To provide the basis for the future research on the nephrotoxicity of Chinese herbal medicine through systematic and comprehensive summary of all the Chinese herbal medicines which may lead to nephrotoxicity. Foreign resources included PubMed and Cochrane library， and domestic research resources was China Food and Drug Administration(CDFA) Adverse Drug Reaction Monitoring Center database. The databases were searched from establishment to January 1， 2017. There was no limitation on research type. 28 English studies were found， including 97 Chinese herbs or prescriptions with the risk of nephrotoxicity. The following six Chinese herbal medicines with the risk of nephrotoxicity had a large number of studies： aristolochic acid(5 studies)， Tripterygium wilfordii(4 studies)， Erycibe obtusifolia(2 studies)， Rheum palmatum(2 studies)， Ephedra sinica(2 studies)， and Atractylodes lances(2 studies). The remaining 91 Chinese medicines were reported with risk of nephrotoxicity in only 1 study respectively. CDFA reported 16 Chinese herbal medicines with the risk of nephrotoxicity， including Ganmaoqing Pian(capsule)， Zhenju Jiangya Pian， T. wilfordii preparation， Vc-Yinqiao Pian， Chuanhuning injection， Shuanghuanglian injection， Qingkailing injection， Lianbizhi injection， herbal decoction containing Aristolochiae Radix， Guanxin Suhe Wan， Shugan Liqi Wan， Ershiwuwei Songshi Wan， herbal decoction containing Aristolochia Fangchi， herbal granules containing root of Kaempfer Dutchmanspipe， Ganmaotong(tablets)， and Longdan Xiegan Wan. Currently， in addition to aristolochic acids， the most reported Chinese herbal medicine with the risk of nephrotoxicity is T. wilfordii preparation.
Aristolochia ; toxicity ; China ; Drugs, Chinese Herbal ; toxicity ; Ephedra sinica ; toxicity ; Humans ; Kidney ; drug effects ; Tripterygium ; toxicity

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-QqQ-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-QqQ-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.
Aristolochia ; chemistry ; Aristolochic Acids ; chemistry ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; chemistry ; Fruit ; chemistry ; Molecular Structure ; Tandem Mass Spectrometry

Aristolochia manshuriensis Kom (AMK) is an herb used as a traditional medicine; however, it causes side effects such as nephrotoxicity and carcinogenicity. Nevertheless, AMK can be applied in specific ways medicinally, including via ingestion of low doses for short periods of time. Non-alcoholic steatohepatitis (NASH) induced the hepatocyte injury and inflammation. The protective effects of AMK against NASH are unclear; therefore, in this study, the protective effects of AMK ethyl acetate extract were investigated in a high-fat diet (HFD)-induced NASH model. We found decreased hepatic steatosis and inflammation, as well as increased levels of lipoproteins during AMK extract treatment. We also observed decreased hepatic lipid peroxidation and triglycerides, as well as suppressed hepatic expression of lipogenic genes in extract-treated livers. Treatment with extract decreased the activation of c-jun N-terminal kinase 1/2 (JNK1/2) and increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). These results demonstrate that the protective effect of the extract against HFD-induced NASH occurred via reductions in reactive oxygen species production, inflammation suppression, and apoptosis related to the suppression of JNK1/2 activation and increased ERK1/2 phosphorylation. Taken together, these results indicate that that ethyl acetate extract of AMK has potential therapeutic effects in the HFD-induced NASH mouse model.
Animals ; Apoptosis ; Aristolochia* ; Diet, High-Fat ; Eating ; Fatty Liver* ; Hepatocytes ; Inflammation ; JNK Mitogen-Activated Protein Kinases ; Lipid Peroxidation ; Lipoproteins ; Liver ; Medicine, Traditional ; Mice* ; Non-alcoholic Fatty Liver Disease ; Phosphorylation* ; Phosphotransferases* ; Reactive Oxygen Species ; Therapeutic Uses ; Triglycerides

The renal toxicity and mutagenicity of aristolochic acid (AA) as well as its carcinogenicity on upper urinary tract transitional epithelial cells have been widely known. Since 2003, drug regulatory departments have successively cancelled the quality standards for AA-containing medicines such as Aristolochiae Radix, Aristolochiae Manshuriensis Caulis and Aristolchiae Fangchi Radix, and adopted measures for strengthening regulation and revising package insert or quality standards for other AA-containing medicines, including Aristolochia Cinnabarina Radix, Aristolochiae Fructus, Aristolochiae Mollissimae Herba, in order to control its safety risk. In recent years, domestic and foreign studies on AA have mainly involved action mechanism and clinical performance of AA toxicity, early-stage diagnosis and treatment method. In this paper, authors gave a brief summary and evaluation on risk factors for using AA-containing medicines, and offered measures and suggestions for preventing and controlling AA toxicity.
Animals ; Aristolochia ; adverse effects ; chemistry ; Aristolochic Acids ; analysis ; therapeutic use ; toxicity ; Drug Therapy ; Drug-Related Side Effects and Adverse Reactions ; epidemiology ; etiology ; Drugs, Chinese Herbal ; analysis ; therapeutic use ; toxicity ; Humans

