leptin and Necrosis

To analyze the prognostic value of adipokines in predicting the course, complications and fatal outcome of acute pancreatitis (AP).. We performed the search of PubMed database and the systemic analysis of the literature for both experimental and human studies on prognostic value of adipokines in AP for period 2002-2012. Only the papers that described the use of adipokines for prediction of severity and/or complications of AP were selected for further analysis. Each article had to contain information about the levels of measured adipokines, diagnosis and verification of AP, to specify presence of pancreatic necrosis, organ dysfunction and/or mortality rates. From the very beginning, study was carried out adhering to the PRISMA checklist and flowchart for systemic reviews. To assess quality of all included human studies, the Quality Assessment of Diagnostic Accuracy Studies tool was used. Because of the high heterogeneity between the studies, it was decided to refrain from the statistical processing or meta-analysis of the available data.. Nine human and three experimental studies were included into review. In experimental studies significant differences between leptin concentrations at 24 and 48 h in control, acute edematous and acute necrotizing pancreatitis groups were found (P = 0.027 and P < 0.001). In human studies significant differences between leptin and resitin concentrations in control and acute pancreatitis groups were found. 1-3 d serum adiponectin threshold of 4.5 μg/mL correctly classified the severity of 81% of patients with AP. This threshold yielded a sensitivity of 70%, specificity 85%, positive predictive value 64%, negative predictive value88% (area under curve 0.75). Resistin and visfatin concentrations differ significantly between mild and severe acute pancreatitis groups, they correlate with severity of disease, need for interventions and outcome. Both adipokines are good markers for parapancreatic necrosis and the cut-off values of 11.9 ng/mL and 1.8 ng/mL respectively predict the high ranges of radiological scores. However, the review revealed that all nine human studies with adipokines are very different in terms of methodology and objectives, so it is difficult to generalize their results. It seems that concentrations of the leptin and resistin increases significantly in patients with acute pancreatitis compared with controls. Serum levels of adiponectin, visfatin and especially resitin (positive correlation with Acute Physiology and Chronic Health Evaluation II, Ranson and C-reactive protein) are significantly different in mild acute pancreatitis and severe acute pancreatitis patients, so, they can serve as a markers for the disease severity prediction. Resistin and visfatin can also be used for pancreatic and parapancreatic necrosis prediction, interventions needs and possible, outcome.. High levels of adipokines could allow for prediction of a severe disease course and outcome even in small pancreatic lesions on computed tomography scans.

Topics: Acute Disease; Adipokines; Humans; Inflammation; Leptin; Necrosis; Nicotinamide Phosphoribosyltransferase; Pancreatitis; Pancreatitis, Acute Necrotizing; Prognosis; Resistin; Sensitivity and Specificity; Time Factors; Treatment Outcome

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The presentation was Nonalcoholic fatty liver disease: Implications for alcoholic liver disease pathogenesis, by Anna Mae Diehl.

Topics: Animals; Apoptosis; Endotoxins; Fatty Liver; Humans; Leptin; Liver; Liver Diseases, Alcoholic; Mice; Mice, Obese; Mitochondria, Liver; Necrosis; Obesity; Reactive Oxygen Species; Signal Transduction; Tumor Necrosis Factor-alpha

