regulation; Inflammation; Kelch-Like ECH-Associated Protein 1; Lung; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Pancreatitis; Protective Agents; Reactive Oxygen Species; Sequestosome-1 Protein; Signal Transduction; Sitagliptin Phosphate

We aimed to evaluate the effects of unilateral vagotomy (right-VR or left-VL) on the severity of caerulein-induced acute pancreatitis (AP).. VR or VL was done in Wistar rats 4 days before AP, except in control, sham operated group. Following 5 h administration of subcutaneous injections of caerulein, the pancreatic blood flow (PBF), serum lipase and IL-10 in caval blood samples were measured. The pancreatic specimens were taken from sacrificed rats for the assessment of MDA-4-HNE and morphology.. PBF decreased from 310 ± 20 ml/min/100 g of tissue in control rats to 130 ± 12 units in AP (p < 0.01). VR and VL alleviated this effect to 234 ± 22 and 229 ± 26 units, respectively, (p < 0.01). There was an immense increase of serum lipase in AP, from 100 ± 7 U/L up to 5220 ± 210 U/L (p < 0.01). Only VL limited this increase to 3469 ± 300 U/L (p < 0.01). Serum IL-10 increased uniformly in AP, without any effect of preceding VR or VL. VL performed in rats subjected subsequently to AP resulted in stronger reduction of histological changes, such as pancreatic edema and leukocyte infiltration, than the above parameters in AP rats with VR. MDA+4-HNE increased from 7.5 ± 0.1 pmol/g of tissue in control group to 30.6 ± 3 units in AP group (p < 0.01). Concentration of MDA+4-HNE in pancreatic tissue achieved 16.48 ± 3 pmol/g after VR and 13.84 ± 4 pmol/g following VL.. Our observation might suggest that protective effect of VL could be stronger than VR in the protection on AP. However changes of PBF seem to be similar in both groups of rats.

Topics: Acute Disease; Aldehydes; Animals; Interleukin-10; Lipase; Male; Malondialdehyde; Organ Size; Pancreas; Pancreatitis; Rats, Wistar; Regional Blood Flow; Vagotomy

Melatonin protects the pancreas from inflammation and free radical damage but the effect of the melatonin metabolite: N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on acute pancreatitis is unknown. This study assessed the effects of AFMK on acute pancreatitis (AP) in the rats in vivo and on pancreatic cell line AR42J in vitro. AFMK (5, 10 or 20 mg/kg) was given intraperitoneally to the rats 30 min prior to the induction of AP by subcutaneous caerulein infusion (25 μg/kg). Lipid peroxidation products (MDA + 4-HNE) and the activity of an antioxidant enzyme glutathione peroxidase (GPx) were measured in pancreatic tissue. Blood samples were taken for evaluation of amylase activity and TNF-α concentration. GPx, TNF-α, proapoptotic Bax protein, antiapoptotic Bcl-2 protein and the executor of apoptosis, caspase-3, were determined by Western blot in AR42J cells subjected to AFMK or to melatonin (both used at 10(-12), 10(-10), or 10(-8)M), without or with addition of caerulein (10(-8)M). AP was confirmed by histological examination and by serum increases of amylase and TNF-α (by 800% and 300%, respectively). In AP rats, pancreatic MDA + 4-HNE levels were increased by 300%, whereas GPx was reduced by 50%. AFMK significantly diminished histological manifestations of AP, decreased serum amylase activity and TNF-α concentrations, reduced MDA + 4-HNE levels and augmented GPx in the pancreas of AP rats. In AR42J cells, AFMK combined with caerulein markedly increased protein signals for GPx, Bax, caspase-3 and reduced these for TNF-α and Bcl-2. In conclusion, AFMK significantly attenuated acute pancreatitis in the rat. This may relate to the antioxidative and anti-inflammatory effects of this molecule and possibly to the stimulation of proapoptotic signal transduction pathway.

