Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by the intake of pyrrolizidine alkaloids (PAs). To date, PAs-induced HSOS has not been extensively studied. In view of the difference in etiology of HSOS be...Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by the intake of pyrrolizidine alkaloids (PAs). To date, PAs-induced HSOS has not been extensively studied. In view of the difference in etiology of HSOS between the West and China, clinical profiles, imaging findings, treatment, and outcomes of HSOS associated with hematopoietic stem cell transplantation or oxaliplatin might be hardly extrapolated to PAs-induced HSOS. Reactive metabolites derived from PAs form pyrrole-protein adducts that result in toxic destruction of hepatic sinusoidal endothelial cells. PAs-induced HSOS typically manifests as painful hepatomegaly, ascites, and jaundice. Laboratory tests revealed abnormal liver function tests were observed in most of the patients with PAs-induced HSOS. In addition, contrast computed tomography and magnetic resonance imaging scan show that patients with PAs-induced HSOS have distinct imaging features, which reveal that radiological imaging provides an effective noninvasive method for the diagnosis of PAs-induced HSOS. Liver biopsy and histological examination showed that PAs-induced HSOS displayed distinct features in acute and chronic stages. Therapeutic strategies for PAs-induced HSOS include rigorous fluid management, anticoagulant therapy, glucocorticoids, transjugular intrahepatic portosystemic shunt, liver transplantation, etc. The aim of this review is to describe the pathogenesis, clinical profiles, diagnostic criteria, treatment, and outcomes of PAs-induced HSOS.展开更多
Three new pyrrolizidine alkaloids, nervosineⅦ（1）, nervosine Ⅷ（2） and nervosine IX （3） were isolated from the whole plant extract of Liparis nervosa. Their structures were elucidated by extensive spectroscopic ...Three new pyrrolizidine alkaloids, nervosineⅦ（1）, nervosine Ⅷ（2） and nervosine IX （3） were isolated from the whole plant extract of Liparis nervosa. Their structures were elucidated by extensive spectroscopic analyses （including 1 D, 2D NMR, and HR-ESI-MS） and chemical methods. Compounds 1-3 were evaluated for their cytotoxic activity against A549, MCF-7and H460 human cancer cell lines.展开更多
Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorig...Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorigenicity, and the metabolic pathways, particular the activation pathways leading to hepatotoxicity and tumorigenicity, of pyrrolizidine alkaloids are briefly discussed, with a focus on the most recent important findings concerning the genotoxic mechanism by which riddelliine liver tumors. This mechanism involves the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and may be general to most carcinogenic pyrrolizidine alkaloids.展开更多
BACKGROUND Treatments for hepatic sinusoidal obstruction syndrome(HSOS)are limited.AIM To evaluate transjugular intrahepatic portosystemic shunting(TIPS)as a treatment for pyrrolidine alkaloid-related HSOS(PA-HSOS).ME...BACKGROUND Treatments for hepatic sinusoidal obstruction syndrome(HSOS)are limited.AIM To evaluate transjugular intrahepatic portosystemic shunting(TIPS)as a treatment for pyrrolidine alkaloid-related HSOS(PA-HSOS).METHODS This retrospective analysis included patients with PA-HSOS admitted to the First Affiliated Hospital of the University of Science and Technology of China(June 2015 to January 2019).Baseline clinical characteristics and follow-up data were extracted from the medical records.All patients included in this study experienced failure of initial therapy.Patients were divided into the TIPS and conservative treatment groups according to the therapy they received.Liver function,maximal ascites depth,imaging characteristics,pathology findings,and survival were compared between groups.RESULTS The TIPS group included 37 patients(28 males),and the conservative treatment group included 17 patients(11 males).Baseline characteristics were similar between groups.There were two deaths in the TIPS group and seven deaths in the conservative treatment group during follow-up(3-48 mo).The 3-,6-,12-and 24-mo survival rates were 94.6%,94.6%,94.6%and 94.6%,respectively,in the TIPS group and 70.6%,57.8%,57.8%and 57.8%,respectively,in the conservative treatment group.Kaplan-Meier analysis revealed significantly longer survival for the TIPS group than for the conservative treatment group(P=0.001).Compared with the pre-treatment value,maximal ascites depth was significantly lower at 1 wk,2 wk,1 mo,and 3 mo for the TIPS group(all P<0.05)but not in the conservative treatment group.Contrast-enhanced computed tomography demonstrated the disappearance of patchy liver enhancement after TIPS.Pathology showed that liver congestion and hepatocyte swelling improved with time after TIPS placement.CONCLUSION TIPS may achieve better outcomes than conventional symptomatic treatment in patients with PA-HSOS.展开更多
