Ulcerative colitis(UC)is characterized by chronic relapsing intestinal inflammation.Currently,there is no effective treatment for the disease.According to our preliminary data,1,8-cineole,which is the main active comp...Ulcerative colitis(UC)is characterized by chronic relapsing intestinal inflammation.Currently,there is no effective treatment for the disease.According to our preliminary data,1,8-cineole,which is the main active compound of Amomum compactum Sol.ex Maton volatile oil and an effective drug for the treatment of pneumonia,showed remarkable anti-inflammatory effects on colitis pathogenesis.However,its mechanism of action and direct targets remain unclear.This study investigated the direct targets and mechanism through which 1,8-cineole exerts its anti-inflammatory effects using a dextran sulfate sodium salt-induced colitis mouse model.The effects of 1,8-cineole on macrophage polarization were investigated using activated bone marrow-derived macrophages and RAW264.7 cells.In addition,1,8-cineole targets were revealed by drug affinity responsive target stability,thermal shift assay,cellular thermal shift assay,and heat shock protein 90(HSP90)adenosine triphosphatases(ATPase)activity assays.The results showed that 1,8-cineole exhibited powerful anti-inflammatory properties in vitro and in vivo by inhibiting the macrophage M1 polarization and protecting intestinal barrier function.Mechanistically,1,8-cineole directly interacted with HSP90 and decreased its ATPase activity,also inhibited nucleotide-binding and oligomerization domain-,leucine rich repeat-,and pyrin domain-containing 3(NLRP3)binding to HSP90 and suppressor of G-two allele of SKP1(SGT1)and suppressed NLRP3 inflammasome activation in macrophages.These results demonstrated that 1,8-cineole is a potential drug candidate for UC treatment.展开更多
在密封反应釜中,以1,8-对孟烷二乙酰胺为原料,正丁醇为溶剂,经氢氧化钠催化水解制备得到1,8-对孟烷二胺。当原料为0.1 mol,正丁醇用量为150 m L,原料与氢氧化钠物质的量之比为1∶5,反应温度175℃,体系自发升压至0.35～0.4 MPa,反应时间1...在密封反应釜中,以1,8-对孟烷二乙酰胺为原料,正丁醇为溶剂,经氢氧化钠催化水解制备得到1,8-对孟烷二胺。当原料为0.1 mol,正丁醇用量为150 m L,原料与氢氧化钠物质的量之比为1∶5,反应温度175℃,体系自发升压至0.35～0.4 MPa,反应时间18 h时,原料转化率为100%,产物选择性大于96%,产物GC含量可达96.47%。与常压工艺相比,密封工艺的反应时间缩短了50%,产物选择性提高了20个百分点;并且当投料量扩大到10倍时,仍保持良好的反应效果,还可适当减少溶剂的添加比例。采用减压蒸馏对密封工艺产品进行分离提纯,减压精馏对常压工艺产品进行分离提纯,结果发现:蒸馏方法使产品提纯用时减少了7/8,溶剂回收率提高了5.3个百分点,且可多次重复利用,产品得率提高了55.7个百分点,产品得率可达85.6%,纯度为96.51%。展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:81830114,82004232,82174253,and 82104707)Guangdong Basic and Applied Basic Research Foundation,China(Grant Nos.:2021A1515011215 and 2022A1515110827)+6 种基金Guangzhou Basic and Applied Basic Research Foundation,China(Grant No.:2023A1515011149)China Postdoctoral Science Foundation(Grant Nos.:2020M683206 and 2021M701443)the Key Area Research and Development Program of Guangdong Province,China(Grant No.:2020B1111100010)Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine,China(Grant No.:202102010014)the Cross-disciplinary Special Project of Jinan University,China(Grant No.:21621115)the State Key Laboratory of Dampness Syndrome of Chinese Medicine,China(Grant No.:SZ2021KF13)the Outstanding Innovative Talents Cultivation Funded Programs for Doctoral Students of Jinan University,China(Grant No.:2021CXB024).
文摘Ulcerative colitis(UC)is characterized by chronic relapsing intestinal inflammation.Currently,there is no effective treatment for the disease.According to our preliminary data,1,8-cineole,which is the main active compound of Amomum compactum Sol.ex Maton volatile oil and an effective drug for the treatment of pneumonia,showed remarkable anti-inflammatory effects on colitis pathogenesis.However,its mechanism of action and direct targets remain unclear.This study investigated the direct targets and mechanism through which 1,8-cineole exerts its anti-inflammatory effects using a dextran sulfate sodium salt-induced colitis mouse model.The effects of 1,8-cineole on macrophage polarization were investigated using activated bone marrow-derived macrophages and RAW264.7 cells.In addition,1,8-cineole targets were revealed by drug affinity responsive target stability,thermal shift assay,cellular thermal shift assay,and heat shock protein 90(HSP90)adenosine triphosphatases(ATPase)activity assays.The results showed that 1,8-cineole exhibited powerful anti-inflammatory properties in vitro and in vivo by inhibiting the macrophage M1 polarization and protecting intestinal barrier function.Mechanistically,1,8-cineole directly interacted with HSP90 and decreased its ATPase activity,also inhibited nucleotide-binding and oligomerization domain-,leucine rich repeat-,and pyrin domain-containing 3(NLRP3)binding to HSP90 and suppressor of G-two allele of SKP1(SGT1)and suppressed NLRP3 inflammasome activation in macrophages.These results demonstrated that 1,8-cineole is a potential drug candidate for UC treatment.
