Human AKR1A1 involves in metabolic activation of carcinogenic aristolochic acidⅠ

OBJECTIVE To investigate whether aldo-keto reductases(AKRs)can act as a nitrore⁃ductase(NR)and bioactivate aristolochic acidⅠ(AA-Ⅰ)to produce AA-Ⅰ-DNA adducts.METHODS①Human-induced hepatocytes(hiHeps)and human bladder RT4 cells were used as tool cells and treated with AA-Ⅰ0,0.5,1.0 and 2μmol·L^(-1)for 24 h.Cell viability was detected using the CCK-8 method,and the half maximal inhibition concentration(IC_(50))was calculated using the CCK-8 method and the level of DNA adduct production was calculated.②hiHeps and RT4 cells were treated with AKR inhibitor luteotin(0,5,10 and 25μmol·L^(-1))+AA-Ⅰ0.2 and 1.0μmol·L^(-1)for 24 h,respectively,and the levels of DNA adducts were detected by a liquid chromatography-tandem mass spectrometer(LC-MS/MS).③hiHeps cells were incubated with 80 nmol·L^(-1)small interfering RNAs(si-AKRs)for 48 h and treated with AA-Ⅰ1.0μmol·L^(-1)for 24 h.Real-time qualitative PCR(RT-qPCR)method was used to detect the mRNA expression of AKRs gene and LC-MS/MS technology was used to investigate the effect of specific AKR gene knockdown on DNA adduct levels.④500 nmol·L^(-1)human AKR recombinant proteins AKR1A1 and AA-Ⅰwere incubated in vitro under anaerobic conditions and the formation of AA-Ⅰ-DNA adducts was detected.RESULTS①The IC_(50)of AA-Ⅰto hiHeps and RT4 cells was 1.9 and 0.42μmol·L^(-1),respec⁃tively.The level of DNA adduct production of the two cell lines was significantly different(P<0.01).②Luteolin≥5μmol·L^(-1)significantly inhibited the production of AA-Ⅰ-DNA adducts in both cells(P<0.05),and there was a concentration-dependent effect in hiHeps cells(P<0.01,R=0.84).③In the AKR family,the knockdown of AKR1A1 gene up to 80%inhibited the generation of AA-Ⅰ-DNA adducts by 30%-40%.④The AA-Ⅰ-DNA adducts were detected in the incubation of recombinant protein AKR1A1 and AA-Ⅰunder anaerobic conditions in vitro,approximately 1 adduct per 107 nucleotides.CONCLU⁃SION AKR1A1 is involved in AA-Ⅰbioactivation,providing a reference for elucidation of the carcino⁃genic mechanism of AA-Ⅰ.

超高效液相-质谱法测定滴通鼻炎水中马兜铃酸Ⅰ、Ⅱ的含量

目的测定滴通鼻炎水中马兜铃酸Ⅰ、马兜铃酸Ⅱ的含量,为其质量控制提供借鉴。方法采用超高效液相-质谱法(UPLC-MS/MS)同时测定滴通鼻炎水中马兜铃酸Ⅰ、马兜铃酸Ⅱ的含量。色谱柱采用Waters-ACQUI UPLC HSS T3 C_(18)(2.1 mm×100 mm,1.8μm),采用乙腈为流动相A,0.1%甲酸含1 mmol·L^(-1)乙酸铵溶液为流动相B,梯度洗脱,电喷雾离子源(ESI),正离子多反应监测模式,以标准曲线法计算含量。结果17批滴通鼻炎水中有9批样品未检出马兜铃酸Ⅰ(检出限0.13 pg),8批样品中检出马兜铃酸Ⅰ,含量在0.41~3.60 ng·mL^(-1)。所有样品中均未检出马兜铃酸Ⅱ(检出限0.41 pg)。结论建立了UPLC-MS/MS同时测定滴通鼻炎水中马兜铃酸Ⅰ、马兜铃酸Ⅱ含量的方法,该方法专属性强、灵敏度高、重复性好,可为滴通鼻炎水中马兜铃酸Ⅰ、马兜铃酸Ⅱ的质量控制提供参考。

