Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite a detailed understanding of their metabolism, mitochondria often behave anomalously. In particular, global suppression of mitochondrial metabolism and metabolite exchange occurs in apoptosis, ischemia and anoxia, cytopathic hypoxia of sepsis and multiple organ failure, alcoholic liver disease, aerobic glycolysis in cancer cells (Warburg effect) and unstimulated pancreatic beta cells. Here, we propose that closure of voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane accounts for global mitochondrial suppression. In anoxia, cytopathic hypoxia and ethanol treatment, reactive oxygen and nitrogen species, cytokines, kinase cascades and increased NADH act to inhibit VDAC conductance and promote selective oxidation of membrane-permeable respiratory substrates like short chain fatty acids and acetaldehyde. In cancer cells, highly expressed hexokinase binds to and inhibits VDAC to suppress mitochondrial function while stimulating glycolysis, but an escape mechanism intervenes when glucose-6-phosphate accumulates and dissociates hexokinase from VDAC. Similarly, glucokinase binds mitochondria of insulin-secreting beta cells, possibly blocking VDAC and suppressing mitochondrial function. We propose that glucose metabolism leads to glucose-6-phosphate-dependent unbinding of glucokinase, relief of VDAC inhibition, release of ATP from mitochondria and ATP-dependent insulin release. In support of the overall proposal, ethanol treatment of isolated rat hepatocytes inhibited mitochondrial respiration and accessibility to adenylate kinase in the intermembrane space, effects that were overcome by digitonin permeabilization of the outer membrane. Overall, these considerations suggest that VDAC is a dynamic regulator, or governator, of global mitochondrial function both in health and disease.
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PMID:Voltage-dependent anion channel (VDAC) as mitochondrial governator--thinking outside the box. 1630 70

Oxysterols are cytotoxic agents that have a range of cellular actions, including impairment of albumin synthesis, cell differentiation, and induction of apoptosis. Their regulations by nutritional factors are poorly described. Our objective was to test the hypothesis that the imposition of food withdrawal and alcohol exposure increases tissue oxysterol concentrations. We measured the concentrations of the oxysterols 7alpha-hydroxycholest-5-en-3beta-ol (7alpha-OH), 7beta-hydroxycholest-5-en-3beta-ol (7beta-OH), and 3beta-hydroxycholest-5-en-7-one (7-keto) in liver and skeletal muscle of fed and fasted (food withdrawal for 1 and 2 days) male Wistar rats. Both oxidative (type I; soleus) and glycolytic (type II; plantaris) muscles were analyzed. We also investigated the effects of a nutritional perturbant induced by a short-term bolus of ethanol (75 mmol/kg weight IP administered 2.5 hours before sacrifice). The results showed that in response to fasting there were significant increases in 7alpha-OH, 7beta-OH, and 7-keto in liver and both type I and II skeletal muscle (P < .001 in all instances). For skeletal muscle, the increases were blunted or ameliorated after 2 days when compared with data from rats starved for 1 day. In contrast, the increases in liver after 1 day's fasting were relatively sustained at 2 days. Short-term ethanol increased 7alpha-OH, 7beta-OH, and 7-keto in type I muscle of fed animals only (P < .001 in all instances) with a significant interaction between fasting and alcohol (P < .001 in all instances). For the first time, we have shown that oxysterols can increase in muscle and liver in response to food withdrawal and in response to an immediately imposed nutritional perturbant (ie, alcohol). Increased oxysterols represent elevated oxidative stress and/or disturbances in their formation or clearance. Because of the reported cytotoxic properties of oxysterols, these data are important in understanding cellular pathology because episodic anorexia and/or oxidative stress occur in a variety of disease conditions including sepsis, cancer cachexia, ischemia, and hormonal imbalance.
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PMID:Skeletal muscle and liver oxysterols during fasting and alcohol exposure. 1632 30

Artemisia vestita Wall., a traditional Tibetan medicine, has wide clinical application for inflammatory diseases. However, its molecular mechanism of anti-inflammatory effect is poorly understood. In the present study, we investigated the anti-inflammatory activity and underlying mechanism of the ethanol extract from Artemisia vestita (AV-ext) on lipopolysaccharide (LPS)-induced sepsis. Pretreatment with AV-ext significantly decreased the levels of tumor necrosis factor-alpha (TNF-alpha) in serum and liver and lung tissues, and improved the survival of mice with experimental sepsis. AV-ext also remarkably reduced the expression levels of TNF-alpha, interleukin-1beta and cyclooxygenase-2 in LPS-stimulated RAW 264.7 macrophages and dose dependently suppressed the activation of mitogen-activated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Furthermore, pretreatment with AV-ext dose dependently inhibited the activation of nuclear factor-kappaB (NF-kappaB), as well as the degradation and phosphorylation of inhibitory kappaB (IkappaB) in LPS-activated RAW 264.7 macrophages. These results collectively reveal that AV-ext inhibits TNF-alpha release from macrophages by suppressing MAPK and NF-kappaB signaling pathways and suggest that AV-ext may be beneficial for the treatment of endotoxin shock or sepsis.
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PMID:Ethanol extract from Artemisia vestita, a traditional Tibetan medicine, exerts anti-sepsis action through down-regulating the MAPK and NF-kappaB pathways. 1659 87

