Design,synthesis and biological evaluation of glutamic acid derivatives as anti-oxidant and anti-inflammatory agents

A series of glutamic acid derivatives was synthesized and evaluated for their antioxidant activity and stability. We found several potent and stable glutamic acid derivatives. Among them, compound 12b exhibited good in vitro activity, chemical stability and cytotoxicity. A prototype compound 12b showed an anti-inflammatory effect in LPS-stimulated RAW 264.7 cell lines and in a zebrafish model.     

FASN-TGF-β1-PD-L1 axis contributes to the development of resistance to NK cell cytotoxicity of cisplatin-resistant lung cancer cells

Cisplatin remains the most effective therapy for non-small cell lung cancer (NSCLC). We previously have found cisplatin-resistant lung cancer cells (A549CisR and H157CisR) were more resistant to natural killer (NK) cell-mediated cytotoxicity than parental cells. We also discovered that fatty acid synthase (FASN) levels in cisplatin-resistant cells were significantly higher than in parental cells. To reveal whether a link exists between the up-regulated FASN levels and higher resistance to NK cell cytotoxicity, we performed inhibition studies using a FASN inhibitor and applied the FASN knockdown approach. In both approaches, we found that the FASN inhibition/knockdown significantly increased the susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We further found such decreased susceptibility was associated with an increased programmed death receptor ligand (PD-L1) level in cisplatin-resistant cells. In mechanisms studies, TGF-β1 was found to be the FASN downstream signaling molecule that was responsible for modulating the PD-L1 levels in cisplatin-resistant cells. Accordingly, TGF-β1 inhibition resulted in significantly increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We suggest that the inhibition of FASN-TGFβ1-PD-L1 axis may improve the efficacy of immunotherapy in treating cisplatin-resistant lung cancer.     

Genome-wide analysis of Hanwoo and Chikso populations using the BovineSNP50 genotyping array

Hanwoo and Chikso are classified as Korean native cattle breeds that are currently registered with the Food and Agriculture Organization. However, there is still a lack of genomic studies to compare Hanwoo to Chikso populations. The objective of this study was to perform genome-wide analysis of Hanwoo and Chikso populations, investigating the genetic relationships between these two populations. We genotyped a total of 319 cattle including 214 Hanwoo and 105 Chikso sampled from Gangwon Province Livestock Technology Research Institute, using the Illumina Bovine SNP50K Beadchip. After performing quality control on the initially generated datasets, we assessed linkage disequilibrium patterns for all the possible SNP pairs within 1 Mb apart. Overall, average r² values in Hanwoo (0.048) were lower than Chikso (0.074) population. The genetic relationship between the populations was further assured by the principal component analysis, exhibiting clear clusters in each of the Hanwoo and Chikso populations, respectively. Overall heterozygosity for Hanwoo (0.359) was slightly higher than Chikso (0.345) and inbreeding coefficient was also a bit higher in Hanwoo (??0.015) than Chikso (??0.035). The average F_ST value was 0.036 between Hanwoo and Chikso, indicating little genetic differentiation between those two breeds. Furthermore, we found potential selection signatures including LRP1B and NTRK2 genes that might be implicated with meat and reproductive traits in cattle. In this study, the results showed that both Hanwoo and Chikso populations were not under severe level of inbreeding. Although the principal component analysis exhibited clear clusters in each of the populations, we did not see any clear evidence that those two populations are highly differentiated each other.     

Decrease in carbamylation of rubisco by high CO2 concentration is due to decrease of rubisco activase in kidney bean

Decrease in rubisco activation at high CO₂ concentration was caused by decrease in carbamylation of rubisco (Rohet al., 1996). However, it is unclear whether decrease in carbamylation rate at high CO₂ concentration is due to decrease in activity itself or content of rubisco activase. To clarify this ambiguity, investigation was performed to determine effects of CO₂ concentration on rubisco activase with kidney bean (Phaseolus vulgaris L.) leaves grown at normal CO₂ (350 ppm) and high CO₂ (650 ppm) concentration. The analysis of Western blotting showed that the 50 and 14.5 kl) polypeptides were identified immunochemically as the large and small subunits of rubisco in the preparation, respectively. For the 14.5 kD small subunit, the degree of intensity at high CO₂ concentration was similar to that at normal CO₂ concentration. For the 50 kD large sububit, however, the intensity of a band at high CO, concentration was significantly higher than that at normal CO₂ concentration, indicating that only the large subunit is affected by high CO₂ concentration. The analysis of Western immunoblotting showed two major polypeptides at 46 and 42 kD which were identified as rubisco activase subunits. The intensities of two bands were shown to be higher at normal CO₂ than high CO₂ concentration. These data indicate that decrease of carbamylation resulting from increase of CO₂ concentration was caused by rubisco activase. Finally, by employing ATP hydrolysis assay and ELISA, we also observed a significant decrease in both activity and content of rubisco activase as CO₂ concentration was raised from normal to high CO₂ concentration. These results suggest that decrease in rubisco carbamylation at high CO₂ concentration is caused by activity itself and/or content of rubisco activase.     

Suppression of acidogenic activities due to rapid temperature drop in anaerobic digestion

A rapid temperature drop during anaerobic acidogenesis in an anaerobic reactor system resulted in the sharp suppression of carbohydrate decomposition and production of volatile fatty acids. When the temperature was dropped from 30°C to 25, 20, 15°C sequentially, the numbers of bacteria were slowly reduced without showing temperature shock. The acidogenesis, however, was dramatically affected after each temperature drop; the removal efficiency of carbohydrate was reduced from 92% to 84%, 72%, 25% with showing the minima of 78%, 52% and 10% due to the rapid temperature drop respectively. This indicates that the acidogens lose the activities momentarily during the rapid temperature drop and require certain period of time to recover the activities at the adjusted fermentation temperature. This revised version was published online in November 2006 with corrections to the Cover Date.     

Role of neutrophils in lung vascular injury and edema after premature birth in lambs

Carlton, David P., Kurt H. Albertine, Soo Chul Cho, MennoLont, and Richard D. Bland. Role of neutrophils in lung vascular injury and edema after premature birth in lambs. J. Appl. Physiol. 83(4): 1307-1317, 1997.Toinvestigate the role of neutrophils in the pathogenesis of respiratorydistress after premature birth, we assessed the relationship betweencirculating neutrophil concentration and neutrophil accumulation in thelung, lung lymph and pleural liquid flow, and extravascular lungwater in 10 chronically catheterized preterm lambs (127 ± 1 days gestation) that were mechanically ventilated for 8 h afterbirth. Circulating neutrophil concentration transiently decreasedwithin 2 h after birth and then returned to prenatal values by 6-8h. The decrease in circulating neutrophil concentration was relateddirectly to the accumulation of neutrophils in the air spaces, drainageof liquid and protein from the lung 6-8 h after delivery, andpostmortem extravascular lung water. In additional studies, weintravenously administered mechlorethamine to 5 fetal lambs to reducecirculating neutrophils before delivery (neutrophil concentrationbefore birth: 9 ± 11 cells/µl). Compared with control lambs,neutrophil-depleted lambs had significantly less drainage of liquid(7.8 ± 5.9 vs. 2.6 ± 1.9 ml/h, respectively) and protein (116 ± 74 vs. 42 ± 27 mg/h, respectively) from the lung 6-8 hafter birth and significantly less extravascular lung water atpostmortem (6.5 ± 0.8 vs. 4.8 0.6 g/g dry lung,respectively). Thus neutrophils contribute to thepathogenesis of respiratory distress after premature birth byincreasing lung vascular protein permeability and promoting lung edema.