Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulated experimental and clinical data suggest that adrenocorticosteroids and/or endogenous ouabain-like substances may play an important role in the mechanism of furosemide diuretic action. It was reported that the drug is highly bound in the adrenals, lungs, kidney, spleen, and liver. In patients with liver cirrhosis, furosemide exerted a markedly decreased natriuretic effect compared with normal subjects, and the plasma levels of circulating endothelin and atrial natriuretic factor (ANF) were significantly elevated. In neonates, after administration of furosemide, the urinary excretion of endothelin-1 and aldosterone increased markedly, and it is known that endothelin may release ANF and aldosterone in a dose-dependent manner. Furosemide was used to stimulate zona glomerulosa, whereas ANF decreased the production of steroids in zona glomerulosa and fasciculata cell culture owing to stimulation by various factors. Because the concomitant use of ANF and furosemide appeared to be diuretically effective in newborns after cardiac surgery, one may suggest that furosemide competes with ANF for its effects on the adrenals. Furosemide administered by inhalation exerted a protective effect on allergic and perennial nonallergic rhinitis and was effective in preventing the postsurgical recurrence of nasal polyposis. The drug can also be used as an antiasthmatic agent. In preterm ventilator-dependent infants with chronic lung disease, aerosolized furosemide improved pulmonary function with no marked effect on diuresis. In adults and children with asthma, furosemide exerted a protective effect against bronchoconstriction induced by several indirect stimuli similar to that of disodium cromoglycate or nedocromil. Aerosolized furosemide had a preventive effect also on bronchoconstriction induced by inhaled lysine acetylsalicylate in patients with aspirin-sensitive asthma. In high-dose beclomethasone-dependent asthma, inhaled lysine acetylsalicylate and furosemide exerted a mutually potentiating antiasthmatic activity, allowing considerable sparing of the inhaled steroid. It is proposed that this effect may be explained by the corticosteroid-sparing action of lysine released from the lysine acetylsalicylate molecule because similar beneficial effects were also obtained after the concomitant use of epsilon-aminocaproic acid (whose chemical structure is almost the same as that of lysine) and prednisone. Furosemide exhibited an anti-inflammatory effect through inhibition of production and release of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha from peripheral mononuclear cells, which may have a beneficial effect on local inflamed tissue imbalance in the ratio of different cytokines, thus improving the sensitivity of target cells to endogenous glucocorticosteroids.
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PMID:Furosemide: progress in understanding its diuretic, anti-inflammatory, and bronchodilating mechanism of action, and use in the treatment of respiratory tract diseases. 1211 21

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC), a life-threatening sequel. However, the factors that affect disease progression to HCC have not been thoroughly elucidated. Genetic polymorphisms in proinflammatory cytokines, the interleukin 1 (IL-1) family (IL-1beta and IL-1ra) and tumor necrosis factor-alpha (TNF-alpha), were studied in 274 Japanese patients with chronic HCV infection and 55 healthy individuals using standard polymerase chain reaction-based genotyping techniques. The association between these polymorphisms and disease status was evaluated while controlling for confounding clinical variables. The proportion of patients with HCC in the IL-1beta-31 T/T (55%, odds ratio to C/C was 2.63, P =.009) genotype was higher than in the T/C (44%, odds ratio to C/C was 1.64, P =.149) and C/C genotypes (35%). The IL-1beta-31 and -511 loci were in near complete linkage disequilibrium, and the IL-1beta-511/-31 haplotype C-T was significantly associated with the presence of HCC (odds ratio of 1.51, P =.02). Polymorphisms in the TNF-alpha gene were not associated with disease. A multivariate analysis revealed that the IL-1beta-31 T/T genotype, alpha-fetoprotein >20 microg/L, presence of cirrhosis, male sex, and age >60 years were associated with the presence of HCC at odds ratios of 3.73 (T/T vs. C/C), 4.12, 4.03, 3.89, and 3.27, respectively. In conclusion, the IL-1beta-31 genotype T/T or the IL-1beta-511/-31 haplotype C-T is associated with the presence of HCC in Japanese patients with chronic HCV infection.
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PMID:Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. 1283 11