Background and Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is caused by toxic injury to sinusoidal endothelial cells in the liver.The intake of pyrrolizidine alkaloids(PAs)in some Chinese herbal remedies/plants ...Background and Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is caused by toxic injury to sinusoidal endothelial cells in the liver.The intake of pyrrolizidine alkaloids(PAs)in some Chinese herbal remedies/plants remains the major etiology for HSOS in China.Recently,new diagnostic criteria for PA-induced HSOS(i.e.PA-HSOS)have been developed;however,the efficacy has not been clinically validated.This study aimed to assess the performance of the Nanjing criteria for PA-HSOS.Methods:Data obtained from consecutive patients in multiple hospitals,which included 86 PA-HSOS patients and 327 patients with other liver diseases,were retrospectively analyzed.Then,the diagnostic performance of the Nanjing criteria and simplified Nanjing criteria were evaluated and validated.The study is registered in www.chictr.org.cn(ID:ChiCTR1900020784).Results:The Nanjing criteria have a sensitivity and specificity of 95.35%and 100%,respectively,while the simplified Nanjing criteria have a sensitivity and specificity of 96.51%and 96.33%,respectively,for the diagnosis of PA-HSOS.Notably,a proportion of patients with Budd-Chiari syndrome(11/49)was misdiagnosed as PA-HSOS on the basis of the simplified Nanjing criteria,and this was mainly due to the overlapping features in the enhanced computed tomography/magnetic resonance imaging examinations.Furthermore,most of these patients(10/11)had occlusion or thrombosis of the hepatic vein,and communicating vessels in the liver were found in 8/11 patients,which were absent in PA-HSOS patients.Conclusions:The Nanjing criteria and simplified Nanjing criteria exhibit excellent performance in diagnosing PA-HSOS.Thus,both could be valuable diagnostic tools in clinical practice.展开更多
Pyrrolizidine alkaloids(PAs)are among the most hepatotoxic natural compounds that are widely distributed throughout the world.Most PAs are metabolically activated to trigger toxicity.Exposure to herbal medicine contai...Pyrrolizidine alkaloids(PAs)are among the most hepatotoxic natural compounds that are widely distributed throughout the world.Most PAs are metabolically activated to trigger toxicity.Exposure to herbal medicine containing PAs and food supplements contaminated by PAs is considered to be one of the two main causes of hepatic sinusoidal obstruction syndrome(HSOS),which is a rare hepatic vascular disease with a high mortality rate.PAs-induced HSOS cases have been reported worldwide.However,there is no clinically effective therapy for PAs-induced HSOS,which is partially because the toxic mechanism is not fully understood.This review focuses on updating the information on the metabolism and the molecular mechanisms of PAs hepatotoxicity,including oxidative stress,apoptosis,and dysfunction of bile acid metabolism,and their interactions.展开更多
Two new pyrrolizidines named lankongensisine A (1), B (2) were isolated from the roots of Ligularia lankongensis collected in Lijiang, Yunnan, and their structures were established by spectroscopic analysis.
Nervosine Ⅶ is one of the known saturated pyrrolizidine alkaloids isolated from the plant of Liparis nervosa.This is first study to investigate the antitumor activity of nervosine Ⅶ in vitro,and the results indicate...Nervosine Ⅶ is one of the known saturated pyrrolizidine alkaloids isolated from the plant of Liparis nervosa.This is first study to investigate the antitumor activity of nervosine Ⅶ in vitro,and the results indicated that nervosine Ⅶ induced autophagy and apoptosis in HCT116 human colorectal cancer cells.Mechanistic studies showed that nervosine Ⅶ-induced apoptosis was associated with the intrinsic pathway by the activation of caspase-9,-3 and-7.Autophagy induced by nervosine Ⅶ was characteristic with the regulation of autophagic markers including the increase of LC3-Ⅱ and beclin 1 proteins,and the decrease of p62 protein.Nervosine Ⅶ simultaneously induced autophagy and apoptosis by activated MAPKs signaling pathway including JNK,ERK1/2 and p38,suppressing the p53 signaling pathway.展开更多
Objective: Qianliguang(Senecio scandens) is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. T...Objective: Qianliguang(Senecio scandens) is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. The presence of hepatotoxic pyrrolizidine alkaloids(PAs)has raised concerns about the safety of using Qianliguang and its products. The present study aims at investigation of different types of PAs present in Qianliguang collected from representative locations in China.Methods: In this study, a simple but specific UHPLC-QTOF-MS method for the determination of toxic PAs was developed, based on the characteristic fragment ions specific to different types of PAs. It was successfully applied for the identification and distinguishing of PAs present in Qianliguang and related Senecio species growing in different locations of China.Results: Significant diversity of the PA types and quantities were revealed among the samples tested. The estimated total amounts of toxic PAs in three of the samples exceed the toxic limits of PA intake restricted by WHO, demonstrating the timely and highly demand for regulating both types and quantities of PAs present in Qianliguang.Conclusions: This study provides the methodology for simultaneous identification and quantification of PAs present in herbs without requiring corresponding standards, which could be further used for more systematic investigations of the PA distribution in Qianliguang and other PA-containing herbs.展开更多
