Porcine reproductive and respiratory syndrome(PRRS)is a globally prevalent contagious disease caused by the positive-strand RNA PRRS virus(PRRSV),resulting in substantial economic losses in the swine industry.Modifyin...Porcine reproductive and respiratory syndrome(PRRS)is a globally prevalent contagious disease caused by the positive-strand RNA PRRS virus(PRRSV),resulting in substantial economic losses in the swine industry.Modifying the CD163 SRCR5 domain,either through deletion or substitution,can eff1ectively confer resistance to PRRSV infection in pigs.However,large fragment modifications in pigs inevitably raise concerns about potential adverse effects on growth performance.Reducing the impact of genetic modifications on normal physiological functions is a promising direction for developing PRRSV-resistant pigs.In the current study,we identified a specific functional amino acid in CD163 that influences PRRSV proliferation.Viral infection experiments conducted on Marc145 and PK-15CD163 cells illustrated that the mE535G or corresponding pE529G mutations markedly inhibited highly pathogenic PRRSV(HP-PRRSV)proliferation by preventing viral binding and entry.Furthermore,individual viral challenge tests revealed that pigs with the E529G mutation had viral loads two orders of magnitude lower than wild-type(WT)pigs,confirming effective resistance to HP-PRRSV.Examination of the physiological indicators and scavenger function of CD163 verified no significant differences between the WT and E529G pigs.These findings suggest that E529G pigs can be used for breeding PRRSV-resistant pigs,providing novel insights into controlling future PRRSV outbreaks.展开更多
Chlorfenapyr is a liposoluble insecticide belonging to the pyrrole family.Chlorfenapyr is activated when the N-ethoxymethyl side chain breaks,forming a toxic metabolite,which uncouples oxidative phosphorylation in the...Chlorfenapyr is a liposoluble insecticide belonging to the pyrrole family.Chlorfenapyr is activated when the N-ethoxymethyl side chain breaks,forming a toxic metabolite,which uncouples oxidative phosphorylation in the mitochondria,inhibits the production of adenosine triphosphate (ATP),and leads to the death of cells and targe organisms.[1] Symptoms of chlorfenapyr poisoning in patients are mild and atypical in the early stage,especially in patients receiving low dose exposure;however,such cases are rare and may be ignored by physicians,often leading to delayed treatment.[2,3].展开更多
This paper proposed a flexibility assessment approach based on and risk assessment methodology. System planners prioritize each planning scheme with consideration of three aspects: reliability, economics, and flexibil...This paper proposed a flexibility assessment approach based on and risk assessment methodology. System planners prioritize each planning scheme with consideration of three aspects: reliability, economics, and flexibility. In the past, there is lack of quantitative indices to measure flexibility of a power system. This paper proposes applying probabilistic risk assessment method to quantify system flexibility. The proposed approach is demonstrated to compare two transmission planning schemes during Guangdong expansion planning process.展开更多
A non-air conducted speech detecting method has been developed in our laboratory by using millimeter wave radar technology. Because of the special attributes of the millimeter wave, this method may considerably extend...A non-air conducted speech detecting method has been developed in our laboratory by using millimeter wave radar technology. Because of the special attributes of the millimeter wave, this method may considerably extend the capabilities of traditional speech detecting methods. However, radar speech is substantially degraded by additive combined noises that include radar harmonic noise, electrocircuit noise, and ambient noise. This study, therefore, proposed an iterative spectral subtraction method which can be adaptively estimate noise spectrum at every iteration, and reduce the musical noise remained in the previous spectral subtraction process. Results from simulations as well as evaluations confirm that the proposed method satisfactorily reduces whole-frequency and musical noises and produces good speech quality.展开更多
Objective:Polygoni Multiflori Radix(PM)is a traditional herbal medicine with repeated reports of liver injury events in recent years.We wondered whether the classical processing method,namely,nine-time steaming and su...Objective:Polygoni Multiflori Radix(PM)is a traditional herbal medicine with repeated reports of liver injury events in recent years.We wondered whether the classical processing method,namely,nine-time steaming and sun drying(NSSD),had toxicity-attenuating effects on PM and the relationships between toxicity and times of processing,as well as with the alteration trends of its compounds.Materials and Methods:The chemical fingerprints of different PM extracts were developed using ultra-high-performance liquid chromatography.The spectrum-toxicity correlation between the chemical fingerprints and hepatocellular toxicity was analyzed with multiple correlation analysis.Results:The results suggested that the hepatotoxicity of NSSD processing products markedly decreased with the repeated steaming and sun drying,which was obviously superior to the product processed by the modern method.Comprehensive analysis revealed that the contents of cis-stilbene glycoside and emodin-8-O-β-D-glucoside related to liver injury susceptibility were reduced with the times of NSSD processing,which was consistent with the decreased trend of hepatocellular toxicity.After the five times of NSSD,the contents of them as well as the hepatotoxicity of PM were steady.Moreover,we found that the contents of catechin and physcion declined rapidly after the one time of NSSD and then remained stable until the nine times of NSSD.Based on the fact,they could be utilized to indicate whether PM products were processed by steaming and sun drying.Conclusions:This paper confirmed that the NSSD had a good influence on the toxicity attenuating to PM and found four compounds which could apply for the quality control of PM.展开更多
Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zh...Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zhuangguguanjiewan pills(ZGW),which contain EF and PF,could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide(LPS)model.This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model.Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats;however,EF or PF alone could lead to liver injury in LPS-treated rats.Moreover,EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats.Furthermore,EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production,implying that IL-1β,which is processed and released by activating the NLRP3 inflammasome,is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity.Thus,EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome.In addition,the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model,suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways.Therefore,EF and PF combination indicates traditional Chinese medicine incompatibility,considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.展开更多
Heshouwu is a traditional non-toxic Chinese medicine commonly used in the clinical setting;however,clinical cases of Heshouwu-induced hepatotoxicity have been frequently reported^([1]).Pharmacoepidemiological studies ...Heshouwu is a traditional non-toxic Chinese medicine commonly used in the clinical setting;however,clinical cases of Heshouwu-induced hepatotoxicity have been frequently reported^([1]).Pharmacoepidemiological studies have found that Heshouwu-induced liver injury occurs only in a small fraction of individuals taking the drug;these patients presented with the typ-展开更多
Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury （DILI） in the United States. However, reliable methods to identify the DILl causality of some herbs, such a...Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury （DILI） in the United States. However, reliable methods to identify the DILl causality of some herbs, such as Heshouwu （dried root ofPolygonum multiflorum）, remain lacking. In this study, a total of 12 307 inpatients with liver dysfunction and 147 literature-reported cases of Heshouwu DILI were screened. A general algorithm indicated that only 22.5% （9/40） and 30.6% （45/147） of all hospitalization and literature case reports, respectively, demonstrate the high probability of DILI causality of Heshouwu. By contrast, 95% （19/20） of all cases prospectively investigated by pharmacognosy, phytochemistry, and metabolomic tests exhibited highly probable causality, including a patient who was previously incorrectly attributed and a case that was excluded from Heshouwu causality by pharmacognostic evidence. Toxin （heavy metals, pesticides, and mycotoxins） contamination was also excluded from Heshouwu DILI causality. The objectivity of these screening methods for Heshouwu DILI diagnosis addresses safety concerns regarding stilbene-containing herbal medicines and dietary supplements.展开更多
The main constituents of a typical medicinal herb, Polygonum multiflorum （Heshouwu in Chinese）, that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic do...The main constituents of a typical medicinal herb, Polygonum multiflorum （Heshouwu in Chinese）, that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide （LPS） and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent ＂knock-out＂ and ＂knock-in＂ strategy, we found that the ethyl acetate （EA） extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4＇-tetrahydroxy trans-stilbene-2-O-p-glucoside （trans-SG） and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization oftrans- SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.展开更多
Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely u...Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely used herbal medicine,has shown to cause idiosyncratic liver injury,but the underlying mechanisms are poorly understood.Increasing evidence has indicated that most cases of IDILI are immune mediated.Here,we report that icarisideⅡ(ICSⅡ),the major active and metabolic constituent of EF,causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation.ICSⅡexacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate(ATP)and nigericin,but not silicon dioxide(SiO2),monosodium urate(MSU)crystal or cytosolic lipopolysaccharide(LPS).Additionally,the activation of NLRC4 and AIM2 inflammasomes is not affected by ICSⅡ.Mechanistically,synergistic induction of mitochondrial reactive oxygen species(mtROS)is a crucial contributor to the enhancing effect of ICSⅡon ATP-or nigericin-induced NLRP3 inflammasome activation.Importantly,in vivo data show that a combination of non-hepatotoxic doses of LPS and ICSⅡcauses the increase of aminotransferase activity,hepatic inflammation and pyroptosis,which is attenuated by Nlrp3 deficiency or pretreatment with MCC950(a specific NLRP3 inflammasome inhibitor).In conclusion,these findings demonstrate that ICSⅡcauses idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICSⅡmay be a risk factor and responsible for EF-induced liver injury.展开更多
Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to ident...Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin(CDN), the major active ingredient of the traditional Chinese medicinal herb Alpinia katsumadai, has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-κB-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner.Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1βproduction induced by LPS in vivo, which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.展开更多
Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remai...Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remains an unsolved public health challenge.Therefore,we used the data of 6.673 million of ADR reports from January 1st,2012 to December 31st,2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation.Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system.By cleaning and standardizing the data fields by the dictionary of synonyms and English translation,we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining.The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years.The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men.The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population,despite known underreporting situation in spontaneous ADR reporting system.The percentage of herbal and traditional medicines(H/TM)L-ADR reports in the whole number was 4.5%,while 80.60%of the H/TM reports were new findings.There was great geographical disparity of reported agents,i.e.more cardiovascular and antineoplastic agents were reported in higher socio-demographic index(SDI)regions and more antimicrobials,especially antitubercular agents,were reported in lower SDI regions.In conclusion,this study presented a large-scale,unbiased,unified,and computer-minable L-ADR database for further investigation.Age-,sex-and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.展开更多
Foreword Note:Some of the document contents may involve certain patents,the identification of which is not the responsibility of the institution that releases the document.Main drafting organizations:Tsinghua Universi...Foreword Note:Some of the document contents may involve certain patents,the identification of which is not the responsibility of the institution that releases the document.Main drafting organizations:Tsinghua University,Specialty Committee of Network Pharmacology of World Federation of Chinese Medicine Societies(WFCMS).展开更多
Optimal power flow(OPF)is one of the key tools for optimal operation and planning of modern power systems.Due to the high complexity with continuous and discrete control variables,modern heuristic optimization algorit...Optimal power flow(OPF)is one of the key tools for optimal operation and planning of modern power systems.Due to the high complexity with continuous and discrete control variables,modern heuristic optimization algorithms(HOAs)have been widely employed for the solution of OPF.This paper provides an overview of the latest applications of advanced HOAs in OPF problems.The most frequently applied HOAs for solving the OPF problem in recent years are covered and briefly introduced,including genetic algorithm(GA),differential evolution(DE),particle swarm optimization(PSO),and evolutionary programming(EP),etc.展开更多
Erratum to Frontiers of Medicine 201711(2):253–265 https://doi.org/10.1007/s11684-017-0508-9 The original version of this article unfortunately contained some mistakes.The panel of“LPS–/drug–”in Fig.3B(Page 259),...Erratum to Frontiers of Medicine 201711(2):253–265 https://doi.org/10.1007/s11684-017-0508-9 The original version of this article unfortunately contained some mistakes.The panel of“LPS–/drug–”in Fig.3B(Page 259),the panels of“LPS–/EtoAc+”and“LPS–/Residue+”in Supplementary Fig.3(Page 7 in the online supplementary materials)should be corrected.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.展开更多
基金supported by the National Natural Science Foundation of China (82230118)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202005)。
基金Major Scientific and Technological Projects in Agricultural Biological Breeding of China(2023ZD0404302)Youth Program of National Natural Science Foundation of China(32202754)。
文摘Porcine reproductive and respiratory syndrome(PRRS)is a globally prevalent contagious disease caused by the positive-strand RNA PRRS virus(PRRSV),resulting in substantial economic losses in the swine industry.Modifying the CD163 SRCR5 domain,either through deletion or substitution,can eff1ectively confer resistance to PRRSV infection in pigs.However,large fragment modifications in pigs inevitably raise concerns about potential adverse effects on growth performance.Reducing the impact of genetic modifications on normal physiological functions is a promising direction for developing PRRSV-resistant pigs.In the current study,we identified a specific functional amino acid in CD163 that influences PRRSV proliferation.Viral infection experiments conducted on Marc145 and PK-15CD163 cells illustrated that the mE535G or corresponding pE529G mutations markedly inhibited highly pathogenic PRRSV(HP-PRRSV)proliferation by preventing viral binding and entry.Furthermore,individual viral challenge tests revealed that pigs with the E529G mutation had viral loads two orders of magnitude lower than wild-type(WT)pigs,confirming effective resistance to HP-PRRSV.Examination of the physiological indicators and scavenger function of CD163 verified no significant differences between the WT and E529G pigs.These findings suggest that E529G pigs can be used for breeding PRRSV-resistant pigs,providing novel insights into controlling future PRRSV outbreaks.
