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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relative importance of molecular biology in clinical practice is often underestimated. However, numerous procedures in clinical diagnosis and new therapeutic drugs have resulted from basic molecular research. Furthermore, understanding of the physiological and physiopathological mechanisms underlying several human diseases has been improved by the results of basic molecular research. For example, cloning of the gene encoding leptin has provided spectacular insights into the understanding of the mechanisms involved in the control of food intake and body weight maintenance in man. In cystic fibrosis, the cloning and identification of several mutations in the gene encoding the chloride channel transmembrane regulator (CFTR) have resolved several important issues in clinical practice: cystic fibrosis constitutes a molecular defect of a single gene. There is a strong correlation between the clinical manifestations or the severity of the disease (phenotype) with the type of mutations present in the CFTR gene (genotype). More recently, identification of mutations in the gene encoding a subunit of the renal sodium channel in the Liddle syndrome has provided important insight into the physiopathological understanding of mechanisms involved in this form of hereditary hypertension. Salt retention and secondary high blood pressure are the result of constitutive activation of the renal sodium channel by mutations in the gene encoding the renal sodium channel. It is speculated that less severe mutations in this channel could result in a less severe form of hypertension which may correspond to patients suffering from high blood pressure with low plasma renin activity. Several tools, most notably PCR, are derived from molecular research and are used in everyday practice, i.e. in prenatal diagnosis and in the diagnosis of several infectious diseases including tuberculosis and hepatitis. Finally, the production of recombinant proteins at lower cost and with fewer side effects is used in everyday clinical practice. Gene therapy remains an extraordinary challenge in correcting severe hereditary or acquired diseases. The use of genetically modified animal cell lines producing growth factors, insulin or erythropoetin, which are subsequently encapsulated and transferred to man, represents an attractive approach for gene therapy.
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PMID:[Is molecular biology useful to the practitioner?]. 919 Jun 68

The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) alpha and IL-18 compared with their lean littermates. Neutralization of TNF-alpha reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-alpha and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-alpha and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear to be essential mediators of T cell-mediated liver injury.
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PMID:Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18. 1068 32

Leptin-deficient ob/ob mice are protected from Con A-induced hepatitis. However, it is unclear whether leptin deficiency or obesity itself is responsible for this protection. To address this question, wild-type (WT) obese mice with high serum leptin levels were generated by injection of gold thioglucose (WT GTG). Both Con A-injected WT and WT GTG mice developed hepatitis, whereas no hepatic damage was observed in ob/ob mice. Moreover, TNF-alpha and IFN-gamma levels as well as expression of the activation marker CD69 were elevated in liver mononuclear cells of WT and WT GTG mice, but not in ob/ob mice following administration of Con A. The liver of WT and WT GTG mice had the same percentage of NK T cells, a lymphocyte population involved in Con A-induced hepatitis. This population decreased equally in both WT and WT GTG mice after Con A injection. In contrast, the liver of ob/ob mice contained 50% less NK T cells compared to WT and WT GTG mice. Furthermore, no decrease in NK T cells was observed in Con A-injected ob/ob mice. We conclude that leptin-deficiency, not obesity, is responsible for protection from Con A-induced hepatitis.
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PMID:Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis. 1182 72

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.
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PMID:Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. 1567 Jun 59

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.
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PMID:Defining the role of T cell-derived leptin in the modulation of hepatic or intestinal inflammation in mice. 1617 53

Experimental T cell-mediated hepatitis induced by concanavalin A (ConA) results in the initiation of an inflammatory response and the production of cytokines. Adiponectin is an adipocytokine produced by adipose tissue that is involved in the reciprocal regulation of other cytokines, including tumor necrosis factor alpha (TNF-alpha). Concanavalin A administration to C57BL/6J mice reduced circulating levels of adiponectin, whereas leptin was markedly increased. Adiponectin messenger RNA expression in adipose tissue was also decreased; however, the expression of both the adiponectin receptors remained unchanged. Neutralization of TNF-alpha reduced ConA-induced liver damage, and this was associated with restored circulating levels of adiponectin. These findings indicate that inflammation-induced TNF-alpha is a critical mediator of adipose-tissue-derived adiponectin in vivo.
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PMID:T cell-mediated hepatic inflammation modulates adiponectin levels in mice: role of tumor necrosis factor alpha. 1654 88