We have previously shown that catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cyclic adenosine monophosphate (cAMP) cascade in normal rats. In the present work, we investigated in vivo and in vitro effects of cAMP-phosphodiesterase inhibitors on protein metabolism in skeletal muscle from rats submitted to a model of acute sepsis. The in vivo muscle protein metabolism was evaluated indirectly by measurements of the tyrosine interstitial concentration using microdialysis. Muscle blood flow (MBF) was monitored by ethanol perfusion technique. Sepsis was induced by cecal ligation and puncture and resulted in lactate acidosis, hypotension, and reduction in MBF (-30%; P < 0.05). Three-hour septic rats showed an increase in muscle interstitial tyrosine concentration (approximately 150%), in arterial plasma tyrosine levels (approximately 50%), and in interstitial-arterial tyrosine concentration difference (approximately 200%; P < 0.05). Pentoxifylline (50 mg/kg of body weight, i.v.) infusion during 1 h after cecal ligation and puncture prevented the tumor necrosis factor alpha increase and significantly reduced by 50% (P < 0.05) the interstitial-arterial tyrosine difference concentration. In situ perfusion with isobutylmethylxanthine (IBMX; 10(-3) M) reduced by 40% (P < 0.05) the muscle interstitial tyrosine in both sham-operated and septic rats. Neither pentoxifylline nor IBMX altered MBF. The addition of IBMX (10(-3) M) to the incubation medium increased (P < 0.05) muscle cAMP levels and reduced proteolysis in both groups. The in vitro addition of H89, a protein kinase A inhibitor, completely blocked the antiproteolytic effect of IBMX. The data show that activation of cAMP-dependent pathways and protein kinase A reduces muscle protein catabolism during basal and septic state.
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PMID:Cyclic adenosine monophosphate-phosphodiesterase inhibitors reduce skeletal muscle protein catabolism in septic rats. 1750 10

Previously we determined that chronic alcohol ingestion (6 weeks) in rats increases lung epithelial permeability in vivo approximately 5-6-fold and promotes flooding of the alveolar airspaces with proteinaceous fluid in response to stresses such as sepsis. In parallel, alveolar epithelial cells isolated from alcohol-fed rats fail to form tight monolayers in vitro, even when cultured for up to 8 days in the absence of alcohol. However, the molecular mechanisms underlying alcohol-induced permeability are unknown. Claudins are key components of tight junctions that restrict the paracellular movement of water, proteins, and solutes across cellular barriers including the alveolar epithelium. In this study, we examined the expression of multiple members of the claudin protein family in the lungs of alcohol-fed versus control-fed rats (Lieber-DeCarli liquid diet with either 36% of calories as alcohol or an isocaloric substitution with maltin-dextrin for 6 weeks). We determined that chronic alcohol ingestion affected the expression of multiple claudins; most striking were decreases in claudin-1 and claudin-7, and an increase in claudin-5, in the whole lung and in alveolar epithelial monolayers derived from alcohol-fed rats. In parallel, immunocytochemistry of alveolar epithelial monolayers from alcohol-fed rats revealed abnormal intracellular accumulation of claudin-7 protein and relatively decreased localization to cell membranes. Claudin-1 and claudin-7 are relatively specific to alveolar epithelial type I pneumocytes that form the vast majority of the alveolar epithelial barrier in vivo, and increases in claudin-5 have been associated with increased epithelial permeability in other systems. Therefore, these findings suggest that changes in claudin expression in the alveolar epithelium produce a "leakier" phenotype that renders the alcoholic lung susceptible to alveolar flooding during acute inflammatory stresses.
Alcohol 2007 Aug
PMID:Chronic alcohol ingestion alters claudin expression in the alveolar epithelium of rats. 1788 13

Alcohol (EtOH) intoxication and burn injury independently activate hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoids, the end product of the HPA axis, play a role in shaping the immune response under those conditions. By utilizing a rat model of acute EtOH intoxication and burn injury, studies in our laboratory have investigated the role of corticosterone (i.e., glucocorticoids in rodents) in altered intestinal immunity and barrier function following a combined insult of EtOH and burn injury. Results from these studies suggest that EtOH intoxication prior to burn injury augments corticosterone release, which in turn suppresses intestinal T cell function by inhibiting mitogen-activated protein kinase (i.e., p38 and ERK) pathway. Furthermore, we found that corticosterone does not directly alter the intestinal barrier function; rather, it up-regulates interleukin-18, which then directly or indirectly contributes to impaired intestinal barrier function. The loss of intestinal immunity/barrier function may result in increased bacterial translocation and thereby contribute to postinjury pathogenesis, leading to sepsis and organ dysfunction in burn patients as well as in patients with a history of EtOH intoxication.
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PMID:A role for corticosterone in impaired intestinal immunity and barrier function in a rodent model of acute alcohol intoxication and burn injury. 1804 Aug 15