In order to identify Aucklandiae Radix, Vladimiriae Radix, Inulae Radix, Aristolochiae Radix and Kadsurae Radix using ITS2 barcodes, genomic DNA from sixty samples was extracted and the ITS2 (internal transcribed spacer) regions were amplified and sequenced. The genetic distances were computed using MEGA 5.0 in accordance with the kimura 2-parameter (K2P) model and the neighbor-joining (NJ) phylogenetic tree was constructed. The results indicated that for Aucklandiae Radix (Aucklandia lappa), Vladimiriae Radix (Vladimiria souliei and V. souliei var. cinerea), Inulae Radix (Inula helenium), Aristolochiae Radix (Aristolochia debilis) and Kadsurae Radix (Kadsura longipedunculata), the intra-specific variation was smaller than inter-specific one. There are 162 variable sites among 272 bp after alignment of all ITS2 sequence haplotypes. For each species, the intra-specific genetic distances were also smaller than inter-specific one. Furthermore, the NJ tree strongly supported that Aucklandiae Radix, Vladimiriae Radix, Inulae Radix, Aristolochiae Radix and Kadsurae Radix can be differentiated. At the same time, V. souliei (Dolomiaea souliei) and V. souliei var. cinerea( D. souliei var. cinerea) belonging to Vladimiriae Radix were clearly identified. In conclusion, ITS2 barcode could be used to identify Aucklandiae Radix, Vladimiriae Radix, Inulae Radix, Aristolochiae Radix and Kadsurae Radix. Our study may provide a scientific foundation for clinical safe use of the traditional Chinese medicines.
Aristolochia ; classification ; genetics ; Base Sequence ; DNA Barcoding, Taxonomic ; methods ; DNA, Plant ; genetics ; DNA, Ribosomal Spacer ; genetics ; Drugs, Chinese Herbal ; chemistry ; classification ; Molecular Sequence Data ; Phylogeny ; Plants, Medicinal ; classification ; genetics ; Quality Control

OBJECTIVETo establish a model of gastric precancerous lesion by using Aristolochic manshuriensis which contains aristolochic acids.

METHODThe SD rats were randomly divided into four groups: control and three different doses of ethanol extractive of A. manshuriensis (EEA) (corresponding to aristolochic acid I 2.5, 5.0, 10.0 mg x kg(-1)), respectively. EEA was intragastrically given to rats every other day. At the end of the 10th, 15th, 20th week, part of the rats in each group was sacrificed and the stomachs were weighed. The gastric tumor was assessed by the weight and the relative stomach weight to the body weight. The stomachs were fixed in 4% neutral formalin, and the paraffin imbedding tissues were sliced and HE stained. Histomorphology was observed under the light microscope to determine gastric hyperplasia, mucosa precancerosis (atypical hyperplasia) and gastric cancer formation.

RESULTThe rats treated with different doses of EEA for 10 weeks induced mucosa papillary, epithelioma hyperplasia. Histological observation showed mucosa precancerosis lesions characterized as atypical hyperplasia at the dose levels corresponding to aristolochic acid I 5.0 and 10.0 mg x kg(-1) treated for 10 weeks. The incidence rate of gastric precancerosis in those two groups was 100% at the 15th week. Malignant tumors were observed in most of the animals in 10.0 mg x kg(-1) group. The animals in 5.0 mg x kg(-1) group were well tolerant compared to 10.0 mg x kg(-1) group during the course of experiment, so the dose of aristolochic acid I 5.0 mg x kg(-1) and 10-15 weeks treatment were considered to be optimum to establish the model of gastric precancerosis.

CONCLUSIONA rat model of gastric precancerosis can be induced within a short duration by giving an oral administration of the ethanol extract of A. manshuriensis which contains aristolochic acids.

Animals ; Aristolochia ; chemistry ; Aristolochic Acids ; administration & dosage ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Male ; Rats ; Stomach Neoplasms ; drug therapy ; pathology

OBJECTIVECombined the blood biochemical markers, the renal histopathological changes and the metabonomics profile were investigated to study the toxicity differences between Aristolochia fangchi and Stephania tetrandra.

METHODTen rats were randomly selected from 70 male Wistar rats as blank control group. The remaining 60 rats were divided into three groups. The two treated groups were orally administrated by 8.1 g x kg(-1) of A. fangchi and S. tetrandra respectively and the control group by equal volume of distilled water for 4weeks. Before the administrated and every 2 weeks, urine and plasma were collected and their 1H-NMR spectra were acquired, and then subjected to data process and PCA. Blood biochemical analysis and histopathological examination were carried out.

