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)

Intestinal epithelial cells are subject to repetitive deformation during peristalsis and villous motility, whereas the mucosa atrophies during sepsis or ileus when such stimuli are abnormal. Such repetitive deformation stimulates intestinal epithelial proliferation via focal adhesion kinase (FAK) and extracellular signal-regulated kinases (ERK). However, the upstream mediators of these effects are unknown. We investigated whether Src and Rac1 mediate deformation-induced FAK and ERK phosphorylation and proliferation in human Caco-2 and rat IEC-6 intestinal epithelial cells. Cells cultured on collagen-I were subjected to an average 10% cyclic strain at 10 cycles/min. Cyclic strain activated Rac1 and induced Rac1 translocation to cell membranes. Mechanical strain also induced rapid sustained phosphorylation of c-Src at Tyr(418), Rac1 at Ser(71), FAK at Tyr(397) and Tyr(576), and ERK1/2 at Thr(202)/Tyr(204). The mitogenic effect of cyclic strain was blocked by inhibition of Src (PP2 or short interfering RNA) or Rac1 (NSC23766). Src or Rac1 inhibition also prevented strain-induced FAK phosphorylation at Tyr(576) and ERK phosphorylation but not FAK phosphorylation at Tyr(397). Reducing FAK using short interfering RNA blocked strain-induced mitogenicity and attenuated ERK phosphorylation but not Src or Rac1 phosphorylation. Src inhibition blocked strain-induced Rac1 phosphorylation, but Rac inhibition did not alter Src phosphorylation. Transfection of a two-tyrosine phosphorylation-deficient FAK mutant Y576F/Y577F prevented activation of cotransfected myc-ERK2 by cyclic strain. Repetitive deformation induced by peristalsis or villus motility may support the gut mucosa by a pathway involving Src, Rac1, FAK, and ERK. This pathway may present important targets for interventions to prevent mucosal atrophy during prolonged ileus or fasting.
 ...
PMID:Repetitive deformation activates focal adhesion kinase and ERK mitogenic signals in human Caco-2 intestinal epithelial cells through Src and Rac1. 1708 51

Platelet-derived microvesicles (PMV) that are shed from the plasma membrane of activated platelets, expose various platelet-type antigens on their surface and are able to adhere to other blood cells and endothelial cells. There are several clinical conditions with markedly increased numbers of PMV, e.g. acute coronary syndrome, thrombotic microangiopathy and sepsis. To prove whether PMV may contribute to an inflammatory response we used DNA microarray technology to study the effect of PMV on gene expression in the prototypic monocytic cell line MonoMac 6 (MM6). PMV were generated by activating human platelets in plasma with collagen and subsequent removal of platelets and plasma by repeated centrifugation. MM6 were incubated for 2 h with PMV in a ratio corresponding to 75 platelets/cell, or saline as control. After RNA isolation, reverse transcription and fluorescence labelling, cDNA was hybridized on a medium density microarray comprising 5308 probes addressing 4868 transcripts of 4730 human genes relevant to inflammation, immune response and related processes. The formation of PMV-MM6 conjugates was associated with significant variations in gene expression, i.e. 93 genes were found to be differentially expressed (P < 0.001; q < 0.087). Among them, 47 genes with annotated transcripts and proteins were identified. Using Ingenuity Pathway Analysis, 37 of the differentially expressed genes were identified as parts of networks associated with functional pathways including cell-to-cell signalling, cellular growth and proliferation, regulation of gene expression and lipid metabolism. For sphingosine kinase-1 the increased expression could be confirmed exemplarily not only by RT-PCR but also on the enzyme activity level. The data indicate that PMV signal differential expression of inflammation-relevant genes in monocytic cells and may represent a novel link between hemostasis and inflammation.
 ...
PMID:Platelet-derived microvesicles induce differential gene expression in monocytic cells: a DNA microarray study. 1712 85

