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

Vascular permeability plays a key role in a wide array of life-threatening and sight-threatening diseases. Vascular endothelial growth factor can increase vascular permeability. Using a model system for nonproliferative diabetic retinopathy, we found that pigment epithelium-derived factor (PEDF) effectively abated vascular endothelial growth factor-induced vascular permeability. A 44-amino acid region of PEDF was sufficient to confer the antivasopermeability activity. Additionally, we identified four amino acids (glutamate-101, isoleucine-103, leucine-112, and serine-115) critical for this activity. PEDF, or a derivative, could potentially abate or restore vision loss from diabetic macular edema. Furthermore, PEDF may represent a superior therapeutic approach to sepsis-associated hypotension, nephrotic syndrome, and other sight-threatening and life-threatening diseases resulting from excessive vascular permeability.
 ...
PMID:Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site. 1509 82

TNF is implicated in the attenuation of neutrophil constitutive apoptosis during sepsis. Antiapoptotic signaling is mediated principally through the TNF receptor-1 (TNFR-1). In adherent neutrophils, when beta-integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling. Previously, we identified the delta-PKC isotype and phosphatidylinositol (PI) 3-kinase as critical regulators of TNF signaling in adherent neutrophils. Both kinases associate with TNFR-1 in response to TNF and are required for TNFR-1 serine phosphorylation, NF-kappaB activation, and inhibition of apoptosis. The purpose of this study was to examine the role of delta-PKC and PI 3-kinase in the assembly of TNFR-1 signaling complex that regulates NF-kappaB activation and antiapoptotic signaling. Coimmunoprecipitation studies established that PI 3-kinase, delta-PKC, and TNFR-1 formed a signal complex in response to TNF. delta-PKC recruitment required both delta-PKC and PI 3-kinase activity, whereas PI 3-kinase recruitment was delta-PKC independent, suggesting that PI 3-kinase acts upstream of delta-PKC. An important regulatory step in control of antiapoptotic signaling is the assembly of the TNFR-1-TNFR-1-associated death domain protein (TRADD)-TNFR-associated factor 2 (TRAF2)-receptor interacting protein (RIP) complex that controls NF-kappaB activation. Inhibition of either delta-PKC or PI 3-kinase decreased TNF-mediated recruitment of RIP and TRAF2 to TNFR-1. In contrast, TRADD recruitment was enhanced. Thus delta-PKC and PI 3-kinase are positive regulators of TNF-mediated association of TRAF2 and RIP with TNFR-1. Conversely, these kinases are negative regulators of TRADD association. These results suggest that delta-PKC and PI 3-kinase regulate TNF antiapoptotic signaling at the level of the TNFR-1 through control of assembly of a TNFR-1-TRADD-RIP-TRAF2 complex.
 ...
PMID:Selective regulation by delta-PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils. 1511 7

Circulating human neutrophils from patients with severe inflammatory disorders such as erysipelas and sepsis are specifically desensitized to complement factor C5a stimulation but not to stimulation with other stimuli like N-formyl-methionyl-leucyl-phenylalanine (FMLP), interleukin-8 (IL-8), leukotriene B4 (LTB4), or platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine). In this study, we raised the question whether factors released from polymorphonuclear leukocytes (PMNs) can specifically down-regulate C5a-dependent neutrophil functions. When neutrophils were preincubated with either neutrophil lysates or neutrophil degranulation supernatants, a complete inhibition of C5a-stimulated beta-glucuronidase release and chemotaxis could be observed, whereas FMLP-, IL-8-, LTB4- or PAF-dependent functions were not affected. Serine protease inhibitors like phenylmethylsulfonyl fluoride, antileukoprotease, or elafin abolished this effect. High-performance liquid chromatography of neutrophil degranulation supernatants revealed pronounced inhibition of C5a-dependent neutrophil functions in fractions exerting elastase or cathepsin G activity, but not in fractions exerting proteinase 3 activity. Using purified human leukocyte elastase (HLE), C5a responses like intracellular calcium influx, beta-glucuronidase release, and chemotaxis were also specifically inhibited. Our experiments show that the release of HLE or cathepsin G from neutrophils specifically down-regulates the responsiveness of neutrophils to C5a. Elastase and cathepsin G may therefore play an important role in the down-regulation of acute inflammation.
 ...
PMID:Human leukocyte elastase and cathepsin G are specific inhibitors of C5a-dependent neutrophil enzyme release and chemotaxis. 1514 22

