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)

This study was performed to investigate a novel strategy to pharmacologically inhibit high-mobility group box 1 protein (HMGB1) expression with sodium butyrate, a short-chain fatty acid. Using a sepsis model induced by cecal ligation and puncture (CLP), 100 male Wistar rats were randomly divided into 4 groups as follows: control group (10 rats), sham operation group (10 rats), CLP group (further randomized into 2, 6, 12, 24, 48, and 72 h post-CLP subgroups, each 10 rats), and sodium butyrate treatment group (further randomized into 12 and 24 h post-CLP subgroups, each 10 rats). Animals of all groups were killed at designated time points, and blood and tissue samples from livers, lungs, kidneys, and small intestines were harvested to determine organ damage-related variables, and HMGB1 mRNA expression was assessed by the reverse-transcription-polymerase chain reaction. In addition, we observed the effect of treatment with sodium butyrate on survival rate in septic rats. The results showed that early treatment with sodium butyrate can markedly reduce serum alanine aminotransferase, creatinine levels at 12 h, and pulmonary myeloperoxidase activity at 24 h post-CLP, and significantly improve the 1- to 6-day survival rates in animals subjected to CLP (P < 0.05-0.01). These findings suggest that HMGB1 is excessively expressed and produced in sepsis. Sodium butyrate can markedly inhibit HMGB1 mRNA expression and may have protective effect on multiple organ damage in sepsis.
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PMID:Sodium butyrate prevents lethality of severe sepsis in rats. 1750 8

Sepsis is the leading cause of death for intensive care patients. Lipopolysaccharide (LPS) administration to animals under anesthesia is a strategy for the study of uncontrolled release of proinflammatory cytokines. Anesthetics have been indicated that they can specially affect immune responses, such as the inflammatory response. Pentobarbital is an anesthetic used mainly in animal studies. Thus, the effect of pentobarbital on tumor necrosis factor-alpha (TNF-alpha) release was determined. The results revealed that pentobarbital suppressed the expression of TNF-alpha mRNA and its proteins, which may result from the decrease in the activities of nuclear factor-kappaB and activator protein 1 and the reduction of the expression of p38 mitogen-activated protein kinase by pentobarbital. After the inhibitory activity of the pentobarbital for TNF-alpha release was proven in vivo, the cytotoxic effects of LPS were examined in vivo with or without pentobarbital treatments. In vivo results indicated that plasma levels of alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, serum urea nitrogen, and amylase decreased dramatically in the anesthetic group with pentobarbital administration. Finally, the effect of pentobarbital on TNF-alpha-related cell death was monitored in vitro, and the results indicated the pentobarbital could directly enhance the viabilities of cells under the treatment of TNF-alpha and protected cells from apoptosis induced by deferoxamine mesylate-induced hypoxia. These results suggest that pentobarbital significantly influences the LPS-induced inflammatory response and protects cells from death directly and indirectly induced by TNF-alpha. The information provides a perspective to re-evaluate the results of the experiments in which animals were anesthetized with pentobarbital. The anti-inflammatory effects of the drugs may have been caused by the synergistic effect of pentobarbital.
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PMID:The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model. 1754 46

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal. A subset of these patients develop advanced fibrosis and cirrhosis and it is believed that this leads to increased posttransplantation mortality. The specific aims of this study were to determine the incidence of advanced fibrosis and those factors associated with this process, and to evaluate causes for mortality in patients with recurrent HCV. A total of 227 patients who underwent LT with chronic HCV were monitored prospectively. The mean age of this group at LT was 49.5 yr; 76% were male and 85% were Caucasian. Fibrosis progression was monitored by protocol liver biopsy, initially performed 6 months after LT and then at 6- to 24-month intervals. Advanced fibrosis, defined as the bridging fibrosis or cirrhosis, developed in 1%, 11%, 25%, and 41% of patients after 1, 3, 5, and 6-10 yr, respectively. Acute cellular rejection hepatic steatosis, a persistent elevation in serum alanine aminotransferase and donor-race were associated with the development of advanced fibrosis. In contrast, the development of advanced fibrosis was not affected by the use of interferon prior to undergoing LT, cytomegalovirus disease, or donor age. A total of 60 patients (26%) died over 15 yr of follow-up. Although graft failure accounted for 45% of deaths in patients with advanced fibrosis, this represented only 8% of all deaths in patients with recurrent HCV. Sepsis was the most common cause of death and this was observed with similar frequency in patients who developed advanced fibrosis (45%) and in those with less advanced fibrosis (47%). In conclusion, approximately 41% of patients with recurrent HCV developed advanced fibrosis 6-10 yr after LT. However, complications associated with sepsis, not recurrent cirrhosis, was the most common cause of death in patients with recurrent HCV and this was similar in patients with or without advanced fibrosis.
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PMID:A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation. 1760 Mar 60

