Vildagliptin preserves the mass and function of pancreatic ß cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes.

AIM: We investigated the molecular mechanisms by which vildagliptin preserved pancreatic ß cell mass and function. METHODS: Morphological, biochemical and gene expression profiles of the pancreatic islets were investigated in male KK-A(y) -TaJcl(KK-A(y) ) and C57BL/6JJcl (B6) mice aged 8 weeks which received either vildagliptin or a vehicle for 4 weeks. RESULTS: Body weight, food intake, fasting blood glucose, plasma insulin and active glucagon-like peptide-1 were unchanged with vildagliptin treatment in both mice. In KK-A(y) mice treated with vildagliptin, increased plasma triglyceride (TG) level and islet TG content were decreased, insulin sensitivity significantly improved, and the glucose tolerance ameliorated with increases in plasma insulin levels. Furthermore, vildagliptin increased glucose-stimulated insulin secretion, islet insulin content and pancreatic ß cell mass in both strains. By vildagliptin, the expression of genes involved in cell differentiation/proliferation was upregulated in both strains, those related to apoptosis, endoplasmic reticulum stress and lipid synthesis was decreased and those related to anti-apoptosis and anti-oxidative stress was upregulated, in KK-A(y) mice. The morphological results were consistent with the gene expression profiles. CONCLUSION: Vildagliptin increases ß cell mass by not only directly affecting cell kinetics but also by indirectly reducing cell apoptosis, oxidative stress and endoplasmic reticulum stress in diabetic mice.

Development and evaluation of components for a totally implantable artificial heart system.

The authors have been developing an electrohydraulic (EH) artificial heart system for total implantation. This system consists of intrathoracic ventricles, an abdominally placed EH actuator, flexible silicone oil conduits, externally coupled transcutaneous energy transfer (TET) system, transcutaneous optical telemetry (TOT) system, internal battery, and internal control drive unit. Fitting was evaluated in chronic animal experiments as a pneumatic system in 11 goats weighing 55.2 +/- 4.2 kg and 3 calves of 52.3 +/- 1.2 kg. The longest survival time in calves was 111 days, and that in goats was 51 days. The assembled EH pump was implanted in two goats of 49 and 50 kg as an acute experiment, and 4.2-6.7 L/min of cardiac output was maintained. For the TET system, an internal coil 3 cm in diameter was implanted to make an arch covered by skin. Electric energy was transmitted from the external to the internal coil, and energy of about 20 W was carried through wires to an external load. The DC-to-DC efficiency of the system was 76-83% for 40 days. The TOT system with internal light emitting diodes and external photodiodes also was evaluated in a goat. Disalignment of up to 12 mm was tolerated. Although more improvement is necessary, most of the components showed characteristics desirable for a totally implantable system.

Studies on amelanotic melanoma with the fluorescence method (Falck and Hillarp) and biochemical analysis of 5-S-cysteinyldopa in the tissues.

Histochemical findings of primary and metastatic amelanotic melanomas were shown by the formaldehyde-induced fluorescence method (Falck and Hillarp). All or some of the amelanotic melanoma cells were discovered to emit green specific fluorescence. Results of the determination of 5-S-cysteinyldopa and DOPA in amelanotic melanoma tissues indicated that the specific fluorescence emitted by these cells is primarily due to the presence of 5-S-cysteinyldopa. The values of 5-S-cysteinyldopa in these tissues were lower than those in melanotic melanoma, but were approximately the same as those in pigmented nevus. When unpigmented tumors were histopathologically revealed to be malignant, amelanotic melanoma could be definitely diagnosed by the fluorescence method of Falck and Hillarp and the biochemical analysis of 5-S-cysteinyldopa in the tissues.

Cysteinyldopa isomers and dopa in lesions and urine of Japanese patients with malignant melanoma.

Cysteinyldopas and Dopa in the urine and tissues of Japanese melanoma patients were investigated quantitatively by means of high-performance liquid chromatography. Cysteinyldopa isomers were detected in the urine of eumelanic Japanese patients. The amount (X +/- SD%) of each isomer of cysteinyldopa in the urine was 80.26 +/- 4.66% in 5-S-cysteinyldopa, 9.39 +/- 1.64% in 2-S-cysteinyldopa, 7.07 +/- 3.33% in 2, 5-S, S-dicysteinyldopa, and 3.28 +/- 1.43% in 6-S-cysteinyldopa. The amount of cysteinyldopa in melanoma tissues was 26-314 times more than that of Dopa. The amount (X +/- SD%) of cysteinyldopa in the tissues was 80.34 +/- 1.75% in 5-S-cysteinyldopa, 11.06 +/- 1.91% in 2-S-cysteinyldopa, 6.27 +/- 1.43% in 2, 5-S, S-dicysteinyldopa, and 2.34 +/- 0.61% in 6-S-cysteinyldopa. The fact that the percentages of each isomer of cysteinyldopa in the urine and in the tissues were approximately constant suggests that the cysteinyldopas secreted from melanoma cells were excreted into the urine without being metabolized.