Hepatic sinusoidal obstruction syndrome(HSOS)via exposure to pyrrolizidine alkaloids(PAs)is with high mortality and there is no effective treatment in clinics.Bear bile powder(BBP)is a famous traditional animal drug f...Hepatic sinusoidal obstruction syndrome(HSOS)via exposure to pyrrolizidine alkaloids(PAs)is with high mortality and there is no effective treatment in clinics.Bear bile powder(BBP)is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis,inflammation,and fibrosis.Here,we aim to evaluate the protective effect of BBP against HSOS induced by senecionine,a highly hepatotoxic PA compound.Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently,which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells,alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells,as well as decreased conventional serum liver function indicators.In addition,BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts,two well-known markers positively associated with the severity of PA-induced HSOS.Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules.BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines,in which taurours-odeoxycholic acid played an important role.What’s more,BBP treatment also decreased the accumulation of hydrophobic bile acids,such as cholic acid,taurocholic acid,glycocholic acid,as well.We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis,preventing liver fibrosis,and alleviating liver inflammation.Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.展开更多
Background and Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is a life-threatening syndrome,and a cause is exposure to pyrrolizidine alkaloid(PA)-containing products.It is well-established that retrorsine(RTS),a r...Background and Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is a life-threatening syndrome,and a cause is exposure to pyrrolizidine alkaloid(PA)-containing products.It is well-established that retrorsine(RTS),a rep-resentative Pas,insults hepatic sinusoidal endothelial cells and ensues congestion of hepatic sinusoids.However,little known about the impact of Pas on gut microbiota and intesti-nal barrier and inflammation in HSOS.Methods:Mice were gavaged with or without nonabsorbable antibiotics(ABX),followed by a single dose of RTS.The gut microbiota was examined by 16S rDNA sequencing.Results:ABX pretreat-ment significantly reversed RTS-induced liver damage.RTS altered gut microbiota composition,increasing Gram-nega-tive bacteria and resulting in a sharp elevation of circulating lipopolysaccharides(LPS)in HSOS mice.Gut decontamina-tion with ABX alleviated RTS-induced intestine inflamma-tion,protected against disruption of the intestinal epithelial barrier and gut vascular barrier(GVB),and suppressed he-patic LPS-NF-κB pathway activation in RTS-induced HSOS.Importantly,the LPS level was positively correlated with MELD score in patients with HSOS.Elevated LPS in patients with HSOS confirmed that Gram-negative bacteria were in-volved in the pathogenesis of HSOS.Conclusions:RTS,a PA,cooperated with gut dysbiosis to cause intestinal inflam-mation and gut barrier compromise that increased transport of gut-derived LPS into the liver through the portal vein,which contributed to the pathology of HSOS.Modulating the gut microbiota,protecting the intestinal barrier,and sup-pressing intestinal inflammation with prebiotics or antibiot-ics might be a useful pharmacologic intervention in HSOS.展开更多
A novel ferroenyl pyrrolizidine derivative containing cyano groups, 2-O-methylphenyl）-3-ferrocenyl-4,4-dicyanpyrrolizidine （C26H25FeN3, Mr = 435.34）, was synthesized in moderate yields via a facile 1.3-dipolar cycl...A novel ferroenyl pyrrolizidine derivative containing cyano groups, 2-O-methylphenyl）-3-ferrocenyl-4,4-dicyanpyrrolizidine （C26H25FeN3, Mr = 435.34）, was synthesized in moderate yields via a facile 1.3-dipolar cycloaddition in refluxing toluene and its crystal structure was determined by single-crystal X-ray diffraction. It crystallizes in monoclinic, space group P2Jc with a = 10.3792（10）, b =11.4485（1 l）, c= 19.1243（15）A, β = 109.496（4）°, V= 2142.2（3）A3, Dc = 1.350 g/cm^3, μ（MoKa） = 0.721 mm-1, Z = 4, T = 113（2） K, F（000） = 912, the final R = 0.0586 and wR = 0.1664.展开更多
Two new metabolites, namely bisline lactone and isolinecic acid lactone, were isolated from the resultant incubates after a scale-up incubation of isoline with rat liver microsomes. Their structures were determined by...Two new metabolites, namely bisline lactone and isolinecic acid lactone, were isolated from the resultant incubates after a scale-up incubation of isoline with rat liver microsomes. Their structures were determined by spectroscopic data, especially those from 1D and 2D NMR experiments.展开更多
We compared herbivory pressure in the native Jacobaea vulgaris (formely Senecio jacobaea) and the alien invasive S. inaequidens in sites where they co-occur in Belgium. We predicted that the alien species experiences ...We compared herbivory pressure in the native Jacobaea vulgaris (formely Senecio jacobaea) and the alien invasive S. inaequidens in sites where they co-occur in Belgium. We predicted that the alien species experiences relaxed herbivory pressure by specialist herbivores (enemy release hypothesis ERH) whereas it is still attacked by generalist herbivores. Impacts of two generalist (gastropods and rabbits) and one specialist (the caterpillar Tyria jacobaeae) herbivores were assessed with field observations and exclusion experiments. The generalist herbivores had a higher impact on the biomass and survival of the seedlings of the alien S. inaequidens than on the native J. vulgaris. On the contrary, the specialist Tyria jacobaeae attacked exclusively the adults of the native species, supporting one of the main predictions of the ERH. These results are discussed in relation to differences in pyrrolizidine alkaloid profiles between the two species.展开更多
