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Objective To investigate the mechanism of action of Astragali Radix (AR) extract in improving aristolochic acid Ⅰ (AAⅠ)-induced acute liver and renal injury in mice by regulating the IL-6/STAT3 signaling pathway. Methods A total of 38 healthy male C57BL/6 mice were randomly divided into normal group with 8 mice, model group with 10 mice, AR group with 10 mice, and N-Acetyl-L-cysteine (NAC) group with 10 mice. The model group mice were intraperitoneally injected with 20 mg/kg AAⅠ once a day for 5 days. Normal mice were intraperitoneally injected with the same volume of Carboxymethyl cellulose sodium. AR group and NAC group received intraperitoneal injection of 20 mg/kg AAⅠ once a day for 3 days; On the 4th day, mice were gavaged with AR 75 mg/kg and NAC 150 mg/kg body mass doses, once a day, for 8 days. NAC was used as a positive control drug. After the end of administration and modeling, the mice were sacrificed to collect serum samples and liver and renal tissue samples. The kit was used to measure the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), and blood urea nitrogen (BUN); HE staining was used to observe liver and renal histopathology; quantitative real-time PCR and immunohistochemistry were used to measure the expression level of p-STAT3 in the liver and renal tissue; ELISA was used to measure the expression levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the liver and renal tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the SNK-q test was used for further comparison between two groups. Results Compared with the normal group, the model group had a significant increase in kidney-to-body ratio (P＜0.05). Compared with the model group, the AR group had significant reductions in the levels of ALT, AST, SCr, and BUN (F=49.29, 31.31, 58.89, and 85.88, all P＜0.01). HE staining showed that AR could effectively alleviate AAⅠ-induced structural damage and inflammatory cell infiltration in the liver and renal tissue; quantitative real-time PCR and immunohistochemistry showed that AR could reduce the expression of p-STAT3 in the liver and renal tissues; ELISA showed that AR could downregulate the expression of IL-6, IL-1β, and TNF-α. NAC and AR had a similar effect with no significant differences. Conclusion AR exerts a protective effect against AAⅠ-induced acute liver and renal injury, possibly by inhibiting the activation of the IL-6/STAT3 signaling pathway and alleviating inflammatory response. [ABSTRACT FROM AUTHOR]

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Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To investigate the molecular mechanism of aristolochic acid I (AAI) inducing acute hepatotoxicity in mice. Methods A total of 15 male C57BL/6 mice were randomly divided into normal group with 6 mice and treatment group with 9 mice. The mice in the treatment group were given intraperitoneal injection of AAI at a dose of 20 mg/kg for 5 consecutive days and were sacrificed to collect samples on day 6. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, and HE staining was used to observe liver histological changes; three liver tissue samples were randomly selected from each group, and RNA was extracted for high-throughput transcriptome sequencing. Bioinformatics analysis and functional prediction were used to screen out differentially expressed genes, and quantitative real-time PCR (qRT-PCR) was used for validation. The t-test was used for comparison of continuous data between two groups. Results Compared with the normal group, the treatment group had significant increases in the activities of ALT and AST (t=4.331 and 4.947, both P < 0.01), as well as disordered structure of hepatic lobules and spotted necrosis in hepatic lobules shown by HE staining. A total of 1352 differentially expressed genes were obtained based on the screening conditions of logFC > 2 and P < 0.05, among which there were 703 upregulated genes and 649 downregulated genes. The GO and KEGG enrichment analyses of these differentially expressed genes showed significant enrichment in GO terms (such as small molecular catabolism, immune response involving neutrophils, cytoplasmic vesicle lumen in secretory granules, cytoplasmic vesicle lumen, extracellular structural organization, and extracellular matrix) and KEGG pathways (such as chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, steroid hormone biosynthesis, transcriptional dysregulation in cancer, protein digestion and absorption, regulation of TRP channel by inflammatory mediators, drug metabolism, complement and coagulation cascade, glutathione metabolism, and the PPAR signaling pathway). A cluster analysis (P < 0.05) showed that significantly downregulated genes included Srd5a1, Lipc, Aqp8, Hba-a1, Slco1a1, and Pklr, which were validated by qRT-PCR (all P < 0.05). Conclusion AA I can lead to significant acute hepatotoxicity, which mainly involves the processes such as chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, steroid hormone biosynthesis, and transcriptional dysregulation in cancer. [ABSTRACT FROM AUTHOR]

