Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinf...Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing challenge.Here,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing SIRT6.RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of MDL-811.We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation.Moreover,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery.Importantly,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational perspective.Taken together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.展开更多
Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of ...Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains unknown.Here,we show that LFHP-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity,but also reduced the interaction of PGAM5 with NRF2,which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia.Furthermore,LFHP-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.展开更多
Five novel biscembranoids,ximaolides H-L(1-5),along with four known related compounds(6-9) were isolated from the Hainan soft coral Sarcophyton tortuosum.The structures of the new compounds were determined by extensiv...Five novel biscembranoids,ximaolides H-L(1-5),along with four known related compounds(6-9) were isolated from the Hainan soft coral Sarcophyton tortuosum.The structures of the new compounds were determined by extensive spectroscopic analysis,quantum chemical calculations,and/or by comparing their CD spectra with those of the known compounds.Compounds 1 and 2 are the first examples of biscembranoids bearing a 1,35-bridged lactone moiety,4 is the first biscembranoid comprising an uncommon oxetane ring,and 5 represents the first 36-peroxyl biscembranoid.Ximaolides Ⅰ(2),K(4) and F(9) exhibited interesting anti-inflammatory activity by the inhibition of LPS-induced TNF-α protein release in RAW264.7 macrophages.展开更多
基金supported by the National Natural Science Foundation of China (81973512, 81925034, 81701235, and 81991514)Double First-Class Project of China Pharmaceutical University(CPU2018GY06 and CPU2018GY20, China)+1 种基金the Fundamental Research Funds for the Central Universities(021414380446, China)supported by the Six Talent Peaks Project of Jiangsu Province (China) to Tao Pang。
文摘Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing challenge.Here,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing SIRT6.RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of MDL-811.We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation.Moreover,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery.Importantly,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational perspective.Taken together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.
基金supported by the National Natural Science Foundation of China(81973512,81822041,21977116,and 81673305)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(No.2018ZX09711002006-013,China)+7 种基金Science&Technology Major Project of Zhongshan City(No.2019A4020,China)Double First-Class Project of China Pharmaceutical University(CPU2018GY06,CPU2018GY18,and CPU2018GY20,China)the Open Project of State Key Laboratory of Natural Medicines(SKLNMZZCX 201824 and SKLNMZZ202029,China)the Open Project Program of the State Key Laboratory of Drug Research(SIMM2004KF-08,China)the Open Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University(Traditional Chinese Pharmacology,China)Zhejiang Chinese Medical University(No.ZYAOX2018001,China)State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(SKL-HIDCA-2018-1,China)supported by the Six Talent Peaks Project of Jiangsu Province to Tao Pang
文摘Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains unknown.Here,we show that LFHP-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity,but also reduced the interaction of PGAM5 with NRF2,which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia.Furthermore,LFHP-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.
基金financially supported by the National Natural Science Foundation of China(NSFC,Nos.81991521,8202290170,42076099)the NSFC/CNRS(Centre National de la Recherche Scientifique)Joint Project(No.81811530284)+3 种基金the National Key Research and Development Program of China(No.2018YFC0310903)the SKLDR/SIMM Project(No.SIMM1903ZZ-04)the Shanghai Rising-Star Program(No.20QA1411100)SA-SIBS Scholarship Program。
文摘Five novel biscembranoids,ximaolides H-L(1-5),along with four known related compounds(6-9) were isolated from the Hainan soft coral Sarcophyton tortuosum.The structures of the new compounds were determined by extensive spectroscopic analysis,quantum chemical calculations,and/or by comparing their CD spectra with those of the known compounds.Compounds 1 and 2 are the first examples of biscembranoids bearing a 1,35-bridged lactone moiety,4 is the first biscembranoid comprising an uncommon oxetane ring,and 5 represents the first 36-peroxyl biscembranoid.Ximaolides Ⅰ(2),K(4) and F(9) exhibited interesting anti-inflammatory activity by the inhibition of LPS-induced TNF-α protein release in RAW264.7 macrophages.
