Objective:To assess the risk of aristolochic acid(AA)-associated cancer in patients with AA nephropathy(AAN).Methods:A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospit...Objective:To assess the risk of aristolochic acid(AA)-associated cancer in patients with AA nephropathy(AAN).Methods:A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014.Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer.The primary endpoint was the incidence of liver cancer,and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014.Results:A total of 337 patients diagnosed with AAN were included in this study.From the initiation of taking AA to the termination of follow-up,39 patients were diagnosed with cancer.No cases of liver cancer were observed throughout the entire follow-up period,with urinary cancer being the predominant type(34/39,87.17%).Logistic regression analysis showed that age,follow-up period,and diabetes were potential risk factors,however,the dosage of the drug was not significantly associated with urinary cancer.Conclusions:No cases of liver cancer were observed at the end of follow-up.However,a high prevalence of urinary cancer was observed in AAN patients.Establishing a direct causality between AA and HCC is challenging.展开更多
Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development.Herein,an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectr...Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development.Herein,an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)was established for direct analysis of metabolites in renal tissue sections.This method was subsequently applied to investigate spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I,a known nephrotoxic drug,aimed to discover metabolites associated with nephrotoxicity.As a result,38 metabolites related to the arginine-creatinine metabolic pathway,the urea cycle,the serine synthesis pathway,metabolism of lipids,choline,histamine,lysine,and adenosine triphosphate were significantly changed in the group treated with aristolochic acid I.These metabolites exhibited a unique distribution in rat kidney and a good spatial match with histopathological renal lesions.This study provides new insights into the mechanisms underlying aristolochic acids nephrotoxicity and demonstrates that AFADESI-MSI-based in situ metabolomics is a promising technique for investigation of the molecular mechanism of drug toxicity.展开更多
More than 80 aristolochic acids(AAs) and aristololactams(ALs) have been found in plants of the Aristolochiaceae family, but relatively few have been fully studied. The present study aimed at developing and validating ...More than 80 aristolochic acids(AAs) and aristololactams(ALs) have been found in plants of the Aristolochiaceae family, but relatively few have been fully studied. The present study aimed at developing and validating a liquid chromatography tandem mass spectrometry(LC/MS^n) for the analysis of these compounds. We characterized the fragmentation behaviors of 31 AAs, ALs, and their analogues via high performance liquid chromatography coupled with electrospray ionization mass spectrometry. We summarized their fragmentation rules and used these rules to identify the constituents contained in Aristolochia contorta, Ar. debilis, Ar. manshurensis, Ar. fangchi, Ar. cinnabarina, and Ar. mollissima. The AAs and ALs showed very different MS behaviors. In MS1 of AAs, the characteristic pseudomolecular ions were [M + NH_4]^+, [M + H]^+, and [M + H - H_2O]^+. However, only [M + H]^+ was found in the MS1 of ALs, which was simpler than that of AAs. Distinct MSn fragmentation patterns were found for AAs and ALs, showing the same skeleton among the different substituent groups. The distribution of the 31 constituents in the 6 species of Aristolochia genus was reported for the first time. 25 Analogues of AAs and ALs were detected in this genus. A hierarchical schemes and a calculating formula of the molecular formula of these nitrophenanthrene carboxylic acids and their lactams were proposed. In conclusion, this method could be applied to identification of similar unknown constituents in other plants.展开更多
Aristolochiae Fructus, a Chinese herbal medicine derived from the fruit of Aristolochia contorta Bge., contains nephrotoxic aristolochic acid analogues(AAAs). According to ancient medical texts, various medicinal part...Aristolochiae Fructus, a Chinese herbal medicine derived from the fruit of Aristolochia contorta Bge., contains nephrotoxic aristolochic acid analogues(AAAs). According to ancient medical texts, various medicinal parts of the fruit of A. contorta were ever used. In order to reveal which part could be safely and effectively used, it is necessary to analyze the chemical profiles of different medicinal parts. Herein we compared the chemical compositions and determined aristolochic acid I(AA-I) and aristolochic acid II(AA-II) in the four parts viz. outer