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)

The loss of lean body mass (muscle wasting) is initiated by cascades or events that precipitate increased proteolysis. Muscle wasting is stimulated by internal and external factors. Humorally related feedback loops stimulated by disease states, e.g., cancer, inflammatory myopathies, leukemia, or sepsis, and initiated as a response to systemic inflammatory response syndrome can cause a downward progression of events, resulting in chronic illness or even death. This article discusses the pathogenesis of muscle wasting, which is often referred to as cachexia.
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PMID:Muscle wasting. 1296 68

To study the impact of T-box transcription factor (T-bet) on initiation and progression of Staphylococcus aureus sepsis and arthritis, T-bet-deficient mice (T-bet(-/-)) and their wild-type controls (T-bet(+/+)) were intravenously inoculated with 8 x 10(6) S. aureus. Already 48 h after inoculation of S. aureus, T-bet-deficient mice displayed increased frequency (62% versus 19%, P = 0.002) as well as severity of arthritis compared with wild-type controls. The bacterial counts were significantly increased in T-bet(-/-) mice compared with T-bet(+/+) as measured in kidneys 72 h after the inoculation (4.3 +/- 1.8 x 10(7) versus 3.2 +/- 3.2 x 10(6) colony-forming units (CFU); P = 0.003). As expected, T-bet-deficient mice displayed significantly decreased production of IFN-gamma (10-15-fold) at 24 and 72 h after bacterial inoculation compared with wild-type mice. Interestingly, in the absence of T-bet, serum IL-4 was decreased at 24 h. IL-6 did not differ at early stage of infection but was sixfold increased in T-bet(-/-) mice over T-bet(+/+) animals at 72 h postinoculation. Ten days after the inoculation, T-bet(-/-) mice still displayed significantly more pronounced weight loss and increased serum IL-6 levels, probably due to increased bacterial burden compared with T-bet(+/+) mice. The cumulative mortality was 19% in T-bet mice (5/27) and 0% (0/27) in control animals (P = 0.05). In conclusion, T-bet plays an important role in early response to S. aureus infection, protecting against bacterial accumulation, cachexia and septic death. Furthermore T-bet downregulates joint inflammation in the early phase of disease.
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PMID:T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis. 1515 85

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunobiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.
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PMID:The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. 1581 93

Atrophy of skeletal muscle is common to a number of conditions, including cancer, sepsis, AIDS, renal failure, diabetes, severe trauma, and burns. In all cases, protein synthesis in skeletal muscle is depressed, whereas protein degradation is increased through an increase in activity and expression of the ubiquitin-proteasome proteolytic pathway. This pathway is not responsive to simple nutritional intervention. Certain agents, including glucocorticoids, cytokines, proteolysis-inducing factor (PIF), and oxidative stress, are thought to be responsible for the induction of the ubiquitin-proteasome pathway in skeletal muscle in catabolic conditions. Insulin suppresses activation of this pathway, and loss of insulin action in diabetes leads to muscle wasting. Cytokines, PIF, and reactive oxygen species (ROS) are thought to induce proteasome expression through activation of the transcription factor nuclear factor kappa B (NF-kappaB). Targets for therapeutic intervention include antagonists of the inducers of proteasome expression, intracellular signaling pathways leading to activation of NF-kappaB, and the enzymes inducing ubiquitin conjugation to the substrate protein (myosin), as well as the proteasome itself. Anticytokine and anti-PIF antibodies are effective in attenuating muscle protein degradation in certain experimental animal models,and glucocorticoid receptor antagonists are effective in the treatment of sepsis. Agents that inhibit NF-kappaB activation, such as resveratrol, thalidomide, ibuprofen, eicosapentaenoic acid, and beta-hydroxy-beta-methylbutyrate, are effective in the preservation of skeletal muscle mass in cachexia. These results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to prevent muscle wasting.
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PMID:The ubiquitin-proteasome pathway as a therapeutic target for muscle wasting. 1591 24

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.
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PMID:Attenuation of skeletal muscle atrophy via protease inhibition. 1597 55