The liver plays an important physiological role in lipopolysaccharide (LPS) detoxification and, in particular, hepatocytes are involved in the clearance of endotoxin of intestinal derivation. In experimental shock models, tumor necrosis factor (TNF)-alpha induces hepatocyte apoptosis and lethal effects are due to secreted TNF-alpha and not to cell-associated TNF-alpha. An exaggerated production of TNF-alpha has been reported in murine viral infections, in which mice become sensitized to low amounts of LPS and both interferon (IFN)-gamma and IFN-alpha/beta are involved in the macrophage-induced release of TNF-alpha. The prominent role of LPS and TNF-alpha in liver injury is also supported by studies of ethanol-induced hepatic damage. In humans, evidence of LPS-induced hepatic injury has been reported in cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis and a decreased phagocytic activity of the reticulo-endothelial system has been found in these diseases. The origin of endotoxemia in hepatitis C virus (HCV) infected patients seems to be multifactorial and LPS may be of exogenous or endogenous derivation. In endotoxemic HCV-positive patients responsive to a combined treatment with IFN-alpha/ribavirin (RIB), endotoxemia was no longer detected at the end of the therapeutic regimen. By contrast, 48% of the non-responders to this treatment were still endotoxemic and their monocytes displayed higher intracellular TNF-alpha and interleukin (IL)-1beta levels than responders. Moreover, in responders, an equilibrium between IFN-gamma and IL-10 serum levels was attained. In the non-responders, serum levels of IL-10 did not increase following treatment. This may imply that an imbalance between T helper (Th)1 and Th2 derived cytokines could be envisaged in the non-responders.
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PMID:The role of the liver in the response to LPS: experimental and clinical findings. 1253 90

Hepatocytes express keratins 8 and 18 (K8/18) as their only cytoskeletal intermediate filament (IF) proteins, and K8/18 mutations predispose their carriers to liver cirrhosis. Transgenic mice that overexpress mutant human K18 (Arg89-->Cys [R89C]) develop mild chronic hepatitis, hepatocyte fragility, keratin filament disruption, and increased susceptibility to drug-induced liver injury. K18 is a major caspase substrate during apoptosis, and K8- or K18-null mice are significantly predisposed to Fas- and possibly tumor necrosis factor (TNF)-mediated apoptosis in the liver. Here we tested the potential role of the K18 R89C mutation on Fas- or TNF-mediated apoptotic liver injury by injecting Fas antibody (Ab) or TNF-alpha plus actinomycin D into mice that overexpress wild-type (WT) human K18 (with intact filament network, termed TG2 mice) or into K18 R89C mice (with disrupted filament network). K18 R89C mice are significantly more susceptible to Fas-mediated liver injury compared with nontransgenic and TG2 mice. This included differences in lethality, histology, apoptosis, and serum transaminase levels. In contrast, K18 WT and R89C mice manifest similar sensitivity to TNF-induced injury. Both Fas- and TNF-induced apoptosis in liver tissues are associated with caspase-mediated K18 degradation and increased keratin phosphorylation on several but not all sites. In conclusion, transgenic mouse K18 mutation and its consequent keratin filament disruption predispose hepatocytes to Fas- but not TNF-mediated apoptotic injury. This supports the association of keratin mutations with cirrhosis in patients with liver disease and suggests that keratins modulate apoptosis induced by Fas but not TNF.
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PMID:Keratin mutation in transgenic mice predisposes to Fas but not TNF-induced apoptosis and massive liver injury. 1271 81

Zinc supplementation has been shown to improve not only liver dysfunction but also glucose intolerance in subjects with liver cirrhosis. In this study, we investigated the effects of zinc supplementation on the changes in circulating levels of tumor necrosis factor-alpha and total antioxidant capacity in mice with thioacetamide-induced liver injury. The protective effect of concurrent zinc administration for thioacetamide-induced hepatotoxicity was also examined. The results showed that zinc treatment significantly attenuated thioacetamide-induced liver injury and hyperglycemia. Furthermore, thioacetamide-induced hepatotoxicity was markedly weakened by the simultaneous zinc administration. These effects might be attributed to reduced tumor necrosis factor-alpha production and elevated total antioxidant capacity induced by the mineral. Our data suggest that zinc supplementation might be beneficial for the subjects with a high susceptibility to liver injury.
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PMID:Zinc supplementation attenuates thioacetamide-induced liver injury and hyperglycemia in mice. 1274 76