Renal ischemia and reperfusion (IR) injury introduces cellular stress and is the main cause of acute kidney damage. Renal cells exposed to noxious stress induce the expression of the pleiotropic hormone leptin. As we have previously revealed a deleterious stress-related role for leptin expression, these results suggested that leptin is also involved in pathological renal remodeling. The systemic functions of leptin preclude the study of its local effects using conventional approaches. We have therefore designed a method to locally perturb leptin activity in specific tissues without affecting its systemic levels. This study explores whether local anti-leptin strategy is renoprotective in a post-IR porcine kidney model.. We induced renal IR injury in pigs by exposing kidneys to ischemia and revascularization. Upon reperfusion, kidneys instantly received an intra-arterial bolus of either a leptin antagonist (LepA) or saline solution. Peripheral blood was sampled to assess systemic leptin, IL-6, creatinine, and BUN levels, and postoperative tissue samples were analyzed by hematoxylin and eosin histochemistry and immunohistochemistry.. Histology of IR/saline kidneys exhibited extensive necrosis of proximal tubular epithelial cells, as well as elevated levels of apoptosis markers and inflammation. In contrast, IR/LepA kidneys showed no signs of necrosis or inflammation with normal IL-6 and tall-like receptor 4 levels. LepA treatment led to upregulation in mRNA levels of leptin, leptin receptor, ERK1/2, STAT3, and transport molecule Na/H exchanger-3.. Local, intrarenal postischemic LepA treatment at reperfusion prevented apoptosis and inflammation and was renoprotective. Selective intrarenal administration of LepA at reperfusion may provide a viable option for clinical implementation.

Topics: Acute Kidney Injury; Animals; Inflammation; Interleukin-6; Ischemia; Kidney; Leptin; Necrosis; Reperfusion Injury; Swine

Obesity is a major health problem threatening humanity in medical, social and psychological dimensions. In this study, we aimed to determine the histological, immunohistochemical and biochemical effects of bee bread, added to diets of obese rats in different doses, on leptin and ghrelin expression. In the study, 40 female Sprague‒Dawley (200‒250 g) rats were randomly divided into 5 equal groups and then assigned to control and obesity groups. The obesity group consisted of four subgroups: high‑fat diet group, 100 and 200 mg/kg/bw groups, and metformin group. Histopathological evaluation revealed structural deterioration and necrotic areas in the epithelium and glands of the obese rats' stomach tissue, while in their serum and gastric tissues, the MDA level was significantly higher than in the other groups. There was a negative correlation between leptin and ghrelin levels. Apoptotic cells increased with obesity, but the application of beebread was similarly effective as metformin administration in reducing this increase (Tab. 5, Fig. 4, Ref. 51). Keywords: bee bread, leptin, ghrelin, stomach, obesity, rat.

Topics: Animals; Female; Ghrelin; Hypoglycemic Agents; Leptin; Metformin; Necrosis; Obesity; Propolis; Rats; Rats, Sprague-Dawley; Stomach

Early prediction of disease severity in acute pancreatitis (AP) is crucial. The aim of this study was to investigate the body-mass index (BMI), plasma leptin, nesfatin-1 and ghrelin levels as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis.. In the study period, 97 consecutive patients with AP were prospectively analysed. Severe AP was defined according to the Atlanta Criteria. BMI was also calculated. To measure plasma Leptin, Nesfatin-1 and Ghrelin concentrations, the blood samples were obtained from patients within 24 hours of admission.. Out of 97 patients, 92(70 females, 22 males) were considered eligible for analysis. Of the 92 patients, 30 patients (32.6%) were assessed as severe pancreatitis. BMI and leptin levels were significantly higher in patients with severe pancreatitis. The pooled sensitivity and specificity of BMI as a predictor for the development of pancreatic necrosis were 0.90(95%CI = 0.56-0.99) and 0.70(95%CI = 0.58-0.79), respectively; with an overall area under curve value of 0.78.The pooled sensitivity and specificity of leptin levels as a predictor for development of pancreatic necrosis were 1(95%CI = 0.69-1) and 0.73(95%CI = 0.62-0.82),respectively; with an overall area under curve value of 0.82.Nesfatin-1 and ghrelin levels showed no significant difference in patients with mild pancreatitis (6.97 ± 0.84 ng/ml and 2.3(1.0-9.9);respectively) and severe pancreatitis (6.74 ± 0.65 ng/ml and 2.0(1.9-9.9); respectively) (p = 0.1923 and 0.8531;respectively).. BMI and plasma leptin levels both were correlated with the severity of pancreatitis. Leptin levels showed better area under the curve, sensitivity and specificity values compared to BMI in prediction of pancreatic necrosis.Nesfatin-1 and ghrelin levels were not found to be predictors of the severity of disease.