We hypothesized that the epsilon-amino group of lysine residues in longlived proteins oxidatively deaminates with age forming the carbonyl compound, allysine (alpha-aminoadipic acid-delta-semialdehyde), which can further oxidize into 2-aminoadipic acid. In the present study, we measured both products in insoluble human skin collagen from n=117 individuals of age range 10-90 years, of which n=61 and n=56 were non-diabetic and diabetic respectively, and a total of n=61 individuals had either acute or chronic renal failure. Allysine was reduced by borohydride into 6-hydroxynorleucine and both products were measured in acid hydrolysates by selective ion monitoring gas chromatography (GC)-MS. The results showed that 2-aminoadipic acid (P<0.0001), but not 6-hydroxynorleucine (P=0.14), significantly increased with age reaching levels of 1 and 0.3 mmol/mol lysine at late age respectively. Diabetes in the absence of renal failure significantly (P<0.0001) increased 2-aminoadipic acid up to <3 mmol/mol, but not 6-hydroxynorleucine (levels<0.4 mmol/mol, P=0.18). Renal failure even in the absence of diabetes markedly increased levels reaching up to <0.5 and 8 mmol/mol for 6-hydroxynorleucine and 2-aminoadipic acid respectively. Septicaemia significantly (P<0.0001) elevated 2-aminoadipic acid in non-diabetic, but not diabetic individuals, and mildly correlated with other glycoxidation markers, carboxymethyl-lysine and the methylglyoxal-derived products, carboxyethyl-lysine, argpyrimidine and MODIC (methylglyoxal-derived imidazolium cross-link). These results provide support for the presence of metal-catalysed oxidation (the Suyama pathway) in diabetes and the possible activation of myeloperoxidase during sepsis. We conclude that 2-aminoadipic acid is a more reliable marker for protein oxidation than its precursor, allysine. Its mechanism of formation in each of these conditions needs to be elucidated.
 ...
PMID:2-aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin: effects of diabetes, renal failure and sepsis. 1731 67

Sepsis is associated with increased production of reactive oxidant species. Oxidative and nitrosative stress can lead to activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), with subsequent loss of cellular functions. Activation of PARP may dramatically lower the intracellular concentration of its substrate, NAD thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. In addition, PARP enhances the expression of various pro-inflammatory mediators, via activation of NF-kappaB, MAP kinase and AP-1 and other signal transduction pathways. Preclinical studies in various rodent and large animal models demonstrate that PARP inhibition or PAR deficiency exerts beneficial effects on the haemodynamic and metabolic alterations associated with septic and haemorrhagic shock. Recent human data also support the role of PARP in septic shock: In a retrospective study in 25 septic patients, an increase in plasma troponin level was related to increased mortality risk. In patients who died, significant myocardial damage was detected, and histological analysis of heart showed inflammatory infiltration, increased collagen deposition, and derangement of mitochondrial criptae. Immunohistochemical staining for poly(ADP-ribose) (PAR), the product of activated PARP was demonstrated in septic hearts. There was a positive correlation between PAR staining and troponin I; and a correlation of PAR staining and LVSSW. Thus, there is significant PARP activation in animal models subjected to circulatory shock, as well as in the hearts of septic patients. Based on the interventional studies in animals and the correlations observed in patients we propose that PARP activation may be, in part responsible for the cardiac depression and haemodynamic failure seen in humans with severe sepsis. Interestingly, recent studies reveal that the protective effects of PARP inhibitors are predominant in male animals, and are not apparent in female animals. Oestrogen, by providing a baseline inhibitory effect on PARP activation, may be partially responsible for this gender difference.
 ...
PMID:Poly (ADP-ribose) polymerase activation and circulatory shock. 1738 Jul 90

