Canavanine induces insulin release via activation of imidazoline I3 receptors

The aim of the present study was to identify the effect of canavanine on the imidazoline receptor because canavanine is a guanidinium derivative that has a similar structure to imidazoline receptor ligands. Transfected Chinese hamster ovary‐K1 cells expressing imidazoline receptors (nischarin (NISCH)‐CHO‐K1 cells) were used to elucidate the direct effects of canavanine on imidazoline receptors. In addition, the imidazoline I₃ receptor has been implicated in stimulation of insulin secretion from pancreatic β‐cells. Wistar rats were used to investigate the effects of canavanine (0.1, 1 and 2.5 mg/kg, i.v.) on insulin secretion. In addition the a specific I₃ receptor antagonist KU14R (4 or 8 mg/kg, i.v.) was used to block I₃ receptors. Canavanine decreased blood glucose by increasing plasma insulin in rats. In addition, canavanine increased calcium influx into NISCH‐CHO‐K1 cells in a manner similar to agmatine, the endogenous ligand of imidazoline receptors. Moreover, KU12R dose‐dependently attenuated canavanine‐induced insulin secretion in HIT‐T15 pancreatic β‐cells and in the plasma of rats. The data suggest that canavanine is an agonist of I₃ receptors both in vivo and in vitro. Thus, canavanine would be a useful tool in imidazoline receptor research.     

Canavanine increases glucose uptake in C2C12 cells through the activation of imidazoline I‐2B receptors

Canavanine is a guanidinium derivative that contains the basic structure of the ligand(s) of imidazoline receptor (I‐R). Canavanine has been reported to activate the imidazoline I‐3 receptor (I‐3R) both in vivo and in vitro. Additionally, the activation of the imidazoline I‐2B receptor (I‐2BR) by guanidinium derivatives may increase glucose uptake. Therefore, the effect of canavanine on the I‐2BR was investigated in the present study. Glucose uptake into cultured C₂C₁₂ cells was determined using the radio‐ligated tracer 2‐[¹⁴C]‐deoxy‐glucose. The changes in 5′ AMP‐activated protein kinase (AMPK) expression were also identified using Western blotting analysis. The canavanine‐induced glucose uptake was inhibited in a dose‐dependent manner by BU224 (0.01–1 μmol/L), which is a specific I‐2BR antagonist, in the C₂C₁₂ cells. Additionally, the canavanine‐stimulated AMPK phosphorylation and glucose transporter (GLUT4) expression were also sensitive to BU224 inhibition in the C₂C₁₂ cells. Moreover, both canavanine‐stimulated glucose uptake and AMPK phosphorylation were attenuated by high concentrations of amiloride (1–2 μmol/L), which is another established I‐2BR inhibitor, in a dose‐dependent manner in C₂C₁₂ cells. Additionally, compound C abolished the canavanine‐induced glucose uptake and AMPK phosphorylation at a concentration (0.1 μmol/L) sufficient to inhibit AMPK. In conclusion, these data demonstrated that canavanine has an ability to activate I‐2BR through the AMPK pathway to increase glucose uptake, which indicates I‐2BR as a new target for diabetic therapy.     

Comparative metabolism and pharmacokinetics of diisobutyl ketone and diisobutyl carbinol in male SD rats

Diisobutyl ketone (DIBK) and diisobutyl carbinol (DIBC) are important organic solvents widely used as industrial intermediates. It was hypothesized that DIBC and DIBK have common metabolic pathways and metabolites, and as such, toxicological data on DIBK could be used to characterize the hazards of DIBC. To confirm or refute this hypothesis a comparative metabolism and pharmacokinetics assessment of DIBK and DIBC was conducted. Dosing was via single oral gavage dosing in male SD rats, followed by blood collection, metabolite identification, major biomarker quantitation, and pharmacokinetics analysis. Overall, the major metabolites of both DIBC and DIBK in blood were their corresponding monohydroxylated metabolites (DIBC alcohol and DIBK alcohol) with the site of hydroxylation at the σ and σ-1 positions, respectively. Quantitative analysis of DIBC, DIBK, DIBC-alcohol, and DIBK-alcohol in blood samples collected from 5 min to 120 h after single dosing indicated the following: (1) DIBC and DIBK are both well absorbed following oral gavage with substantial evidence of enterohepatic recirculation of DIBK, DIBC, DIBK-alcohol, and DIBC-alcohol; (2) DIBK and DIBC are interconverted metabolically in rats; (3) DIBC and DIBK have similar bioavailability after oral administration; (4) higher systemic exposure was found for DIBK-alcohol than DIBC-alcohol, implying that DIBC-alcohol may be more easily conjugated and eliminated in bile. In summary, the metabolic similarities and the difference in systemic exposure to metabolites between these substances observed in the current study support the hypothesis that DIBC might have a lower potential toxicity than that of DIBK. The current study results support that toxicological data on DIBK could be used to characterize the hazards of DIBC     

Serum soluble programmed death-1 levels predict the spontaneous HBeAg seroclearance in chronic hepatitis B

Journal of Gastroenterology - In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed...     