EFFECTS OF PROSTAGLANDIN E1 ON THE PROGRESSION OF ARISTOLOCHIC ACID NEPHROPATHY

Objective To investigate the effects of prostaglandin E1 (PGE1) on the progression of aristolochic acid nephropathy (AAN). Methods Twenty-four patients diagnosed as AAN with serum creatinine (Scr) between 1.5 mg/dL and 4 mg/dL during September 2001 to August 2003 were randomly divided into 2 groups. All patients had ingested long dan xie gan wan con-taining aristolochic acid (0.219 mg/g) for at least 3 months. Twelve patients were injected with Alprostadil (10 μg/d for 10 days in one month, summing up to 6 months). Except for PGE1, the other therapy was same in both groups. Renal function was assessed using reciprocal serum creatinine levels (1/Scr). Results The level of Scr and serum hemoglobin (Hgb) was similar in both groups prior to therapy. During follow-up, 1/Scr levels in PGE1 group were significantly higher than control group (P < 0.01), and Hgb levels in PGE1 group were sig-nificantly increased compared with control (P < 0.05).Conclusion PGE1 can slow the progression of renal failure and increase Hgb level of AAN patient.

NMR Studies on the Subacute Biochemical Effects of Aristolochic Acid on Rat Serum

The subacute effect of aristolochic acid （AA） on rat serum was studied by NMR method. The biochemical effects induced by AA were characterized by an increase in the amounts of creatinine, trimethylamine N-oxide, acetoacetate, acetate and 3-D-hydroxybutyrate and lactate in serum from ^1H NMR spectra. Principal component analysis was used for further comparing the similarities of ^1H NMR spectral profiles of serum from rats treated with AA and model toxins.

超高效液相色谱串联质谱法测定复方胃痛胶囊中马兜铃酸Ⅰ、马兜铃酸Ⅱ的含量

目的建立UPLC-MS/MS同时测定复方胃痛胶囊中马兜铃酸Ⅰ和马兜铃酸Ⅱ含量的方法。方法采用Agilent Poroshell SB-C18色谱柱(100 mm×2.1 mm,2.7μm);流动相为乙腈和含5 mmol/L甲酸铵的0.1%甲酸溶液,梯度洗脱,流速为0.3 mL/min,柱温为30℃;采用三重四级杆质谱检测器,电喷雾离子源(ESI)正离子模式下多反应监测(MRM)模式进行质谱检测。结果马兜铃酸Ⅰ和马兜铃酸Ⅱ分别在1.05~210 ng/mL(r=0.9996)和1.00~200 ng/mL(r=0.9998)有良好的线性关系。马兜铃酸Ⅰ的回收率为95.90%,RSD为2.11%;马兜铃酸Ⅱ的回收率为93.22%,RSD为1.17%。马兜铃酸Ⅰ的定量限为0.3 pg、检出限为0.1 pg;马兜铃酸Ⅱ的定量限为0.7 pg、检出限为0.2 pg。结论该方法专属性好,灵敏度高,准确可靠,能够用于测定复方胃痛胶囊中马兜铃酸Ⅰ和马兜铃酸Ⅱ的含量。

Nephrotoxicity and carcinogenesis of aristolochic acids and their derivates

Aristolochic acids （AAs）, a natural mixture of 8-methoxy-6-nitro-phenanthro-（3,4-d）-1,3-dioxolo-5-carboxylic acid （AAI）and 6-nitro-phenanthro-（3,4-d）-1,3-dioxolo-5-carboxylic acid （AAII）, derived from aristolochiaceae species, has beenreported to cause AAS-induced nephropathy and upper urothelial cancer. In this review, we summarize the informationon the nephrotoxicity and carcinogenesis of AAs and their derivatives. AAs nephrotoxicity can lead to apoptosis andoxidative stress of renal tubular cells, and inhibition of the expression of aquaporins. AAs can also reduce the capabilityfor renal tubular epithelial cell repair after acute injury and further produce renal fibrosis by activating TGF-β-Smadsignaling and promoting the migration of macrophages. Moreover, AAs-induced carcinogenesis may be due to theformation of covalent adducts with DNA which can lead to the mutation in certain tumor suppressor genes orproto-oncogenes and the different catalyzing capacity of the microsomal cytochrome P450 of individuals in AAImetabolism.