Topics: Acute Disease; Aldehydes; Amylases; Animals; Anti-Inflammatory Agents; Antioxidants; bcl-2-Associated X Protein; Caspase 3; Cell Line, Tumor; Glutathione Peroxidase; Kynuramine; Male; Malondialdehyde; Melatonin; Pancreas; Pancreatitis; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; Tumor Necrosis Factor-alpha

Oxidative stress and inflammation contribute to hepatic injury after hemorrhage/resuscitation (H/R). Natural plant polyphenols, i.e., green tea extract (GTE) possess high anti-oxidant and anti-inflammatory activities in various models of acute inflammation. However, possible protective effects and feasible mechanisms by which plant polyphenols modulate pro-inflammatory, apoptotic, and oxidant signaling after H/R in the liver remain unknown. Therefore, we investigated the effects of GTE and its impact on the activation of NF-kappaB in the pathogenesis of hepatic injury induced by H/R.. Twenty-four female LEWIS rats (180-250 g) were fed a standard chow (ctrl) or a diet containing 0.1% polyphenolic extracts (GTE) from Camellia sinensis starting 5 days before H/R. Rats were hemorrhaged to a mean arterial pressure of 30 ± 2 mmHg for 60 min and resuscitated (H/R and GTE H/R groups). Control groups (sham, ctrl, and GTE) underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested.. Plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increased 3.5-fold and fourfold, respectively, in vehicle-treated rats as compared to GTE-fed rats. Histopathological analysis revealed significantly decreased hepatic necrosis and apoptosis in GTE-fed rats after H/R. Real-time PCR showed that GTE diminished gene expression of pro-apoptotic caspase-8 and Bax, while anti-apoptotic Bcl-2 was increased after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress as well as systemic IL-6 level and hepatic IL-6 mRNA were markedly reduced in GTE-fed rats compared with controls after H/R. Plant polyphenols also decreased the activation of both JNK and NFκB.. Taken together, GTE application blunts hepatic damage, apoptotic, oxidative, and pro-inflammatory changes after H/R. These results underline the important roles of JNK and NF-kappaB in inflammatory processes after H/R and the beneficial impact of plant polyphenols in preventing their activation.

Topics: Acute Disease; Alanine Transaminase; Aldehydes; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspase 8; Female; Gene Expression Regulation; Hemorrhage; Inflammation; Interleukin-6; L-Lactate Dehydrogenase; Liver; NF-kappa B; Oxidative Stress; Plant Extracts; Polyphenols; Rats; Rats, Inbred Lew; Resuscitation; RNA; Tea; Tyrosine

Our laboratory has shown that λ-carrageenan-induced peripheral inflammatory pain (CIP) can alter tight junction (TJ) protein expression and/or assembly leading to changes in blood-brain barrier xenobiotic permeability. However, the role of reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e., superoxide) are known to cause cellular damage in response to pain/inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain barrier (BBB) in CIP rats. During CIP, increased staining of nitrosylated proteins was detected in hind paw tissue and enhanced presence of protein adducts containing 3-nitrotyrosine occurred at two molecular weights (i.e., 85 and 44 kDa) in brain microvessels. Tempol, a pharmacological ROS scavenger, attenuated formation of 3-nitrotyrosine-containing proteins in both the hind paw and in brain microvessels when administered 10 min before footpad injection of λ-carrageenan. Similarly, CIP increased 4-hydroxynoneal staining in brain microvessels and this effect was reduced by tempol. Brain permeability to [(14)C]sucrose and [(3)H]codeine was increased, and oligomeric assemblies of occludin, a critical TJ protein, were altered after 3 h CIP. Tempol attenuated both [(14)C]sucrose and [(3)H]codeine brain uptake as well as protected occludin oligomers from disruption in CIP animals, suggesting that ROS production/oxidative stress is involved in modulating BBB functional integrity during pain/inflammation. Interestingly, tempol administration reduced codeine analgesia in CIP animals, indicating that oxidative stress during pain/inflammation may affect opioid delivery to the brain and subsequent efficacy. Taken together, our data show for the first time that ROS pharmacological scavenging is a viable approach for maintaining BBB integrity and controlling central nervous system drug delivery during acute inflammatory pain.

