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)

The dissemination of Pseudomonas aeruginosa to the bloodstream increases the likelihood of developing fatal sepsis. In experimental models, the ability to disseminate is linked to expression of the exoenzyme S pathway. Genetic and biochemical analysis of the pathway has led to the identification of the two structural genes encoding exoenzyme S, exoS and exoT. A key regulator of several loci of the pathway has been identified as a DNA-binding protein with transcriptional activation properties. Preliminary evidence suggests that exoenzyme S and the Yop virulence determinants of yersiniae share homology among proteins involved in their synthesis and secretion. With the addition of exoS and exoT to the molecular arsenal, questions concerning in vivo toxicity and target specificities of exoenzyme S can be directly addressed.
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PMID:Genetic analysis of exoenzyme S expression by Pseudomonas aeruginosa. 859 51

Proinflammatory cytokines released by hepatic macrophages (Kupffer cells) have a central role in the pathogenesis of liver injury and the cardiovascular abnormalities of sepsis. Because cytokine release is controlled primarily at the level of gene expression, intracellular signalling mechanisms that control the transcription of cytokine genes are critical links to organ injury. Oxidant stress up-regulates and antioxidants down-regulate the pleiotropic transcription factor NF-kappa B, a DNA-binding protein that induces the expression of cytokines and vascular adhesion molecules. Thiol-bearing molecules are also important inhibitors of NF-kappa B activation, but whether this inhibition represents an antioxidant effect is unknown. This study was undertaken to determine whether important endogenous and pharmacological thiols modulate the activation of NF-kappa B and the release of tumour necrosis factor alpha (TNF-alpha) from Kupffer cells and to ascertain whether these effects are mediated through glutathione. Exposure of rat Kupffer cells to a physiologically relevant concentration of lipopolysaccharide (10 ng/ml) activated NF-kappa B within 1 h and induced the release of TNF-alpha over 5 h. Cellular glutathione content remained unchanged after lipopolysaccharide exposure, but both glutathione monoethyl ester and N-acetyl-L-cysteine increased cellular glutathione levels, blocked NF-kappa B activation and inhibited the release of TNF-alpha. Inhibition of glutathione synthesis prevented the NAC-induced increase in Kupffer cell glutathione, yet it did not prevent the inhibition of TNF-alpha release by NAC. Thus the inhibition of NF-kappa B activation by pharmacological thiols such as NAC might reflect a more general role of the intracellular thiol redox status in NF-kappa B regulation rather than the antioxidant properties of these agents.
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PMID:Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells. 900 92

Effective therapies against overwhelming Gram-negative bacteremia, or sepsis, have eluded successful development. The discovery that tumor necrosis factor (TNF), a host-derived inflammatory mediator, was both necessary and sufficient to recapitulate Gram-negative sepsis raised cautious optimism for developing a targeted therapeutic. However, the rapid kinetics of the TNF response to infection defined an extremely narrow window of opportunity during which anti-TNF therapeutics could be successfully administered. HMGB1 was previously studied as a DNA-binding protein involved in DNA replication, repair, and transcription; and as a membrane-associated protein that mediates neurite outgrowth. A decade-long search has culminated in our identification of HMGB1 as a late mediator of endotoxemia. HMGB1 is released by macrophages upon exposure to endotoxin, activates many other pro-inflammatory mediators, and is lethal to otherwise healthy animals. Elevated levels of HMGB1 are observed in the serum of patients with sepsis, and the highest levels were found in those patients that died. The delayed kinetics of HMGB1 release indicate that it may be useful to target this toxic cytokine in the development of future therapies.
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PMID:Dual roles for HMGB1: DNA binding and cytokine. 1171 86

Despite the considerable advances made in understanding the pathophysiology of systemic inflammation during critical illness, clinical progress has been elusive as it remains a very deadly condition. Cortisol and thyroid hormone levels can be as predictive of outcome as the commonly used severity parameters (i.e. APACHE). Indeed, levels of endocrine humoral substances such as arachidonic acids, nitric oxide, endothelin, calcitonin precursors, leptin and adenosine correlate with the severity and outcome of critical illness. Furthermore, calcitonin precursors represent a potentially new hormokine paradigm, being transcriptionally activated in all cells in response to infection. The cytokines are immune markers that often correlate with severity and outcome, but their release is transient. In contrast, the so-called acute phase proteins, such as C-reactive protein and serum amyloid A, are highly sensitive to inflammatory activity and can be important markers of severity and outcome. Leukocyte esterase, adhesion molecules, platelet activating factor and activated protein C are additional humoral immune markers; the replacement of the latter has been shown to be a promising therapeutic option. Natriuretic peptides are neurocrine humoral markers that have important cardiovascular implications. The level of macrophage migrating inhibitory factor, released by the pituitary, is elevated in sepsis and counteracts glucocorticoid action. Cellular markers to severe stress include the enhanced expression of protective substances in the form of heat shock proteins. High mobility group-1 is a DNA-binding protein and a late mediator of the inflammatory response. Apoptotic markers such as the soluble fas ligand are also elevated in inflammation. In summary, during critical illness, the endocrine, immune and nervous systems elaborate a multitude of humoral markers, the roles of which merit further scrutiny in order to improve therapeutic outcome.
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PMID:Humoral markers of severity and prognosis of critical illness. 1180 May 23