Severe burn induces the activation of an inflammatory cascade that contributes to the development of subsequent immunosuppression, increased susceptibility to sepsis, as well as generation of reactive oxygen radicals and lipid peroxidation, leading to multiple organ failure. In the present study, we investigated whether rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand is protective against burn-induced remote organ injury. Under brief ether anaesthesia, shaved dorsum of the rats were exposed to 90 degrees C (burn group) or 25 degrees C (control group) water bath for 10s. Rosiglitazone (4 mg/kg) or saline was administered intraperitoneally immediately after and at the 12th hour of the burn. Rats were decapitated 24h after injury and the tissue samples from lung, liver, and kidney were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, and creatinine, blood urea concentrations (BUN) were determined to assess liver and kidney function, respectively. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and lactate dehydrogenase (LDH) were also assayed. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, and significant increases in MDA level, MPO activity and collagen content of tissues. Similarly, serum ALT, AST and BUN levels, as well as LDH, IL-1 beta and TNF-alpha were elevated in the burn group as compared to the control group. Rosiglitazone treatment reversed all these biochemical indices. According to the findings of the present study, rosiglitazone possesses a anti-inflammatory effect that prevents burn-induced damage in remote organs and protects against organ damage.
 ...
PMID:Rosiglitazone, a PPAR-gamma ligand, protects against burn-induced oxidative injury of remote organs. 1746 12

C1 inhibitor therapy improves outcome in several animal models of inflammatory disease. These include sepsis and Gram negative endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury. Furthermore, some data suggest a beneficial effect in human inflammatory disease. In many inflammatory conditions, complement system activation plays a role in pathogenesis. The contact system also very likely is involved in mediation of damage in inflammatory disease. Therefore, the beneficial effect of C1 inhibitor has been assumed to result from inhibition of one or both of these systems. Over the past several years, several other potential anti-inflammatory effects of C1 inhibitor have been described. These effects do not appear to require protease inhibition and depend on non-covalent interactions with other proteins, cell surfaces or lipids. In the first, C1 inhibitor binds to a variety of extracellular matrix components including type IV collagen, laminin, entactin and fibrinogen. The biologic role of these reactions is unclear, but they may serve to concentrate C1 inhibitor at extravascular inflammatory sites. The second is a non-covalent interaction with C3b that results in inhibition of formation of the alternative pathway C3 convertase, a function analogous to that of factor H. The third is an interaction with E and P selectins on endothelial cells that is mediated by the Lewis(x) tetrasaccharides that are expressed on C1 inhibitor. These interactions result in suppression of leukocyte rolling and transmigration. The fourth interaction is the binding of C1 inhibitor to Gram negative bacterial endotoxin that results in suppression of endotoxin shock by interference with the interaction of endotoxin with its receptor complex on macrophages. Lastly, C1 inhibitor binds directly to Gram negative bacteria, which leads to suppression of the development of sepsis, as demonstrated in the cecal ligation and puncture model. These observations suggest that C1 inhibitor is a multi-faceted anti-inflammatory protein that exerts its effects through a variety of mechanisms including both protease inhibition and several different non-covalent interactions that are unrelated to protease inhibition.
 ...
PMID:C1 inhibitor: biologic activities that are independent of protease inhibition. 1754 16

The administration of insulin is recommended to patients with severe sepsis and hyperglycemia. Previously, we demonstrated that insulin may have direct anti-inflammatory properties and counteracted fluid losses from the circulation by normalizing the interstitial fluid pressure (P(IF)). P(IF) is one of the Starling forces determining fluid flux over the capillary wall, and a lowered P(IF) is one of the driving forces in early edema formation in inflammatory reactions. Here we demonstrate that insulin restores a lipopolysaccharide (LPS)-lowered P(IF) via a mechanism involving integrin alpha(v)beta(3). In C57 black mice (n = 6), LPS lowered P(IF) from -0.2 +/- 0.2 to -1.6 +/- 0.3 (P < 0.05) and after insulin averaged -0.8 +/- 0.2 mmHg (P = 0.098 compared with after LPS). Corresponding values in wild-type BALB/c mice (n = 5) were -0.8 +/- 0.1, -2.1 +/- 0.3 (P < 0.05), and -0.8 +/- 0.3 mmHg (P < 0.05 compared with LPS) after insulin administration. In BALB/c integrin beta(3)-deficient (beta(3)(-/-)) mice (n = 6), LPS lowered P(IF) from -0.1 +/- 0.2 to -1.5 +/- 0.3 mmHg (P < 0.05). Insulin did not, however, restore P(IF) in these mice (averaged -1.7 +/- 0.3 mmHg after insulin administration). Cell-mediated collagen gel contraction can serve as an in vitro model for in vivo measurements of P(IF). Insulin induced alpha(v)beta(3)-integrin-dependent collagen gel contraction mediated by C2C12 cells. Our findings suggest a beneficiary effect of insulin for patients with sepsis with regard to the fluid balance, and this effect may in part be due to a normalization of P(IF) by a mechanism involving the integrin alpha(v)beta(3).
 ...
PMID:Integrin alphavbeta3 acts downstream of insulin in normalization of interstitial fluid pressure in sepsis and in cell-mediated collagen gel contraction. 1855 65