Topics: Acute Disease; Aldehydes; Analgesics, Opioid; Animals; Antioxidants; Blood-Brain Barrier; Capillary Permeability; Carbon Radioisotopes; Codeine; Cyclic N-Oxides; Cysteine Proteinase Inhibitors; Hyperalgesia; Male; Membrane Proteins; Neuralgia; Neuritis; Occludin; Oxidative Stress; Rats; Rats, Sprague-Dawley; Spin Labels; Sucrose; Tight Junctions; Tyrosine; Xenobiotics

Lipid peroxidation is highly associated with chronic degenerative diseases such as cancer. 4-hydroxy-2-nonenal is one of the major products of lipid peroxidation. 4-hydroxy-2-nonenal can interact with biomolecules, changing their conformation and activity. This study presents 4-hydroxy-2-nonenal-protein adducts formation in the first stages of Long-Evans Cinnamon rat hepatitis, a well recognized model for oxidative stress-associated hepatocarcinogenesis. 4-hydroxy-2-nonenal-protein adducts appeared in hepatocyte cytoplasm before the beginning of hepatitis and their presence was very strong during hepatitis, while a transient perinuclear expression of 4-hydroxy-2-nonenal-protein adducts was shown mainly at early hepatitis stages. 4-hydroxy-2-nonenal-protein adducts formation correlated to the expression of the tumour marker glutathione S-transferase P-form. These results show that lipid peroxidation modification of proteins might be implicated in the first stages of hepatocyte cancer initiation in Long-Evans Cinnamon rats.

Topics: Acute Disease; Aldehydes; Animals; Disease Models, Animal; Hepatitis B; Lipid Peroxidation; Liver Neoplasms; Male; Oxidative Stress; Penicillamine; Precancerous Conditions; Proteins; Rats; Rats, Inbred LEC

Following traumatic brain injury (TBI), mitochondrial function becomes compromised. Mitochondrial dysfunction is characterized by intra-mitochondrial Ca(2+) accumulation, induction of oxidative damage, and mitochondrial permeability transition (mPT). Experimental studies show that cyclosporin A (CsA) inhibits mPT. However, CsA also inhibits calcineurin. In the present study, we conducted a dose-response analysis of NIM811, a non-calcineurin inhibitory CsA analog, on mitochondrial dysfunction following TBI in mice, and compared the effects of the optimal dose of NIM811 (10 mg/kg i.p.) against an optimized dose of CsA (20 mg/kg i.p.). Male CF-1 mice were subjected to severe TBI utilizing the controlled cortical impact model. Mitochondrial respiration was assessed from animals treated with either NIM811, CsA, or vehicle 15 min post-injury. The respiratory control ratio (RCR) of mitochondria from vehicle-treated animals was significantly (p<0.01) lower at 3 or 12 h post-TBI, relative to shams. Treatment of animals with either NIM811 or CsA significantly (p<0.03) attenuated this reduction. Consistent with this finding, both NIM811 and CsA significantly reduced lipid peroxidative and protein nitrative damage to mitochondria at 12 h post-TBI. These results showing the ability of NIM811 to fully duplicate the mitochondrial protective efficacy of CsA supports the conclusion that inhibition of the mPT may be sufficient to explain CsA's protective effects.

Topics: Acute Disease; Aldehydes; Animals; Biomarkers; Brain Injuries; Cyclosporine; Dose-Response Relationship, Drug; Immunoblotting; Lipid Peroxidation; Male; Mice; Mitochondrial Diseases; Oxidative Stress; Oxygen Consumption; Structure-Activity Relationship; Tyrosine

The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production.. (1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia-reperfusion in rats with NASH.. Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H(2)O(2) synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)-protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia-reperfusion injury.. NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE-protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia-reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress.. Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia-reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.

Topics: Acute Disease; Adenosine Triphosphatases; Adenosine Triphosphate; Adult; Aldehydes; Animals; Disease Progression; Fatty Liver; Female; Humans; Ion Channels; Liver; Male; Membrane Potential, Mitochondrial; Middle Aged; Mitochondria, Liver; Mitochondrial Proteins; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Uncoupling Protein 2