A 3 1/2-year-old boy presented with megaloblastic anemia and recurrent episodes of severe lactic acidosis and coma. At age 4 years, he developed sepsis and died; postmortem examination failed to show any gross abnormality in any tissue. Biochemical analysis of muscle showed decreased activities for all respiratory chain enzymes except complex II. Muscle histochemistry revealed diffuse cytochrome c oxidase deficiency. Southern blot analysis of mitochondrial DNA from muscle, liver, and blood showed a heteroplasmic single mitochindrial DNA deletion of 2.4 kb, which removed the genes for cytochrome c oxidase I and II and the transfer ribonucleic acid genes for serine and aspartic acid. Single large-scale deletions in mitochondrial DNA have been associated with Pearson's syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. This patient's presentation is unusual and suggests an overlap between Pearson's syndrome and Kearns-Sayre syndrome.
 ...
PMID:Mitochondrial DNA deletion in a child with megaloblastic anemia and recurrent encephalopathy. 1516 90

Whole body insulin resistance has been demonstrated in septic patients and in infected animals. In this study, we demonstrate that sepsis induces insulin resistance and that pretreatment with aspirin inhibits sepsis-induced insulin resistance. Sepsis was observed to lead to serine phosphorylation of IRS-1, a phenomenon which was reversed by aspirin in muscle and WAT, in parallel with a reduction in JNK activity. In addition, our data show an impairment of insulin activation of IR and IRS-1 tyrosine phosphorylation in septic rats and, consistent with the reduction of IRS-1 serine phosphorylation observed in septic animals pretreated with aspirin, there was an increase in IRS-1 protein levels and tyrosine phosphorylation in muscle and WAT. Overall, these results provide important new insights into the mechanism of sepsis-induced insulin resistance.
 ...
PMID:Aspirin inhibits serine phosphorylation of IRS-1 in muscle and adipose tissue of septic rats. 1524 Jan 46

Hemorrhage, sepsis, burn injury, surgical trauma and critical illness all induce insulin resistance. Recently we found that trauma and hemorrhage acutely induced hepatic insulin resistance in the rat. However, the mechanisms of this hemorrhage-induced acute hepatic insulin resistance are unknown. Here we report on the mechanisms of this hepatic insulin resistance. Protein levels and phosphorylation of the insulin receptor and insulin receptor substrate-1/2 (IRS-1/2) were measured, as was the association between IRS-1/2 and phosphatidylinositol 3-kinase (PI3K). Also examined were the hepatic expression of TNFalpha and TNFalpha-induced serine phosphorylation of IRS-1. Insulin receptor and IRS-1/2 protein levels and insulin-induced tyrosine phosphorylation of the insulin receptor were unaltered. In contrast, insulin-induced tyrosine phosphorylation of IRS-1/2 and association between IRS-1/2 and PI3K were dramatically reduced after hemorrhage. Hepatic levels of TNFalpha mRNA and protein were increased as was phosphorylation of IRS-1 serine 307 after hemorrhage. Our data provide the first evidence that compromised IRS-1/2 tyrosine phosphorylation and their association with PI3K contribute to hemorrhage-induced acute hepatic insulin resistance. Increased local TNFalpha may play a role in inducing this hepatic insulin resistance after trauma and hemorrhage.
 ...
PMID:Mechanisms of hemorrhage-induced hepatic insulin resistance: role of tumor necrosis factor-alpha. 1529 37

Nine quinolone resistant (minimal inhibitory concentration [MIC] was > 32 microg/mL for nalidixic acid, > 1 microg/mL for ciprofloxacin) isolates of Escherichia coli have been found in wild birds with septicemia. All of the isolates were aerobactin positive. The mechanisms of resistance were characterised by sequencing the quinolone resistance-determining region (QRDR) of the gyrA, gyrB, parC, and parE genes. Sequence analysis of the gyrA gene in all isolates identified only 1 nucleotide substitution at codon Serine-83 for Leucine-83. Sequence analysis of the gyrB, parC, and parE QRDR genes revealed no mutations in any of the isolates. This study was conducted to determine the importance of these genes in the susceptibility of E. coli strains isolated from wild birds to quinolones.
 ...
PMID:Molecular basis of quinolone resistance in Escherichia coli from wild birds. 1535 51