Improved preparation and identification of aristolochic acid-DNA adducts by solid-phase extraction with liquid chromatography-tandem mass spectrometry

Aristolochic acid （AA） is a known nephrotoxin and potential carcinogen, which can form covalent DNA adducts after metabolic activation in vivo and in vitro. A simple method for preparation and characterization of aristolochic acid-DNA adducts was developed. Four AA-adducts were synthesized by a direct reaction of AAI/AAII with 2′-deoxynucleosides. The reaction mixture was first cleaned-up and pre-concentrated using solid phase extraction （SPE）, and further purified by a reversed-phase high performance liquid chromatography （HPLC）. By the application of developed SPE procedure, matrices and byproducts in reaction mixture could be greatly reduced and adducts of high purity （more than 94% as indicated by HPLC） were obtained. The purified AA-DNA adducts were identified and characterized with liquid-electrospray ionization-quadrupole-time of flight-mass spectrometry （LC-ESI-Q-TOF-MS/MS） and LC-Diode array detector-fluorescence （LC-DAD-FL） analysis. This work provides a robust tool for possible large-scale preparation of AA-DNA adduct standards, which can promote the further studies on carcinogenic and mutagenic mechanism of aristolochic acids.

人参再造丸中马兜铃酸Ⅰ的检测方法研究

目的建立人参再造丸中马兜铃酸Ⅰ的专属性检测方法,为人参再造丸的质量控制提供理论依据。方法通过液相色谱-质谱联用法对人参再造丸中的马兜铃酸Ⅰ进行含量测定。采用Poroshell 120 SB-C18色谱柱(100 mm×2.1 mm,2.7μm)进行分离,以0.1%甲酸溶液(含5 mmol/L甲酸铵)-乙腈为流动相进行梯度洗脱,柱温30℃,流速0.3 mL/min,在电喷雾离子化正离子模式下,进行多反应监测(MRM),外标法定量。结果马兜铃酸Ⅰ在0.2~40 ng/mL范围内线性关系良好(r=0.9993),平均回收率为112.3%(RSD=1.6%),方法重复性及精密度均良好。结论该方法操作简单,可用于人参再造丸中马兜铃酸Ⅰ的含量测定。

A NEW ARISTOLOCHIC ACID FROM ARISTOLOCHIA CINNABARINA

A new compound, aristolochoc acid Ⅲ a- 6-0-β-D-glucoside, was isolated along with four known compounds from Aristolochia cinnabarina. The structure of the new,compound was elucidated on the basis of spectral evidences

Electrochemistry of aristolochic acid interacting with guanine

Interaction of Aristolochic acid （AA） and guanine （G） was studied by electrochemical techniques in this paper. When AA was added into the guanine solution, the oxidation peak currents of mixture solution decreased, while the peak potential and the electrochemical kinetic parameters remained the same as when AA was absent, except that the electrode process of guanine that involved two protons and two electrons changed from adsorption controlled to diffusion controlled. It is suggested that an electrochemical inactive supramolecular adduct AA-Gua （1：1） was formed in the system. The adduct cannot be oxidized on the glassy carbon electrode, which indirectly results in the decrease of the free concentration of guanine in the reaction solution and the decrease of peak currents. The binding constant （13） of this adduct is calculated as 7.14× 10^3 mol/L. The possible mechanism for the interaction of Aristolochic acid and DNA was proposed, that may provide a possible pathway for the nosogenesis research of aristolochic acid.