基金supported by a grant from the National Key R&D Program of China (2019YFC16063000)。
文摘Chlorfenapyr is a liposoluble insecticide belonging to the pyrrole family.Chlorfenapyr is activated when the N-ethoxymethyl side chain breaks,forming a toxic metabolite,which uncouples oxidative phosphorylation in the mitochondria,inhibits the production of adenosine triphosphate (ATP),and leads to the death of cells and targe organisms.[1] Symptoms of chlorfenapyr poisoning in patients are mild and atypical in the early stage,especially in patients receiving low dose exposure;however,such cases are rare and may be ignored by physicians,often leading to delayed treatment.[2,3].
文摘This paper proposed a flexibility assessment approach based on and risk assessment methodology. System planners prioritize each planning scheme with consideration of three aspects: reliability, economics, and flexibility. In the past, there is lack of quantitative indices to measure flexibility of a power system. This paper proposes applying probabilistic risk assessment method to quantify system flexibility. The proposed approach is demonstrated to compare two transmission planning schemes during Guangdong expansion planning process.
文摘A non-air conducted speech detecting method has been developed in our laboratory by using millimeter wave radar technology. Because of the special attributes of the millimeter wave, this method may considerably extend the capabilities of traditional speech detecting methods. However, radar speech is substantially degraded by additive combined noises that include radar harmonic noise, electrocircuit noise, and ambient noise. This study, therefore, proposed an iterative spectral subtraction method which can be adaptively estimate noise spectrum at every iteration, and reduce the musical noise remained in the previous spectral subtraction process. Results from simulations as well as evaluations confirm that the proposed method satisfactorily reduces whole-frequency and musical noises and produces good speech quality.
基金funded by the National Natural Science Foundation of China(Grant No.81630100)the National Industry Program of China(Grant No.201507002)
文摘Objective:Polygoni Multiflori Radix(PM)is a traditional herbal medicine with repeated reports of liver injury events in recent years.We wondered whether the classical processing method,namely,nine-time steaming and sun drying(NSSD),had toxicity-attenuating effects on PM and the relationships between toxicity and times of processing,as well as with the alteration trends of its compounds.Materials and Methods:The chemical fingerprints of different PM extracts were developed using ultra-high-performance liquid chromatography.The spectrum-toxicity correlation between the chemical fingerprints and hepatocellular toxicity was analyzed with multiple correlation analysis.Results:The results suggested that the hepatotoxicity of NSSD processing products markedly decreased with the repeated steaming and sun drying,which was obviously superior to the product processed by the modern method.Comprehensive analysis revealed that the contents of cis-stilbene glycoside and emodin-8-O-β-D-glucoside related to liver injury susceptibility were reduced with the times of NSSD processing,which was consistent with the decreased trend of hepatocellular toxicity.After the five times of NSSD,the contents of them as well as the hepatotoxicity of PM were steady.Moreover,we found that the contents of catechin and physcion declined rapidly after the one time of NSSD and then remained stable until the nine times of NSSD.Based on the fact,they could be utilized to indicate whether PM products were processed by steaming and sun drying.Conclusions:This paper confirmed that the NSSD had a good influence on the toxicity attenuating to PM and found four compounds which could apply for the quality control of PM.