Bacterial endotoxin (lipopolysaccharide, LPS), at high concentration is responsible for sepsis, and neonatal mortality, however low concentration of LPS protected the pancreas against acute damage. The aim of this study was to investigate the effect of exposition of suckling rats to LPS on the course of acute pancreatitis at adult age. Suckling rat (30-40g) received intraperitoneal (i.p.) injection of saline (control) or LPS from Escherichia coli or Salmonella typhi (5, 10 or 15 mg/kg-day) during 5 consecutive days. Two months later these rats have been subjected to i.p. cearulein infusion (25 microg/kg) to produce caerulein-induced pancreatitis (CIP). The following parameters were tested: pancreatic weight and morphology, plasma amylase and lipase activities, interleukin 1beta (IL-1 beta), interleukin 6 (IL-6), and interleukin 10 (IL-10) plasma concentrations. Pancreatic concentration of superoxide dismutase (SOD) and lipid peroxidation products; malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) have been also measured. Caerulein infusion produced CIP in all animals tested, that was confirmed by histological examination. In the rats, which have been subjected in the neonatal period of life to LPS at doses 10 or 15 mg/kg-day x 5 days, all manifestations of CIP have been reduced. In these animals acute inflammatory infiltration of pancreatic tissue and pancreatic cell vacuolization have been significantly diminished. Also pancreatic weight, plasma lipase and alpha-amylase activities, as well as plasma concentrations of IL-1beta and IL-6 have been markedly decreased, whereas plasma anti-inflammatory IL-10 concentration was significantly increased in these animals as compared to the control rats, subjected in the infancy to saline injection instead of LPS. Caerulein-induced fall in pancreatic SOD concentration was reversed and accompanied by significant reduction of MDA + 4 HNE in the pancreatic tissue. The effects of LPS derived from E. coli or S. typhi were similar. Pretreatment of suckling rats with LPS at dose of 10 mg/kg-day x 5 days resulted in the most prominent attenuation of acute pancreatitis at adult age, whereas LPS at dose of 5 mg/kg-day x 5 days given to the neonatal rats failed to affect significantly acute pancreatitis induced in these animals 2 months later. We conclude that: 1/ Prolonged exposition of suckling rats to bacterial endotoxin attenuated acute pancreatitis induced in these animals at adult age. 2/ This effect could be related to

Topics: Acute Disease; Aldehydes; alpha-Amylases; Animals; Animals, Newborn; Ceruletide; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxemia; Interleukins; Lipase; Lipid Peroxidation; Lipopolysaccharides; Male; Malondialdehyde; Organ Size; Pancreas; Pancreatitis; Rats; Rats, Wistar; Severity of Illness Index; Superoxide Dismutase; Time Factors

Increased hepatic sympathetic activity affects hepatic metabolism and hemodynamics and subsequently causes acute hepatic injury. We examined whether the vesicovascular reflex evoked by bladder overdistension could affect hepatic function, specifically reactive oxygen species (ROS)-induced inflammation and apoptosis, through activation of the hepatic sympathetic nerve. We evaluated the hepatic hemodynamics, hepatic sympathetic nervous activities, and cystometrograms in anesthetized rats subjected to acute urinary retention. We used a chemiluminescence method, an in situ nitro blue tetrazolium perfusion technique, and a DNA fragmentation/apoptosis-related protein assay to demonstrate de novo and colocalize superoxide production and apoptosis formation in rat liver. Acute urinary retention increased the hepatic sympathetic-dependent vesicovascular reflex, which caused hepatic vasoconstriction/hypoxia and increased superoxide anion production from the periportal Kupffer cells and hepatocytes, which were aggravated by the increase in volume and duration of urinary retention. The ROS-enhanced proinflammatory NF-kappaB, activator protein-1, and ICAM-1 expression also promoted proapoptotic mechanisms, including increases in the Bax/Bcl-2 ratio, CPP32 expression, poly-(ADP-ribose)-polymerase cleavages, and DNA fragmentation and apoptotic cells in the liver. The proinflammatory and proapoptotic mechanisms were significantly attenuated in rats treated with hepatic sympathetic nerve denervation or catechin (antioxidant) supplement. In conclusion, our results suggest that acute urine retention enhances hepatic sympathetic activity, which causes hepatic vasoconstriction and evokes proinflammatory and proapoptotic oxidative injury in the rat liver. Reduction of the hepatic sympathetic tone or antioxidant supplement significantly attenuates these injuries.