Extracts of several British butterfly species were tested and shown to possess powerful bactericidal activity against gram-positive bacteria (tested on Staphylococcus aureus and Bacillus anthracis). The active compoun...Extracts of several British butterfly species were tested and shown to possess powerful bactericidal activity against gram-positive bacteria (tested on Staphylococcus aureus and Bacillus anthracis). The active compounds in the grass-feeding species were identified as hydroxylated pyrrolizidine alkaloids (PAs) related to loline with nitrogen at C-1. Lolines are known insecticidal and insect-deterrent compounds that are produced in grasses infected by endophytic fungal symbionts. Lolines also increase resistance of endophyte-infected grasses to insect herbivores. The butterfly-isolated pyrrolizidine alkaloids appear to be novel and non-toxic to human cells such as HaCat human skin keratinocytes and Hep-2 human epithelial cells. The discovery of novel agents from butterflies could lead to the development of new antimicrobials.展开更多
Non-ribosomal peptides are a group of structurally diverse natural products with various important therapeutic and agrochemical applications.Bacterial pyrrolizidine alkaloids(PAs),containing a scaffold of two fused fi...Non-ribosomal peptides are a group of structurally diverse natural products with various important therapeutic and agrochemical applications.Bacterial pyrrolizidine alkaloids(PAs),containing a scaffold of two fused five-membered ring system with a nitrogen atom at the bridgehead,have been found to originate from a multidomain non-ribosomal peptide synthetase to generate indolizidine intermediates,followed by multistep oxidation,catalysed by single Bayer-Villiger(BV)enzymes,to yield PA scaffolds.Although bacterial PAs are rare in natural product inventory,bioinformatics analysis suggested that the biosynthetic gene clusters(BGCs)that are likely to be responsible for the production of PA-like metabolites are widely distributed in bacterial genomes.However,most of the strains containing PA-like BGCs are not deposited in the public domain,therefore preventing further assessment of the chemical spaces of this group of bioactive metabolites.Here,we report a genomic scanning strategy to assess the potential of PA metabolites production in our culture collection without prior knowledge of genome information.Among the strains tested,we found fifteen contain the key BV enzymes that are likely to be involved in the last step of PA ring formation.Subsequently one-strain-many-compound(OSMAC)method,supported by a combination of HR-MS,NMR,SMART 2.0 technology,and GNPS analysis,allowed identification and characterization of a new[5+7]heterobicyclic carbamate,legoncarbamate,together with five known PAs,bohemamine derivatives,from Streptomyces sp.CT37,a Ghanaian soil isolate.The absolute stereochemistry of legoncarbamate was determined by comparison of measured and calculated ECD spectra.Legoncarbamate displays antibacterial activity against E.coli ATCC 25922 with an MIC value of 3.1μg/mL.Finally,a biosynthetic model of legoncarbamate and other bohemamines was proposed based on the knowledge we have gained so far.展开更多
Five new pyrrolizidine alkaloids,bohemamines J—N(1-5),were isolated from Streptomyces sp.CPCC 200497.Their structures were assigned based on detailed spectroscopic analysis and semisynthesis.Bohemamine J(1)possesses ...Five new pyrrolizidine alkaloids,bohemamines J—N(1-5),were isolated from Streptomyces sp.CPCC 200497.Their structures were assigned based on detailed spectroscopic analysis and semisynthesis.Bohemamine J(1)possesses a new chimeric skeleton derived from bohemamine A(6)and phenylacetaldehyde.Inspired by the nonenzymatic formation mechanism of the methylene-bridged dimers isolated from this strain,we synthesized a series of chimeric derivatives(8,9,and 12-23)through natural product chimera strategy.Compounds 13,15,19,and 21 showed significant antioxidant activity.展开更多
基金Supported by National Natural Science Foundation of China,No.81570555 and No.81770582
文摘Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by the intake of pyrrolizidine alkaloids (PAs). To date, PAs-induced HSOS has not been extensively studied. In view of the difference in etiology of HSOS between the West and China, clinical profiles, imaging findings, treatment, and outcomes of HSOS associated with hematopoietic stem cell transplantation or oxaliplatin might be hardly extrapolated to PAs-induced HSOS. Reactive metabolites derived from PAs form pyrrole-protein adducts that result in toxic destruction of hepatic sinusoidal endothelial cells. PAs-induced HSOS typically manifests as painful hepatomegaly, ascites, and jaundice. Laboratory tests revealed abnormal liver function tests were observed in most of the patients with PAs-induced HSOS. In addition, contrast computed tomography and magnetic resonance imaging scan show that patients with PAs-induced HSOS have distinct imaging features, which reveal that radiological imaging provides an effective noninvasive method for the diagnosis of PAs-induced HSOS. Liver biopsy and histological examination showed that PAs-induced HSOS displayed distinct features in acute and chronic stages. Therapeutic strategies for PAs-induced HSOS include rigorous fluid management, anticoagulant therapy, glucocorticoids, transjugular intrahepatic portosystemic shunt, liver transplantation, etc. The aim of this review is to describe the pathogenesis, clinical profiles, diagnostic criteria, treatment, and outcomes of PAs-induced HSOS.
