c-peptide and Necrosis

Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone-releasing hormone antagonist-induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms.

Topics: Apoptosis; C-Peptide; Cell Death; Humans; Insulin; Necrosis

The therapeutic potential of adipose-derived stem cell conditioned medium (ASC-CM) was studied in the rabbit model of critical limb ischemia (CLI).. Rabbits received treatment with ASC-CM or placebo. Gastrocnemius muscle tissue was collected 35 days after ischemia induction. Ischemic changes were evaluated in hematoxylin-eosin stained tissues for early (necrotic lesions/granulation tissue) and late (fibrous scars) phases of tissue repair. The expression of proangiogenic miR-126 was also evaluated using in situ hybridization. The levels of cytokines, insulin, and C-peptide were measured in blood.. Early repair phases were observed more often in placebo-treated samples (45.5%) than in ASC-CM-treated ones (22.2%). However, the difference was not statistically significant. We demonstrated a statistically significant positive correlation between the early healing phases in tissue samples and C-peptide levels in peripheral blood. The expression of proangiogenic miR-126 was also shown in a number of structures in all phases of ischemic tissue healing.. Based on our results, we believe that treatment with ASC-CM has the potential to accelerate the healing process in ischemic tissues in the rabbit model of CLI. The whole healing process was accompanied by miR-126 tissue expression. C-peptide could be used to monitor the course of the tissue healing process.

Topics: Adult; Animals; C-Peptide; Cicatrix; Culture Media, Conditioned; Cytokines; Diabetes Mellitus, Experimental; Diabetic Foot; Disease Models, Animal; Fibrosis; Granulation Tissue; Hindlimb; Humans; In Situ Hybridization; Insulin; Ischemia; Male; Mesenchymal Stem Cells; MicroRNAs; Muscle, Skeletal; Necrosis; Neovascularization, Physiologic; Rabbits; Wound Healing

Neuronal apoptosis has been demonstrated to be a significant factor in neurological deficiencies associated with diabetes, and these deficiencies are exaggerated following ischemia. Diabetic rats have an increased basal level of apoptosis compared to non-diabetics and it has been previously demonstrated that infarct volumes were greater in diabetic animals following middle cerebral artery occlusion (MCAO) when compared to non-diabetics. In this study, we evaluated both the acute and chronic effects of insulin and/or C-peptide on CNS necrosis and apoptosis in non-diabetic and streptozotocin-induced diabetic rats following MCAO with reperfusion. Two brain areas, the sensori-motor cortex (layers-5 and 6) and the CA1 and CA3 sectors (pyramidal cell layers) of the hippocampus, were analyzed for apoptosis using TUNEL and Caspase-3 immunoreactivity. The chronic administration of a low maintenance concentration of insulin (2 U/kg), or the acute administration of insulin (2 U/kg) with or without C-peptide, did not alter the lesion volume or basal levels of apoptosis or the apoptotic levels in animals subjected to 2-h MCAO followed by 24-h reperfusion. However, both the acute or chronic administration of a high concentration of insulin (12 U/kg) significantly decreased lesion volume and apoptosis subsequent to 2-h MCAO followed by 24-h reperfusion. High dose insulin treatment also decreased the basal level of apoptosis. We conclude that in diabetic rats subjected to ischemia and reperfusion chronic insulin treatment decreased the basal apoptotic level, and both acute and chronic insulin decreased the MCAO-induced lesion volume and apoptosis. Maintenance insulin concentrations with or without C-peptide were without effect.

Topics: Animals; Apoptosis; Blood Glucose; Brain Ischemia; C-Peptide; Caspase 3; Caspases; Diabetes Mellitus, Experimental; Hypoglycemic Agents; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Insulin; Insulin Resistance; Male; Necrosis; Rats; Rats, Wistar; Reperfusion Injury

Infected pancreatic necrosis (IPN) is the main cause of death in patients with severe acute pancreatitis. Therefore an early prediction of IPN is of utmost importance.. Analysis of new blood variables as potential early predictors to differentiate between IPN and sterile pancreatic necrosis (SPN).. 64 consecutive patients with acute pancreatitis were enrolled in this prospective study; 29 were suffering from acute oedematous pancreatitis (AIP), and 35 from necrotising disease (NP) as diagnosed by contrast enhanced computed tomography.. Procalcitonin (PCT) and granulocyte colony stimulating factor (G-CSF) in the serum were examined and compared with C reactive protein (CRP). CRP was measured with a turbidimetric immunoassay (Autokit CRP; Wako, Osaka, Japan), and PCT and G-CSF by ELISA (Lumitest PCT; Brahms Diagnostica, Berlin, Germany; G-CSF-Elisa; R&D Systems, Abingdon, Oxon, UK). Monitoring was performed daily and related to the onset of symptoms.. Within the first week, all three variables (CRP, PCT, and G-CSF) were significantly higher in patients with NP than in those with AIP (CRP, p<0.001; G-CSF, p<0. 001; PCT, p<0.001). During the course of the study, 12 of the 35 patients with NP developed late IPN after a median of 20.5 (range 3-49) days. Neither the peak nor the lowest concentrations during the monitoring period were of any value for predicting IPN (median peak values in SPN v IPN: PCT, 0.93 v 1.93 ng/ml; G-CSF, 347 v 421 pg/ml; CRP, 270 v 325 mg/l).. Serum PCT, G-CSF, and CRP concentrations are of similar value for early differentiation between mild and severe acute pancreatitis. However, these variables are not suitable for the early prediction of IPN.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Biomarkers; C-Peptide; Calcitonin; Calcitonin Gene-Related Peptide; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Necrosis; Pancreatitis, Acute Necrotizing; Protein Precursors

Results of dynamic investigation of beta-endorphins and hormonal state were analysed in 34 patients with pancreonecrosis aged from 23 to 54 years. The dependency of this indexes on the severity of clinical course and presence of complications was determined. The correction ways of injurious action of stress-reaction in pancreonecrosis were proposed.

Topics: Adrenal Cortex Hormones; Adult; C-Peptide; Endorphins; Female; Hormones; Humans; Insulin; Male; Middle Aged; Necrosis; Pancreatitis; Pituitary Hormones; Radioimmunoassay; Stress, Physiological; Thyroid Hormones

This study was designed to investigate the long-term effects of early pancreatic resection for acute necrotizing pancreatitis. During 1973-1978 40 resections were performed in our clinic. Eleven patients died initially (28 per cent). None of the four further deaths was due to pancreatitis or associated disorders. Twenty-four patients were re-examined 5-11 years after resection--one patient refused to participate. Five had not been able to return to work because of severe polyneuropathy; one more had retired because of chronic pancreatitis in the pancreatic remnant. Polyneuropathy was found in five further patients. The reason for this high incidence of polyneuropathy (42 per cent) remains unknown. Eight patients still drank excessive alcohol; three of them had had recurrent pancreatitis and dyspepsia, and insulin requiring diabetes. All but 2 (92 per cent) had diabetes, 14 needing insulin--half of them at 6 months to 6 years after the resection. Moreover, 11 patients (46 per cent) suffered from dyspeptic symptoms. The results suggest that because of the high frequency of late complications, in addition to the early complications, early resection of pancreas should be critically re-evaluated as the treatment for acute necrotizing pancreatitis. If resection is used in patients with extreme pancreatic necrosis, careful and continuous postoperative follow-up will be needed.

Topics: Acute Disease; Adult; Aged; C-Peptide; Follow-Up Studies; Humans; Middle Aged; Necrosis; Pancreas; Pancreatectomy; Pancreatitis; Postoperative Complications; Time Factors