The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyz...The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2),which is in turn further metabolized by cyclooxygenases(COXs)and lipoxygenases(LOXs)and cytochrome P450(CYP)enzymes to a spectrum of bioactive mediators that includes prostanoids,leukotrienes(LTs),epoxyeicosatrienoic acids(EETs),dihydroxyeicosatetraenoic acid(diHETEs),eicosatetraenoic acids(ETEs),and lipoxins(LXs).Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases(CVD),cancers,and inflammatory diseases.This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer.progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2.Thus,we herein present a synopsis of AA metabolism in human health,cardiovascular and cancer biology,and the signaling pathways involved in these processes.To explore the role of the AA metabolism and potential therapies,we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.展开更多
Chang'E-1 lunar Orbiter was launched by Long March 3A rocket from Xichang Satel-lite Launch Center at 18:05BT(Beijing Time) Oct.24,2007.It is the first step of its ambitious three-stage moon program,a new mileston...Chang'E-1 lunar Orbiter was launched by Long March 3A rocket from Xichang Satel-lite Launch Center at 18:05BT(Beijing Time) Oct.24,2007.It is the first step of its ambitious three-stage moon program,a new milestone in the Chinese space exploration history.The primary science objectives of Chang'E-1 lunar orbiter are to obtain three-Dimension(3D) stereo images of the lunar surface,to analyze the distribution and abundance of elements on the surface,to investigate the thickness of lunar soil,evaluate helium-3 resources and other characteristics,and to detect the space environment around the moon.To achieve the above four mission objectives,eight sets of scientific instruments are chosen as the payloads of the lunar orbiter,including a CCD stereo camera(CCD),a Sagnac-based interferometer spectrometer(ⅡM),a Laser Altimeter(LAM),a Microwave Radiometer(MRM),a Gamma-Ray Spectrometer(GRS),an X-ray spectrometer(XRS),a High-Energy Particle Detector(HPD),and two Solar Wind Ion Detectors(SWID).The detected data of the payloads show that all payloads work well.This paper introduces the status of payloads in the first phase and preliminary scientific results.展开更多
The global lunar image of the first phase of Chinese Lunar Exploration Program is the first image that covered all over the surface of the Moon. It will serve as a critical foundation for succeeding exploration and sc...The global lunar image of the first phase of Chinese Lunar Exploration Program is the first image that covered all over the surface of the Moon. It will serve as a critical foundation for succeeding exploration and scientific research. In this paper, the acquisition, characteristics, and data quality of Chang'E-1 CCD image data are described in detail. Also described are the methodology and procedure of data processing. According to rule of planetary cartography, the image data have been processed, geometrically corrected, and then mosaicked and merged in a scale of 1:2.5 million. The results of data processing and charting show that the image data of Chang'E-1 CCD and their geometric precision meet the demand of charting a map in the scale of 1:2.5 million. The relative geometric positioning precision of the global image is better than 240 m, and the absolute geometric positioning precision is slightly better than that of the ULCN2005 and Clementine lunar basemap (V2.0). The plane positioning precision is approximately 100-1500 m. This global image proves to be the best global image of the Moon so far in terms of space coverage, image quality, and positioning precision.展开更多
The Laser AltiMeter (LAM), as one of the main payloads of Chang'E-1 probe, is used to measure the topography of the lunar surface. It performed the first measurement at 02:22 on November 28th, 2007. Up to December...The Laser AltiMeter (LAM), as one of the main payloads of Chang'E-1 probe, is used to measure the topography of the lunar surface. It performed the first measurement at 02:22 on November 28th, 2007. Up to December 4th 2008, the total number of measurements was approximately 9.12 million, covering the whole surface of the Moon. Using the LAM data, we constructed a global lunar Digtal Elevation Model (DEM) with 3 km spatial resolution. The model shows pronounced morphological