pericarp, inner pericarp, septum, and seed. Ultra-high performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry(UHPLC-QTOF-MS) was applied for chemical profiling. Ultra-high performance liquid coupled with triple quadrupole mass spectrometry(UHPLC-Qq Q-MS) was employed to quantify AA-I and AA-II in different parts. It was found that the chemical compositions of the four parts varied both qualitatively and quantitatively. A total of 10 AAAs, including 5 aristolochic acids and 5 aristolactams, together with 3 alkaloids, were unambiguously or tentatively identified by UHPLC-QTOF-MS. The quantitatively analytical results obtained by UHPLC-Qq Q-MS showed that AA-I and AA-II exclusively accumulate in the seeds of A. contorta. These findings provide supporting data for the rational selection of medicinal parts.展开更多
Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese...Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese herbs nephropathy,a term replaced later by AA nephropathy.Evidence indicates that AA is nephrotoxic,genotoxic,and carcinogenic in humans;and it also induces tumors in the forestomach,kidney,renal pelvis,urinary bladder,and lung of rats and mice.Therefore,plants containing AA have been classified as carcinogenic to humans(Group 1)bytheInternational AgencyforResearchonCancer.In our laboratories,we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks.Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney,liver,and spleen of rats,as well as significant alteration of gene expression in both its target and nontarget tissues.AA treatments altered mutagenesis-or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling.We also applied benchmark dose(BMD)modeling to the 3-month AA-induced genotoxicity data.The obtained BMDL10(the lower 95%confidence interval of the BMD10 that is a 10%increase over the background level)for AA-induced mutations in the kidney of rats was about 7μg/kg body weight per day.This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression,microRNA expression,and proteomics;and presents updated information focused on AA-induced genotoxicity in rodents.展开更多
Aristolochic acids(AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I(AAI) reacts with DNA to form covalent aristolactam(AL)-DNA adducts,leading to subsequent A to T t...Aristolochic acids(AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I(AAI) reacts with DNA to form covalent aristolactam(AL)-DNA adducts,leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in China's Mainland. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI-DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.展开更多
Objective: To investigate the protective effects of Schisandra chinensis oil(SCEO) against aristolochic acid Ⅰ(AAⅠ)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism.Methods: C57BL/6...Objective: To investigate the protective effects of Schisandra chinensis oil(SCEO) against aristolochic acid Ⅰ(AAⅠ)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism.Methods: C57BL/6 mice were randomly divided into 5 groups according to a random number table, including control group, AAⅠ group, and AAⅠ+SCEO(0.25, 0.5 and 1 g/kg) groups(n=5 per group). Pretreatment with SCEO was done for 2 days by oral administration, while the control and AAⅠ groups were treated with sodium carboxymethyl cellulose. Mice of all groups except for the control group were injected intraperitoneally with AAⅠ(5 mg/kg) from day 3 until day 7. Histopathological examination and apoptosis of kidney tissue were observed by hematoxylin and eosin and TdT-mediated dUTP nick-end labeling(TUNEL) staining, respectively. The levels of serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), blood urea nitrogen(BUN), and serum creatinine(SCr), as well as renal malondialdehyde(MDA), glutathione, r-glutamyl cysteingl+glycine(GSH), and superoxide dismutase(SOD) were analyzed using enzyme-linked immunosorbent assay(ELISA).Expressions of hepatic cytochrome P450 1A1(CYP1A1), CYP1A2, and nad(p)hquinonedehydrogenase1(NQO1) were analyzed using ELISA, quantitative real-time polymerase chain reaction(qPCR) and Western blot,respectively. In vitro, SCEO(40 μg/mL) was added 12 h before treatment with AAⅠ(40 μmol/mL for 48 h) in human renal proximal tubule cell line(HK-2), then apoptosis and reactive oxygen species(ROS) were analyzed by flow cytometry. Results: SCEO 0.5 and 1 g/kg ameliorated histopathological changes and TUNEL+ staining in the kidney tissues of mice with AAⅠ-induced nephrotoxicity, and reduced serum levels of ALT, AST, BUN and SCr(P<0.01 or P<0.05). SCEO 0.5 and 1 g/kg alleviated the ROS generation in kidney, containing MDA,GSH and SOD(P<0.01 or P<0.05). SCEO 1 g/kg increased the expressions of CYP1A1 and CYP1A2 and decreased NQO1 level in the liver tissues(P<0.01 or P<0.05). Besides, in vitro studies also demonstrated that SCEO 40 μg/mL inhibited apoptosis and ROS generation(P<0.05 or P<0.01). Conclusions: SCEO can alleviate AAⅠ-induced kidney damage both in vivo and in vitro. The protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and ROS production.展开更多
Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recen...Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recently,accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma,though the mechanisms are poorly defined.Methods:Here,we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I(AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing(scRNA-seq)and proteomics techniques.We established the first single-cell atlas of mouse livers in response to AAI.Results:In hepatocytes,our results indicated that AAI activated NF-κB and STAT3 signaling pathways,which may contribute to the inflammatory response and apoptosis.In liver sinusoidal endothelial cells(LSECs),AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis.Importantly,AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation.Conclusions:Collectively,our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a singlecell level and suggests future treatment options for AAs associated hepatotoxicity.展开更多
Aristolochic acid nephropathy(AAN)is a rapidly progressive interstitial nephritis leading to end-stage renal disease and urothelial malignancy.It was originally reported in Belgium in a group of more than 100 patients...Aristolochic acid nephropathy(AAN)is a rapidly progressive interstitial nephritis leading to end-stage renal disease and urothelial malignancy.It was originally reported in Belgium in a group of more than 100 patients who had ingested slimming pills containing powdered root extracts of a Chinese herb,Aristolochia fangchzi.展开更多
Objective:Although some studies have linked Asari Radix et Rhizoma(Asari Radix)administration to hepatocellular carcinoma(HCC),few studies have examined the association between the development of HCC and use of Asari ...Objective:Although some studies have linked Asari Radix et Rhizoma(Asari Radix)administration to hepatocellular carcinoma(HCC),few studies have examined the association between the development of HCC and use of Asari Radix among patients in China's Mainland.This study aimed to evaluate the realworld association between Asari Radix and HCC in patients to strengthen the understanding of Asari Radix safety.Methods:A retrospective cohort study among hepatitis B virus(HBV)-monoinfected patients and nonHBV-monoinfected patients were performed.Patients over 18 years of age were eligible for inclusion.Prescription records of inpatients and outpatients were inquired to distinguish Asari Radix users and nonusers.The risk of developing HCC among Asari Radix users and nonusers in the HBV cohort and the non-HBV cohort was analyzed.Results:There were 49500 HBV and 133148 non-HBV patients involved in the two cohorts.Among HBV patients(2901 users;46599 nonusers),the prevalence of HCC in Asari Radix users was lower than that in nonusers(145.70 vs.265.43 per 105).Among non-HBV patients(5042 users;128106 nonusers),the prevalence of HCC in Asari Radix users was lower than that in nonusers(81.62 vs.134.11 per 105).None of the hazard ratios(HRs)of Asari Radix exposure ranging from 1 g to 200 g in the two cohorts showed correlation between Asari Radix exposure and hepatocarcinogenesis.Conclusion:An obvious irrelevancy was found between the consumption of Asari Radix and HCC development both in patients with and in those without HBV infection.Use of Asari Radix under 200 g appears safe in terms of HCC risk in the Chinese population;further prospective studies are needed to confirm our results.展开更多
基金Supported by National Key Technology R&D Program(No.2018zX09101002-001-002)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202005)the Science and Technology Project Affiliated to the Education Department of Chongqing Municipality(No.KJQN202215119)。
文摘Objective:To assess the risk of aristolochic acid(AA)-associated cancer in patients with AA nephropathy(AAN).Methods:A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014.Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer.The primary endpoint was the incidence of liver cancer,and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014.Results:A total of 337 patients diagnosed with AAN were included in this study.From the initiation of taking AA to the termination of follow-up,39 patients were diagnosed with cancer.No cases of liver cancer were observed throughout the entire follow-up period,with urinary cancer being the predominant type(34/39,87.17%).Logistic regression analysis showed that age,follow-up period,and diabetes were potential risk factors,however,the dosage of the drug was not significantly associated with urinary cancer.Conclusions:No cases of liver cancer were observed at the end of follow-up.However,a high prevalence of urinary cancer was observed in AAN patients.Establishing a direct causality between AA and HCC is challenging.
