Herein,we report the first asymmetric synthesis of illihenin A,an antiviral sesquiterpenoid bearing a cage-like tricyclo[6.2.2.01,5]dodecane skeleton.Starting from an abundant feedstock(-)-α-cedrene,this19-step synth...Herein,we report the first asymmetric synthesis of illihenin A,an antiviral sesquiterpenoid bearing a cage-like tricyclo[6.2.2.01,5]dodecane skeleton.Starting from an abundant feedstock(-)-α-cedrene,this19-step synthesis approach features a novel ring-reorganization strategy that includes early stage C7-hydroxylation of the cedrane skeleton and a later-stage ring disassembly-reassembly procedure,affording the desired product with high synthetic efficiency and minimal chiral manipulation.The key transformations include the following:(i)a hydroxy group-directed SmI2-mediated reductive coupling to construct the congested tertiary 7-OH cedrane,(ii)aβ-fragmentation triggered by an alkoxy radical to release a spiro[4.5]decane,and(iii)an intramolecular Aldol reaction,concomitant withα-epimerization,to furnish the tricyclic framework.In addition,preliminary investigation of antiviral activity against CVB3 revealed that illihenin A can significantly inhibit ROS production and apoptosis.展开更多
Influenza A viruses(IAV)are responsible for seasonal flu epidemics,which can lead to high morbidity and mortality each year.Like other viruses,influenza virus can hijack host cellular machinery for its replication.Hos...Influenza A viruses(IAV)are responsible for seasonal flu epidemics,which can lead to high morbidity and mortality each year.Like other viruses,influenza virus can hijack host cellular machinery for its replication.Host cells have evolved diverse cellular defense to resist the invasion of viruses.As the main components of promyelocytic leukemia protein nuclear bodies(PML-NBs),PML can inhibit the replication of many medically important viruses including IAV.However,the mechanism of PML against IAV is unclear.In the present study,we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication,whereas knockdown of endogenous PML expression could enhance IAV replication.Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2,which negatively regulated IAV replication during infection.Moreover,PML stabilized RIG-I to promote the production of typeⅠIFN.Collectively,these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.展开更多
Four stereoisomers of 3,5-bis（2-hydroxybut-3-en-1-yl）-l,2,4-thiadiazole, named insatindigothiadia- zoles A-D （1a-1d）, were isolated from the roots oflsatis indigotica. Their structures were determined by spectrosc...Four stereoisomers of 3,5-bis（2-hydroxybut-3-en-1-yl）-l,2,4-thiadiazole, named insatindigothiadia- zoles A-D （1a-1d）, were isolated from the roots oflsatis indigotica. Their structures were determined by spectroscopic analysis; specifically, the absolute configurations were assigned by using the MPA determination rule based on △δrs values of MPA esters, and supported by electronic CD （ECD） calculations. Proposed biosynthetic pathways and preliminary investigations of the biological activities of la-1d against influenza virus A （H3N2）, Coxsackie virus B3, and/or HSV-1 are also discussed.展开更多
A pair of indole alkaloid enantiomers with a novel bisindolylacetamide skeleton, insatindibisindolamides A and B（1a and 1b）, was isolated from an aqueous extract of Isatis indigotica roots. The enantiomers were sepa...A pair of indole alkaloid enantiomers with a novel bisindolylacetamide skeleton, insatindibisindolamides A and B（1a and 1b）, was isolated from an aqueous extract of Isatis indigotica roots. The enantiomers were separated by chiral HPLC. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, including 2D NMR, X-ray crystallography, and electronic CD（ECD） calculation. The proposed biosynthetic pathway and preliminary investigations of the biological activity of compounds 1a and 1b are also discussed.展开更多
The screening practices for hepatitis D virus(HDV)are diverse and nonstandardized worldwide,and the exact prevalence of HDV is uncertain.AIM To estimate HDV prevalence and investigate viral marker quantity trends in p...The screening practices for hepatitis D virus(HDV)are diverse and nonstandardized worldwide,and the exact prevalence of HDV is uncertain.AIM To estimate HDV prevalence and investigate viral marker quantity trends in patients with hepatitis D.METHODS We collected 5594 serum samples from patients with hepatitis B in Jilin Province,China(3293 males and 2301 females,age range of 2 to 89 years).We then conducted tests for hepatitis B surface antigen(HBsAg),hepatitis B Virus(HBV)DNA,anti-hepatitis D antigen(HDAg),and HDV RNA.RESULTS We found that the prevalence of anti-HDAg and HDV RNA among hepatitis B patient were 3.6%(3.2-4.2%)and 1.2%(0.9-1.5%),respectively,87.69%of hepatitis D patients were 51-70 years old.HDV infection screening positive rate of patients with HBV DNA levels below 2000 IU/mL(2.0%)was higher than those above 2000 IU/mL(0.2%).Among anti-HDAg positive patients,the HDV RNA positive rate was positively correlated with the HBsAg level and anti-HDAg level.There was a weak correlation between HBsAg and anti-HDAg levels among hepatitis D patients.CONCLUSION Our study highlights the importance of considering multiple factors when assessing the severity of HDV infection,comprehensive evaluation of patients’clinical and laboratory parameters is necessary for proper diagnosis and treatment.展开更多