基金financially supported by the National Natural Science Foundation of China (Nos. 81402803, 31171695)the Science and Technology Support Programs of Sichuan Province (No. 2013SZ0083, 2015GZ0233)+2 种基金the Research Foundation for Educational Commission of Sichuan Province (No. 15TD0048)the Fundamental Research Funds for Central Universities (No. 2682014RC15)national undergraduate training programs for innovation and entrepreneurship (No. 201510613065)
文摘Three new pyrrolizidine alkaloids, nervosineⅦ（1）, nervosine Ⅷ（2） and nervosine IX （3） were isolated from the whole plant extract of Liparis nervosa. Their structures were elucidated by extensive spectroscopic analyses （including 1 D, 2D NMR, and HR-ESI-MS） and chemical methods. Compounds 1-3 were evaluated for their cytotoxic activity against A549, MCF-7and H460 human cancer cell lines.
基金This article is not an official U.S. Food and Drug Administration guidance or policy statement. No official support or endorsement by the U.S. Food and DrugAdministration is intended or should be inferred.
文摘Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorigenicity, and the metabolic pathways, particular the activation pathways leading to hepatotoxicity and tumorigenicity, of pyrrolizidine alkaloids are briefly discussed, with a focus on the most recent important findings concerning the genotoxic mechanism by which riddelliine liver tumors. This mechanism involves the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and may be general to most carcinogenic pyrrolizidine alkaloids.
基金Supported by China Hepatitis Prevention and Treatment Foundation Scientific Research Subject,No. TQGB20180247Anhui Province Natural Science Foundation Projects,No.1808085MH254
文摘BACKGROUND Treatments for hepatic sinusoidal obstruction syndrome(HSOS)are limited.AIM To evaluate transjugular intrahepatic portosystemic shunting(TIPS)as a treatment for pyrrolidine alkaloid-related HSOS(PA-HSOS).METHODS This retrospective analysis included patients with PA-HSOS admitted to the First Affiliated Hospital of the University of Science and Technology of China(June 2015 to January 2019).Baseline clinical characteristics and follow-up data were extracted from the medical records.All patients included in this study experienced failure of initial therapy.Patients were divided into the TIPS and conservative treatment groups according to the therapy they received.Liver function,maximal ascites depth,imaging characteristics,pathology findings,and survival were compared between groups.RESULTS The TIPS group included 37 patients(28 males),and the conservative treatment group included 17 patients(11 males).Baseline characteristics were similar between groups.There were two deaths in the TIPS group and seven deaths in the conservative treatment group during follow-up(3-48 mo).The 3-,6-,12-and 24-mo survival rates were 94.6%,94.6%,94.6%and 94.6%,respectively,in the TIPS group and 70.6%,57.8%,57.8%and 57.8%,respectively,in the conservative treatment group.Kaplan-Meier analysis revealed significantly longer survival for the TIPS group than for the conservative treatment group(P=0.001).Compared with the pre-treatment value,maximal ascites depth was significantly lower at 1 wk,2 wk,1 mo,and 3 mo for the TIPS group(all P<0.05)but not in the conservative treatment group.Contrast-enhanced computed tomography demonstrated the disappearance of patchy liver enhancement after TIPS.Pathology showed that liver congestion and hepatocyte swelling improved with time after TIPS placement.CONCLUSION TIPS may achieve better outcomes than conventional symptomatic treatment in patients with PA-HSOS.