Collagen degradation by matrix metalloproteinases is the limiting step in reversing liver fibrosis. Although collagen production in cirrhotic livers is increased, the expression and/or activity of matrix metalloproteinases could be normal, increased in early fibrosis, or decreased during advanced liver cirrhosis. Hepatic stellate cells are the main producers of collagens and matrix metalloproteinases in the liver. Therefore, we sought to investigate whether they simultaneously produce alpha1(I) collagen and matrix metalloproteinase-13 mRNAs. In this communication we show that expression of matrix metalloproteinase-13 mRNA is reciprocally modulated by tumor necrosis factor-alpha and transforming growth factor-beta1. When hepatic stellate cells are co-cultured with hepatocytes, matrix metalloproteinase-13 mRNA is up-regulated and alpha1(I) collagen is down-regulated. Injuring hepatocytes with galactosamine further increased matrix metalloproteinase-13 mRNA production. Confocal microscopy and differential centrifugation of co-cultured cells revealed that matrix metalloproteinase-13 is localized mainly within hepatic stellate cells. Studies performed with various hepatic stellate cell lines revealed that they are heterogeneous regarding expression of matrix metalloproteinase-13. Those with myofibroblastic phenotypes produce more type I collagen whereas those resembling freshly isolated hepatic stellate cells express matrix metalloproteinase-13. Overall, these findings strongly support the notion that alpha1(I) collagen and matrix metalloproteinase-13 mRNAs are reciprocally modulated.
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PMID:Reciprocal modulation of matrix metalloproteinase-13 and type I collagen genes in rat hepatic stellate cells. 1275 35

Liver cirrhosis is characterized by a severe impairment of the growth hormone/insulin-like growth factor-1 (GH-IGF-1) axis, that is, acquired GH resistance. The condition of the GH-IGF-1 axis in the phase of chronic liver disease (CLD) preceding cirrhosis, however, remains uncertain. The origin of GH resistance during CLD is multifactorial, and to date, the liver functional mass is considered to play a major role. Although proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, were found to be elevated in patients with CLD and were shown to induce a state of GH resistance in other disease models, their involvement in the pathogenesis of GH resistance during CLD has never been investigated. We characterized the GH-IGF-1 axis by analyzing the individual components of the axis (GH, IGF-1, IGF-binding protein-3 [IGFBP-3], acid-labile subunit [ALS]) and the corresponding ratios (GH/IGF-1, GH/IGFBP-3, and GH/ALS) and verified the links with circulating proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), in 34 patients with CLD and 12 healthy controls. Evolution of CLD from chronic hepatitis (CH, n = 17) to cirrhosis (CIR, n = 17) was associated with a progressive increase of GH resistance indices (e.g., GH/IGF-1 ratio: controls 0.5 +/- 0.9, CH 15.9 +/- 31.2, p < 0.01 vs. controls; CIR 188.4 +/- 282.7 mU/nmol, p < 0.001 vs. CH and controls), indicating its onset also in the early stages of CLD. The progressive increase in GH resistance indices matched the increase of circulatory TNF-alpha (e.g., TNF-alpha vs. GH/IGF-1, r = 0.54, p < 0.001). A similar trend was found for IL-6 without reaching statistical significance (r = 0.23, p = 0.13). We found undetectable levels of IL-1beta in our sample of patients and controls. We conclude that proinflammatory cytokines play an important role in the pathogenesis of GH resistance in CLD, but TNF-alpha is a major factor. In addition, GH resistance is present in CLD from the early stages. These results could begin new therapeutic lines of attack in the management of CLD.
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PMID:TNF-alpha and growth hormone resistance in patients with chronic liver disease. 1280 65