Topics: Acute Disease; Aldehydes; Animals; Bile; DNA Fragmentation; Female; Gene Expression; Hepatitis; Intercellular Adhesion Molecule-1; Liver; Nitroblue Tetrazolium; Rats; Rats, Wistar; Reactive Oxygen Species; Reflex; Staining and Labeling; Sympathetic Nervous System; Urinary Bladder; Urinary Retention

4-Hydroxynonenal (HNE) is a putative pro-fibrogenic product of oxidative stress able to elicit apoptosis and cytotoxicity in several cell types. This study has been performed to evaluate its 'in vivo' levels in injured liver and whether HNE may induce apoptosis and/or affect selected phenotypic responses in activated human hepatic stellate cells (HSC/MF).. During the development of acute liver injury induced by CCl(4), liver tissue HNE levels were in the range 0.5-10 microM, as shown by high performance liquid chromatography analysis. Cultured human HSC/MF, developed cytotoxicity only if exposed to very high HNE concentrations (25-50 microM) without any sign of induction of classic, caspase-dependent apoptosis, as assessed by evaluating morphology and biochemical parameters of cell death. HNE, at non-cytotoxic doses, up-regulated procollagen type I and tissue inhibitor of metalloproteinases-1 gene expression and/or protein synthesis without significantly affecting chemotaxis (wound healing and haptotaxis assay), matrix metalloproteinases 1 and 2 mRNA expression and activity as well as basal DNA synthesis.. HNE, at concentrations compatible with those detected in vivo, does not elicit HSC/MF classic apoptosis but, rather, may act as a potent pro-fibrogenic stimulus for the expression of genes involved in excess extracellular matrix deposition and proposed as survival signals for HSC/MF.

Topics: Actins; Acute Disease; Aldehydes; Animals; Apoptosis; Carbon Tetrachloride; Cell Death; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytoskeleton; Dose-Response Relationship, Drug; Extracellular Matrix; Gene Expression; Humans; Liver; Liver Cirrhosis; Liver Diseases; Male; Osmolar Concentration; Phenotype; Rats; Rats, Wistar; Signal Transduction

Melatonin, produced from L-tryptophan, protects the pancreas against acute damage by improving the antioxidative status of tissue. Melatonin receptors have been detected in the brain, but the contribution of these receptors to the pancreatic protection is unknown. The aim of our study was to compare the effects of melatonin precursor; L-tryptophan given intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) on the course of acute pancreatitis. Acute pancreatitis was induced by subcutaneous infusion of caerulein (5 microg/kg-h x 5 h). L-tryptophan was given i.p. (2.5, 25 or 250 mg/kg) or administered into right cerebral ventricle (0.02, 0.2 or 2.0 mg/rat) 30 min prior to the start of caerulein infusion. Plasma amylase, lipase and TNF alpha activities were measured to determine the severity of caerulein-induced pancreatitis (CIP). The lipid peroxidation products: malonylodialdehyde and 4-hydroksynonenal (MDA + 4-HNE) and activity of superoxide dismutase (SOD) were measured in the pancreas of intact or CIP rats with or without L-tryptophan pretreatment. Melatonin blood level was measured by RIA. CIP was confirmed by histological examination and manifested as an edema and rises of plasma levels of amylase, lipase and TNF alpha (by 550%, 1000% and 600%). MDA + 4-HNE was increased by 600%, whereas SOD activity was reduced by 75% in the pancreas of CIP rats. All manifestations of CIP were significantly reduced by pretreatment of the rats with L-tryptophan given i.c.v. at doses of 0.2 or 2.0 mg/rat, or by peripheral administration of this amino acid used at dose of 250 mg/kg i.p. In control rats plasma level of melatonin averaged about 40 +/- 2 pg/ml and was not significantly affected by CIP, by central application of L-tryptophan (0.02, 0.2 or 2.0 mg/rat) or by peripheral administration of this melatonin precursor used at doses of 2.5 or 25 mg/kg i.p. Plasma melatonin level was markedly increased by pretreatment of the rats with L-tryptophan given i.p. at dose of 250 mg/kg. We conclude that central administration of melatonin precursor; L-tryptophan, as well as peripheral application of high dose of this melatonin precursor prevented the pancreatic damage produced by CIP. The favorable effect of peripherally administered L-tryptophan could be related to the rise of melatonin plasma level and to pancreatoprotective action of this indoleamine. The beneficial effect of centrally administered L-tryptophan could be mediated through activation of central recep

Topics: Acute Disease; Aldehydes; Amylases; Animals; Ceruletide; Dose-Response Relationship, Drug; Drug Administration Schedule; Infusions, Parenteral; Injections, Intraperitoneal; Injections, Intraventricular; Lipase; Male; Malondialdehyde; Melatonin; Organ Size; Pancreas; Pancreatitis; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Tryptophan; Tumor Necrosis Factor-alpha