As indicated by its name, tumor necrosis factor (TNF), cloned in 1985, was originally described as a macrophage-derived endogenous mediator that can induce hemorrhagic necrosis of solid tumors and kill some tumor cell lines in vitro. Unfortunately, its promising use as an anticancer agent was biased by its toxicity, which was clear soon from the first clinical trials with TNF in cancer. Almost at the same time TNF was being developed as an anticancer drug, it became clear that TNF was identical to a mediator responsible for cachexia associated with sepsis, which was termed cachectin. This research led to the finding that TNF is, in fact, the main lethal mediator of sepsis and to the publication of a huge number of articles showing that TNF inhibits the toxic effects of bacterial endotoxins, which are now described as systemic inflammatory response. Although the clinical trials with anti-TNF in sepsis have not been successful thus far, undoubtedly as a result of the complexity of this clinical setting, these studies ultimately led to the identification of TNF as a key inflammatory mediator and to the development of anti-TNF molecules (soluble receptors and antibodies) for important diseases including rheumatoid arthritis and Crohn's disease. On the other side, the mechanisms by which TNF and related molecules induce cell death have been studied in depth, and their knowledge might, in the future, suggest means of improve the therapeutic index of TNF in cancer.
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PMID:Tumor necrosis factor as a pharmacological target. 1623 Jul 74

Oxysterols are cytotoxic agents that have a range of cellular actions, including impairment of albumin synthesis, cell differentiation, and induction of apoptosis. Their regulations by nutritional factors are poorly described. Our objective was to test the hypothesis that the imposition of food withdrawal and alcohol exposure increases tissue oxysterol concentrations. We measured the concentrations of the oxysterols 7alpha-hydroxycholest-5-en-3beta-ol (7alpha-OH), 7beta-hydroxycholest-5-en-3beta-ol (7beta-OH), and 3beta-hydroxycholest-5-en-7-one (7-keto) in liver and skeletal muscle of fed and fasted (food withdrawal for 1 and 2 days) male Wistar rats. Both oxidative (type I; soleus) and glycolytic (type II; plantaris) muscles were analyzed. We also investigated the effects of a nutritional perturbant induced by a short-term bolus of ethanol (75 mmol/kg weight IP administered 2.5 hours before sacrifice). The results showed that in response to fasting there were significant increases in 7alpha-OH, 7beta-OH, and 7-keto in liver and both type I and II skeletal muscle (P < .001 in all instances). For skeletal muscle, the increases were blunted or ameliorated after 2 days when compared with data from rats starved for 1 day. In contrast, the increases in liver after 1 day's fasting were relatively sustained at 2 days. Short-term ethanol increased 7alpha-OH, 7beta-OH, and 7-keto in type I muscle of fed animals only (P < .001 in all instances) with a significant interaction between fasting and alcohol (P < .001 in all instances). For the first time, we have shown that oxysterols can increase in muscle and liver in response to food withdrawal and in response to an immediately imposed nutritional perturbant (ie, alcohol). Increased oxysterols represent elevated oxidative stress and/or disturbances in their formation or clearance. Because of the reported cytotoxic properties of oxysterols, these data are important in understanding cellular pathology because episodic anorexia and/or oxidative stress occur in a variety of disease conditions including sepsis, cancer cachexia, ischemia, and hormonal imbalance.
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PMID:Skeletal muscle and liver oxysterols during fasting and alcohol exposure. 1632 30

The term cachexia originates from the Greek root kakos hexis, which translates into "bad condition," recognized for centuries as a progressive deterioration of body habitus. Cachexia is commonly associated with a number of disease states, including acute inflammatory processes associated with critical illness and chronic inflammatory diseases, such as cancer, congestive heart failure, chronic obstructive pulmonary disease, and human immunodeficiency virus infection. Cachexia is responsible for the deaths of 10%-22% of all patients with cancer and approximately 15% of the trauma deaths that occur from sepsis-induced organ dysfunction and malnutrition days to weeks after the initial traumatic event. The abnormalities associated with cachexia include anorexia, weight loss, a preferential loss of somatic muscle and fat mass, altered hepatic glucose and lipid metabolism, and anemia. Anorexia alone cannot fully explain the development of cachexia; metabolic alterations in carbohydrate, lipid, and protein metabolism contribute to the severe tissue losses. Despite significant advances in our understanding of specific disease processes, the mechanisms leading to cachexia remain unclear and multifactorial. Although complex, increasing evidence from both animal models and clinical studies suggests that an inflammatory response, mediated in part by a dysregulated production of proinflammatory cytokines, plays a role in the genesis of cachexia, associated with both critical illness and chronic inflammatory diseases. These cytokines are further thought to induce an acute phase protein response (APR) and produce the alterations in lipid and carbohydrate metabolism identified as crucial markers of acute inflammation in states of malignancy and critical illness. Although much is still unknown about the etiology of cachexia, there is growing appreciation that cachexia represents the endproduct of an inappropriate interplay between multiple cytokines, neuropeptides, classic stress hormones, and intermediary substrate metabolism.
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PMID:The origins of cachexia in acute and chronic inflammatory diseases. 1643 72

