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)

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

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-alpha (TNFalpha), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P <.01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-kappaB and Sp1. These effects are partially mediated by TNFalpha autocrine stimulation, as anti-TNFalpha antibodies significantly decrease chemokine and adhesion molecule responses (P </=.002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.
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PMID:Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. 1245 6

HMGB1 (high mobility group box chromosomal protein 1), historically known as an abundant, nonhistone architectural chromosomal protein, is extremely conserved across species. As a nuclear protein, HMGB1 stabilizes nucleosomes and allows bending of DNA that facilitates gene transcription. Unexpectedly, recent studies identified extracellular HMGB1 as a potent macrophage-activating factor, signaling via the receptor for advanced glycation end-products to induce inflammatory responses. It is released as a late mediator during inflammation and participates in the pathogenesis of systemic inflammation after the early mediator response has resolved. HMGB1 occupies a critical role as a proinflammatory mediator passively released by necrotic but not apoptotic cells. Necrotic Hmgb1(-/-) cells mediate minimal inflammatory responses. Stimulated macrophages actively secrete HMGB1 to promote inflammation and in turn, stimulate production of multiple, proinflammatory cytokines. HMGB1 mediates endotoxin lethality, acute lung injury, arthritis induction, activation of macrophages, smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction. HMGB1 is structurally composed of three different domains: two homologous DNA-binding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain contains the proinflammatory cytokine functionality of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis, even when initial treatment was delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
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PMID:HMGB1 as a DNA-binding cytokine. 1248 89

HMGB1 is an abundant nuclear and cytoplasmic protein present in mammalian cells. It is traditionally known as a DNA binding protein involved in maintenance of nucleosome structure and regulation of gene transcription. Beyond these intracellular roles, we recently discovered that HMGB1 is released from activated macrophages and functions as a late mediator of lethal endotoxemia. Addition of HMGB1 to macrophage cultures activates cytokine release. When released into the extracellular milieu, HMGB1 causes systemic inflammatory responses including acute lung injury, epithelial barrier dysfunction, and death. Passive immunization with anti-HMGB1 antibodies confers significant protection against lethality induced by LPS administration and sepsis caused by cecal perforation in mice. Truncation of HMGB1 into individual structural domains revealed that the HMGB1 A box, a DNA-binding motif, specifically antagonizes the activity of HMGB1 and rescues mice from lethal sepsis caused by cecal perforation. Thus, strategies that target HMGB1 with specific antibodies or antagonists have potential for treating lethal systemic inflammatory diseases characterized by excessive HMGB1 release.
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PMID:HMGB1 as a cytokine and therapeutic target. 1269 92

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

HMGB1 is a member of the high-mobility group protein superfamily that has been widely studied as nuclear proteins that bind DNA, stabilize nucleosomes and facilitate gene transcription. A series of recent discoveries revealed a cytokine activity of HMGB1, that when secreted into the extracellular milieu, mediates downstream inflammatory responses in endotoxemia, arthritis and sepsis. HMGB1 is properly defined as a cytokine because it stimulates proinflammatory responses in monocytes/macrophages, is produced during inflammatory responses in vivo in standardized models of systemic and local inflammation, mediates delayed endotoxin lethality, and is required for the full expression of inflammation in animal models of endotoxemia, sepsis and arthritis. HMGB1 is either actively secreted by monocytes/macrophages or passively released from necrotic cells from any tissue. These pathways are central for the biology of HMGB1 as a cytokine, since they provide key mechanisms that integrate the inflammatory response to infectious and non-infectious cell injuries. Receptor signal transduction of HMGB1 occurs in part through the receptor for advanced glycation end-products (RAGE) expressed on monocytes/macrophages, endothelial cells, neurons and smooth-muscle cells. HMGB1 is a late-acting cytokine, because it first appears in the extracellular milieu 8-12 h after the initial macrophage response to proinflammatory stimuli. Knowledge of the cytokine role of HMGB1 has implications for understanding downstream cytokine cascades, regulation of delayed innate immune responses and targeting treatment towards these processes. Effectiveness of delayed treatment with HMGB1 blockade up to 24 h after induction of experimental sepsis offers a unique window of opportunities to allow rescue from lethal sepsis.
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PMID:HMGB1 in sepsis. 1462 Jan 38

Sepsis and septic shock are the leading causes of death in intensive care units in developed countries despite recent advances in critical care medicine. Sepsis is the systemic inflammatory response to infection frequently associated with hypoperfusion followed by tissue injury and organ failure. The activation of monocytes/macrophages and neutrophils, with the consecutive release of pro-inflammatory mediators and activation of the coagulation cascade, seems to play a key role in the pathogenesis of sepsis. Elimination of the septic focus, anti-microbial therapy and supportive treatment are the cornerstones of sepsis therapy. In addition, the application of small doses hydrocortisone to patients with refractory septic shock and the treatment of patients with septic multiple organ failure with activated protein C are two adjunctive therapeutic strategies. Promising new experimental treatment options are interference with MIF, HMGB1, C5a or TREM-1 signal transduction pathways and an inhibition of apoptosis, which may further improve the prognosis of septic patients in the future.
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PMID:The systemic inflammatory response syndrome. 1521 39

High mobility group box-1 protein (HMGB1, formerly known as HMG-1), a highly conserved ubiquitous protein, has been for a long time described as a nuclear DNA-binding protein involved in nucleosome stabilization and gene transcription. Recent discoveries indicate that HMGB1 is released from activated innate immune cells or necrotic cells and functions as an important mediator of endotoxemia, sepsis, arthritis, and local inflammation. Therapeutic agents that inhibit HMGB1 release or action confer significant protection against endotoxemia, sepsis, and arthritis in animal models and thus hold potential for the clinical management of various inflammatory diseases.
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PMID:Extracellular HMGB1 as a proinflammatory cytokine. 1521 6

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

Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.
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PMID:Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. 1551 7


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