基金supported by the National Key Research and Development Program of China(No.2017YFC1704000)Outstanding Talent Support Program of Beijing,China(No.2017000020124G272)
文摘Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development.Herein,an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)was established for direct analysis of metabolites in renal tissue sections.This method was subsequently applied to investigate spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I,a known nephrotoxic drug,aimed to discover metabolites associated with nephrotoxicity.As a result,38 metabolites related to the arginine-creatinine metabolic pathway,the urea cycle,the serine synthesis pathway,metabolism of lipids,choline,histamine,lysine,and adenosine triphosphate were significantly changed in the group treated with aristolochic acid I.These metabolites exhibited a unique distribution in rat kidney and a good spatial match with histopathological renal lesions.This study provides new insights into the mechanisms underlying aristolochic acids nephrotoxicity and demonstrates that AFADESI-MSI-based in situ metabolomics is a promising technique for investigation of the molecular mechanism of drug toxicity.
基金supported by the National Natural Science Foundation of China(Grant Nos.30873466,81173494&81274073)National Science and Technology Major Project(No 2014ZX09304307-001-012)
文摘More than 80 aristolochic acids(AAs) and aristololactams(ALs) have been found in plants of the Aristolochiaceae family, but relatively few have been fully studied. The present study aimed at developing and validating a liquid chromatography tandem mass spectrometry(LC/MS^n) for the analysis of these compounds. We characterized the fragmentation behaviors of 31 AAs, ALs, and their analogues via high performance liquid chromatography coupled with electrospray ionization mass spectrometry. We summarized their fragmentation rules and used these rules to identify the constituents contained in Aristolochia contorta, Ar. debilis, Ar. manshurensis, Ar. fangchi, Ar. cinnabarina, and Ar. mollissima. The AAs and ALs showed very different MS behaviors. In MS1 of AAs, the characteristic pseudomolecular ions were [M + NH_4]^+, [M + H]^+, and [M + H - H_2O]^+. However, only [M + H]^+ was found in the MS1 of ALs, which was simpler than that of AAs. Distinct MSn fragmentation patterns were found for AAs and ALs, showing the same skeleton among the different substituent groups. The distribution of the 31 constituents in the 6 species of Aristolochia genus was reported for the first time. 25 Analogues of AAs and ALs were detected in this genus. A hierarchical schemes and a calculating formula of the molecular formula of these nitrophenanthrene carboxylic acids and their lactams were proposed. In conclusion, this method could be applied to identification of similar unknown constituents in other plants.
基金financially supported by the National Natural Science Foundation of China(No.81322051)the Project Funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions and the Fundamental Research Funds for the Central Universities(No.G140026)
文摘Aristolochiae Fructus, a Chinese herbal medicine derived from the fruit of Aristolochia contorta Bge., contains nephrotoxic aristolochic acid analogues(AAAs). According to ancient medical texts, various medicinal parts of the fruit of A. contorta were ever used. In order to reveal which part could be safely and effectively used, it is necessary to analyze the chemical profiles of different medicinal parts. Herein we compared the chemical compositions and determined aristolochic acid I(AA-I) and aristolochic acid II(AA-II) in the four parts viz. outer pericarp, inner pericarp, septum, and seed. Ultra-high performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry(UHPLC-QTOF-MS) was applied for chemical profiling. Ultra-high performance liquid coupled with triple quadrupole mass spectrometry(UHPLC-Qq Q-MS) was employed to quantify AA-I and AA-II in different parts. It was found that the chemical compositions of the four parts varied both qualitatively and quantitatively. A total of 10 AAAs, including 5 aristolochic acids and 5 aristolactams, together with 3 alkaloids, were unambiguously or tentatively identified by UHPLC-QTOF-MS. The quantitatively analytical results obtained by UHPLC-Qq Q-MS showed that AA-I and AA-II exclusively accumulate in the seeds of A. contorta. These findings provide supporting data for the rational selection of medicinal parts.