Topics: Acute Disease; Area Under Curve; Biomarkers; Body Mass Index; Calcium-Binding Proteins; Cohort Studies; DNA-Binding Proteins; Early Diagnosis; Female; Ghrelin; Humans; Leptin; Male; Necrosis; Nerve Tissue Proteins; Nucleobindins; Pancreas; Pancreatitis; Prognosis; Prospective Studies; Sensitivity and Specificity

This study is aimed to evaluate the protective effect of fermented Angelicae gigantis Radix (AGR) with Monascus purpureus strain on carbon tetrachloride (CCl(4))-induced hepatotoxicity and oxidative stress in rats. The activities of liver marker enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and the levels of lipid peroxidation were increased when CCl(4) was treated but these parameters were significantly decreased by fermented AGR treatment. CCl(4) treatment exhibited decrease in serum concentrations of triglyceride, total cholesterol, HDL-cholesterol, and free fatty acids, and these were also decreased by fermented AGR administration. The level of serum leptin was significantly lower in fermented AGR administration than that in normal control group. CCl(4) treatment significantly increased the concentration of liver triglyceride. The current study observed significant elevations of the thiobarbituric acid-reactive substances (TBARS) levels in the liver homogenate, mitochondrial, and microsomal fractions of CCl(4) control group compared with normal control group. CCl(4) treatment resulted in a significant decrease in the levels of plasma and hepatic glutathione, but these reductions were significantly increased by fermented AGR administration. CCl(4) induced the marked hepatocytes necrosis and fatty accumulation around the central veins. Accordingly, fermented AGR may be an ideal candidate for the hepatoprotective effect in animal model.

Topics: Adipose Tissue, White; Angelica; Animals; Body Weight; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Coumarins; Drinking; Eating; Enzymes; Fermentation; Glutathione; Leptin; Lipids; Liver; Male; Microsomes, Liver; Mitochondria, Liver; Monascus; Necrosis; Organ Size; Oxidative Stress; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Zinc

Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.

Topics: Acute Disease; Acute-Phase Reaction; Adipose Tissue; Amylases; Animals; Calcium; Disease Susceptibility; Female; Gene Expression Regulation; Interferon-gamma; Interleukin-12; Interleukin-18; Interleukin-6; Leptin; Lipase; Lithostathine; Mice; Mice, Obese; Necrosis; Obesity; Pancreatitis; Pancreatitis-Associated Proteins; Proteins; RNA, Messenger; Time Factors

We have used total enteral nutrition (TEN) to moderately overfeed rats high-polyunsaturated fat diets to develop a model for nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were fed by TEN a 187 kcal.kg(-3/4).day(-1) diet containing 5% (total calories) corn oil or a 220 kcal.kg(-3/4).day(-1) diet in which corn oil constituted 5, 10, 25, 35, 40, or 70% of total calories for 21 or 65 days. Rats fed the 5% corn oil, 220 kcal.kg(-3/4).day(-1)diet had greater body weight gain (P < or = 0.05), fat mass (P < or = 0.05), and serum leptin and glucose levels (P < or = 0.05), but no liver pathology. A dose-dependent increase in hepatic triglyceride deposition occurred with increase in percent corn oil in the 220 kcal.kg(-3/4).day(-1) groups (P < or = 0.05). Steatosis, macrophage infiltration, apoptosis, and focal necrosis were present in the 70% corn oil group, accompanied by elevated serum alanine aminotransferase (ALT) levels (P < or = 0.05). An increase in oxidative stress (thiobarbituric acid-reactive substances) and TNF-alpha expression (P < or = 0.05) was observed in the 70% corn oil group, as well as an increase in hepatic CYP2E1 and CYP4A1 expression (P < or = 0.05). Significant positive correlations were observed between the level of dietary corn oil and the degree of pathology, ALTs, oxidative stress, and inflammation. Liver pathology was progressive with increased necrosis, accompanied by fibrosis, observed after 65 days of TEN. Increased expression of CD36 and l-fabp mRNA suggested development of steatosis was associated with increased fatty acid transport. These data suggest that intragastric infusion of a high-polyunsaturated fat diet at a caloric level of 17% excess total calories results in pathology similar to clinical NASH.