Chemical profiling of principle active and toxic constituents in herbs containing aristolochic acids

Objective:To clear the amounts of the principal active/toxic components in herbs containing aristolochic acids(HCAAs),which are still used as medicine and/or seasoning in many ethnic minority areas of China.Methods:In this study,six major active and toxic components in HCAAs were extracted with ultrasonic extraction.With 6-O-methyl guanosine as internal standard,the target compounds were analyzed qualitatively and quantitatively by using ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry(UPLC-ESI-MS/MS)with multiple reaction monitoringinformation dependent acquisition-enhanced production ion scanning mode(MRM-IDA-EPI)combined with dynamic background subtraction(DBS)function.Results:The method showed good linearity in the linear range of the six analytes.The limit range of detection was from 0.01 ng/mL to 0.27 ng/mL.All of the detection repeatability,extraction repeatability and accuracy of the method were good.After extraction,the samples remained stable at 15℃ within 24 h.Six analytes were all found in samples except aristolactam(AL)in sample 2,and the contents varied greatly.The contents of these compounds decreased in fruits,leaves and stems of Aristolochia delavayi successively.Conclusion:This method has the advantages of less sample dosage,simple operation,short analysis cycle,high sensitivity,specificity and accuracy.It laid a good foundation for guiding the safety of HCAAs,the indepth study of pharmacological and toxicological effects and the scientific and standardized processing and compatibility of HCAAs.

No Incidence of Liver Cancer Was Observed in A Retrospective Studyof Patients with Aristolochic Acid Nephropathy

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.

Activation of LONP1 by 84-B10 alleviates aristolochic acid nephropathy via re-establishing mitochondrial and peroxisomal homeostasis

Pharmaceutical formulations derived from Aristolochiaceae herbs, which contain aristolochic acids(AAs), are widely used for medicinal purposes. However, exposure to these plants and isolated AAs is linked to renal toxicity, known as AA nephropathy(AAN). Currently, the mechanisms underlying AAN are not fully understood, leading to unsatisfactory treatment strategies. In this study, we explored the protective role of 84-B10(5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl) phenyl] amino]-5-oxo-3-phenylpentanoic acid) against AAN. RNA-seq analysis revealed that the mitochondrion and peroxisome were the most affected cellular components following 84-B10 treatment in AAN mice. Consistently, 84-B10 treatment preserved mitochondrial ultrastructure, restored mitochondrial respiration, enhanced the expression of key transporters(carnitine palmitoyltransferase 2) and enzymes(acylCoenzyme A dehydrogenase, medium chain) involved in mitochondrial fatty acid β-oxidation, and reduced mitochondrial ROS generation in both aristolochic acid I(AAI)-challenged mice kidneys and cultured proximal tubular epithelial cells. Additionally, 84-B10 treatment increased the expression of key transporters(ATP binding cassette subfamily D) and rate-limiting enzymes(acyl-CoA oxidase 1) involved in peroxisomal fatty acid β-oxidation and restored peroxisomal redox balance. Knocking down LONP1 expression diminished the protective effects of 84-B10 against AAN, suggesting LONP1-dependent protection. In conclusion, our study provides evidence that AAN is associated with significant disturbances in both mitochondrial and peroxisomal functions. The LONP1 activator 84-B10 demonstrates therapeutic potential against AAN, likely by maintaining homeostasis in both mitochondria and peroxisomes.