基金This study was funded in full by the National Natural Science Foundation of China,with grant numbers 8157040652 and 81900552the Key Project of Nanjing Health and Technology Development,with grant number ZKX19015。
文摘Background and Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is caused by toxic injury to sinusoidal endothelial cells in the liver.The intake of pyrrolizidine alkaloids(PAs)in some Chinese herbal remedies/plants remains the major etiology for HSOS in China.Recently,new diagnostic criteria for PA-induced HSOS(i.e.PA-HSOS)have been developed;however,the efficacy has not been clinically validated.This study aimed to assess the performance of the Nanjing criteria for PA-HSOS.Methods:Data obtained from consecutive patients in multiple hospitals,which included 86 PA-HSOS patients and 327 patients with other liver diseases,were retrospectively analyzed.Then,the diagnostic performance of the Nanjing criteria and simplified Nanjing criteria were evaluated and validated.The study is registered in www.chictr.org.cn(ID:ChiCTR1900020784).Results:The Nanjing criteria have a sensitivity and specificity of 95.35%and 100%,respectively,while the simplified Nanjing criteria have a sensitivity and specificity of 96.51%and 96.33%,respectively,for the diagnosis of PA-HSOS.Notably,a proportion of patients with Budd-Chiari syndrome(11/49)was misdiagnosed as PA-HSOS on the basis of the simplified Nanjing criteria,and this was mainly due to the overlapping features in the enhanced computed tomography/magnetic resonance imaging examinations.Furthermore,most of these patients(10/11)had occlusion or thrombosis of the hepatic vein,and communicating vessels in the liver were found in 8/11 patients,which were absent in PA-HSOS patients.Conclusions:The Nanjing criteria and simplified Nanjing criteria exhibit excellent performance in diagnosing PA-HSOS.Thus,both could be valuable diagnostic tools in clinical practice.
基金supported by the National Natural Science Foundation of China(grant number 81603384)the Shanghai Nature Science Foundation(grant number 16ZR1434200)+2 种基金Shanghai Rising-Star Program(grant number 17QA1403600)Program of Shanghai Academic/Technology Research Leader(grant number 17XD1403500)Programof Shanghai Municipal Commission of Health and Family Planning(grant number ZY(2018e2020)-CCCX-5002).
文摘Pyrrolizidine alkaloids(PAs)are among the most hepatotoxic natural compounds that are widely distributed throughout the world.Most PAs are metabolically activated to trigger toxicity.Exposure to herbal medicine containing PAs and food supplements contaminated by PAs is considered to be one of the two main causes of hepatic sinusoidal obstruction syndrome(HSOS),which is a rare hepatic vascular disease with a high mortality rate.PAs-induced HSOS cases have been reported worldwide.However,there is no clinically effective therapy for PAs-induced HSOS,which is partially because the toxic mechanism is not fully understood.This review focuses on updating the information on the metabolism and the molecular mechanisms of PAs hepatotoxicity,including oxidative stress,apoptosis,and dysfunction of bile acid metabolism,and their interactions.
文摘Two new pyrrolizidines named lankongensisine A (1), B (2) were isolated from the roots of Ligularia lankongensis collected in Lijiang, Yunnan, and their structures were established by spectroscopic analysis.
基金This work was supported by the National Natural Science Foundation of China(No.81402803).
文摘Nervosine Ⅶ is one of the known saturated pyrrolizidine alkaloids isolated from the plant of Liparis nervosa.This is first study to investigate the antitumor activity of nervosine Ⅶ in vitro,and the results indicated that nervosine Ⅶ induced autophagy and apoptosis in HCT116 human colorectal cancer cells.Mechanistic studies showed that nervosine Ⅶ-induced apoptosis was associated with the intrinsic pathway by the activation of caspase-9,-3 and-7.Autophagy induced by nervosine Ⅶ was characteristic with the regulation of autophagic markers including the increase of LC3-Ⅱ and beclin 1 proteins,and the decrease of p62 protein.Nervosine Ⅶ simultaneously induced autophagy and apoptosis by activated MAPKs signaling pathway including JNK,ERK1/2 and p38,suppressing the p53 signaling pathway.
基金Research Grant Council of Hong Kong(GRF Grants no.471310 and 469712)CUHK Direct Grant(2041744)
文摘Objective: Qianliguang(Senecio scandens) is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. The presence of hepatotoxic pyrrolizidine alkaloids(PAs)has raised concerns about the safety of using Qianliguang and its products. The present study aims at investigation of different types of PAs present in Qianliguang collected from representative locations in China.Methods: In this study, a simple but specific UHPLC-QTOF-MS method for the determination of toxic PAs was developed, based on the characteristic fragment ions specific to different types of PAs. It was successfully applied for the identification and distinguishing of PAs present in Qianliguang and related Senecio species growing in different locations of China.Results: Significant diversity of the PA types and quantities were revealed among the samples tested. The estimated total amounts of toxic PAs in three of the samples exceed the toxic limits of PA intake restricted by WHO, demonstrating the timely and highly demand for regulating both types and quantities of PAs present in Qianliguang.Conclusions: This study provides the methodology for simultaneous identification and quantification of PAs present in herbs without requiring corresponding standards, which could be further used for more systematic investigations of the PA distribution in Qianliguang and other PA-containing herbs.