Topics: Adiposity; Alanine Transaminase; Animals; Apoptosis; Blood Glucose; Body Weight; CD36 Antigens; Corn Oil; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Disease Models, Animal; Enzyme Induction; Fatty Acid-Binding Proteins; Fatty Acids; Fatty Liver; Leptin; Liver; Macrophages; Male; Necrosis; Overnutrition; Oxidative Stress; Parenteral Nutrition, Total; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

Severe acute pancreatitis is characterized by lipase-induced peripancreatic fat cell necrosis. Because adipocytes secret several highly active molecules, the aim of the present study was to investigate the hypothesis that adipocytokines could serve as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis.. A total of 23 patients (11 females, 12 males) with acute pancreatitis were included and a computed tomography (CT) examination was available in 20 patients. Balthazar score, Schröder score, pancreatic necrosis score, Ranson score and APACHE II score were calculated, correlated with biochemical parameters and analyzed using receiver-operator characteristics (ROC) analysis. Adipocytokine serum levels were measured daily by enzyme-linked immunosorbent assay (ELISA) over 10 days after admission.. Resistin and leptin were significantly elevated in patients with severe pancreatitis and were correlated with a radiological scoring system for extrapancreatic necrosis. Whereas resistin correlated positively with clinical scoring systems, time until discharge and the need for interventions, leptin was correlated positively with C-reactive protein (CRP) levels. Resistin levels measured on the day of admittance had a positive predictive value of 93.3% (cut-off: >6.95 ng/mL) in predicting a Schröder score >3.. Resistin, and to a lesser extent leptin, but not adiponectin levels are novel potential markers for extrapancreatic necrosis and severity of acute pancreatitis and should therefore be tested in larger cohorts of patients.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; APACHE; Female; Humans; Leptin; Male; Middle Aged; Necrosis; Pancreas; Pancreatitis; Pilot Projects; Predictive Value of Tests; Resistin; Severity of Illness Index

Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor alpha (TNF-alpha) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-alpha activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-alpha and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-alpha and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 microg/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD.

Topics: Adiponectin; Adult; Antigens, CD; Case-Control Studies; Diagnosis, Differential; Fatty Liver; Female; Hepatitis; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Multivariate Analysis; Necrosis; Prognosis; Proteins; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Solubility; Tumor Necrosis Factor-alpha

To investigate the role of leptin in the development of viral myocarditis and cardiac necrosis, we used a murine model of viral myocarditis. We intraperitoneally injected encephalomyocarditis virus (500 plaque-forming units/mouse) for wild type C57 BL/6 mice (WT) and leptin-deficient ob/ob mice (OB) (n = 20 for each). Ten-day survival rate was 25% in OB, whereas it was 95% in WT. Heart weights on day 10 were significantly elevated in OB compared with those in WT (107.2 +/- 9.4 vs. 96.6 +/- 7.9 mg, n = 4 for each). Thymus weights were significantly diminished in OB compared with those in WT on days 6 and 10. Histological score (grade 1 to 4 according to the size of involved area) for myocardial necrosis were significantly higher in OB than in WT (1.5 +/- 0.5 vs. 0.8 +/- 0.5, n = 4 for each). On day 4, viral titer in hearts was significantly elevated in OB compared with that in WT (3.3 +/- 0.5 vs. 1.9 +/- 0.2 TCID50/mg, n = 3 for each). Comparative expression of TNF-alpha mRNA in hearts from OB were significantly increased compared with those in WT on day 7 (n = 3 for each). Natural killer cell activities in spleens from OB were significantly lower than from WT on day 4 (27 +/- 5 vs. 42 +/- 8%, n = 4 for each). Thus, leptin deficiency could enhance severity of myocardial necrosis and mortality due to viral myocarditis.

