Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently discovered that the vascular responsiveness to adrenomedullin (AM), a potent vasoactive peptide, decreased during sepsis and hemorrhage in the rat and was markedly improved by its novel binding protein (AMBP-1). Moreover, AM/AMBP-1 appears to be one of the leading candidates for further development to treat sepsis and hemorrhage. However, the extremely high cost of commercial AMBP-1 limits the development of human AM and AMBP-1 as therapeutic agents. The purpose of this study was to isolate and purify AMBP-1 from normal human serum and test its stability and biological activity under in vitro and in vivo conditions. AMBP-1 was isolated and purified from normal human serum with a yield of about 3.0 mg per 100 mL and purity of >99%. The purified AMBP-1 has a AM-binding capacity similar to that of the commercial AMBP-1. Human AM and human AMBP-1 in combination significantly inhibited lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production from macrophages. The biological activity of the purified human AMBP-1 was well preserved when stored at 45 degrees C for 5 d in solution or at 100 degrees C for 1 h in powder. Moreover, administration of AM and purified AMBP-1 to hemorrhaged rats attenuated tissue injury and neutrophil accumulation. Purified AMBP-1 in combination with AM also suppressed the hemorrhage-induced rise in serum cytokines TNF-alpha and IL-6. Thus, we have successfully purified biologically active AMBP-1 from human normal serum and demonstrated the stability of purified human AMBP-1. This technique will enable us to further develop human AM/AMBP-1 as a novel treatment for safe and effective therapy of patients with hemorrhagic shock, sepsis, and ischemic injury.
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PMID:Purification and characterization of human adrenomedullin binding protein-1. 1849 85

We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52-amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12-48 microg/kg body weight) was administered in combination with human AMBP-1 (40-160 microg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP. The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP. Proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP. Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%-80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis.
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PMID:Reversing established sepsis in rats with human vasoactive hormone adrenomedullin and its binding protein. 1900 24

Sepsis is a serious complication for patients with obstructive jaundice. Although administration of adrenomedullin (AM) in combination with its binding protein (AMBP-1) is protective after injury, it remains unknown whether AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in the setting of biliary obstruction. The aim of this study is, therefore, to test the efficacy of human AM/AMBP-1 in a rat model of obstructive jaundice and polymicrobial sepsis. To study this, obstructive jaundice was induced in male adult rats (275-325g) by common bile duct ligation (BDL). One week after BDL, the rats were subjected to sepsis by cecal ligation and puncture (CLP). Plasma levels of AM and AMBP-1 were measured at 20h after CLP. In additional groups of BDL+CLP rats, human AM/AMBP-1 (24/80microg/kg body weight (BW)) or vehicle (i.e., human albumin) was administered intravenously at 5h after CLP. Blood and tissue samples were collected at 20h after CLP for various measurements. To determine the long-term effect of human AM/AMBP-1 after BDL+CLP, the gangrenous cecum was removed at 20h after CLP and 7-day survival was recorded. Our results showed that plasma levels of AM were significantly increased while AMBP-1 levels were markedly decreased after BDL+CLP (n=8, P<0.05). Administration of human AM/AMBP-1 attenuated tissue injury and inflammatory responses after BDL+CLP. Moreover, human AM/AMBP-1 significantly increased the survival rate from 21% (n=14) to 53% (n=15). Thus, human AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in jaundiced rats. Human AM/AMBP-1 can be further developed as a novel treatment for sepsis in jaundiced patients.
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PMID:Human adrenomedullin and its binding protein ameliorate sepsis-induced organ injury and mortality in jaundiced rats. 2013 52

Bikunin, a chondroitin sulfate (CS) proteoglycan clinically used to treat acute inflammation and sepsis, contains a CS chain with more than 20 monosaccharide units. To understand the function of the CS chain of bikunin, synthesis of long CS chains is needed. After exploring multiple glycosylation approaches and protective group chemistry, we report herein the successful generation of the longest CS chain to date (24-mer) in an excellent overall yield on a multi-mg scale. The anti-inflammatory activities of both bikunin and the synthetic 24-mer were determined, and the results demonstrate that both the glycan and the core protein are important for anti-inflammatory activities of bikunin by reducing macrophage production of proinflammatory cytokines.
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PMID:Chemical Synthesis and Anti-Inflammatory Activity of Bikunin Associated Chondroitin Sulfate 24-mer. 3260 38


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