基金This work was supported by Shanghai Natural Science Foundation(20ZR1473300)Shanghai Talents Development Foundation(2020099)+1 种基金the Program of Shanghai Municipal Commission of Health and Family Planning(ZY(2018-2020)-CCCX-5002)the Xinglin Scholar Program of Shanghai University of Traditional Chinese Medicine(B1-GY21-409-04-06).
文摘Hepatic sinusoidal obstruction syndrome(HSOS)via exposure to pyrrolizidine alkaloids(PAs)is with high mortality and there is no effective treatment in clinics.Bear bile powder(BBP)is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis,inflammation,and fibrosis.Here,we aim to evaluate the protective effect of BBP against HSOS induced by senecionine,a highly hepatotoxic PA compound.Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently,which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells,alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells,as well as decreased conventional serum liver function indicators.In addition,BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts,two well-known markers positively associated with the severity of PA-induced HSOS.Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules.BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines,in which taurours-odeoxycholic acid played an important role.What’s more,BBP treatment also decreased the accumulation of hydrophobic bile acids,such as cholic acid,taurocholic acid,glycocholic acid,as well.We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis,preventing liver fibrosis,and alleviating liver inflammation.Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.
基金the National Natural Science Foundation of China(No.81974078,81570530,81370550 to LY,No.8190034336 to WW)Natural Science Founda-tion of Hubei Province(No.2019ACA133 to LY)。
文摘Background and Aims:Hepatic sinusoidal obstruction syndrome(HSOS)is a life-threatening syndrome,and a cause is exposure to pyrrolizidine alkaloid(PA)-containing products.It is well-established that retrorsine(RTS),a rep-resentative Pas,insults hepatic sinusoidal endothelial cells and ensues congestion of hepatic sinusoids.However,little known about the impact of Pas on gut microbiota and intesti-nal barrier and inflammation in HSOS.Methods:Mice were gavaged with or without nonabsorbable antibiotics(ABX),followed by a single dose of RTS.The gut microbiota was examined by 16S rDNA sequencing.Results:ABX pretreat-ment significantly reversed RTS-induced liver damage.RTS altered gut microbiota composition,increasing Gram-nega-tive bacteria and resulting in a sharp elevation of circulating lipopolysaccharides(LPS)in HSOS mice.Gut decontamina-tion with ABX alleviated RTS-induced intestine inflamma-tion,protected against disruption of the intestinal epithelial barrier and gut vascular barrier(GVB),and suppressed he-patic LPS-NF-κB pathway activation in RTS-induced HSOS.Importantly,the LPS level was positively correlated with MELD score in patients with HSOS.Elevated LPS in patients with HSOS confirmed that Gram-negative bacteria were in-volved in the pathogenesis of HSOS.Conclusions:RTS,a PA,cooperated with gut dysbiosis to cause intestinal inflam-mation and gut barrier compromise that increased transport of gut-derived LPS into the liver through the portal vein,which contributed to the pathology of HSOS.Modulating the gut microbiota,protecting the intestinal barrier,and sup-pressing intestinal inflammation with prebiotics or antibiot-ics might be a useful pharmacologic intervention in HSOS.
基金Financially supported by the Science and Technology Support Plan Project of Hebei Province (11207184D)the Fund of Hebei Provincial Higher Education Scientific Research Plan Project (No. Q2012021)
文摘A novel ferroenyl pyrrolizidine derivative containing cyano groups, 2-O-methylphenyl）-3-ferrocenyl-4,4-dicyanpyrrolizidine （C26H25FeN3, Mr = 435.34）, was synthesized in moderate yields via a facile 1.3-dipolar cycloaddition in refluxing toluene and its crystal structure was determined by single-crystal X-ray diffraction. It crystallizes in monoclinic, space group P2Jc with a = 10.3792（10）, b =11.4485（1 l）, c= 19.1243（15）A, β = 109.496（4）°, V= 2142.2（3）A3, Dc = 1.350 g/cm^3, μ（MoKa） = 0.721 mm-1, Z = 4, T = 113（2） K, F（000） = 912, the final R = 0.0586 and wR = 0.1664.
基金supported by the National Natural Science Foundation of China(NNSFC)for outstanding young scientists for Dr.Zheng-tao Wang(No.39825129).
文摘Two new metabolites, namely bisline lactone and isolinecic acid lactone, were isolated from the resultant incubates after a scale-up incubation of isoline with rat liver microsomes. Their structures were determined by spectroscopic data, especially those from 1D and 2D NMR experiments.