Inflammation is commonly observed in liver diseases and is frequently complicated by fibrosis and cirrhosis in end-stage disease. The only curative treatment for cirrhotic patients is liver transplantation. However, organ shortage as well as an increasing organ demand call for early treatment of liver disease and prevention of fibrosis. Experimental data have shown the critical role of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the development of liver injury. Here, we review our work on the role of endogenously produced interleukin-10 (IL-10), a potent anti-inflammatory cytokine, in several experimental models of acute and chronic liver injury. First, in acute macrophage-mediated hepatitis induced by galactosamine/lipopolysaccharide administration, IL-10 neutralisation led to a more severe liver damage, whereas IL-10 injection, even delayed, was able to limit liver necrosis. A similar protective effect of IL-10 was observed in acute T cell-mediated hepatitis induced by concanavalin A (Con A) injection. The immunoregulatory role of IL-10 was then established after repeated exposition to Con A. In carbon tetrachloride liver injury, two other properties of IL-10 have been suggested: modulation of hepatocyte proliferation and modulation of liver fibrosis. Finally, the potential therapeutic applications in human liver disease as well as the potential side effects are discussed.
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PMID:Modulation of liver injury by interleukin-10. 1281 43

The mechanisms leading to the hemostatic changes of acute liver injury are poorly understood. To study these further we have assessed coagulation and immune changes in patients with acute paracetamol overdose and compared the results to patients with chronic cirrhosis and normal healthy controls. The results demonstrate that in paracetamol overdose coagulation factors (F)II, V, VII and X were reduced to a similar degree and were significantly lower than FIX and FXI (mean levels 0.28, 0.16, 0.13, 0.19, 0.51 and 0.72 IU mL(-1), respectively). In cirrhosis, by contrast, FII, FV, FVII, FIX and FX were equally reduced whilst FXI was lower than the other factors (mean levels 0.64, 0.69, 0.62, 0.60, 0.66 and 0.40 IU mL-1, respectively). FVIII was raised in paracetamol overdose patients but normal in those with cirrhosis (mean levels 1.95 and 1.01 IU mL(-1), respectively). Interleukin-6 and tumor necrosis factor-alpha levels were raised in both patient groups, but higher levels were found in paracetamol overdose, compared to cirrhosis. Thrombin-antithrombin and soluble tissue factor levels were higher in those with acute liver injury but normal in cirrhosis. Antithrombin levels were reduced in both acute liver injury and cirrhosis. From these data we put forward a novel mechanism for the coagulation changes in acute paracetamol induced liver injury. We propose that immune activation leads to tissue factor-initiated consumption of FII, FV, FVII and FX, but that levels of FIX and FXI are better preserved because antithrombin inhibits the thrombin induced positive feedback loop that activates these latter factors.
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PMID:Effects of acute liver injury on blood coagulation. 1287 12

Hepatitis C virus (HCV) is a major etiologic agent for chronic hepatitis worldwide often leading to the development of cirrhosis and hepatocellular carcinoma. However, the mechanism for development of chronic hepatitis or hepatocarcinogenesis by HCV remains unclear. HCV NS5A protein possesses many intriguing properties, including sequestration of p53 in the cytoplasm, downregulation of p21 protein, activation of STAT3, and inhibition of tumor necrosis factor-alpha-mediated apoptosis. Thus, we investigated whether this viral protein has oncogenic property in vivo. In the absence of an efficient cell culture system for virus growth and a suitable small animal model for HCV infection, transgenic FVB mice were generated by targeting the HCV NS5A genomic region cloned under the control of a liver-specific apoE promoter or mouse major urinary promoter (MUP). The apoE promoter is constitutively expressed in liver, on the other hand, the MUP is developmentally regulated and expressed in the liver after birth. Reverse transcription polymerase chain reaction and Western blot analysis indicated establishment of HCV NS5A transgene expression in several lines from both groups of mice. Immunohistochemical studies suggested the presence of NS5A in the cytoplasm of hepatocytes. The transgenic animals were phenotypically similar to their normal littermates and did not exhibit a major histological change within the liver up to 24 months of age. Our results suggested HCV NS5A protein is not directly cytopathic or oncogenic in this FVB transgenic mouse model, although this viral protein promotes cell growth in vitro. These animals will be a valuable model of HCV immunopathology as well as for evaluation of siRNA, interferon and other cytokine therapies.
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PMID:Expression of hepatitis C virus non-structural 5A protein in the liver of transgenic mice. 1467 68


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