黄芪提取物调节IL-6/STAT3信号通路治疗马兜铃酸Ⅰ诱导肝肾损伤小鼠模型的效果观察

目的探讨黄芪提取物(AR)改善马兜铃酸Ⅰ(AAⅠ)致小鼠急性肝、肾损伤效果及其调控IL-6/STAT3信号通路的作用机制。方法健康雄性C57BL/6小鼠38只,采用简单随机分组法分为正常组(n=8)、模型组(n=10)、AR组(n=10)和N-乙酰半胱氨酸(NAC)组(n=10)。模型组小鼠以20 mg/kg AAⅠ腹腔注射,1次/d,持续5 d。正常组小鼠腹腔注射相同容积羧甲基纤维素钠。AR组、NAC组20 mg/kg AAⅠ腹腔注射,1次/d,持续3 d;第4天分别按AR 75 mg/kg、NAC 150 mg/kg小鼠体质量剂量灌胃,1次/d,持续8 d。NAC为阳性对照药。给药造模结束后,处死小鼠并收集血清及肝、肾组织。试剂盒检测血清ALT、AST、肌酐(SCr)、尿素氮(BUN)水平;HE染色观察肝、肾组织病理;荧光PCR及免疫组化分析肝、肾组织中p-STAT3表达量;酶联免疫吸附实验检测肝、肾组织IL-6、IL-1β及TNF-α表达水平。计量资料多组间比较采用单因素方差分析,进一步两组间比较采用SNK-q检验。结果与正常组小鼠相比,模型组小鼠肾体比上升(P<0.05);与模型组相比,AR组ALT、AST、SCr和BUN水平显著降低(F值分别为49.29、31.31、58.89、85.88,P值均<0.01);HE染色结果表明,AR可有效减轻AAⅠ导致的肝、肾组织结构破坏和炎性细胞浸润;荧光PCR及免疫组化染色结果表明,AR可减少肝、肾组织p-STAT3表达;酶联免疫吸附检测发现,AR可下调IL-6、IL-1β及TNF-α表达。NAC与AR效应相似,两者间无明显差异。结论AR对AAⅠ所致急性肝、肾损伤有保护作用,其部分作用机制可能与抑制IL-6/STAT3信号通路激活,减轻炎症反应有关。

Synthesis, Crystal Structure and Antitumor Activity of a Na(Ⅰ) Coordination Polymer Based on 2-Propyl-4,5-imidazoledicarboxylic Acid and 1,10-Phenanthroline Ligands

A new Na(I) coordination polymer,[Na2(Hpimdc)(H2 pimdc)(phen)2]n(1), has been synthesized by the reaction of NaOH with 2-propyl-4,5-imidazoledicarboxylic acid(H3 pimdc)and 1,10-phenanthroline(phen). The Na(I) coordination polymer 1 was characterized by single-crystal X-ray diffraction analysis and elemental analysis. In 1, the bridged ligand H3 pimdc adopts two modes(singly deprotonated and doubly deprotonated) to coordinate with the Na(I) ion.The Na(1) ion is six-coordinated with three N atoms from a phen ligand and a H2 pimdc ligand,three O atoms from a Hpimdc ligand and two other different H2 pimdc ligands. The Na(2) ion is also six-coordinated with three N atoms from a phen ligand and a Hpimdc ligand, three O atoms from a H2 pimdc ligand and other two different Hpimdc ligands. Complex 1 exhibits a 1 D chain structure built up by μ-H2 pimdc-and μ-Hpimdc2-ligands. The antitumor activities of complex 1 against human SGC7901, A549 and H08910 cells have been tested.

超高效液相色谱-串联质谱法测定止嗽化痰丸中马兜铃酸Ⅰ和马兜铃酸Ⅱ的含量

建立止嗽化痰丸中马兜铃酸Ⅰ和马兜铃酸Ⅱ的含量测定方法,了解市售制剂中马兜铃酸Ⅰ和马兜铃酸Ⅱ的含量状况,为保障用药安全提供参考。采用超高效液相色谱-串联质谱法(UPLC-MS/MS),电喷雾离子源,正离子和多反应监测模式,对17批次止嗽化痰丸样品进行测定。结果显示,17批次止嗽化痰丸样品中,7批次样品同时检出马兜铃酸Ⅰ和马兜铃酸Ⅱ,马兜铃酸Ⅰ的含量范围为12.7~16.8μg/g,马兜铃酸Ⅱ的含量范围为1.4~1.8μg/g,其余样品均未检出马兜铃酸Ⅰ和马兜铃酸Ⅱ。研究建立的止嗽化痰丸中马兜铃酸Ⅰ和马兜铃酸Ⅱ的UPLC-MS/MS检测方法准确、可靠,可用于止嗽化痰丸中马兜铃酸Ⅰ和马兜铃酸Ⅱ的检测分析;同时,检测结果表明,部分止嗽化痰丸中马兜铃酸Ⅰ含量超出4.0μg/g,存在较大的安全风险,亟需建立相应的限量标准,控制该制剂中马兜铃酸Ⅰ的含量,保障用药安全。