Azvudine(FNC)is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase(RdRp).Recently,we discovered FNC an agent against SARS-CoV-2,and have taken it into Phase III trial for COVID-19 patients.FNC monoph...Azvudine(FNC)is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase(RdRp).Recently,we discovered FNC an agent against SARS-CoV-2,and have taken it into Phase III trial for COVID-19 patients.FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC_(50) between 1.2 and 4.3 μM,depending on viruses or cells,and selective index(SI)in 15-83 range.Oral administration of FNC in rats revealed a substantial thymus-homing feature,with FNC triphosphate(the active form)concentrated in the thymus and peripheral blood mononuclear cells(PBMC).Treating SARS-CoV-2 infected rhesus macaques with FNC(0.07 mg/kg, qd,orally)reduced viral load,recuperated the thymus,improved lymphocyte profiles,alleviated in flammation and orga n damage,and lessened grou nd・glass opacities in chest X-ray.Sin gle-cell seque ncing suggested the promotion of thymus function by FNC.A randomized,single-arm clinical trial of FNC on compassionate use(n=31)showed that oral FNC(5 mg,qd)cured all COVID-19 patients,with 100%viral ribonucleic acid negative conversion in 3.29±2.22 days(range:1-9 days)and 100%hospital discharge rate in 9.00±4.93 days(range:2-25 days).The side-effect of FNC is minor and transient dizziness and nausea in 16.12%(5/31)patients.Thus,FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus,followed by promoted immunity.展开更多
Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suit...Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suitable for clinical application.Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs.Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis.However,it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo.Here,we have shown that(-)-blebbistatin(Ble),a non-muscle myosin II inhibitor,displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo.We found that Ble reduced the stiffness of fibrotic tissues from the early stage,which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix(ECM).Moreover,Ble also reduced the activation of myofibroblasts induced by TGF-β1,which is the most potent pro-fibrotic cytokine.Mechanistically,Ble reduced mechanical contraction,which inhibited the assembly of stress fibers,decreased the F/G-actin ratio,and led to the exnucleation of YAPJ and MRTF-A.Finally,we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis.Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance,rather than just a characteristic of activation,suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.展开更多
基金financially supported by the National Natural Science Foundation of China(No.22177135)the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2023-I2M-2-006)。
文摘Herein,we report the first asymmetric synthesis of illihenin A,an antiviral sesquiterpenoid bearing a cage-like tricyclo[6.2.2.01,5]dodecane skeleton.Starting from an abundant feedstock(-)-α-cedrene,this19-step synthesis approach features a novel ring-reorganization strategy that includes early stage C7-hydroxylation of the cedrane skeleton and a later-stage ring disassembly-reassembly procedure,affording the desired product with high synthetic efficiency and minimal chiral manipulation.The key transformations include the following:(i)a hydroxy group-directed SmI2-mediated reductive coupling to construct the congested tertiary 7-OH cedrane,(ii)aβ-fragmentation triggered by an alkoxy radical to release a spiro[4.5]decane,and(iii)an intramolecular Aldol reaction,concomitant withα-epimerization,to furnish the tricyclic framework.In addition,preliminary investigation of antiviral activity against CVB3 revealed that illihenin A can significantly inhibit ROS production and apoptosis.
基金financially supported by National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(2018ZX09711003)CAMS Initiative for Innovative Medicine(CAMS-I2M-1-010)National Natural Science Foundation of China(81630089)。
文摘Influenza A viruses(IAV)are responsible for seasonal flu epidemics,which can lead to high morbidity and mortality each year.Like other viruses,influenza virus can hijack host cellular machinery for its replication.Host cells have evolved diverse cellular defense to resist the invasion of viruses.As the main components of promyelocytic leukemia protein nuclear bodies(PML-NBs),PML can inhibit the replication of many medically important viruses including IAV.However,the mechanism of PML against IAV is unclear.In the present study,we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication,whereas knockdown of endogenous PML expression could enhance IAV replication.Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2,which negatively regulated IAV replication during infection.Moreover,PML stabilized RIG-I to promote the production of typeⅠIFN.Collectively,these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.
基金Financial support from the National Natural Science Foundation of China (Nos. 81373287 and 30825044)the Beijing Excellent Talent Training Project (No. 2013D009008000002)the National Science and Technology Project of China (Nos. 2012ZX09301002002 and 2011ZX09307-002-01)
文摘Four stereoisomers of 3,5-bis（2-hydroxybut-3-en-1-yl）-l,2,4-thiadiazole, named insatindigothiadia- zoles A-D （1a-1d）, were isolated from the roots oflsatis indigotica. Their structures were determined by spectroscopic analysis; specifically, the absolute configurations were assigned by using the MPA determination rule based on △δrs values of MPA esters, and supported by electronic CD （ECD） calculations. Proposed biosynthetic pathways and preliminary investigations of the biological activities of la-1d against influenza virus A （H3N2）, Coxsackie virus B3, and/or HSV-1 are also discussed.
