Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

An analysis of more than 22,000 ozone profiles from Stratospheric Aerosol and Gas Experiment I (SAGE I) (1979–1981) and SAGE II (1984–1987) between 50°N and 50°S is used in conjunction with 9 years (1979–1987) of daily global depictions of total ozone from the Total Ozone Mapping Spectrometer (TOMS) instrument aboard Nimbus 7 to investigate the spatial distribution and seasonal cycle of the integrated amount of ozone in the troposphere. In the tropics, highest concentrations are found in the eastern Atlantic Ocean downwind (west) of Africa and maximize during the time when biomass burning is most prevalent, between July and October. A different seasonal cycle in the tropics is also observed over Indonesia where a relative maximum is present in the March–April time frame, likewise consistent with when biomass burning is most prevalent. At mid‐latitudes, highest concentrations are found downwind of Asia and maximize in the summer. Relatively higher amounts of tropospheric ozone are similarly observed downwind of North America and Europe. At mid‐latitudes, the ratio between the amount of tropospheric ozone in the northern hemisphere and the amount in the southern hemisphere is 1.4, in good agreement with in situ measurements. A detailed comparison of this satellite technique with available ozonesonde measurements suggests that the accuracy of this method for deriving the climatology of tropospheric ozone is probably better than 10% in the tropics and 15% at mid‐latitudes. We also show that TOMS total ozone measurements in the tropics can often be used independently to provide important qualitative insight into the behavior of tropospheric ozone at these low latitudes.

The paraoxonase gene family contains at least three members: PON1, PON2, and PON3. The physiological roles of the corresponding gene products are still uncertain. Until recently, only the serum paraoxonase/arylesterase (PON1) had been purified and characterized. Here we report the purification, cloning, and characterization of rabbit serum PON3. PON3 is a 40-kDa protein associated with the high density lipoprotein fraction of serum. In contrast to PON1, PON3 has very limited arylesterase and no paraoxonase activities but rapidly hydrolyzes lactones such as statin prodrugs (e.g. lovastatin). These differences facilitated the complete separation of PON3 from PON1 during purification. PON3 hydrolyzes aromatic lactones and 5-or 6-member ring lactones with aliphatic substituents but not simple lactones or those with polar substituents. We cloned PON3 from total rabbit liver RNA and expressed it in mammalian 293T/17 cells. The recombinant PON3 has the same apparent molecular mass and substrate specificity as the enzyme purified from serum. Rabbit serum PON3 is more efficient than rabbit PON1 in protecting low density lipoprotein from copper-induced oxidation. This is the first report that identifies a second PON enzyme in mammalian serum and the first to describe an enzymatic activity for PON3.

Aims/Hypothesis: Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A 1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.Methods: Sixteen patients with type 2 diabetes (age, 48 Ϯ 3 yr; body mass index, 34.4 Ϯ 1.7 kg/m 2 ; hemoglobin A 1c , 9.0 Ϯ 0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-3 H-glucose iv and 1-14 C-glucose orally).Results: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02 Ϯ 0.06 vs. 0.74 Ϯ 0.06 mg⅐kg Ϫ1 ⅐min Ϫ1 ; P ϭ 0.004), and insulin secretion rate increased by 21% (P ϭ 0.003) despite significant reduction in mean plasma glucose (213 Ϯ 4 vs. 230 Ϯ 4 mg/dl; P ϭ 0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P ϭ 0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P Ͻ 0.02). The decline in EGP was positively correlated (r ϭ 0.55; P Ͻ 0.03) with the decrease in fasting plasma glucose (change ϭ Ϫ14 mg/dl). Conclusions

Objective-To determine whether paraoxonases (PONs) are expressed in macrophages and to analyze the oxidative stress effect on their expression and activities. Methods and Results-We demonstrated the presence (mRNA, protein, activity) of PON2 and PON3 but not PON1 in murine macrophages, whereas in human macrophages, only PON2 was expressed. Under oxidative stress as present in mouse peritoneal macrophages (MPMs) from apoE-deficient (E 0 ) mice as well as in C57BL6 mice, MPMs that were incubated with buthionine sulfoximine, with angiotensin II, with 7-ketocholesterol, or with oxidized phosphatidylcholine, PON2 mRNA levels and lactonase activity toward dihydrocoumarin significantly increased (by 50% to 130%). In contrast, PON3 lactonase activity toward lovastatin was markedly reduced (by 29% to 57%) compared with control cells. The supplementation of E 0 mice with dietary antioxidants (vitamin E, pomegranate juice) significantly increased macrophage PON3 activity (by 23% to 40%), suggesting that oxidative stress was the cause for the reduced macrophage PON3 activity. Incubation of purified PON2 or PON3 with E 0 mice MPMs resulted in reduced cellular lipid peroxides content by 14% to 19% and inhibition of cell-mediated LDL oxidation by 32% to 39%. Key Words: macrophages Ⅲ oxidative stress Ⅲ paraoxonase Ⅲ antioxidants Ⅲ pomegranate juice P araoxonases (PONs) 1, 2, and 3 are members of a multigene family. 1 These genes share 65% identity at the amino acid level, but all PON2 and PON3 cDNAs sequenced to date lack the three nucleotides residues of codon 106, which are present in PON1. 1-3 PON1 is an esterase associated in serum with HDL. 4 Recent studies in PON1 knockout mice 5 and PON1 overexpressing mice 6 revealed that PON1 acts as an antiatherogenic agent. In vitro studies demonstrate that PON1 protects against oxidative stress 7-10 by hydrolyzing specific oxidized lipids in lipoproteins, 7,8 macrophages, 9 and atherosclerotic lesions. 10 Human and rabbit PON3 are also HDL associated 11,12 and rabbit PON3 is more efficient than rabbit PON1 in protecting LDL against oxidation. 12 Under oxidative stress, which is associated with enhanced atherosclerosis, 13 PON1 is inactivated, 14,15 and antioxidants preserve its activity. 14 Serum PON1 levels and activities are lower in patients with cardiovascular heart disease compared with healthy subjects 16 -18 and also in rabbits and mice fed an atherogenic diet. 19,20 PON1 and PON3 mRNA are predominantly expressed in liver, whereas PON2 mRNA is found in different tissues, 21 including human endothelial and aortic smooth muscle cells, 22 but its presence in macrophages has not been analyzed. PON2 protein is not detectable in HDL 22 and, therefore, was thought to function within cells. PON2 overexpression in HeLa cells was shown to lower intracellular oxidative state and these cells were less able to oxidize LDL. 22 PON2 and PON3 can modulate oxidative stress, but it is unknown whether these proteins are inactivated when cells are oxidatively stressed or whether expression le...