Transgenic mice overexpressingγ-aminobutyric acid transporter subtypeⅠ develop obesity

Transgenic mice ubiquitously overexpressing murine γ aminobutyric acid transporter subtype Ⅰ were created. Unexpectedly, these mice markedly exhibited heritable obesity, which features significantly increased body weight and fat deposition. Behavioral examination revealed that transgeinc mice have slightly reduced spontaneous locomotive capacity and altered feeding pattern. Tills preliminary finding indicates that the inappropriate level of γ-aminobutyric acid transporters may be directly or indirectly involved in the pathogenic mechanism underlying certain types of obesity.

HPLC-MS/MS法同时测定龙胆泻肝丸中高毒成分马兜铃酸Ⅰ与鬼臼毒素

目的建立液相色谱-质谱联用法同时测定龙胆泻肝丸中高毒成分马兜铃酸Ⅰ与鬼臼毒素的研究方法,为龙胆泻肝丸的质量控制提供技术依据。方法采用Agilent InfinityLab Poroshell 120 EC-C_(18)色谱柱(100 mm×2.1 mm,2.7μm)分离,以0.1%甲酸溶液(含5 mmol·L^(-1)乙酸铵)-0.1%甲酸乙腈为流动相进行梯度洗脱,柱温35℃,流速0.3 mL·min-1,进样量为5μL。在电喷雾离子源正离子模式下,采用多反应监测方式测定,外标法定量。结果马兜铃酸Ⅰ与鬼臼毒素线性关系良好,线性范围分别为9.5~94.9 ng·mL^(-1)、10.0~99.7 ng·mL^(-1),r均大于0.9950。马兜铃酸Ⅰ与鬼臼毒素平均回收率大蜜丸分别为81.89%(RSD=8.55%)、84.34%(RSD=8.67%);小蜜丸分别为82.19%(RSD=7.63%)、96.05%(RSD=6.18%);浓缩丸分别为67.99%(RSD=6.70%)、94.98%(RSD=5.01%);水丸分别为75.98%(RSD=11.37%)、93.88%(RSD=6.01%)(n=18)。结论该方法操作简单,结果可行,可快速测定龙胆泻肝丸中高毒成分马兜铃酸Ⅰ与鬼臼毒素含量。

透明质酸联合注射血小板血浆及A型肉毒毒素对猪真皮Ⅰ型胶原蛋白表达的影响

目的探讨透明质酸联合A型肉毒毒素(botulinum toxin type-A,Botox A)和富含血小板血浆(platelet rich plasma,PRP)进行猪真皮内注射,检测真皮层成纤维细胞数目及Ⅰ型胶原蛋白mRNA分泌代谢的变化。方法采用巴马猪建立动物模型,使用交联透明质酸(cross-linked hyaluronic acid,HA)和非交联透明质酸(non-cross-linked hyaluronic acid,N-HA)分别与Botox A、PRP联合作为实验组(HA组、HA+Botox A组、HA+PRP组、N-HA组、N-HA+Botox A组、N-HA+PRP组),并与生理盐水组和正常组比较。于注射第1和4周后,通过组织切片染色、实时荧光定量聚合酶链反应(PCR)等方法,定性定量观察、比较真皮层成纤维细胞数量变化,真皮层Ⅰ型胶原蛋白mRNA分泌表达变化。结果HA组的成纤维细胞数量、Ⅰ型胶原蛋白mRNA表达量在第1周和第4周时比N-HA组高,并且HA+PRP组的成纤维细胞数量、Ⅰ型胶原蛋白mRNA表达水平显著高于同期HA+Botox A组、生理盐水组和正常组(P<0.05)。结论应用HA与PRP联合注射更易促进成纤维细胞的增殖和Ⅰ型胶原蛋白mRNA的表达,其主要机制可能是通过改变细胞外基质的理化性质进而促进真皮层细胞因子的合成,从而影响胶原合成。

含马兜铃酸的中药现状及相关问题思考

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