Topics: Animals; Disease Models, Animal; Encephalomyocarditis virus; Heart; Histological Techniques; Killer Cells, Natural; Leptin; Mice; Mice, Mutant Strains; Myocarditis; Myocardium; Necrosis; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spleen; Statistics, Nonparametric; Survival Analysis; Thymus Gland; Tumor Necrosis Factor-alpha

Profound impairment of liver regeneration in rodents with dysfunctional leptin signaling has been attributed to non-alcohol-induced fatty liver disorders (NAFLD). Our aim was to establish whether defective liver regeneration in ob/ob mice is a direct consequence of leptin-dependent, intracellular signaling mechanisms controlling cell-cycle regulation in hepatocytes.. After exposure to a single hepatotoxic dose of (CCl(4)), the regenerative response to hepatic injury was studied in leptin-deficient ob/ob and control mice. The effects of leptin supplementation (100 microg x kg(-1) x day(-1)) were examined. We assessed entry into and progression through the cell cycle and activation of key signaling intermediates and transcriptional regulators.. CCl(4)-induced liver injury was equally severe in ob/ob and control mice. In leptin-deficient mice, it was associated with exaggerated activation of NF-kappa B and STAT3 during the priming phase, abrogation of tumor necrosis factor (TNF) and interleukin (IL)-6 release at the time of G1/S transition, and failure of hepatocyte induction of cyclin D1 and cell cycle entry. Leptin replacement corrected these defects in ob/ob mice by restoring TNF and IL-6 release and inducing cyclin D1. Hepatocytes entered S phase and progressed, as in wild-type mice, to vigorous mitosis and normal hepatic regenerative response. In ob/ob mice, low doses of TNF before CCl(4) also were associated with restitution of TNF release and proliferative capabilities.. Impaired liver regeneration in ob/ob mice is caused by leptin deficiency. We propose that altered cytokine production in ob/ob mice is part of the mechanisms responsible for impaired proliferation in response to hepatic injury.

Topics: Animals; Carbon Tetrachloride; Cell Division; Chemical and Drug Induced Liver Injury; Cyclin D1; Fatty Liver; Interleukin-6; Leptin; Liver; Liver Regeneration; Mice; Mice, Inbred C57BL; Mice, Obese; Necrosis; Proliferating Cell Nuclear Antigen; Recombinant Proteins; Signal Transduction; Tumor Necrosis Factor-alpha

Leptin is a hormone primarily produced by adipocytes and serum leptin is elevated in obese persons. One risk factor associated with adenocarcinoma of the esophagus is obesity. We hypothesized that leptin would have stimulatory effects on esophageal adenocarcinoma and alter apoptosis in vitro.. Barrett's esophageal adenocarcinoma cells (BIC-1 and SEG-1) were cultured with human recombinant leptin (80 ng/mL) for 24 hours. Cell growth was determined by MTT assay. Apoptosis and necrosis was measured after 16 hours of treatment with leptin using a Cell Death Kit.. Exogenous leptin stimulated cell proliferation in both cell lines. No changes in apoptosis or necrosis resulted between control and leptin-treated groups.. We have shown that leptin increases the proliferation of human esophageal adenocarcinoma, but does not alter cell apoptosis or necrosis. The data suggest that leptin stimulates esophageal adenocarcinoma growth by nonapoptotic mechanisms. Leptin antagonism may have potential efficacy in esophageal cancer therapy.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Division; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Humans; Leptin; Necrosis; Recombinant Proteins; Stimulation, Chemical; Tumor Cells, Cultured