High mobility group box 1 (HMGB), a ubiquitous DNA-binding protein, has been implicated as a proinflammatory cytokine and late mediator of lethal endotoxemia. HMGB1 is released by activated macrophages. It amplifies and extends the inflammatory response by inducing cytokine release and mediating acute lung injury, anorexia, and the inflammatory response to tissue necrosis. The kinetics of HMGB1 release provide a wide therapeutic window for endotoxemia because extracellular levels of HMGB1 begin to increase 12 to 24 h after exposure to inflammatory stimuli. Here, we demonstrate that a DNA-binding domain of HMGB1, the B box, recapitulates the cytokine activity of full length HMGB1 and efficiently activates macrophages to release tumor necrosis factor (TNF) and other proinflammatory cytokines. Truncation of the B box revealed that the TNF-stimulating activity localizes to 20 amino acids (HMGB1 amino acids 89 to 108). Passive immunization of mice with antibodies raised against B box conferred significant protection against lethal endotoxemia or sepsis, induced by cecal perforation. These results indicate that a proinflammatory domain of HMGB1 maps to the highly conserved DNA-binding B box, making this primary sequence a suitable target in the design of therapeutics.
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PMID:Structural basis for the proinflammatory cytokine activity of high mobility group box 1. 1276 38

For the second time in recent history, studies directed at the pathogenesis of infectious disease have led to the identification of an endogenous mediator of arthritis. HMGB1, a 30-kD nuclear and cytoplasmic protein widely studied as a DNA-binding protein, is a newly described cytokine and a necessary and sufficient mediator of lethal sepsis. HMGB1 is passively released during cell necrosis, but not apoptosis; it activates an inflammatory response to necrosis,but not apoptosis. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes in a process that requires acetylation of the molecule, enabling a translocation from the nucleus to secretory lysosomes. Recent evidence indicates that HMGB1 is a mediator of arthritis because of the following: (1) it is produced at the site of joint inflammation, (2) it causes the development of arthritis when applied to normal joints, and (3) therapies that inhibit HMGB1 prevent the progression of collagen-induced arthritis in rodents. Anti-HMGB1 may be studied in future clinical trials of diseases of excessive production of HMGB1, such as severe sepsis and arthritis.
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PMID:HMGB1 as a mediator of necrosis-induced inflammation and a therapeutic target in arthritis. 1526 45

High mobility group box 1 (HMGB1) protein, a DNA-binding protein that can also act as a pro-inflammatory cytokine if released from cells, is an important amplification signal in various forms of inflammation. The concentration of HMGB1 in serum taken at admission was increased in falciparum malaria in sixteen African children, more so in fatal cases than in those who subsequently recovered (P<0.001). Serum from both non-fatal (P=0.0048) and fatal (P<0.001) cases contained significantly more circulating HMGB1 than did serum from healthy Caucasian adults. These data provide an additional argument that malaria is fundamentally a systemic inflammatory state. In keeping with its developing role in sepsis, HMGB1 may enhance and prolong the inflammatory processes, and thus illness, in malaria.
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PMID:High mobility group box 1 (HMGB1) protein: possible amplification signal in the pathogenesis of falciparum malaria. 1565 18

HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
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PMID:High-mobility group box 1 (HMGB1) protein: friend and foe. 1651 9

High-mobility group box 1 (HMGB1) is a DNA-binding protein that also exhibits proinflammatory cytokine-like activity. HMGB1 is passively released by necrotic cells and also is actively secreted by immunostimulated macrophages, dendritic cells, and enterocytes. Although circulating HMGB1 levels are increased relative to healthy controls in patients with infections and severe sepsis, plasma or serum HMGB1 concentrations do not discriminate reliably between infected and uninfected critically ill patients. Nevertheless, administration of drugs that block HMGB1 secretion or of anti-HMGB1 neutralizing antibodies has been shown to ameliorate organ dysfunction and/or improve survival in numerous animal models of critical illness. Because HMGB1 tends to be released relatively late in the inflammatory response (at least in animal models of endotoxemia or sepsis), this protein is an attractive target for the development of new therapeutic agents for the treatment of patients with various forms of critical illness.
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PMID:Bench-to-bedside review: High-mobility group box 1 and critical illness. 1790 10

HMGB1/Amphoterin is a ubiquitous, highly conserved DNA-binding protein that can be also released to the extracellular space by various cell types. Extracellular HMGB1 regulates migratory responses of several cell types through binding to RAGE that communicates with the cytoskeleton to regulate cell motility. HMGB1-induced cell signalling has been associated with mechanisms of several diseases, including cancer, sepsis, rheumatoid arthritis, stroke and atherosclerosis. This article reviews the evidence linking the functional roles of HMGB1 to RAGE signalling. Furthermore, we discuss the molecular and cellular mechanisms that may explain the roles of HMGB1/RAGE in diverse disease processes.
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PMID:RAGE as a receptor of HMGB1 (Amphoterin): roles in health and disease. 1833 Dec 30


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