To investigate the effect of astragaloside IV on the polarization of RAW264.7 cells induced by aristolochia acid to M1-type, and to explore its possible mechanism. Aristolocholic acid and Lipopolysaccharide (LPS) were used to stimulate RAW264.7 cells for 24 h successively, with or without astragaloside IV for drug intervention. Cell counting kit-8 (CCK-8) was used to detect the change of cell activity, flow cytometry was used to detect the type of macrophages, and enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of interleukin-6 (IL-6) and tumor necrosis factor - α(TNF-α) in cell supernatant. The expression of IL-6 and TNF-αmRNA in RAW264.7 cells were detected by real-time quantitative reverse transcription PCR (RT-qPCR). The protein expression levels of p-p38 and p38 MAPK in RAW264.7 cells were detected by Western blot. The results of CCK8 indicated that astragaloside IV had no obvious toxicity to RAW264.7 macrophages in the concentration range of 5-50 滋g/ mL, and 10 滋g/ mL was selected as the experimental intervention concentration in this study. Astragaloside IV could significantly improve the increase of macrophage activity induced by aristolochic acid (P<0.05), and decreased the secretion and expression levels of IL-6, TNF-αand mRNA expression (all P<0.05), inhibit the increase of M1/M2 macrophage ratio induced by aristolochic acid and LPS (P<0.05). Astragaloside IV could partially inhibited the increased phosphorylation of p38 MAPK in macrophages induced by aristolochic acid (P<0.05). Astragaloside IV can reduce the M1-type polarization of macrophages, reduce the levels of inflammatory cytokines IL-6 and TNF-α, and reduce the activity of macrophages, thus playing a role in slowing the renal damage of aristolochian acid. The mechanism of action may be related to the partial inhibition of p38 MAPK signaling activity. [ABSTRACT FROM AUTHOR]

In order to study the variation of volatile components from dried leaves of different Aristolochia delavayi populations, solid-phase microextraction followed by gas chromatography coupled with mass spectrometry detection was used to analyze the chemical composition of these plants. The relative amount of each compound was determined by area normalization method. The results showed that the main volatile component of dry leaves was (E)-2-Decenal, which accounted for 63.5%, 79.3%, 69.9%, 79.6% of the total volatile components, detected in the four populations of Shangri-La, Lijiang, Chuxiong, Luquan, respectively. However, the samples belonging to the Huangping population, Heqing County, showed a different volatile component pattern. The main volatile component from this population was bornyl acetate(30.1%) and (E)-2-Decenal only accounted for 4.5%, which was significantly lower than that of in the samples of the other four populations, and the possible reasons for the difference were analyzed and discussed. By analyzing the content of volatiles components in the leaves of A. delavayi, we identified the excellent germplasm of A. delavayi. At the same time, the healthy and safe eating methods were put forward according to the situation of aristolochic acid contained in the plant. The study also provides technical guidance and theoretical support for rational use of this traditional medicinal plant species and protection this endangered species in China. [ABSTRACT FROM AUTHOR]