Excessive inflammatory response is one of the major causes of early mortality in acute pancreatitis (AP).. To evaluate the serum profiles of E-selectin, interleukin (IL)-6, and IL-10 along with their correlation to the markers of oxidative stress and neutrophil activation in patients with AP and patients with nonpancreatic acute abdominal pain (NPAAP).. This prospective clinical study included 56 patients with AP (28 with mild AP and 28 with severe AP) as well as 15 patients with NPAAP.. Serum concentrations of E-selectin, IL-10, and IL-6 and plasma concentrations of polymorphonuclear leukocyte elastase (determined on days 1-3, 5, and 10 after admission) were the highest in severe AP during the first 3 days and then declined. At day 10, the E-selectin level in severe AP was still higher than that in mild AP, and the IL-10 concentration increased again. There was no elevation in the E-selectin concentration in NPAAP patients, and IL-10 levels remained unchanged in mild AP. Oxidative stress, measured by serum malondialdehyde and 4-hydroxyalkenals levels, was the most pronounced in severe AP.. The serum E-selectin concentration is markedly elevated in severe AP and is less in mild AP but not in NPAAP. It may result from stimulation with different inflammatory mediators or indicate vascular endothelium injury mediated by oxidative stress, especially in the severe form of AP.

Topics: Abdominal Pain; Acute Disease; Adult; Aged; Aged, 80 and over; Aldehydes; Biomarkers; E-Selectin; Female; Humans; Interleukin-10; Interleukin-6; Leukocyte Elastase; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pancreatitis; Statistics as Topic

Reactive oxygen radicals play an important role in various forms of liver injury. In this study, we evaluated the efficacy of edaravone, a newly synthesized free radical scavenger, in its clinical dosage on an experimental model of acute liver injury in rats.. The clinical dose of edaravone (3 mg/kg) was intravenously administered immediately and 3 h after intraperitoneal administration of carbon tetrachloride (CCl4) in rats. Histological evaluation including apoptosis and cytokine profiles were examined.. Fatty degeneration and necrosis with marked elevation of serum alanine aminotransferase and lactate dehydrogenase levels developed after CCl4 administration were significantly reduced by edaravone. In addition, the apoptotic index assessed by TUNEL method was significantly lowered in the edaravone treated group. Serum and liver transcription levels of interleukin-6, tumor necrosis factor-alpha, interleukin-4, and interleukin-10 were increased following CCl4 administration, and they were attenuated by edaravone treatment. The formation of malondialdehyde, 4-hydroxynonenal adduct and one of the markers for oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, was also inhibited by edaravone treatment.. Edaravone has a remarkable protective effect on acute liver injury caused by oxygen radicals through not only attenuating the membrane lipid peroxidation, but also inhibiting the production of inflammatory cytokines. We theorize that edaravone may have a clinical benefit in the treatment of various liver injuries.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Alanine Transaminase; Aldehydes; Animals; Antipyrine; Apoptosis; Cell Death; Cytokines; Deoxyguanosine; Edaravone; Free Radical Scavengers; Growth Inhibitors; Immunohistochemistry; In Situ Nick-End Labeling; Interleukin-10; Interleukin-4; Interleukin-6; Liver; Male; Models, Chemical; Necrosis; Oxygen; Rats; Rats, Wistar; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Lipid peroxidation (LPO) is considered a major factor in damage spread after spinal cord injury (SCI). Therapies that limit LPO after SCI have demonstrated some utility in clinical trials, but more effective treatments are needed. In the present study the effects of augmenting SC levels of the endogenous antioxidant glutathione (GSH) on LPO after SCI were studied in a rat contusion injury model. A significant decrease in GSH occurred 1h after SCI which was paralleled by increases of 123% in malondialdehyde (MDA) and >500% in the 4-hydroxyalkenals (4-HA's), two LPO products. SC irrigation with gamma-glutamylcysteine (GC) preserved GSH and reduced 4-HA's below naive levels but had no effect on MDA. By 24 h after SCI, MDA returned to naive levels but 4-HA's were still elevated. Once again, GC treatment reduced 4-HA's. 4-HA's are much more reactive than MDA and are considered among the most toxic LPO products. These results suggest that (1) conditions after SCI may favor particular branches of the LPO pathway leading to differential LPO product levels, (2) MDA measurement is not by itself an adequate test for the presence or magnitude of LPO after SCI, (3) binding of GSH to 4-HA's may be an important mechanism by which the GSH system confers protection against LPO after SCI, and (4) SC GSH can be augmented after trauma by local irrigation with GC. These results also suggest that GSH augmentation may be an effective strategy for curtailment of LPO-mediated damage in acute phase SCI.

