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)

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
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PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64

TNF-alpha is a mediator of insulin resistance in sepsis, obesity, and type 2 diabetes and is known to impair insulin signaling in adipocytes. Akt (protein kinase B) is a crucial signaling mediator for insulin. In the present study we examined the posttranslational mechanisms by which short-term (<6-h) exposure of 3T3-L1 adipocytes to TNF-alpha decreases Akt levels. TNF-alpha treatment both increased the ubiquitination of Akt and decreased its protein level. The decrease in protein was associated with the presence of an (immunoreactive) Akt fragment after TNF-alpha treatment, indicative of Akt cleavage. The broad-spectrum caspase inhibitor t-butoxycarbonyl-Asp(O-Me)-fluoromethyl ketone markedly suppressed these effects of TNF-alpha. The caspase-6 inhibitor Z-Val-Glu(OMe)-Ile-Asp(OMe)-CH(2)F potently suppressed Akt ubiquitination, degradation, and fragment formation, whereas the proteasome inhibitor Z-Leu-Leu-Leu-CHO modestly attenuated the decline in Akt levels. Exposure to TNF-alpha also enhanced the association of Akt with an E3 ligase activity. Adipocytes preexposed to TNF-alpha for 5 h and then stimulated with insulin for 30 min exhibited decreased levels of Akt, phosphorylated Akt, as well as phosphorylated Mdm2, which is a known direct substrate of Akt, and glucose uptake. Caspase inhibition attenuated these inhibitory effects of TNF-alpha. Collectively, our results suggest that TNF-alpha induces the caspase-dependent degradation of Akt via the cleavage and ubiquitination of Akt, which results in its degradation through the 26S proteasome. Furthermore, the caspase- and proteasome-mediated degradation of Akt due to TNF-alpha exposure leads to impaired Akt-dependent insulin signaling in adipocytes. These findings expand the mechanism by which TNF-alpha impairs insulin signaling.
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PMID:Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. 1574 49

Mortality of obese patients with sepsis has been reported to be significantly higher than lean patients. The underlying basis for this difference is not currently known. However, it has been suggested that obesity is associated with an altered immune response to a septic or inflammatory insult. Since obesity is based on exclusion in many sepsis trials, little is known about how obesity affects mortality or whether obese individuals respond differently to therapeutic interventions. In this study, obese and non-obese mice were given intra-peritoneal injection of saline or LPS and the livers were harvested 2 hours later. RNA from these livers were subjected to DNA microarray. Analysis showed distinct differences in gene expression between lean and obese animals. The expression of one hundred and seventeen genes was found to be different among the groups. In the obese animals treated with LPS, the expression of 20 genes showed a significant change. Ontology analysis revealed increased expression of 15 genes and significant decrease in expression of 5 genes. This study shows different gene expression of liver in response to LPS in lean versus obese animals. These genes might play a role in the outcome of sepsis.
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PMID:Differential RNA expression of hepatic tissue in lean and obese mice after LPS-induced systemic inflammation. 1576 70

THE PREGNANT PATIENT: Age; maternal disease; prophylactic antibiotics; gastroesophageal reflux; obesity; starvation; genotyping; coagulopathy; infection; substance abuse; altered drug responses in pregnancy; physiological changes of pregnancy. THE FETUS: Fetal monitoring; intrauterine surgery. THE NEWBORN: Breastfeeding; maternal infection, fever, and neonatal sepsis evaluation. OBSTETRIC COMPLICATIONS: Embolic phenomena; hemorrhage; preeclampsia; preterm delivery. OBSTETRIC MANAGEMENT: External cephalic version and cervical cerclage; elective cesarean delivery; fetal malpresentation; vaginal birth after cesarean delivery; termination of pregnancy. OBSTETRIC ANESTHESIA: Analgesia for labor and delivery; anesthesia for cesarean delivery; anesthesia for short obstetric operations; complications of anesthesia. MISCELLANEOUS: Consent; ethics; history; labor support; websites/books/leaflets/journal announcements.
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PMID:What's new and novel in obstetric anesthesia? Contributions from the 2003 scientific literature. 1579 48

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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PMID:Cytokine dysregulation, inflammation and well-being. 1616 5