基金supported by the National Natural Science Foundation of China(Nos.81874368 and 81630100)the Beijing Nova Program(No.Z181100006218001)+2 种基金the National Key Technology R&D Program(No.2015ZX 09501-004-001-008)the National Key R&D Program of China(No.2018YFC1707000)the National TCM Industry Science and Technology Program(No.201507004-4-2).
文摘Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zhuangguguanjiewan pills(ZGW),which contain EF and PF,could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide(LPS)model.This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model.Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats;however,EF or PF alone could lead to liver injury in LPS-treated rats.Moreover,EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats.Furthermore,EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production,implying that IL-1β,which is processed and released by activating the NLRP3 inflammasome,is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity.Thus,EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome.In addition,the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model,suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways.Therefore,EF and PF combination indicates traditional Chinese medicine incompatibility,considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.
基金supported by the National Natural Science Foundation of China(81503350)the National Key Technology R&D Program(2015ZX09501-004-001-008)+1 种基金the National TCM Industry Science and Technology Program(201507004-04)the Open Research Fund of State Key Laboratory Breeding Base of Systematic research,Development and Utilization of Chinese Medicine Resources and China Postdoctoral Science Foundation(2016M590065)
文摘Heshouwu is a traditional non-toxic Chinese medicine commonly used in the clinical setting;however,clinical cases of Heshouwu-induced hepatotoxicity have been frequently reported^([1]).Pharmacoepidemiological studies have found that Heshouwu-induced liver injury occurs only in a small fraction of individuals taking the drug;these patients presented with the typ-
基金Acknowledgements This work was supported by the National Key Technology R＆D Program （No. 2015ZX09501-004-001-008）, the National TCM Industry Science and Technology Program （No. 201507004-04）, the National Natural Science Foundation of China （Nos. 81373984, 81503350, and 81403126）, and the Beijing Natural Science Foundation （No. 7152142）. The authors wish to acknowledge Jiyan Chen for providing photographs of fraudulent Heshouwu, Yonghe Zhang for determining the pesticides, and Dongping Xu for his suggestion regarding the scale table of ECCIA.
文摘Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury （DILI） in the United States. However, reliable methods to identify the DILl causality of some herbs, such as Heshouwu （dried root ofPolygonum multiflorum）, remain lacking. In this study, a total of 12 307 inpatients with liver dysfunction and 147 literature-reported cases of Heshouwu DILI were screened. A general algorithm indicated that only 22.5% （9/40） and 30.6% （45/147） of all hospitalization and literature case reports, respectively, demonstrate the high probability of DILI causality of Heshouwu. By contrast, 95% （19/20） of all cases prospectively investigated by pharmacognosy, phytochemistry, and metabolomic tests exhibited highly probable causality, including a patient who was previously incorrectly attributed and a case that was excluded from Heshouwu causality by pharmacognostic evidence. Toxin （heavy metals, pesticides, and mycotoxins） contamination was also excluded from Heshouwu DILI causality. The objectivity of these screening methods for Heshouwu DILI diagnosis addresses safety concerns regarding stilbene-containing herbal medicines and dietary supplements.
文摘The main constituents of a typical medicinal herb, Polygonum multiflorum （Heshouwu in Chinese）, that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide （LPS） and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent ＂knock-out＂ and ＂knock-in＂ strategy, we found that the ethyl acetate （EA） extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4＇-tetrahydroxy trans-stilbene-2-O-p-glucoside （trans-SG） and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization oftrans- SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.