Prognostic significance of N-terminal pro-atrial natriuretic factor (1-98) in acute myocardial infarction: comparison with atrial natriuretic factor (99-126) and clinical evaluation.

OBJECTIVE--To evaluate the prognostic significance of plasma N-terminal pro-atrial natriuretic factor (1-98) concentrations measured in the subacute phase after acute myocardial infarction, and to compare the predictive value of measurement of N-terminal pro-atrial natriuretic factor (1-98) with the measurement of atrial natriuretic factor (99-126) and with clinical assessment of the degree of heart failure. DESIGN--Prospective observational. SETTING--Norwegian central hospital. PATIENTS--139 patients (mean (SD) age 66.9 (11.1) years, 71.2% males) with acute myocardial infarction. Patients in cardiogenic shock or with severe heart failure (New York Heart Association class IV) were excluded. MAIN OUTCOME MEASURE--Cardiovascular death within 12 months. RESULTS--During the follow up period 15 patients died. In a univariate Cox proportional hazards model N-terminal pro-atrial natriuretic factor (1-98) was significantly related to mortality (p = 0.0003). In a multivariate model the prognostic value of N-terminal pro-atrial natriuretic factor (1-98) was better than that of atrial natriuretic factor (99-126) and clinical assessment of heart failure (N-terminal pro-atrial natriuretic factor (1-98), p = 0.0003; atrial natriuretic factor (99-126), p = 0.4513; heart failure, p = 0.0719). The odds ratio estimate of patients in whom plasma concentrations of N-terminal pro-atrial natriuretic factor (1-98) were greater than 2000 pmol/l was 25 (95% confidence interval 2.8-225.0) compared with patients with plasma concentrations less than 1000 pmol/l. CONCLUSIONS--These results suggest that determination of plasma N-terminal pro-atrial natriuretic factor (1-98) in the subacute phase of myocardial infarction may provide clinically relevant prognostic information that is superior to that obtained from atrial natriuretic factor (99-126) measurements and clinical evaluation.     

Modification of ventricular fibrillation latency following coronary artery occlusion in the conscious pig.

Abrupt occlusion of the left anterior descending coronary artery was performed on 45 unanesthetized farm pigs in order to evaluate the relative effects on the latency to ventricular fibrillation (VFL) of 1) adaptation of the animals to the laboratory, and 2) beta-receptor blockade by propranolol. Compared to control values, VFL was greatly lengthened (i.e., VF delayed or prevented) by adaptation (P smaller than 0.01), was shortened by large (2 MG/KG) doses of racemic propranolol in unadapted animals (P smaller than 0.02), and was again increased while under the influence of the drug, by adaptation (P smaller than 0.051). Neither a lower (0.02 mg/kg) dose of racemic propranolol, 2 mg/kg of dextropropranolol, nor ventricular pacing to a higher heart rate had an effect on VFL. The results suggest that reduced psychological stress was very effective in retarding or preventing the onset of VF, that low doses of propranolol were ineffective, and that higher doses were deleterious in unadapted animals.     

The MYSTerious MOZ,a histone acetyltransferase with a key role in haematopoiesis

The MOnocytic leukaemia Zing finger (MOZ; MYST3 or KAT6A¹) gene is frequently found translocated in acute myeloid leukaemia. MOZ encodes a large multidomain protein that contains, besides others, a histone acetyl transferase catalytic domain. Several studies have now established the critical function of MOZ in haematopoiesis. In this review we summarize the recent findings that underscore the relevance of the different biological activities of MOZ in the regulation of haematopoiesis.     

Inflammation and Hras signaling control epithelial–mesenchymal transition during skin tumor progression

Epithelial–mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%–30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduced levels of Hras and Egfr signaling, and frequent Ink4/Arf deletions. Deletion of Hras from the mouse germline also leads to a strong reduction in squamous tumor development, but tumors now acquire activating Kras mutations and exhibit more aggressive metastatic properties. We propose that invasive carcinomas can arise by different genetic and biological routes dependent on exposure to chronic inflammation and possibly from different target cell populations within the skin. Our data have implications for the use of inhibitors of inflammation or of Ras/Egfr pathway signaling for prevention or treatment of invasive cancers.