characteristics, legible and vivid details of the lunar surface. The plane positioning accuracy of the DEM is 445 m (1σ), and the vertical accuracy is 60 m (1σ). From this DEM model, we measured the full range of the altitude difference on the lunar sur-face, which is about 19.807 km. The highest point is 10.629 km high, on a peak between crater Korolev and crater Dirichlet-Jackson at (158.656°W, 5.441°N) and the lowest point is -9.178 km in height, inside crater Antoniadi (172.413°W, 70.368°S) in the South Pole-Aitken Basin. By comparison, the DEM model of Chang'E-1 is better than the USA ULCN2005 in accuracy and resolution and is probably identical to the DEM of Japan SELENE, but the DEM of Chang'E-1 reveals a new lowest point, clearly lower than that of SELENE.展开更多
【目的】探讨不同干燥方式对甘薯叶功能成分含量及抗氧化能力的影响,为甘薯叶综合开发和干燥加工工艺优化提供理论依据。【方法】以甘薯品种‘台农71’和‘胜南’的叶片为材料,研究蒸干结合热风干燥、真空冷冻干燥、60℃/50℃/40℃热风...【目的】探讨不同干燥方式对甘薯叶功能成分含量及抗氧化能力的影响,为甘薯叶综合开发和干燥加工工艺优化提供理论依据。【方法】以甘薯品种‘台农71’和‘胜南’的叶片为材料,研究蒸干结合热风干燥、真空冷冻干燥、60℃/50℃/40℃热风干燥共5种干燥方式对甘薯叶功能成分(总酚、总黄酮、绿原酸类成分、β-胡萝卜素、维生素D_(3),、维生素E、抗坏血酸、维生素B;、维生素B;)、抗氧化能力(采用DPPH、ABTS;自由基清除法测定)和外观色泽(叶绿素、色值)的影响,并分析各功能成分间及功能成分与抗氧化活性的关系。【结果】甘薯叶中检测到的游离酚酸主要包括新绿原酸、绿原酸、隐绿原酸、咖啡酸、异绿原酸A、异绿原酸B和异绿原酸C。5种干燥方式对甘薯叶中功能成分有不同程度的影响。真空冷冻干燥下,‘台农71’叶片中游离酚酸总量最高,达到38.4 mg·g^(-1)DW,是其在60℃热风干燥下含量的25.6倍。真空冷冻干燥和蒸干结合热风干燥下,叶片中总酚、总黄酮和抗坏血酸含量差异相对较小,但都显著高于60℃/50℃/40℃3种热风干燥。真空冷冻干燥下,两个材料的总酚和总黄酮含量最高,分别是3种热风干燥的1.7—5.3倍和1.7—3.8倍。抗坏血酸在真空冷冻干燥下有较好的保留(175.3—441.1 mg/100 g DW),而在热风干燥中含量极低(3.4—5.7 mg/100 g DW)。维生素D_(3),和α-生育酚在蒸干结合热风干燥下含量最高。抗氧化活性分析表明,不同干燥方式下甘薯叶甲醇提取物抗氧化活性差异显著(P<0.05),其中真空冷冻干燥和蒸干结合热风干燥的自由基清除率较高,显著高于3种热风干燥。相关性分析表明,总酚、总黄酮、总绿原酸、维生素D_(3),、α-生育酚之间存在极显著相关性(P<0.01);甘薯叶抗氧化能力与总酚、总黄酮及各绿原酸类成分的含量也存在极显著相关(P<0.01)。【结论】真空冷冻展开更多
The strategic plan for the development of the unmanned Chinese Lunar Exploration Program is characterized by three distinct stages: "orbiting around", "landing on" and "returning from" th...The strategic plan for the development of the unmanned Chinese Lunar Exploration Program is characterized by three distinct stages: "orbiting around", "landing on" and "returning from" the Moon. The first Chinese lunar probe, Chang'E-1, which was successfully launched on October 24th, 2007 at Xichang Satellite Launch Center, and guided to crash on the Moon on March 1st, 2009, at 52.36°E, 1.50°S, in the north of Mare Fecunditatis, is the first step towards the "orbiting around" stage. The Chang'E-1 mission lasted 495 days, exceeding the expected life-span by about four months. A total of 1.37 TB raw data was received from Chang'E-1. It was then processed into 4 TB scientific data products at various levels. Many scientific results have been obtained by analyzing these data, including especially the "global lunar image from the first Chinese lunar explora- tion mission". All scientific goals of Chang'E-1 have been achieved. It provides much useful materials for further advances of lunar sciences and planetary chemistry. Meanwhile, these results will serve as a firm basis for future Chinese lunar missions.展开更多
Chang'E-1 is the first lunar mission in China,which was successfully launched on Oct.24th,2007.It was guided to crash on the Moon on March 1,2009,at 52.36°E,1.50°S,in the north of Mare Fecunditatis.The t...Chang'E-1 is the first lunar mission in China,which was successfully launched on Oct.24th,2007.It was guided to crash on the Moon on March 1,2009,at 52.36°E,1.50°S,in the north of Mare Fecunditatis.The total mission lasted 495 days,exceeding the designed life-span about four months.1.37Terabytes raw data was received from Chang'E-1.It was then processed into 4Terabytes science data at different levels.A series of science results have been achieved by analyzing and applicating these data,especially "global image of the Moon of China's first lunar exploration mission".Four scientific goals of Chang'E-1 have been achieved.It provides abundant materials for the research of lunar sciences and cosmochemistry.Meanwhile these results will serve for China's future lunar missions.展开更多
Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem ce...Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.展开更多
Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.Ho...Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.展开更多
基金supported in part by National Nature Science Foundation of China(Nos.81790624,81700333,81900363,and 81900244)the Deutsche Forschungsgemeinschaft:SFB1039/A6(to I.F.).