Toxic neutrophils exhibit a variety of nuclear and cytoplasmic abnormalities in Romanowsky-stained blood smears, and are associated with inflammation and infection. The purpose of the retrospective study reported here was to investigate the association of toxic neutrophils with clinicopathologic characteristics, diseases, and prognosis in cats. Cats with toxic neutrophils (n = 150) were compared with negative-control cats (n = 150). Statistical analyses included Fisher exact, independent t-, nonparametric Mann-Whitney, and chi-squared tests. Cats with toxic neutrophils had significantly (P < .05) higher prevalence of fever, icterus, vomiting, diarrhea, depression, dehydration, weakness, and cachexia, as well as leukocytosis, neutrophilia, left shift, neutropenia, anemia, hypokalemia, and hypocalcemia. The prevalence of shock, sepsis, panleukopenia, peritonitis, pneumonia, and upper respiratory tract diseases was significantly higher among these cats, as were infectious (viral and bacterial) and metabolic disorders. Control cats had a significantly higher prevalence of feline asthma, as well as allergic, idiopathic, and vascular disorders. Hospitalization duration and treatment cost were significantly (P < .001) higher in cats with toxic neutrophils. In 53 and 47% of the cats with toxic neutrophils, the leukocyte and neutrophil counts were normal, respectively, whereas in 43%, both abnormalities and left shift were absent, and toxic neutrophils were the only hematologic evidence of inflammation or infection. In conclusion, toxic neutrophils were found to be associated with certain clinicopathologic abnormalities, and when present, may aid in the diagnosis, as well as the assessment of hospitalization duration and cost. The evaluation of blood smears for toxic neutrophils provided useful clinical information.
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PMID:Toxic neutrophils in cats: clinical and clinicopathologic features, and disease prevalence and outcome--a retrospective case control study. 1649 19

In advanced stages of polycystic liver disease, often associated with polycystic kidney disease, a curative therapy is liver or combined liver-kidney transplantation. However, little is known about long-term outcome and quality of life. Between 1990 and 2003, 36 patients (32 female, 4 male) with polycystic liver or combined liver-kidney disease underwent liver (n = 21) or liver-kidney (n = 15) transplantation at our center. Main indications for liver transplantation were cachexia, muscle atrophy, loss of weight, recurrent cyst infections, portal hypertension, and ascites. Apart from clinical parameters, 2 anonymous questionnaires (standard short form 36 and self-designed) addressing quality of life and social status were evaluated. Five patients (14 %) died due to sepsis or myocardial infarction with pneumonia, all within 61 days after transplantation. The follow-up time of the remaining 31 patients ranged from 5 to 156 months, with a mean of 62 months. Of the 23 (74%) answered the questionnaires, 91% of patients felt "much better" or "better," only 9% felt "worse" than before, and 52% of patients participated in sports regularly. Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after transplantation. Physical attractiveness and interest in sex increased as well. Professional occupation did not change for 71% of patients. Family situation before and after transplantation changed in 1 case only. Finally, 78% of patients said they would opt for transplantation again, while 17% were undecided; 1 patient would not repeat transplantation. In conclusion, patients with advanced polycystic liver or polycystic liver-kidney disease have an excellent survival rate and an improved quality of life after liver or combined liver-kidney transplantation.
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PMID:Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation. 1686 56


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