The effect of alcohol ingestion on short-term outcomes for trauma patients is indeterminate. Experimental and clinical reports often conflict. The objective of this study was to investigate the prevalence of positive alcohol screens, the effect of alcohol ingestion on injury patterns, severity, and outcomes in patients who were involved in motor vehicle crashes (MVC). MVC patients aged > 10 years treated in any of the 13 trauma centers in Los Angeles County during the calendar year 2003 were studied. All patients underwent routine alcohol screening on admission. The alcohol negative group ("no ETOH") had a blood alcohol level (BAL) of < or = 0.005 g/dL. Low and high alcohol groups ("low ETOH" and "high ETOH") had a BAL of > 0.005 g/dL to < 0.08 g/dL and > or = 0.08 g/dL, respectively. Logistic regression was performed to compare injury severity, complications, survival, and length of hospital stay among the three groups. Of the 3025 patients studied, 2013 (67%) were in the no ETOH group, 216 (7%) were in the low ETOH group, and 796 (26%) were in the high ETOH group. Levels were not associated with injury severity, Emergency Department hypotension, or Intensive Care Unit length of stay. Patients with an injury severity score > 15 and a high BAL had a higher incidence of severe head trauma (head abbreviated injury score > 3) and increased incidence of sepsis. However, in this group of severely injured, the high ETOH group had a significantly better survival rate than patients in the no ETOH group (adjusted odds ratio 0.41, 95% confidence interval 0.16-0.94, p = 0.05). Severely injured MVC victims with a high BAL have a higher incidence of severe head trauma and septic complications than no ETOH patients. However, the high ETOH group had superior adjusted survival rates.
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PMID:Motor vehicle crashes: the association of alcohol consumption with the type and severity of injuries and outcomes. 1854 72

Sepsis continues to be a challenge in clinic. Therapeutic strategies focus on local host defenses and the inhibition of overwhelming inflammation response. The present study aimed to investigate the protective effects and the underlying mechanisms of the ethanol extract of Alpinia katsumadai Hayata seeds (EAKH) on polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. It was shown that oral administration of EAKH at 1 h before and 2 h after CLP significantly elevated the survival rate and the mean arterial pressure of mice. Histological examination and serum ALT/AST assessment demonstrated that EAKH protected the animals from lung and liver tissue injury and dysfunction. Although EAKH was devoid of direct bacteriostatic or bacteriocidal activities, it facilitated peritoneal bacteria clearance and increased leukocyte migration into peritoneal cavity of septic mice. Furthermore, EAKH remarkably decreased serum pro-inflammatory cytokine (TNF-alpha, IL-1beta and NO) levels in septic mice. These findings demonstrated that EAKH has preventive effects on mouse sepsis induced by CLP, which may be attributed to elevating local defense via promoting leukocyte migration to infection focus and attenuating systemic inflammation.
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PMID:Alpinia katsumadai Hayata prevents mouse sepsis induced by cecal ligation and puncture through promoting bacterial clearance and downregulating systemic inflammation. 1884 87

Fourteen herbs were extracted in water, 95% ethanol, and ether, and tested in vitro for antimicrobial activities against Aeromonas hydrophila, a fish pathogen causing motile Aeromonas septicemia. Using swab paper disc assays and minimal inhibitory concentration (MIC) determinations, we noted that the ethanol extract of Psidium guajava leaf exhibited the strongest antimicrobial activity. The extract allowed growth-inhibited A. hydrophila cells to regrow in fresh BHI broth indicating a bacteriostatic mode of action. In a pathogenicity test, the median lethal dose (LD(50)) of A. hydrophila for tilapia (Oreochromis niloticus) by intraperitoneal injection was 3.44 x 10(6) CFU/ml. In vivo experiments showed that fish diets containing either dry leaf powder of P. guajava or dried ethanol extract of P. guajava leaf reduced mortality of A. hydrophila infected tilapia with no detected adverse effect on the fish. This study suggests that P. guajava leaf has the potential to control fish diseases caused by A. hydrophila.
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PMID:Potential of Psidium guajava supplemented fish diets in controlling Aeromonas hydrophila infection in tilapia (Oreochromis niloticus). 1911 36

This article highlights the research presented at the Alcohol and Trauma Satellite Symposium at the 30th Annual Meeting of the Shock Society. The satellite meeting was held on June 8 and 9 in Baltimore, MD. Its purpose was to discuss recent findings in the areas of alcohol and injury, including the effect of alcohol use on patients in the trauma unit of hospitals. The meeting consisted of three sessions, with plenary talks by invited speakers, short talks from selected abstracts, and a poster session. Participants presented data on the effects of alcohol on organ function, healing, and immune processes after a variety of injuries including burn, hemorrhagic shock, sepsis, and ischemia reperfusion.
Alcohol 2009 May
PMID:Alcohol and trauma: a summary of the Satellite Symposium at the 30th Annual Meeting of the Shock Society. 1939 63


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