Nutrition support in the critically ill patient is challenging but is even more difficult in a morbidly obese patient. This case report chronicles the care of a 6-foot-tall, 256-kg male (body mass index 76.5 kg/m(2)) who spent over a month in the intensive care unit for respiratory failure, sepsis, and acute renal failure. Parenteral nutrition was provided throughout his critical care course. One of the major difficulties encountered was determining his nutritional needs. A hypocaloric nutritional regimen was used, along with moderate protein provisions. Numerous electrolyte imbalances occurred, including hypercalcemia that did not resolve by eliminating calcium from the parenteral nutrition solution. Enteral nutrition was desired but was not used initially because of a need for vasopressors, a diagnosis of pancreatitis, difficulty in documenting feeding tube placement because of diagnostic limitations secondary to the patient's large size, and concern about managing stools. Eventually, oral intake and supplemental enteral feeding were initiated. Nutrition support team members worked closely with the interdisciplinary care team to develop strategies to manage the nutritional problems related to his obesity. A discussion of the various nutritional issues encountered in the care of this patient is provided. Reasonable nutritional status was achieved, but this case reflects some of the challenges encountered in caring for the nutritional needs of select patient populations in clinical practice and the need for increased research and guidelines in this area.
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PMID:Nutrition support in the morbidly obese, critically ill patient. 1621 17

The problem of obesity has reached epidemic proportions in the USA. More than 50% of adults are obese or overweight. The only therapeutic intervention that provides effective long-term weight loss for the severely obese is bariatric surgery. Roux-en-Y gastric bypass is the most commonly performed bariatric operation in the USA. Anastomotic leaks can cause life-threatening sepsis in the immediate postoperative period or delayed presentations with fistulas. Fibrin sealant and bovine pericardium have been used to reinforce the anastomosis in order to decrease the rate of this dreaded complication. This review will summarize current literature on the subject.
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PMID:Staple-line buttressing material in gastric-bypass surgery. 1629 71

Pyruvic acid, an intermediate metabolite of glucose, an effective scavenger of reactive oxygen species (ROS), inhibits tumor necrosis factor-alpha production and NF-kappaB signaling pathways, reduces circulating levels of HMGB1 (high mobility group B1), decreases COX-2 (cyclo-oxygenase-2), iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) mRNA expression in liver, ileal mucosa, and colonic mucosa in animal models with endotoxemia. These studies suggest that pyruvate has potent anti-oxidant and anti-inflammatory actions. Insulin influences the production of pyruvate by its action on glucose metabolism and pyruvate is an insulin secretagogue. This suggests that in metabolic syndrome X, obesity, hypertension, diabetes mellitus, and cancer (where insulin resistance is common due to enhanced TNF-alpha production) pyruvate plays a role. This may have relevance to the use of glucose-insulin-potassium regimen in these clinical conditions, sepsis, and cancer.
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PMID:Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. 1664 87

With nearly a third of American adults considered be obese, it is increasingly important that orthopaedic surgeons be familiar with management issues pertinent to these patients. Preoperative examination must assess cardiopulmonary status and other comorbid conditions, most notably diabetes. Intraoperative considerations include requirements for special equipment, patient positioning, intravenous line placement, central monitoring lines, and anesthesia specific to the physiologic changes in obese patients. Postoperatively, obese patients have higher rates of deep vein thrombosis and wound sepsis than do nonobese patients, and they may differ from other patients in supplemental oxygen requirements, medication dosing, and outcomes in intensive care units. Obese patients can successfully undergo virtually all orthopaedic procedures; however, the procedures are frequently more technically challenging, and obese patients appear to have higher rates of prosthetic failure, infection, hardware failure, and fracture malunion, although many of these complications can be minimized by appropriate countermeasures.
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PMID:Perioperative management of the obese orthopaedic patient. 1682 90

The blood-brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation. Insulin transport is also regulated. For example, treatment of mice with lipopolysaccharide (LPS) increases insulin transport across the BBB by about threefold. Since many of the actions of CNS insulin oppose those of peripheral insulin and since LPS releases proinflammatory cytokines, enhanced transport of insulin across the BBB could be a mechanism which promotes insulin resistance in sepsis. The brain endothelial cells which comprise the BBB secrete many substances including cytokines. Such secretion can be stimulated from one side of the BBB with release into the other side. For example, it appears that adiponectin can inhibit release of interleukin-6 from brain endothelial cells. Overall, the BBB represents an important interface in mediating gut-brain axes.
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PMID:The blood-brain barrier as a regulatory interface in the gut-brain axes. 1690 39


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