The objectives of this research were to investigate the leptin levels among Chronic Hepatitis B Virus (HBV), Chronic Hepatitis C Virus (HCV) and non-alcoholic steatosis hepatitis (NASH) diseases of Thai patients compared with controls. Twenty of each HBV, HCV and NASH patients compared with sixty people as the control group from the Outpatient Department at the Hospital for Tropical Diseases, Bangkok, Thailand were investigated. Fasting blood samples were collected for investigation of leptin concentration, liver enzyme function tests and hematological variables. The serum leptin concentration of liver patients was significantly higher than that of control subjects. It might be due to the accumulations of fat cells in liver disease patients. However, there is no relationship between leptin level and other parameters such as BMI, ALT, AST, ALP and hematological variables. Liver enzyme functions levels are much higher in patients groups. White blood cells counts, platelets and hematocrit values are slightly lower in liver disease patients. Therefore, it is concluded that physiological regulation of leptin maintains in relation to body fat, even in chronic viral liver diseases. This finding and the apparent stage suggest the possibility that in the course of chronic viral diseases, serum leptin levels may reflect the extent of liver dysfunction.
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PMID:Serum leptin concentrations in chronic hepatitis. 1669 95

There is accumulating evidence that leptin has a pleiotropic role in hematopoiesis, immune response, fibrogenesis, and hepatocarcinogenesis. We investigated the expression of leptin and leptin receptor (OB-R) at the protein level by flow cytometry and also quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) the two major leptin receptor isoforms (OB-Rl, OB-Rs) in peripheral blood mononuclear cells (PBMCs) of patients with hepatitis B (HBV; n = 31), hepatitis C (HCV; n = 34), and nonviral liver disease (n = 25), and healthy controls (n = 36), as well as in liver tissues of HBV (n = 8), HCV (n = 7), and healthy individuals (n = 6). Serum leptin levels were measured in all participants (N = 126). We observed significantly lower OB-Rl and OB-Rs mRNA levels in PBMCs of HBV and HCV patients compared with healthy controls and nonviral liver disease patients (P < 0.05). Flow cytometry analysis confirmed the real-time RT-PCR results. Expression of leptin and OB-Rl was significantly increased in viral hepatitis liver tissues compared with healthy tissues (P < 0.01). OB-Rl mRNA levels were not associated with hepatitis patients' clinical status (inactive, chronic hepatitis, or cirrhosis). We also found decreased serum leptin in HBV and HCV patients compared with healthy individuals and the nonviral liver disease group. Leptin was expressed in 3 of 34 HCV (8.8%) and 19 of 25 (76%) nonviral liver disease patients. Moreover, expression of OB-Rl and OB-Rs were associated when all individuals were grouped together (r = 0.78, P < 0.001). In conclusion, our findings may suggest the involvement of the leptin system in the immunopathology of chronic viral hepatitis.
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PMID:Leptin receptor isoforms mRNA expression in peripheral blood mononuclear cells from patients with chronic viral hepatitis. 1706 Jun 87

Immunity and metabolism are closely linked. The liver is an important metabolic organ in the body. However, the interactions between hepatocytes and the immune system are poorly understood. In mice developing concanavalin A (ConA)-induced hepatitis (CIH), we found extensive lipid accumulation in hepatocytes. Critical enzyme involved in fat synthesis such as stearoyl-CoA desaturase 1 (SCD1) was upregulated. When we injected ConA to SCD1-deficient mice, we found these mice to be highly resistant to CIH. The mechanisms of the protective effect of SCD1 deficiency might be attributed to the reduced leptin levels in those mice, which modulated critical cytokines and signaling pathways in CIH pathogenesis. In conclusion, our study suggests that SCD1 deficiency protects mice from liver injury in a leptin-dependent manner.
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PMID:Stearoyl-CoA desaturase 1 deficiency protects mice from immune-mediated liver injury. 1900 12

Leptin-deficient ob/ob mice are resistant to dextran sulfate sodium (DSS)-induced colitis and Concanavalin A (Con A)-induced hepatitis. However, the signal transduction pathways involved have not been identified. The present study investigated the effect of leptin-induced STAT3 signaling in the DSS and Con A models. Mice carrying a leptin receptor (LEPR) gene mutant for Y1138 (s/s mice), with abrogated leptin-induced STAT3 signaling, were compared with wild-type (WT) and LEPR-deficient db/db mice. Administration of DSS to s/s mice resulted in a clinical score and colon shortening of intermediate severity compared with disease induced in WT and db/db mice-the latter group having the lowest disease severity. A comparable degree of inflammatory infiltrate and epithelial damage was observed in the colon of WT and s/s mice, and these parameters were reduced in db/db mice. Levels of IFN-gamma, IL-6, IL-10, and TNF-alpha were comparable in the colon of s/s and db/db mice, and a similar trend was observed for CXCL2. s/s and WT mice developed severe liver disease in response to Con A, whereas db/db mice were protected. However, Con A-induced serum IL-6 and TNF-alpha levels in s/s mice mimicked levels observed in db/db rather than WT mice. In conclusion, lack of leptin-induced STAT3 signaling is associated with reduced cytokine production following DSS and Con A administration, but it appears to sensitize mice to the effects of proinflammatory mediators.
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PMID:Role of leptin receptor-induced STAT3 signaling in modulation of intestinal and hepatic inflammation in mice. 1905 44


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