文摘Aristolochic acid(AA)is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines.AA is a causative agent for Chinese herbs nephropathy,a term replaced later by AA nephropathy.Evidence indicates that AA is nephrotoxic,genotoxic,and carcinogenic in humans;and it also induces tumors in the forestomach,kidney,renal pelvis,urinary bladder,and lung of rats and mice.Therefore,plants containing AA have been classified as carcinogenic to humans(Group 1)bytheInternational AgencyforResearchonCancer.In our laboratories,we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks.Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney,liver,and spleen of rats,as well as significant alteration of gene expression in both its target and nontarget tissues.AA treatments altered mutagenesis-or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling.We also applied benchmark dose(BMD)modeling to the 3-month AA-induced genotoxicity data.The obtained BMDL10(the lower 95%confidence interval of the BMD10 that is a 10%increase over the background level)for AA-induced mutations in the kidney of rats was about 7μg/kg body weight per day.This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression,microRNA expression,and proteomics;and presents updated information focused on AA-induced genotoxicity in rodents.
基金supported by National Major Scientific and Technological Special Project for “Significant New Drugs Development” (2018ZX09101002,2018ZX09101002-001-001,and 2018ZX09101002-001-002,China)sponsored by National Natural Science Foundation of China (81830054,91859205,81988101,81722034,and 81802878)+1 种基金Shanghai Pujiang Program (2019PJD059,China),Shanghai Sailing Program (18YF1400200,China)Key Discipline Project of Shanghai Municipal Education Commission (201901070007E00065,China)。
文摘Aristolochic acids(AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I(AAI) reacts with DNA to form covalent aristolactam(AL)-DNA adducts,leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in China's Mainland. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI-DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.
基金Supported by the Major National Science and Technology Project (No. 2018ZX09101-002)。
文摘Objective: To investigate the protective effects of Schisandra chinensis oil(SCEO) against aristolochic acid Ⅰ(AAⅠ)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism.Methods: C57BL/6 mice were randomly divided into 5 groups according to a random number table, including control group, AAⅠ group, and AAⅠ+SCEO(0.25, 0.5 and 1 g/kg) groups(n=5 per group). Pretreatment with SCEO was done for 2 days by oral administration, while the control and AAⅠ groups were treated with sodium carboxymethyl cellulose. Mice of all groups except for the control group were injected intraperitoneally with AAⅠ(5 mg/kg) from day 3 until day 7. Histopathological examination and apoptosis of kidney tissue were observed by hematoxylin and eosin and TdT-mediated dUTP nick-end labeling(TUNEL) staining, respectively. The levels of serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), blood urea nitrogen(BUN), and serum creatinine(SCr), as well as renal malondialdehyde(MDA), glutathione, r-glutamyl cysteingl+glycine(GSH), and superoxide dismutase(SOD) were analyzed using enzyme-linked immunosorbent assay(ELISA).Expressions of hepatic cytochrome P450 1A1(CYP1A1), CYP1A2, and nad(p)hquinonedehydrogenase1(NQO1) were analyzed using ELISA, quantitative real-time polymerase chain reaction(qPCR) and Western blot,respectively. In vitro, SCEO(40 μg/mL) was added 12 h before treatment with AAⅠ(40 μmol/mL for 48 h) in human renal proximal tubule cell line(HK-2), then apoptosis and reactive oxygen species(ROS) were analyzed by flow cytometry. Results: SCEO 0.5 and 1 g/kg ameliorated histopathological changes and TUNEL+ staining in the kidney tissues of mice with AAⅠ-induced nephrotoxicity, and reduced serum levels of ALT, AST, BUN and SCr(P<0.01 or P<0.05). SCEO 0.5 and 1 g/kg alleviated the ROS generation in kidney, containing MDA,GSH and SOD(P<0.01 or P<0.05). SCEO 1 g/kg increased the expressions of CYP1A1 and CYP1A2 and decreased NQO1 level in the liver tissues(P<0.01 or P<0.05). Besides, in vitro studies also demonstrated that SCEO 40 μg/mL inhibited apoptosis and ROS generation(P<0.05 or P<0.01). Conclusions: SCEO can alleviate AAⅠ-induced kidney damage both in vivo and in vitro. The protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and ROS production.
