Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

Ji, Hongjian; Li, Jiayuan; Wu, Shifei; Wu, Wenyong; Yao, Changliang; Shuai, Yao; Guo, Dan

doi:10.3390/molecules26010044

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…AA and its derivatives cause nephrotoxicity and urinary tract tumors, an effect that has been widely recognized in the past few decades. 23 , 48 It has also been reported that long-term use of AAs-containing herbal remedies has been linked to tumors in multiple organs, including kidney, stomach, bladder, and subcutaneous tumors. 11 Although herbal preparations containing AAs have been phased out in multiple countries such as Japan, Canada, the UK, the USA, Australia, and Europe, 5 , 49 there are still some regions in which people are exposed to AAs by inadvertently taking certain herbal medicines.…”

Section: Discussionmentioning

confidence: 99%

“…Secondly, microenvironmental alterations associated with carcinogenesis due to AAI inducing A→T transversions will be needed. Thirdly, under the conditions of long-term induction of liver cancer by AAI and the presence of A→T transversions and AAI–DNA adducts, 20 , 23 it is urgent to dissect the development of liver carcinogenesis by single-cell sequencing and multi-omics combined analysis strategies.…”

Section: Discussionmentioning

confidence: 99%

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Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics

Luo

Chen

Zhang

et al. 2022

Precision Clinical Medicine

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Background Aristolochic acids (AAs), a class of carcinogenic and mutagenic natural products from Aristolochia and Asarum plants, are well-known 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 and results Here, we aimed to dissect the underlying cellular and molecular mechanisms of the 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. In hepatocytes, our results indicated that AAI activated NF-κB and STAT3 signaling pathways, which may contribute to 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 single-cell level and suggests future treatment options for AAs associated hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics

Luo

Chen

Zhang

et al. 2022

Precision Clinical Medicine

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“…The content of aristolochic acid (AA)-I in AR was limited to 0.001% by the Chinese pharmacopoeia in 2005. However, recent studies have shown that AAs such as AA-II, AA-III, AA-IVa, AA-VIIa, and aristololactam I (AL-I) possibly existing in AR [ 11 , 12 ] are also cytotoxic to renal tubular epithelial cells as AA-I more or less [ 13 – 16 ]. The standards of pharmacopoeia may neglect the toxicity of AAs other than AA-I.…”

Section: Introductionmentioning

confidence: 99%

Rapid and Simultaneous Quantification of Six Aristolochic Acids and Two Lignans in Asari Radix et Rhizoma Using Ultra-Performance Liquid Chromatography-Triple Quadrupole Tandem Mass Spectrometry

Liu

Cheng

Guan

et al. 2022

Journal of Analytical Methods in Chemistry

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Asari Radix et Rhizoma (AR) is a widely-used Chinese herbal medicine containing multiple active lignans and rare nephrotoxic components-aristolochic acids derivatives (AAs). However, the current quality control method carried out by Chinese Pharmacopoeia has defects in trace AAs detection and insufficient marker ingredients, which is unable to comprehensively evaluate the efficacy and safety of AR. To improve the quality control method of AR, a rapid, sensitive, and reliable chromatographic analytic method based on ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-QqQ-MS) was established for the simultaneous analysis of multiple AAs and lignans in AR samples. Positive electrospray ionization mode with multiple reaction monitoring (MRM) was applied for the detection of the eight analytes. The method showed available linearity (R2 ≥ 0.991), the limit of quantification (2–5 ng/mL), precision (RSD <8.12%), and accuracy (89.78–112.16%). A total of 6 AAs and 2 lignans were quantified for their content in 15 AR samples. The content of AA-IVa, AA-VIIa, and aristololactam I (AL-I) was much higher than the AA-I controlled by pharmacopoeia. Considering the potential toxicity of AAs, AA-IVa, AA-VIIa, and AL-I should also be controlled in AR. A considerable amount of active sesamin was detected in AR, suggesting that it could be added as a quality marker for the quality control of AR. The newly developed analytical method could be applied for the fast evaluation of toxic AA’s content and quality during quality control of AR or preparations containing AR.

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“…This kidney disease was first detected in Belgium in 1992, and since then, cases have been detected all over the world, eventually being defined as aristolochic acid nephropathy (AAN) [ 11 , 12 ]. Numerous data have shown that AA-containing plants and their derivatives are nephrotoxic, mutagenic, and carcinogenic to humans [ 2 , 13 , 14 ]. The International Agency for Research on Cancer (IARC) has classified AAs and the plants that contain them as Group I carcinogens [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Uptake, Translocation, and Fate of Carcinogenic Aristolochic Acid in Typical Vegetables in Soil−Plant Systems

Zhang

Wang

et al. 2022

Molecules

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When Aristolochia plants wilt and decay, aristolochic acids (AAs) are released into the soil, causing soil contamination. It has been demonstrated that aristolochic acid can be accumulated and enriched in crops through plant uptake. However, there is a lack of systematic studies on the migration and accumulation of AAs in a realistic simulated soil environment. In this study, Aristolochia herbal extracts were mixed with soil for growing three typical vegetables: lettuce, celery, and tomato. The contents of AAs in the above-mentioned plants were determined by an established highly sensitive LC-MS/MS method to study the migration and accumulation of AAs. We found that AAs in the soil can be transferred and accumulated in plants. AAs first entered the roots, which were more likely to accumulate AAs, and partially entered the above-ground parts. This further confirms that AAs can enter the food chain through plants and can have serious effects on human health. It was also shown that plants with vigorous growth and a large size absorbed AAs from the soil at a faster rate. The more AAs present in the soil, the more they accumulated in the plant.

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Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

Cited by 10 publications

References 28 publications

Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics

Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics

Rapid and Simultaneous Quantification of Six Aristolochic Acids and Two Lignans in Asari Radix et Rhizoma Using Ultra-Performance Liquid Chromatography-Triple Quadrupole Tandem Mass Spectrometry

Uptake, Translocation, and Fate of Carcinogenic Aristolochic Acid in Typical Vegetables in Soil−Plant Systems

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