Topics: Acute Disease; Aldehydes; Animals; Antioxidants; Female; Glutathione; Glutathione Disulfide; Glutathione Transferase; Infusion Pumps, Implantable; Lipid Peroxidation; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries

Reactive oxygen species have been implicated in the pathogenesis of acute pancreatitis. Few studies have focused on the loss of endogenous antioxidants and molecular oxidative damage. Two acute pancreatitis models in rats; taurocholate (3% intraductal infusion) and cerulein (10 microg/kg/h), were used to study markers of oxidative stress: Glutathione, ascorbic acid, and their oxidized forms (glutathione disulfide and dehydroascorbic acid), malondialdehyde, and 4-hydroxynoneal in plasma and pancreas, as well as 7-hydro-8-oxo-2'-deoxyguanosine in pancreas. In both models, pancreatic glutathione depleted by 36-46% and pancreatic ascorbic acid depleted by 36-40% (p <.05). In the taurocholate model, plasma glutathione was depleted by 34% (p <.05), but there were no significant changes in plasma ascorbic acid or in plasma and pancreas dehydroascorbic acid, malondialdehyde, and 4-hydroxynoneal, and no significant changes in the pancreas glutathione disulfide/glutathione ratio. While pancreas glutathione disulfide/glutathione ratio increased in the cerulein model, there were no significant changes in plasma glutathione, plasma, or pancreas ascorbic acid, dehydroascorbic acid, 4-hydroxynoneal, and malondialdehyde, or in pancreas 7-hydro-8-oxo-2'-deoxyguanosine. Reactive oxygen species have a minor role in the intermediate stages of pancreatitis models.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Aldehydes; Animals; Ascorbic Acid; Biomarkers; Ceruletide; Dehydroascorbic Acid; Deoxyguanosine; Glutathione; Glutathione Disulfide; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Pancreatitis; Rats; Rats, Wistar; Reactive Oxygen Species; Taurocholic Acid

Free radical-mediated injury is believed to play a key role in the pathogenesis of acute pancreatitis (AP). Therefore, oxidative damage of proteins may be an important event in the development of AP. The present study was performed to investigate oxidative protein modification, quantified as 2,4-dinitrophenylhydrazine-reactive protein-carbonyls, during the time course of taurocholate-induced pancreatitis of the rat and to analyze oxidatively modified proteins by Western blotting. Protein modification in pancreatic homogenates was found as early as 30 min after induction of severe AP with 3% taurocholate preceding the elevation of serum amylase activity and the increase of malondialdehyde in the tissue. A correlation of protein-carbonyl contents to a score of pancreatic macroscopic alterations (r = .69) and to the wet weight/dry weight ratio (r = .65) was found. Infusion of 5% taurocholate resulted in fulminant AP with high lethality during the 24 h of the experiment. However, rats surviving showed significantly lower level of protein-carbonyls than animals that died between 20-24 h after AP induction. The quantitative data were confirmed by the intensity of immunostained protein-carbonyls. The present data show a rather uniform increase in the staining pattern not revealing single, selectively damaged proteins. The aldehydic product of lipid peroxidation 4-hydroxynonenal (HNE) is known for its reactivity towards proteins. Interestingly, an antibody raised against protein-bound HNE did not indicate an increased protein modification by this aldehyde. In conclusion, experimental AP is characterized by an early oxidative protein modification, possibly contributing to functional impairment of the pancreas. This protein alteration may not be mediated by HNE.

Topics: Acute Disease; Aldehydes; Amylases; Animals; Blotting, Western; Kinetics; Lipid Peroxidation; Male; Malondialdehyde; Oxidation-Reduction; Pancreatitis; Phenylhydrazines; Proteins; Rats; Rats, Wistar; Taurocholic Acid