To investigate clinical course and outcome of dengue with acute respiratory failure (ARF), and to identify related risk factors for acquiring ARF in dengue, we retrospectively studied 11 dengue patients with ARF. From June to December 2002, a total of 606 adult patients were diagnosed as having dengue. Eleven (1.8%) of 606 dengue patients had complications of ARF. The main causes of ARF were sepsis (n = 6, 54.5%) and upper gastrointestinal (UGI) bleeding (n = 3, 27.3%). The mortality rate was 72.7% (n = 8). Additionally, univariate analysis showed that age, dyspnea, cough, prothrombin time, activated partial thromboplastin time, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, albumin, renal insufficiency, acute renal failure, acute hepatic failure, UGI bleeding, and combination bacterial infection were significantly predictive variables associated with dengue patients with ARF.
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PMID:Acute respiratory failure in adult patients with dengue virus infection. 1762 Jun 47

Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
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PMID:Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. 1763

We investigated in vivo the effect of recombinant bactericidal/permeability-increasing protein (rBPI21) on high-mobility group box 1 protein (HMGB1) expression in sepsis and its potential mechanism. Using a sepsis model induced by cecal ligation and puncture (CLP), rats were randomly divided into four groups as follows: normal control group, sham-operated group, CLP group, and BPI treatment group. Animals were killed at designated time points, and blood and tissue samples from liver, lungs, kidneys, and small intestine were harvested to determine related variables. In addition, we observed the effect of treatment with rBPI21 on survival rate in septic rats. The results showed that endotoxin content and expression levels of HMGB1 and LPS binding protein/CD14 mRNA in various organs were significantly increased at 12 and 24 h after CLP, which can be attenuated by treatment with rBPI21 (P<0.05-0.01). Meanwhile, treatment with rBPI21 in septic rats can markedly reduce serum alanine aminotransferase, creatinine levels, and pulmonary myeloperoxidase activity at 12 and 24 h after CLP, increase diamine oxidase activity at both time points (P<0.05-0.01), and improve the 1- to 10-day survival rates in animals subjected to CLP (P=0.012). These findings suggest that treatment with rBPI21 can significantly reduce endotoxin contents and expression levels of HMGB1 and LPS binding protein/CD14 mRNA in various organs in sepsis induced by CLP, and can protect against multiple organ damage resulting from sepsis. The effect of rBPI21 inhibiting HMGB1 gene expression in sepsis might be associated with endotoxin-dependent mechanisms.
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PMID:Recombinant bactericidal/permeability-increasing protein inhibits endotoxin-induced high-mobility group box 1 protein gene expression in sepsis. 1769 35

Biliary complications after liver transplantation (LT) using organs retrieved from donors after cardiac death are not well characterized. The aim of this study was to evaluate the severity of biliary complications and outcomes after donation after cardiac death liver transplantation (DCD-LT). A retrospective evaluation of 20 DCD-LTs from 1997-2006 was performed. The recipient age was 53+/-8.7, and the donor age was 35+/-11 years. The warm ischemia time, cold ischemia time, peak alanine aminotransferase level, and peak aspartate aminotransferase level were 33+/-12 minutes, 8.7+/-2.7 hours, 1757+/-1477 U/L, and 4020+/-3693 U/L, respectively. The bilirubin and alkaline phosphatase levels at hospital discharge after LT were 3.2+/-5.4 mg/dL and 248+/-200 U/L, respectively. During a median follow-up of 7.5 months (range: 1-73), 5 patients (25%; 1 death after re-LT) died (3 from sepsis, 1 from recurrent hepatocellular carcinoma at 4 months, and 1 from a cardiac event at 46 months), and additionally, 4 patients (20%) required re-LT (1 because of hepatic artery thrombosis, 1 because of primary graft nonfunction, and 2 because of biliary strictures). Twelve (60%) developed biliary complications, and of these, 11 (55%) had serious biliary complications. The biliary complications were as follows: a major bile leak for 2 patients (10%; both eventually underwent retransplantation), anastomotic strictures for 5 patients (25%), hilar strictures for 7 patients (35%), extrahepatic donor duct strictures for 9 patients (45%), intrahepatic strictures for 10 patients (50%), stones for 1 patients (5%), casts for 7 patients (35%), and debris for 2 patients (10%). More than 1 biliary complication was seen in most patients, and these were unpredictable and required multiple diagnostic or therapeutic procedures. Serious biliary complications are common after DCD-LT, and research should focus on identifying donor and recipient factors that predict and prevent serious biliary complications.
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PMID:Biliary complications and outcomes of liver transplantation from donors after cardiac death. 1804 64