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0908000)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-C-202002)+3 种基金the National Natural Science Foundation of China(Grants No.82074098 and 81841001)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grants No.ZXKT18003,ZZ14-YQ-050,ZZ14-ND-010,ZZ15-ND-10,ZZ14-FL-002,ZZ14-YQ-059,and ZZ15-YQ-063)the Shenzhen Science and Technology Innovation Commission(Grants No.JCYJ20210324115800001 and JCYJ20210324114014039)the National Key R&D Program of China Key Projects for International Cooperation on Science,Technology and Innovation(Grant No.2020YFE0205100).
文摘Background:Aristolochic acids(AAs),a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants,are well-known to be responsible for inducing nephrotoxicity and urothelial carcinoma.Recently,accumulating evidence suggests that exposure to AAs could also induce hepatotoxicity and even hepatocellular carcinoma,though the mechanisms are poorly defined.Methods:Here,we aimed to dissect the underlying cellular and molecular mechanisms of aristolochic acid I(AAI)-induced hepatotoxicity by using advanced single-cell RNA sequencing(scRNA-seq)and proteomics techniques.We established the first single-cell atlas of mouse livers in response to AAI.Results:In hepatocytes,our results indicated that AAI activated NF-κB and STAT3 signaling pathways,which may contribute to the inflammatory response and apoptosis.In liver sinusoidal endothelial cells(LSECs),AAI activated multiple oxidative stress and inflammatory associated signaling pathways and induced apoptosis.Importantly,AAI induced infiltration of cytotoxic T cells and activation of proinflammatory macrophage and neutrophil cells in the liver to produce inflammatory cytokines to aggravate inflammation.Conclusions:Collectively,our study provides novel knowledge of AAs-induced molecular characteristics of hepatotoxicity at a singlecell level and suggests future treatment options for AAs associated hepatotoxicity.
文摘Aristolochic acid nephropathy(AAN)is a rapidly progressive interstitial nephritis leading to end-stage renal disease and urothelial malignancy.It was originally reported in Belgium in a group of more than 100 patients who had ingested slimming pills containing powdered root extracts of a Chinese herb,Aristolochia fangchzi.
基金supported by grants from "the National Science and Technoloyg Major Project" Key New Drug Creation and Manufacturing Program (2018ZX09101002-001-002)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No:ZYYCXTD-C-202005)
文摘Objective:Although some studies have linked Asari Radix et Rhizoma(Asari Radix)administration to hepatocellular carcinoma(HCC),few studies have examined the association between the development of HCC and use of Asari Radix among patients in China's Mainland.This study aimed to evaluate the realworld association between Asari Radix and HCC in patients to strengthen the understanding of Asari Radix safety.Methods:A retrospective cohort study among hepatitis B virus(HBV)-monoinfected patients and nonHBV-monoinfected patients were performed.Patients over 18 years of age were eligible for inclusion.Prescription records of inpatients and outpatients were inquired to distinguish Asari Radix users and nonusers.The risk of developing HCC among Asari Radix users and nonusers in the HBV cohort and the non-HBV cohort was analyzed.Results:There were 49500 HBV and 133148 non-HBV patients involved in the two cohorts.Among HBV patients(2901 users;46599 nonusers),the prevalence of HCC in Asari Radix users was lower than that in nonusers(145.70 vs.265.43 per 105).Among non-HBV patients(5042 users;128106 nonusers),the prevalence of HCC in Asari Radix users was lower than that in nonusers(81.62 vs.134.11 per 105).None of the hazard ratios(HRs)of Asari Radix exposure ranging from 1 g to 200 g in the two cohorts showed correlation between Asari Radix exposure and hepatocarcinogenesis.Conclusion:An obvious irrelevancy was found between the consumption of Asari Radix and HCC development both in patients with and in those without HBV infection.Use of Asari Radix under 200 g appears safe in terms of HCC risk in the Chinese population;further prospective studies are needed to confirm our results.
