The diabetes-prone NZO/Hl strain. Proliferation capacity of beta cells in hyperinsulinemia and hyperglycemia

New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity onset hyperinsulinemia. Approximately 50% transit to chronic hyperglycemia. Here we report on the proliferation of beta cells in relation to both the individual's metabolic status and structural parameters of the endocrine pancreas. Proliferating beta cells were quantified in pancreas sections by immunoenzymatic double staining of Ki-67 protein, as a marker for proliferating cells, and endocrine non-beta cells in order to distinguish them from beta cells. In normoglycemic NZO/Hl males Ki-67 labelling indices (IKi-67) of beta cells varied between 0.14 and 1.5%, and correlated significantly with both serum insulin levels and beta cell size. There was no correlation with the glycemic status. In diabetic males, beta cell size was increased. IKi-67 varied between 1 and 3%. The data suggest that the secretory activity of beta cells triggered by glucose, entailed changes in both beta cell hypertrophy and proliferation. As shown by morphometric measurements, beta cell expansion in diabetic mice was limited, in spite of high IKi-67 values. This suggested increased death rates of beta cells.     

Actinide speciation in relation to biological processes

In case of accidental release of radionuclides into the environment, actinides represent a severe health risk to human beings following internal contamination (inhalation, ingestion or wound). For a better understanding of the actinide behaviour in man (in term of metabolism, retention, excretion) and in specific biological systems (organs, cells or biochemical pathways), it is of prime importance to have a good knowledge of the relevant actinide solution chemistry and biochemistry, in particular of the thermodynamic constants needed for computing actinide speciation. To a large extent, speciation governs bioavailability and toxicity of elements and has a significant impact on the mechanisms by which toxics accumulate in cell compartments and organs and by which elements are transferred and transported from cell to cell. From another viewpoint, speciation is the prerequisite for the design and success of potential decorporation therapies. The purpose of this review is to present the state of the art of actinide knowledge within biological media. It is also to discuss how actinide speciation can be determined or predicted and to highlight the areas where information is lacking with the aim to encourage new research efforts.     

Genetic control of neutrophil superoxide production in diabetes-resistant ALR/Lt mice

The neutrophil oxidative burst reaction differentiates ALR/Lt mice, known for an unusual systemic elevation of antioxidant defenses, from ALS/Lt mice, a related strain known for reduced ability to withstand oxidative stress. Neutrophils from marrow of ALS mice produced a normal neutrophil oxidative burst following phorbol ester stimulation. In contrast, ALR mice exhibited a markedly suppressed superoxide burst. F1 progeny from reciprocal outcrosses between ALR and ALS mice exhibited an intermediate burst level, higher than ALR but significantly lower than ALS. To elucidate the genetic basis for this strain difference, F1 mice were backcrossed to ALS mice, and marrow neutrophils isolated from the progeny were phenotyped for oxidative burst capacity. A genome-wide sweep using polymorphic markers distinguishing the two parental strains was performed to map the trait. A 1:1 phenotypic distribution was observed, and a locus (Suppressor of superoxide production, Susp) controlling this phenotype was mapped to Chromosome 3 near D3Mit241 at 33.1 cM. This locus probably represents an important regulatory element in the overall ALR strain resistance to oxidative stress, since diminished ability to mount a neutrophil burst in backcross segregants correlated with elevated hepatic superoxide dismutase 1 (SOD1) activity, an ALR strain characteristic.     

Nitric oxide and voluntary exercise together promote quadriceps hypertrophy and increase vascular density in female 18-mo-old mice

Age-related sarcopenia reduces the size, strength, and function of muscle, and the diameter of muscle fibers. It also disrupts the dystrophin-glycoprotein complex, dislocating nitric oxide synthase 1 (NOS-1) and reducing sarcolemmal integrity. This study of quadriceps muscle in 18-mo-old mice showed that NO-donor treatment with isosorbide dinitrate (I) for 6 wk, in combination with voluntary exercise for 3 wk, increased muscle mass by 25% and stimulated cell proliferation. The resulting fiber hypertrophy was accompanied by a lower ratio of protein:DNA, consistent with myogenic-cell hyperplasia. Treatment enhanced the ratio of NOS-1:β-dystroglycan in correlation with fiber diameter, improved sarcolemmal integrity, and increased vascular density after an increase in vascular endothelial growth factor protein at 3 wk. Results demonstrate that age-related muscle refractoriness to exercise can be overcome with NO-donor treatment. Since activation of muscle stem cells and vascular perfusion are limiting factors in the maintenance, regeneration, and growth of aged muscle, results suggest the feasibility of using NO-donor drugs to combat atrophy and muscle ischemia. Improved function and quality of life from the NO-amplified effects of exercise may be useful in aging and other conditions such as disuse, insulin resistance, or microgravity.     

Stabilization of a tetrameric enzyme (α-amino acid ester hydrolase from Acetobacter turbidans) enables a very improved performance of ampicillin synthesis

The stabilized derivative of the enzyme α-amino acid ester hydrolase from Acetobacter turbidans has been found to be very adequate as biocatalyst of the synthesis of the very relevant antibiotic ampicillin. This enzyme resulted much more adequate than the Penicillin G Acylase (PGA) from Escherichia coli (the most used enzyme). The stabilization of the enzyme was required because under optimal conditions (absence of phosphate and 40% of MeOH), no-stabilized derivatives or soluble enzyme from A. turbidans become very rapidly inactivated. Under these conditions, this new stabilized derivative exhibited a very high selectivity for the transferase activity compared to the esterase one, as well as a very low hydrolytic activity towards the antibiotic. Moreover, this new biocatalyst did not recognize -phenylglycine as substrate in the synthetic process. By using the racemic mixture of / phenylglycine methyl ester, 85% of the -ester could be transformed to ampicillin. In contrast, the enzyme from E. coli exhibited a high hydrolytic activity for the ampicillin yielding low synthetic yields. This enzyme also resulted much less enantioselective producing both isomers of the antibiotic.