In the course of isolating preventive agents from sepsis based on the in vivo assay model from the EtOAc extract of the roots of Saururus chinensis, twelve lignans, sarisan (1), erythro-austrobailignan-6 (2), meso-dihydroguaiaretic acid (3), saucerneol B (4), manassantin B (5), manassantin A (6), rel-(8R,8'R)-dimethyl-(7S,7'R)-bis(3,4-methylenedioxyphenyl)tetrahydro-furan (7), (+)-saururinone (8), sauchinone (9), sauchinone B (10), nectandrin B (11) and machilin D (12), were isolated. Compounds 9 and 10, at a dose of 10 mg/kg, increased survival rates to 80% from 20% for the control experiment, and decreased the plasma levels of tumor necrosis factor-alpha (TNF-alpha) and alanine aminotransferase (ALT) activity in mice administered LPS/D-GalN.
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PMID:Protective effect of lignans against sepsis from the roots of Saururus chinensis. 1831 Sep 23

Hepatic ischemia should be considered in serious liver injury, liver tumor resection and liver transplantation. There are other conditions that decrease hepatic blood flow and cause hepatic ischemia, such as hemorrhagic shock, sepsis, hepatic artery ligation, trauma, and certain vascular lesions. In this study, effects of nimodipine (a calcium channel blocker) and pentoxyfylline (a derivative of methylxanthine) on duration and degree of hepatic ischemia in rats at normothermic and hypothermic conditions are investigated. This study was performed on 6 groups of Wistar Albino type rats, each group consisting of 7 rats. Groups were separated into normothermic (A) and hypothermic (B) conditions AI-Control group, AII-Nimodipine group and AIII-Pentoxyfylline group, B IV-Control group, BV-Nimodipine group and BVI-Pentoxyfylline group respectively. After hepatic pedicle occlusion lasting 45 min, blood samples were drawn from the rats for evaluation of alanine aminotransferase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) values. Moreover, hepatic biopsies were taken to assess pathological changes under electron microscopy. These changes were evaluated through a grading system. As a result; it has been shown that both nimodipine and pentoxyfylline delayed effects of hepatic ischemia in a statistically significant manner in comparison with the control group and these effects were found to be more significant in hypothermic conditions.
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PMID:Effects of nimodipine and pentoxyfylline in prevention of hepatic ischemic damage in rats at normal and hypothermic conditions. 1849 96

Severe sepsis remains a leading cause of death and disability because of less effective therapy available for this disease. A complex interplay between the inflammatory factors and the coagulation pathways seems to be the fundamental mechanisms for the pathogenesis of sepsis. Here we report that recombinant fibrinogenase II (rF II) from Agkistrodon acutus plasmin-independently degraded the thrombi, and inhibited inflammatory responses by direct and specific degradation of tumor necrosis factor alpha (TNF-alpha) induced by lipopolysaccharide (LPS) without showing proteolytic activities on interleukin-1 (IL-1), cluster of differentiation 68 (CD68) and some other serum proteins. We also report that rF II effectively protected against LPS induced sepsis in a rabbit model. Administration of rF II reduced hepatic and renal damage, decreased the levels of alanine aminotransferase (ALT) and blood urea nitrogen (BUN), and increased survival rate in LPS-induced sepsis rabbits. We further confirmed the rescue effect of rF II on severe sepsis in rat caecal ligation and puncture (CLP) model. Our findings suggest that rF II could effectively protect against sepsis via direct degradation of microthrombi and inflammatory factor TNF-alpha as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.
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PMID:Recombinant fibrinogenase from Agkistrodon acutus venom protects against sepsis via direct degradation of fibrin and TNF-alpha. 1863 54


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