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Gemigliptin Attenuates Renal Fibrosis Through Down- Regulation of the NLRP3 Inflammasome
서정범,최연경,우혜인,정연아,이성우,이승형,박미향,이인규,정관수,박근규 대한당뇨병학회 2019 Diabetes and Metabolism Journal Vol.43 No.6
Background: The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis. Methods: We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins Results: Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with the in vivo results, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells. Conclusion: The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.
서보성,최우정,박현진,백누리,박서우,신은서,오양열,강방훈 한국토양비료학회 2023 한국토양비료학회지 Vol.56 No.3
Reclaimed tidelands (RTLs) in the southwestern coastal areas of South Korea has been used for rice (Oryza sativa L.) cultivation due to high salinity of the soils. However, there is increased social pressure to utilize the RTLs for upland crop cultivation due to decreased rice consumption. In this study, salinity and sodicity of 16 RTLs located were investigated to explore the suitability of RTLs for upland crop cultivation. Surface (0 - 20 cm) soil samples were collected from 241 paddy fields in the 16 RTL districts and analyzed for electrical conductivity of saturated soil paste extracts (ECe), exchangeable sodium percentage (ESP), and pH at 1:5 of soil:water ratio (pH1:5). The ECe (range: 2.5 - 15.8 dS m-1), ESP (1.6 - 67.2%), and pH1:5 (6.6 - 9.0) of the RTL soils differed (P < 0.001) with RTL districts. Though there are indications of decreased ECe, ESP, and pH1:5 with rice cultivation year after reclamation, this pattern was not statistically significant, suggesting that land management practices such as liming and organic matter application are required to facilitate desalinization and desodification of RTLs. Of the 16 RTLs, normal soils (ECe < 4.0 dS m-1, ESP < 15%, and pH1:5 < 8.5) were found in seven RTLs including Wolchen, Sanae, and Baiksoo RTLs. The proportion of normal soils in these three RTLs were 75%, 56%, and 47%, respectively. Therefore, these RTLs are found to be more suitable for upland crop cultivation than other RTLs. However, because the growth of upland crops are also susceptible to soil moisture stress, more information such as groundwater levels and soil drainage is required for successful upland crop cultivation in these RTLs.
서승언,민경진,우선민,권택규 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
Multiple cancer cells highly express cathepsin S, which has pro-tumoral effects. However, it was previously unknown whether knockdown or a pharmacological inhibitor (ZFL) of cathepsin S acts as an inducer of ER stress. Here, ZFL and knockdown of cathepsin S markedly induced ER stress through the up-regulation of calcium levels in the cytosol. Induction of calcium levels by inhibition of cathepsin S is markedly blocked by an inhibitor of the IP3 receptor and the ryanodine receptor Ca2+ channel in the ER, but an inhibitor of a mitochondrial Ca2+ uniporter had no effect on ZFL-induced calcium levels. Furthermore, production of mitochondrial ROS by ZFL was associated with an increase in cytosolic calcium levels. ZFL-mediated ER stress enhanced anti-cancer drug-induced apoptotic cell death, and pretreatment with chemical chaperones or down-regulation of ATF4 and CHOP by small interfering RNA markedly reduced ZFL plus oxaliplatin-induced apoptosis. Taken together, our findings reveal that inhibition of cathepsin S is an inducer of ER stress; these findings may contribute to the enhancement of therapeutic efficiency in cancer cells.