Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhib...Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.展开更多
[提示]2003年12月30日,伊朗内政部官员30日向媒体表示,根据伊朗有关方面目前的估计,2003年12月26日凌晨发生的伊朗巴姆大地震所造成的死亡人数可能会"达到约5万"。而几天之前发生在美国加州的同样级别的地震,其死亡人数仅2人...[提示]2003年12月30日,伊朗内政部官员30日向媒体表示,根据伊朗有关方面目前的估计,2003年12月26日凌晨发生的伊朗巴姆大地震所造成的死亡人数可能会"达到约5万"。而几天之前发生在美国加州的同样级别的地震,其死亡人数仅2人。这是为什么?本文作了详实分析。其中原因之一是:…somebuilders disregarded the codes to make bigger profits.这使我们想起了不久前湖南衡阳火灾发生的悲剧。本文的表达不乏可圈可点之处,如:quake-prone(易发生地震的)Italy／the building will give(塌陷)展开更多
伊拉克成为最近世界的新闻热点。美国对伊拉克的进攻迫在眉睫,世界的反战呼声一浪高过一浪。一个美国的中学生身穿反战T-恤衫,被校长拖进办公室,校长并就此事询问学校的律师。结果学生被允许有此穿衣自由。学生的反战T-恤衫到底写了什么...伊拉克成为最近世界的新闻热点。美国对伊拉克的进攻迫在眉睫,世界的反战呼声一浪高过一浪。一个美国的中学生身穿反战T-恤衫,被校长拖进办公室,校长并就此事询问学校的律师。结果学生被允许有此穿衣自由。学生的反战T-恤衫到底写了什么呢?只有一句话:Who would Jesus bomb?(耶稣究竟要轰炸谁?)投稿人未能对此言做进一步解释。澳大利亚作家Denise对此句的解释是:Jesus refers to Jesus Christ,believed by Christians to be the Son of Cod.The question asks which side Jesus would be on if a war broke out.展开更多
文摘Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.
文摘[提示]2003年12月30日,伊朗内政部官员30日向媒体表示,根据伊朗有关方面目前的估计,2003年12月26日凌晨发生的伊朗巴姆大地震所造成的死亡人数可能会"达到约5万"。而几天之前发生在美国加州的同样级别的地震,其死亡人数仅2人。这是为什么?本文作了详实分析。其中原因之一是:…somebuilders disregarded the codes to make bigger profits.这使我们想起了不久前湖南衡阳火灾发生的悲剧。本文的表达不乏可圈可点之处,如:quake-prone(易发生地震的)Italy／the building will give(塌陷)
文摘伊拉克成为最近世界的新闻热点。美国对伊拉克的进攻迫在眉睫,世界的反战呼声一浪高过一浪。一个美国的中学生身穿反战T-恤衫,被校长拖进办公室,校长并就此事询问学校的律师。结果学生被允许有此穿衣自由。学生的反战T-恤衫到底写了什么呢?只有一句话:Who would Jesus bomb?(耶稣究竟要轰炸谁?)投稿人未能对此言做进一步解释。澳大利亚作家Denise对此句的解释是:Jesus refers to Jesus Christ,believed by Christians to be the Son of Cod.The question asks which side Jesus would be on if a war broke out.