基金Financial support from the National Natural Science Foundation of China(NNSFCNos.81373287 and 30825044)+1 种基金the Program for Changjiang Scholars and Innovative Research Team in University(PCSIRT,No.IRT1007)the National Science and Technology Project of China(Nos.2012ZX09301002-002 and 2011ZX0 9307-002-01)
文摘A pair of indole alkaloid enantiomers with a novel bisindolylacetamide skeleton, insatindibisindolamides A and B（1a and 1b）, was isolated from an aqueous extract of Isatis indigotica roots. The enantiomers were separated by chiral HPLC. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, including 2D NMR, X-ray crystallography, and electronic CD（ECD） calculation. The proposed biosynthetic pathway and preliminary investigations of the biological activity of compounds 1a and 1b are also discussed.
基金the National Natural Science Foundation of Jilin Provence,No.YDZJ202201ZTYS016and Jilin Provincial Health Commission,No.2022JC053.
文摘The screening practices for hepatitis D virus(HDV)are diverse and nonstandardized worldwide,and the exact prevalence of HDV is uncertain.AIM To estimate HDV prevalence and investigate viral marker quantity trends in patients with hepatitis D.METHODS We collected 5594 serum samples from patients with hepatitis B in Jilin Province,China(3293 males and 2301 females,age range of 2 to 89 years).We then conducted tests for hepatitis B surface antigen(HBsAg),hepatitis B Virus(HBV)DNA,anti-hepatitis D antigen(HDAg),and HDV RNA.RESULTS We found that the prevalence of anti-HDAg and HDV RNA among hepatitis B patient were 3.6%(3.2-4.2%)and 1.2%(0.9-1.5%),respectively,87.69%of hepatitis D patients were 51-70 years old.HDV infection screening positive rate of patients with HBV DNA levels below 2000 IU/mL(2.0%)was higher than those above 2000 IU/mL(0.2%).Among anti-HDAg positive patients,the HDV RNA positive rate was positively correlated with the HBsAg level and anti-HDAg level.There was a weak correlation between HBsAg and anti-HDAg levels among hepatitis D patients.CONCLUSION Our study highlights the importance of considering multiple factors when assessing the severity of HDV infection,comprehensive evaluation of patients’clinical and laboratory parameters is necessary for proper diagnosis and treatment.
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(No.2020-I2M-1-003,2020-I2M-2-010,2020HY320001,China)The Drug Innovation Major Project(No.2018ZX09711001-003-002,China)+2 种基金National Natural Science Foundation(No.81621064,China)National key R&D project(No.2019YFC170890,China)CAMS Innovation Fund for Medical Sciences(No.2021-1-I2M-009,2021-1-I2M-030).
文摘Azvudine(FNC)is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase(RdRp).Recently,we discovered FNC an agent against SARS-CoV-2,and have taken it into Phase III trial for COVID-19 patients.FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC_(50) between 1.2 and 4.3 μM,depending on viruses or cells,and selective index(SI)in 15-83 range.Oral administration of FNC in rats revealed a substantial thymus-homing feature,with FNC triphosphate(the active form)concentrated in the thymus and peripheral blood mononuclear cells(PBMC).Treating SARS-CoV-2 infected rhesus macaques with FNC(0.07 mg/kg, qd,orally)reduced viral load,recuperated the thymus,improved lymphocyte profiles,alleviated in flammation and orga n damage,and lessened grou nd・glass opacities in chest X-ray.Sin gle-cell seque ncing suggested the promotion of thymus function by FNC.A randomized,single-arm clinical trial of FNC on compassionate use(n=31)showed that oral FNC(5 mg,qd)cured all COVID-19 patients,with 100%viral ribonucleic acid negative conversion in 3.29±2.22 days(range:1-9 days)and 100%hospital discharge rate in 9.00±4.93 days(range:2-25 days).The side-effect of FNC is minor and transient dizziness and nausea in 16.12%(5/31)patients.Thus,FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus,followed by promoted immunity.
基金the Institute of Zoology,Chinese Academy of Sciences for their technical assistance.This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030400 to W.L.)the National Key Research and Development Program(2018YFC1004500 to Y.Z.and 2017YFA0103803 to Q.Z.)+3 种基金the National Natural Science Foundation of China(31621004 to Q.Z.and W.L.)CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.)the China Postdoctoral Science Foundation(2019M650841 to Z.H.)the National Natural Science Foundation of China(31900510 to Y.L.).
文摘Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suitable for clinical application.Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs.Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis.However,it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo.Here,we have shown that(-)-blebbistatin(Ble),a non-muscle myosin II inhibitor,displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo.We found that Ble reduced the stiffness of fibrotic tissues from the early stage,which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix(ECM).Moreover,Ble also reduced the activation of myofibroblasts induced by TGF-β1,which is the most potent pro-fibrotic cytokine.Mechanistically,Ble reduced mechanical contraction,which inhibited the assembly of stress fibers,decreased the F/G-actin ratio,and led to the exnucleation of YAPJ and MRTF-A.Finally,we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis.Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance,rather than just a characteristic of activation,suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.