Group B Streptococcus (GBS) is a major etiologic agent of neonatal bacterial infections and is the most common cause of sepsis and pneumonia in newborns. Surface and secreted molecules of GBS are often essential virulence factors which are involved in the adherence of the bacteria to host cells or are required to suppress the defense mechanisms of hosts. We analyzed the peptidase profiles of GBS by detection of proteolytic activities on SDS-PAGE containing copolymerized gelatin as substrate. Based on the inhibition by o-phenathroline and EGTA, three distinct peptidases of 220, 200 and 180 kDa were identified in the culture medium, besides one major cell-associated proteolytic activity, a 200-kDa metallopeptidase, suggesting that all were zinc-metallopeptidases. GBS culture supernatants, rich in metallotype peptidases, also cleaved fibronectin, laminin, type IV collagen, fibrinogen and albumin. Cleavage of the host extracellular matrix by GBS may be a relevant factor in the process of bacterial dissemination and/or invasion. Notably, metallopeptidase inhibitors strongly blocked GBS growth as well as its interaction with human cell lineages. Understanding the contribution of peptidases to the pathogenesis of GBS disease may broaden our perception of how this significant pathogen causes severe infections in newborn infants.
 ...
PMID:Metallopeptidases produced by group B Streptococcus: influence of proteolytic inhibitors on growth and on interaction with human cell lineages. 1857 84

Acute respiratory distress syndrome and acute lung injury for a part of a devastating syndrome characterized by acute onset, hypoxemia and bilateral infiltrates in the chest x-ray with absence of heart failure signs. Acute lung injury is the response of the lung to a local or systemic aggression, resulting in local inflammation and coagulation disorders, this leading to increased inflammatory pulmonary edema. Acute lung injury/acute respiratory distress syndrome are associated with increased procoagulant and reduced fibrinolytic activities mainly in alveoli and interstitial spaces in the lung. Fibrin deposits, which are the hallmark of early phase acute lung injury, stimulate fibroblast aggregation and collagen secretion, participating to the constitution of pulmonary fibrosis. The only clinical intervention found to have a significant impact on mortality in acute respiratory distress syndrome, despite the significant pro - gress in the understanding of the disease made over the past 10 years, is the use of low tidal volume ventilation. In severe sepsis, only recombinant human activated protein C administration has demonstrated a mortality reduction, together with faster improvement in respiratory dysfunction and shorter duration of mechanical ventilation. Future clinical trials should consider the potential benefit of anticoagulants administrated systemically or locally in the lungs to determine the role of anticoagulants in the treatment of acute pulmonary injury/acute respiratory distress syndrome.
 ...
PMID:[Role of coagulation in acute pulmonary lesion physiopathology. Parallelism with sepsis]. 1860 38

Subcapsular hematoma and/or rupture of the graft is uncommon but serious complication of liver transplantation. It may develop spontaneously or following parenchymal injuries or percutaneous transhepatic invasive procedures. This report describes three cases of subcapsular hematoma and/or rupture of the graft with different courses among 350 liver transplantations. In the first case, the patient died due to graft rupture caused by a pseudoaneurysm after biopsy. In the second case, a small injury of the donor liver resulted in a deep rupture, which required partial resection of the graft. The patient died in sepsis later. The third patient presented with a large subcapsular haematoma during transplantation, which was successfully treated. The authors' strategies developed intraoperatively for the management of hematomas. These involve opening and removing of the haematoma, haemostasis with Argon coagulation, which resulted in an adherent Glisson's capsule to the parenchyma and covering with collagen fleece coated with fibrinogen and thrombin.
 ...
PMID:[Subcapsular hematoma and rupture of the liver graft]. 1879 7


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