RESULTOn the 2nd weekend, the BUN of the two treated groups, the AST of A. fangchi group were all markedly higher than that of the control group (P < 0.05). Compared with the A. fangchi group, the SCr higher in the S. tetrandra group (P < 0.05). The kidney pathological changes were apparently in the two treated groups and the pathological changes in the liver apparently in the S. tetrandra group. Along with the lasting of administration to the 4th week, the BUN, ALT and AST of the two treated groups, the SCr of A. fangchi group were all significantly higher than that of the control group (P < 0.01). The renal and liver injuries in the two treated groups were all become more seriously. Comparing the A. fangchi group, the BUN, SCr and AST were all higher in the S. tetrandra group (P < 0.05). Compared with control group, the urinary concentrations of citrate, 2-oxo-glutarate, taurine, hippurate, TMAO, creatine and the plasma concentrations of 3-D-hydroxybutyrate, acetone, NAC, OAC, creatinine were all changed.

CONCLUSIONThe A. fangchi and S. tetrandra all can induce the renal and liver lesion and its seriousness is correspondent to the lasting of administration. The liver and kidney toxicity of S. tetrandra are all more serious than the A. fangchi.

Animals ; Aristolochia ; chemistry ; Blood Chemical Analysis ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal ; administration & dosage ; adverse effects ; metabolism ; Kidney ; chemistry ; drug effects ; metabolism ; pathology ; Liver ; chemistry ; drug effects ; metabolism ; pathology ; Male ; Metabolomics ; Random Allocation ; Rats ; Rats, Wistar ; Stephania tetrandra ; chemistry ; Urine ; chemistry

OBJECTIVETo study the chemical constituents of the fruit of Aristolochia contorta.

METHODThe compounds were isolated by chromatographic techniques and crystalization, the structures were elucidated by spectrum analysis.

RESULTFifteen compounds were isolated from the dry fruit of A. contorta, which were six aristolochic acids: aristolochic acid I, aristolochic acid III a, aristolochic acid IVa, aristolochic acid II, aristolochic acid III and aristolochic acid VIIa. Three aristolactams: aristololactam I, aristololactam II and aristololactam IIIa. Three phenolic acids syringic acid, vanillic acid and p-coumaric acid. Three other type compounds: pentacosane acid, beta-sitosterol and daucossterol.

CONCLUSIONAristolochic acid III, aristolochic acid VIIa, aristololactam IIIa, and penfacosane acid were isolated from A. contorta for the first time, and compounds 4-13 were isolated from the furit of A. contorta for the first time.

Aristolochia ; chemistry ; Fruit ; chemistry ; Plant Extracts ; analysis ; isolation & purification

OBJECTIVETo evaluate the toxicity of Radix Aristolochiae supplied experimental evidence of rational use of drug in clinic.

METHODAfter treatment with small dose Radix Aristolochiae, Guanxin Suhe Wan (with Radix Aristolochiae) and Guanxin Suhe Wan (without Radix Aristolochiae) in different group for a long- term, respectively, the biochemical indicator of PT, ALT, AST, ALB, ALP, Crea and BUN were detected, and the kidney, liver, stomach and urinary bladder were examined by pathologic assaying.

RESULTIn Radix Aristolochiae group and Guanxin Suhe Wan (with Radix Aristolochiae) group, all of biochemical indicator were changed significantly, and hepatonecrosis, renal tubular necrosis, gastric carcinoma and bladder carcinoma were discovered.

CONCLUSIONRadix Aristolochiae and Guanxin Suhe Wan (with Radix Aristolochiae) can damage kidney and liver, and cause gastric carcinoma and bladder carcinoma by intensive toxicity.

Animals ; Aristolochia ; chemistry ; toxicity ; Drugs, Chinese Herbal ; toxicity ; Kidney ; drug effects ; metabolism ; pathology ; Liver ; drug effects ; metabolism ; pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Stomach Neoplasms ; chemically induced ; Urinary Bladder ; drug effects ; metabolism ; pathology ; Urinary Bladder Neoplasms ; chemically induced

OBJECTIVETo analyze LC-MS fingerprints of Aristolochia manshuriensis for quality assessment with two different chemical pattern recognition models.

METHODLC-MS fingerprints of A. manshuriensis were established from 24 batches of samples from different habitats. SIMCA and Clustering analysis were used to compare the parameters of the 29 common peaks.

RESULTTwo methods had good consistency, while they reflected the inherent sample information from different perspectives, respectively.

CONCLUSIONModern equipment analysis technology and multivariable chemical pattern recognition would be an efficient way for quality control and variety identification of A. manshuriensis.

Aristolochia ; chemistry ; classification ; Chromatography, Liquid ; Cluster Analysis ; Drugs, Chinese Herbal ; chemistry ; Mass Spectrometry ; Phylogeny ; Quality Control