基金supported by National Natural Science Foundation of China(81874368,81630100,and 81903891)Beijing Nova Program(Z181100006218001,China)+1 种基金National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(2017ZX09301022 and 2018ZX09101002-001-002,China)the Innovation Groups of the National Natural Science Foundation of China(81721002)
文摘Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely used herbal medicine,has shown to cause idiosyncratic liver injury,but the underlying mechanisms are poorly understood.Increasing evidence has indicated that most cases of IDILI are immune mediated.Here,we report that icarisideⅡ(ICSⅡ),the major active and metabolic constituent of EF,causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation.ICSⅡexacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate(ATP)and nigericin,but not silicon dioxide(SiO2),monosodium urate(MSU)crystal or cytosolic lipopolysaccharide(LPS).Additionally,the activation of NLRC4 and AIM2 inflammasomes is not affected by ICSⅡ.Mechanistically,synergistic induction of mitochondrial reactive oxygen species(mtROS)is a crucial contributor to the enhancing effect of ICSⅡon ATP-or nigericin-induced NLRP3 inflammasome activation.Importantly,in vivo data show that a combination of non-hepatotoxic doses of LPS and ICSⅡcauses the increase of aminotransferase activity,hepatic inflammation and pyroptosis,which is attenuated by Nlrp3 deficiency or pretreatment with MCC950(a specific NLRP3 inflammasome inhibitor).In conclusion,these findings demonstrate that ICSⅡcauses idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICSⅡmay be a risk factor and responsible for EF-induced liver injury.
基金supported by the National Key Technology R&D Program(No.2017ZX09301022)the National Key Technology R&D Program(No.2015ZX09501-004-001-008)+1 种基金the BeijingNova program(No.Z181100006218001)the National Natural Science Foundation of China(No.81630100)
文摘Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin(CDN), the major active ingredient of the traditional Chinese medicinal herb Alpinia katsumadai, has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-κB-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner.Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1βproduction induced by LPS in vivo, which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.
基金This work was financially supported by the National Natural Science Foundation of China(grant numbers Nos.82074112,81630100 and 81721002)the National Science and Technology Directorate Major Project(2015ZX09501-004-001-008,China)+3 种基金the National Industry Program of China(201507004-04)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202005,China)the Beijing Talent Youth Program(JQ21026,China)the Project of China PLA General Hospital(2019-JQPY-003 and 2019MBD-023).
文摘Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remains an unsolved public health challenge.Therefore,we used the data of 6.673 million of ADR reports from January 1st,2012 to December 31st,2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation.Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system.By cleaning and standardizing the data fields by the dictionary of synonyms and English translation,we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining.The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years.The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men.The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population,despite known underreporting situation in spontaneous ADR reporting system.The percentage of herbal and traditional medicines(H/TM)L-ADR reports in the whole number was 4.5%,while 80.60%of the H/TM reports were new findings.There was great geographical disparity of reported agents,i.e.more cardiovascular and antineoplastic agents were reported in higher socio-demographic index(SDI)regions and more antimicrobials,especially antitubercular agents,were reported in lower SDI regions.In conclusion,this study presented a large-scale,unbiased,unified,and computer-minable L-ADR database for further investigation.Age-,sex-and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.
文摘Foreword Note:Some of the document contents may involve certain patents,the identification of which is not the responsibility of the institution that releases the document.Main drafting organizations:Tsinghua University,Specialty Committee of Network Pharmacology of World Federation of Chinese Medicine Societies(WFCMS).
基金This work was partially supported by Hong Kong RGC Theme Based Research Scheme Grants No.T23-407/13 N and T23-701/14 N.
文摘Optimal power flow(OPF)is one of the key tools for optimal operation and planning of modern power systems.Due to the high complexity with continuous and discrete control variables,modern heuristic optimization algorithms(HOAs)have been widely employed for the solution of OPF.This paper provides an overview of the latest applications of advanced HOAs in OPF problems.The most frequently applied HOAs for solving the OPF problem in recent years are covered and briefly introduced,including genetic algorithm(GA),differential evolution(DE),particle swarm optimization(PSO),and evolutionary programming(EP),etc.
文摘Erratum to Frontiers of Medicine 201711(2):253–265 https://doi.org/10.1007/s11684-017-0508-9 The original version of this article unfortunately contained some mistakes.The panel of“LPS–/drug–”in Fig.3B(Page 259),the panels of“LPS–/EtoAc+”and“LPS–/Residue+”in Supplementary Fig.3(Page 7 in the online supplementary materials)should be corrected.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.