文摘We compared herbivory pressure in the native Jacobaea vulgaris (formely Senecio jacobaea) and the alien invasive S. inaequidens in sites where they co-occur in Belgium. We predicted that the alien species experiences relaxed herbivory pressure by specialist herbivores (enemy release hypothesis ERH) whereas it is still attacked by generalist herbivores. Impacts of two generalist (gastropods and rabbits) and one specialist (the caterpillar Tyria jacobaeae) herbivores were assessed with field observations and exclusion experiments. The generalist herbivores had a higher impact on the biomass and survival of the seedlings of the alien S. inaequidens than on the native J. vulgaris. On the contrary, the specialist Tyria jacobaeae attacked exclusively the adults of the native species, supporting one of the main predictions of the ERH. These results are discussed in relation to differences in pyrrolizidine alkaloid profiles between the two species.
文摘Extracts of several British butterfly species were tested and shown to possess powerful bactericidal activity against gram-positive bacteria (tested on Staphylococcus aureus and Bacillus anthracis). The active compounds in the grass-feeding species were identified as hydroxylated pyrrolizidine alkaloids (PAs) related to loline with nitrogen at C-1. Lolines are known insecticidal and insect-deterrent compounds that are produced in grasses infected by endophytic fungal symbionts. Lolines also increase resistance of endophyte-infected grasses to insect herbivores. The butterfly-isolated pyrrolizidine alkaloids appear to be novel and non-toxic to human cells such as HaCat human skin keratinocytes and Hep-2 human epithelial cells. The discovery of novel agents from butterflies could lead to the development of new antimicrobials.
基金QF and HD are grateful to the University of Aberdeen Elphinstone Scholarship and Scottish Funding Council/ScotCHEM for financial support through the PEER/PERCE Funding.HD and SW thank the financial supports of Biotechnology and Biological Sciences Research Council UK(BBSRC,BB/P00380X/1)HD,SAM and CP thank Business Interaction Vouchers(BIV009)from BBSRC funded Natural Products discovery and bioengineering Network(NPRONET)+2 种基金H.D.and K.K.thank the financial supports of Leverhulme Trust-Royal Society Africa award(AA090088)the jointly funded UK Medical Research Council-UK Department for International Development(MRC/DFID)Concordat agreement African Research Leaders Award(MR/S00520X/1)YZ and HD thank National Natural Science Foundation of China(31929001).
文摘Non-ribosomal peptides are a group of structurally diverse natural products with various important therapeutic and agrochemical applications.Bacterial pyrrolizidine alkaloids(PAs),containing a scaffold of two fused five-membered ring system with a nitrogen atom at the bridgehead,have been found to originate from a multidomain non-ribosomal peptide synthetase to generate indolizidine intermediates,followed by multistep oxidation,catalysed by single Bayer-Villiger(BV)enzymes,to yield PA scaffolds.Although bacterial PAs are rare in natural product inventory,bioinformatics analysis suggested that the biosynthetic gene clusters(BGCs)that are likely to be responsible for the production of PA-like metabolites are widely distributed in bacterial genomes.However,most of the strains containing PA-like BGCs are not deposited in the public domain,therefore preventing further assessment of the chemical spaces of this group of bioactive metabolites.Here,we report a genomic scanning strategy to assess the potential of PA metabolites production in our culture collection without prior knowledge of genome information.Among the strains tested,we found fifteen contain the key BV enzymes that are likely to be involved in the last step of PA ring formation.Subsequently one-strain-many-compound(OSMAC)method,supported by a combination of HR-MS,NMR,SMART 2.0 technology,and GNPS analysis,allowed identification and characterization of a new[5+7]heterobicyclic carbamate,legoncarbamate,together with five known PAs,bohemamine derivatives,from Streptomyces sp.CT37,a Ghanaian soil isolate.The absolute stereochemistry of legoncarbamate was determined by comparison of measured and calculated ECD spectra.Legoncarbamate displays antibacterial activity against E.coli ATCC 25922 with an MIC value of 3.1μg/mL.Finally,a biosynthetic model of legoncarbamate and other bohemamines was proposed based on the knowledge we have gained so far.
基金the National Natural Science Foundation of China(41806086,U1906213,41876172)。
文摘Five new pyrrolizidine alkaloids,bohemamines J—N(1-5),were isolated from Streptomyces sp.CPCC 200497.Their structures were assigned based on detailed spectroscopic analysis and semisynthesis.Bohemamine J(1)possesses a new chimeric skeleton derived from bohemamine A(6)and phenylacetaldehyde.Inspired by the nonenzymatic formation mechanism of the methylene-bridged dimers isolated from this strain,we synthesized a series of chimeric derivatives(8,9,and 12-23)through natural product chimera strategy.Compounds 13,15,19,and 21 showed significant antioxidant activity.