Aristolochic acids (AAs), derived from aristolochia plant species, are a mixture of structural-related compounds. Aristolochic acid Ⅰ and aristolochic acid Ⅱ are reported to be the major components that are associated with kidney damage toxicity and carcinogenic mutagenicity toxicity. Since the toxicity mechanism of action of Aristolochic acids are still unclear, it is necessary to develop a sensitive analytical method to facilitate these studies. In this work, a rapid and sensitive method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was applied for the determination of aristolochic acid Ⅰ, aristolochic acid Ⅱ and their major metabolites in samples from in vitro metabolism studies. Aristolochic acid Ⅰ and aristolochic acid Ⅱ were incubated with rat liver microsome S9 fractions under aerobic and anaerobic conditions. The incubation samples were analyzed by HPLC-MS/MS. The obtained results showed that the in vitro metabolic pathways of aristolochic acid Ⅰ and aristolochic acid Ⅱ are different. The metabolites of aristolochic acid Ⅰ was detected and characterized as aristolochic acid Ⅰa under aerobic condition and aristololactam Ⅰ under anaerobic condition, respectively; however, in the case of aristolochic acid Ⅱ, the only metabolite of aristolochic acid Ⅱ was identified as aristololactam Ⅱ under the anaerobic condition. Besides, the fragmentation behaviors of aristolochic acid Ⅰ, aristolochic acid Ⅱ and their metabolites in rat liver microsomes S9 fractions were characterized and summarized. The results indicated that the production of aristololactams is the main cause of the toxicity of aristolochic acid Ⅰ and aristolochic acid Ⅱ in the metabolism of rat liver microsome S9. This study have a certain significance for better understanding of the toxicity mechanism of action of aristolochic acid Ⅰ and aristolochic acid Ⅱ, as well as for toxicity monitoring of aristolochia plants. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the changes in renal oxygenation in rats with acute aristolochic acid nephropathy using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) at 7.0T., Methods: Wistar rats were randomly divided into AAN group ( n =18) and control group ( n =6) for intraperitoneal injections of AAI at 40 mg/kg and PEG400, respectively, on a daily basis for 6 consecutive days. All the control rats and 6 rats from AAN group underwent BOLD MRI scan before and at 2, 4, and 6 days after the initial injection for measuring renal cortical and medullary R2 * values. At each of the 4 time points, 3 rats in AAN group were sacrificed for histological evaluation; the control rats were examined at 6 days after the initial injection., Results: The cortical and medullary R2 * values of the rats in AAN group on days 4 and 6 were significantly higher than those in the control group ( P &lt; 0.05). In AAN group, the cortical R2 * values showed no obvious changes on day 2 as compared with the baseline values, but increased significantly on day 4 ( P &lt; 0.05) and day 6 ( P &lt; 0.01); the medullary R2 * values increased progressively and were significantly higher than the baseline values on day 4 ( P &lt; 0.01) and day 6 ( P &lt; 0.01). In the control group, no significant changes were detected in either cortical or medullary R2 * values throughout the experiment., Conclusions: BOLD MRI allows non-invasive measurement of renal oxygenation levels in rats with AAN. The increase of renal cortical and medullary R2 * values, and particularly the latter, indicates a lowered renal oxygenation level, which provides potentially useful information for clinical decisions.

On October 18th, 2017, a research article named "Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia" was published on Science Translational Medicine. This article pointed out that herbs containing aristolochic acids could cause liver cancer by inducing the specific "aristolochic acids mutational signature". The public was also suggested to avoid the intake of herbs containing aristolochic acids. Since 2000, CFDA has gradually abolished the medicinal standards for herbs containing aristolochic acids such as caulis aristolochiae manshuriensis, aristolochia heterophylla and radix aristolochiae. Related drugs have been strengthened supervision since then. Chinese Pharmacopoeia has also removed the records of a series of related herbs. State Administration of Traditional Chinese Medicine held a conference on the "toxicity" of aristolochic acids as soon as the article was published. After a discussion of the studies on the toxicity of aristolochic acids, experts attending the meeting discovered several problems, including the unclearness of exposure history, tumor-producing dose and latent period, the absence of some key factors such as hepatitis B, the small sample size, miscellaneous factors, incomplete evidence chains, the missing of analyses between data with huge differences, the insufficiency of fundamental research arguments, etc. In order to understand the toxicity of aristolochic acids and the carcinogenic risks, as well as guide clinical safe medication, the experts suggested that：①Complete the systematical evaluation of aristolochic acids carcinogenicity as soon as possible. Scientifically elucidate the relationship between aristolochic acids and the genesis of liver cancer. ②Establish medication risk warnings of aristolochic acids and strengthen the supervision. ③Make an in-depth study of the toxicity of traditional Chinese medicine. Find out the adverse effects of all traditional Chinese medicine step by step., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

It is urgent to establish the limit standard of toxic components of Chinese herbal medicine, since the safety of traditional Chinese medicine (TCM) has attracted more and more attention.This paper analyzes the present situation and problems in the study of the limit standard of toxic components of Chinese herbal medicine. In addition, the current methods for setting the limit standards of toxic ingredients of TCM are reviewed in this paper, and we also propose a theoretical calculation method for setting the limit standards of toxic ingredients of TCM. Employing aristolochic acid as a case study, we formulate the limit standard of toxic components of Chinese herbal medicine. We believe this paper would provide some useful suggesting for formulating limits standard of toxic components of TCM., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)