Inflammation is an important indicator of tissue injury. In the acute form, there is usually accumulation of fluids and plasma components in the affected tissues. Platelet activation and the appearance in blood of abnormally increased numbers of polymorphonucleocytes, lymphocytes, plasma cells and macrophages usually occur. Infectious disorders such as sepsis, meningitis, respiratory infection, urinary tract infection, viral infection, and bacterial infection usually induce an inflammatory response. Chronic inflammation is often associated with diabetes mellitus, acute myocardial infarction, coronary artery disease, kidney diseases, and certain auto-immune disorders, such as rheumatoid arthritis, organ failures and other disorders with an inflammatory component or etiology. The disorder may occur before inflammation is apparent. Markers of inflammation such as C-reactive protein (CRP) and urinary trypsin inhibitors have changed our appraisal of acute events such as myocardial infarction; the infarct may be a response to acute infection and (or) inflammation. We describe here the pathophysiology of an anti-inflammatory agent termed urinary trypsin inhibitor (uTi). It is an important anti-inflammatory substance that is present in urine, blood and all organs. We also describe the anti-inflammatory agent bikunin, a selective inhibitor of serine proteases. The latter are important in modulating inflammatory events and even shutting them down.
 ...
PMID:Pathophysiology and diagnostic value of urinary trypsin inhibitors. 1565 36

The NF-kappaB family plays a crucial role in the pathogenesis of highly lethal septicemia by modulating transcription of many innate and adaptive immunity genes. Two phases of NF-kappaB activation occur: cytosolic activation and nuclear transactivation. Septicemia with multiorgan failure is associated with chronic activation of cytosolic NF-kappaB with translocation and accumulation of increased levels of nuclear p65 in blood leukocytes. Paradoxically, NF-kappaB-dependent transcription of many proinflammatory genes responding to bacterial LPS endotoxin (LPS) is persistently repressed during septicemia; this phenomenon of LPS tolerance is associated with immunosuppression and poor prognosis. This report suggests an explanation for this paradox. Using an in vitro human leukocyte model and chromatin immunoprecipitation assays, we find that both the cytosolic activation and nuclear transactivation phases of NF-kappaB occur in LPS responsive THP-1 promonocytes with recruitment and binding of NF-kappaB p65 at the IL-1beta promoter. However, transcriptionally repressed LPS-tolerant THP-1 cells do not bind NF-kappaB p65 at the IL-1beta promoter, despite cytosolic activation and accumulation of p65 in the nucleus. In contrast, NF-kappaB p50, which also accumulates in the nucleus, constitutively binds to the IL-1beta promoter NF-kappaB site in both LPS-responsive and LPS-tolerant cells. The level of p65 binding correlates with a binary shift in nucleosome remodeling between histone H3 phosphorylation at serine 10 and methylation of histone H3 at lysine 9. We conclude that LPS tolerance disrupts the transactivating stage of NF-kappaB p65 and altered nucleosome remodeling at the IL-1beta promoter in human leukocytes.
 ...
PMID:Endotoxin tolerance disrupts chromatin remodeling and NF-kappaB transactivation at the IL-1beta promoter. 1597 80

Skeletal muscle atrophy in response to a number of muscle wasting conditions, including disuse, involves the induction of increased protein breakdown, decreased protein synthesis, and likely a variable component of apoptosis. The increased activation of specific proteases in the atrophy process presents a number of potential therapeutic targets to reduce muscle atrophy via protease inhibition. In this study, mice were provided with food supplemented with the Bowman-Birk inhibitor (BBI), a serine protease inhibitor known to reduce the proteolytic activity of a number of proteases, such as chymotrypsin, trypsin, elastase, cathepsin G, and chymase. Mice fed the BBI diet were suspended for 3-14 days, and the muscle mass and function were then compared with those of the suspended mice on a normal diet. The results indicate that dietary supplementation with BBI significantly attenuates the normal loss of muscle mass and strength following unloading. Furthermore, the data reveal the existence of yet uncharacterized serine proteases that are important contributors to the evolution of disuse atrophy, since BBI inhibited serine protease activity that was elevated following hindlimb unloading and also slowed the loss of muscle fiber size. These results demonstrate that targeted reduction of protein degradation can limit the severity of muscle mass loss following hindlimb unloading. Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity.
 ...
PMID:Attenuation of skeletal muscle atrophy via protease inhibition. 1597 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>