文摘The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2),which is in turn further metabolized by cyclooxygenases(COXs)and lipoxygenases(LOXs)and cytochrome P450(CYP)enzymes to a spectrum of bioactive mediators that includes prostanoids,leukotrienes(LTs),epoxyeicosatrienoic acids(EETs),dihydroxyeicosatetraenoic acid(diHETEs),eicosatetraenoic acids(ETEs),and lipoxins(LXs).Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases(CVD),cancers,and inflammatory diseases.This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer.progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2.Thus,we herein present a synopsis of AA metabolism in human health,cardiovascular and cancer biology,and the signaling pathways involved in these processes.To explore the role of the AA metabolism and potential therapies,we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
文摘Chang'E-1 lunar Orbiter was launched by Long March 3A rocket from Xichang Satel-lite Launch Center at 18:05BT(Beijing Time) Oct.24,2007.It is the first step of its ambitious three-stage moon program,a new milestone in the Chinese space exploration history.The primary science objectives of Chang'E-1 lunar orbiter are to obtain three-Dimension(3D) stereo images of the lunar surface,to analyze the distribution and abundance of elements on the surface,to investigate the thickness of lunar soil,evaluate helium-3 resources and other characteristics,and to detect the space environment around the moon.To achieve the above four mission objectives,eight sets of scientific instruments are chosen as the payloads of the lunar orbiter,including a CCD stereo camera(CCD),a Sagnac-based interferometer spectrometer(ⅡM),a Laser Altimeter(LAM),a Microwave Radiometer(MRM),a Gamma-Ray Spectrometer(GRS),an X-ray spectrometer(XRS),a High-Energy Particle Detector(HPD),and two Solar Wind Ion Detectors(SWID).The detected data of the payloads show that all payloads work well.This paper introduces the status of payloads in the first phase and preliminary scientific results.
文摘The global lunar image of the first phase of Chinese Lunar Exploration Program is the first image that covered all over the surface of the Moon. It will serve as a critical foundation for succeeding exploration and scientific research. In this paper, the acquisition, characteristics, and data quality of Chang'E-1 CCD image data are described in detail. Also described are the methodology and procedure of data processing. According to rule of planetary cartography, the image data have been processed, geometrically corrected, and then mosaicked and merged in a scale of 1:2.5 million. The results of data processing and charting show that the image data of Chang'E-1 CCD and their geometric precision meet the demand of charting a map in the scale of 1:2.5 million. The relative geometric positioning precision of the global image is better than 240 m, and the absolute geometric positioning precision is slightly better than that of the ULCN2005 and Clementine lunar basemap (V2.0). The plane positioning precision is approximately 100-1500 m. This global image proves to be the best global image of the Moon so far in terms of space coverage, image quality, and positioning precision.
文摘The Laser AltiMeter (LAM), as one of the main payloads of Chang'E-1 probe, is used to measure the topography of the lunar surface. It performed the first measurement at 02:22 on November 28th, 2007. Up to December 4th 2008, the total number of measurements was approximately 9.12 million, covering the whole surface of the Moon. Using the LAM data, we constructed a global lunar Digtal Elevation Model (DEM) with 3 km spatial resolution. The model shows pronounced morphological characteristics, legible and vivid details of the lunar surface. The plane positioning accuracy of the DEM is 445 m (1σ), and the vertical accuracy is 60 m (1σ). From this DEM model, we measured the full range of the altitude difference on the lunar sur-face, which is about 19.807 km. The highest point is 10.629 km high, on a peak between crater Korolev and crater Dirichlet-Jackson at (158.656°W, 5.441°N) and the lowest point is -9.178 km in height, inside crater Antoniadi (172.413°W, 70.368°S) in the South Pole-Aitken Basin. By comparison, the DEM model of Chang'E-1 is better than the USA ULCN2005 in accuracy and resolution and is probably identical to the DEM of Japan SELENE, but the DEM of Chang'E-1 reveals a new lowest point, clearly lower than that of SELENE.
文摘【目的】探讨不同干燥方式对甘薯叶功能成分含量及抗氧化能力的影响,为甘薯叶综合开发和干燥加工工艺优化提供理论依据。【方法】以甘薯品种‘台农71’和‘胜南’的叶片为材料,研究蒸干结合热风干燥、真空冷冻干燥、60℃/50℃/40℃热风干燥共5种干燥方式对甘薯叶功能成分(总酚、总黄酮、绿原酸类成分、β-胡萝卜素、维生素D_(3),、维生素E、抗坏血酸、维生素B;、维生素B;)、抗氧化能力(采用DPPH、ABTS;自由基清除法测定)和外观色泽(叶绿素、色值)的影响,并分析各功能成分间及功能成分与抗氧化活性的关系。【结果】甘薯叶中检测到的游离酚酸主要包括新绿原酸、绿原酸、隐绿原酸、咖啡酸、异绿原酸A、异绿原酸B和异绿原酸C。5种干燥方式对甘薯叶中功能成分有不同程度的影响。真空冷冻干燥下,‘台农71’叶片中游离酚酸总量最高,达到38.4 mg·g^(-1)DW,是其在60℃热风干燥下含量的25.6倍。真空冷冻干燥和蒸干结合热风干燥下,叶片中总酚、总黄酮和抗坏血酸含量差异相对较小,但都显著高于60℃/50℃/40℃3种热风干燥。真空冷冻干燥下,两个材料的总酚和总黄酮含量最高,分别是3种热风干燥的1.7—5.3倍和1.7—3.8倍。抗坏血酸在真空冷冻干燥下有较好的保留(175.3—441.1 mg/100 g DW),而在热风干燥中含量极低(3.4—5.7 mg/100 g DW)。维生素D_(3),和α-生育酚在蒸干结合热风干燥下含量最高。抗氧化活性分析表明,不同干燥方式下甘薯叶甲醇提取物抗氧化活性差异显著(P<0.05),其中真空冷冻干燥和蒸干结合热风干燥的自由基清除率较高,显著高于3种热风干燥。相关性分析表明,总酚、总黄酮、总绿原酸、维生素D_(3),、α-生育酚之间存在极显著相关性(P<0.01);甘薯叶抗氧化能力与总酚、总黄酮及各绿原酸类成分的含量也存在极显著相关(P<0.01)。【结论】真空冷冻
文摘The strategic plan for the development of the unmanned Chinese Lunar Exploration Program is characterized by three distinct stages: "orbiting around", "landing on" and "returning from" the Moon. The first Chinese lunar probe, Chang'E-1, which was successfully launched on October 24th, 2007 at Xichang Satellite Launch Center, and guided to crash on the Moon on March 1st, 2009, at 52.36°E, 1.50°S, in the north of Mare Fecunditatis, is the first step towards the "orbiting around" stage. The Chang'E-1 mission lasted 495 days, exceeding the expected life-span by about four months. A total of 1.37 TB raw data was received from Chang'E-1. It was then processed into 4 TB scientific data products at various levels. Many scientific results have been obtained by analyzing these data, including especially the "global lunar image from the first Chinese lunar explora- tion mission". All scientific goals of Chang'E-1 have been achieved. It provides much useful materials for further advances of lunar sciences and planetary chemistry. Meanwhile, these results will serve as a firm basis for future Chinese lunar missions.
文摘Chang'E-1 is the first lunar mission in China,which was successfully launched on Oct.24th,2007.It was guided to crash on the Moon on March 1,2009,at 52.36°E,1.50°S,in the north of Mare Fecunditatis.The total mission lasted 495 days,exceeding the designed life-span about four months.1.37Terabytes raw data was received from Chang'E-1.It was then processed into 4Terabytes science data at different levels.A series of science results have been achieved by analyzing and applicating these data,especially "global image of the Moon of China's first lunar exploration mission".Four scientific goals of Chang'E-1 have been achieved.It provides abundant materials for the research of lunar sciences and cosmochemistry.Meanwhile these results will serve for China's future lunar missions.
基金supported by the National Natural Science Foundation of China(NSFC)[81672119 and 81725010 to W.Z.]W Z is a scholar of‘the National Science Fund for Distinguished Young Scholars’(NSFC)[81725010]+4 种基金the Strategic Priority Research Program of the Chinese Academy of Science(XDA16020400 to P.H.)Ministry of Science and Technology of China(2017YFA0102700 to P.H.)National Natural Science Foundation of China(32170804 to PH)P.H.the fellowship of China Postdoctoral Science Foundation(2021TQ0207,2021M702184 to J.S.)the‘Basic research project of Shanghai Sixth People’s Hospital’(ynqn202102 to J.S.)。
文摘Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.
基金funded by the National Natural Science Foundation of China(32270161,32100117,32100118)the Natural Science Foundation of Jiangsu Province of China(BK20210899,BK20210900,BK20210901)+1 种基金Research Grant of Jiangsu Commission of Health,China(ZD2021036)the Starting Grant for Talents of Xuzhou Medical University(D2021007,D2021008).
文摘Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.
