Research Article: Worldwide research trends on aristolochic acids (1957–2017): Suggestions for researchers

Date Published: May 2, 2019

Publisher: Public Library of Science

Author(s): Qiang Zhou, Jin Pei, Josiah Poon, Alexander Y. Lau, Li Zhang, Yuhua Wang, Chang Liu, Linfang Huang, Vincenzo De Luca.


Aristolochic acids and their derivatives are components of many traditional medicines that have been used for thousands of years, particularly in Asian countries. To study the trends of research into aristolochic acids and provide suggestions for future study, we performed the following work. In this paper, we performed a bibliometric analysis using CiteSpace and HistCite software. We reviewed the three phases of the development of aristolochic acids by using bibliometrics. In addition, we performed a longitudinal review of published review articles over 60 years: 1,217 articles and 189 review articles on the history of aristolochic acid research published between 1957 and 2017 were analyzed. The performances of relevant countries, institutions, and authors are presented; the evolutionary trends of different categories are revealed; the history of research into aristolochic acids is divided into three phases, each of which has unique characteristics; and a roadmap of the historical overview of aristolochic acid research is finally established. Finally, five pertinent suggestions for future research into aristolochic acid are offered: (1) The study of the antitumor efficacy of aristolochic acids is of value; (2) The immune activity of aristolochic acids should be explored further; (3) Researchers should perform a thorough overview of the discovery of naturally occurring aristolochic acids; (4) More efforts should be directed toward exploring the correlation between aristolochic acid mutational signature and various cancers; (5) Further efforts should be devoted to the research and review work related to analytical chemistry. Our study is expected to benefit researchers in shaping future research directions.

Partial Text

Aristolochic acids (AAs) and their derivatives have attracted worldwide attention owing to concerns about their safety. In October 2017, an article published in Science Translational Medicine indicated that AAs and their derivatives were implicated widely in liver cancer in Taiwan and throughout Asia [1], which once again raised questions on the safety of traditional medicines containing AAs and their derivatives. During their application, reports of adverse effects on kidney failure and urothelial cancers related to AAs have continued to emerge [2–7]. In the early 1990s, inadvertent treatment with AA-containing herbs at a weight-loss clinic in Belgium resulted in kidney failure in approximately 100 women [8, 9]. In the early 20th century in China, an incident with Gentian purging liver pills (which once contained Aristolochia manshuriensis) triggered widespread panic about the safety of traditional Chinese medicines [10]. In 2007, scientists claimed that advances in the understanding of endemic nephropathy favored the causative role of AA in endemic (Balkan) nephropathy [11]. Thus, the use of AA-containing herbal remedies has been gradually prohibited in many countries and regions [12–14]. In 2001, the Food and Drug Administration issued warnings and an import alert that herbal products were unsafe if they contained or were suspected to contain AA [15]. In 2012, the International Agency for Research on Cancer, the WHO cancer agency, categorized AA I, AA II, and aristolactam as proven group 1 human carcinogens [16]. It should be noted that, although AA-containing plants have been used in China for thousands of years in traditional prescriptions, the Chinese government banned the use of AA-containing herbs for safety reasons and removed them from the Chinese Pharmacopoeia in 2003. At the end of October 2017, the China Food and Drug Administration produced lists in which they indicated 43 Chinese patent medicines and 24 Aristolochiaceae herbs that may contain AA (; Owing to the contradiction between the long history of traditional applications and the well-defined toxicity, a panorama of AA research is needed to identify the trends in the research into AA in various domains and to determine any scientific issues that have not been fully explored.

The Thomson-Reuter’s Web of Science (WoS) was used to compile the literature dataset because this database provides a comprehensive and standardized set of data for export and has been used extensively in academia. The first article on AA was published in 1957; thus, the timespan for the retrieval of the experiments in this study was from 1957 to 2017 to investigate the global scientific trends in AA research over a long period. The search was conducted in January 2018. In the initial step of the bibliometric literature analysis, we used “aristolochic acid” as the search term in the WoS database and retrieved 1,603 documents. As part of the search, we performed several queries in succession, such as using “aristolochic acids” or “aristolochic acids and derivatives” as the search term. Finally, we used “aristolochic acid” as the retrieval term because it led to almost every relevant search result. From the different types of relevant literature (e.g., articles, proceedings, reviews, and book chapters), only research articles and review papers were selected for further analysis. Finally, 1,217 articles and 189 reviews were analyzed. Almost all the obtained articles were in English (1,174 or 96.5%); the others were in nine different languages, mainly German (14 or 1.1%), Chinese (11 or 0.9%), and French (11 or 0.9%). The retrieval strategy of the experiments is shown in Fig 1.

This current study is the first comprehensive review of the various aspects of AA-related studies using bibliometric methods. In total, 1,217 articles and 189 review articles related to AA research between 1957 and 2017 have been analyzed. Five clear suggestions are presented and can be summarized as follows: (1) The anti-tumor efficacy of aristolochic acids is a valuable topic for study. Indeed, researchers discovered the tumor-suppressive activity of AA in the early stages of research and eventually slowed because of the identified toxicity of AA. However, structural modification, Chinese medicine processing methods, or some other biological methods should be considered. (2) The immune activity of AAs should also be further explored. Given the results of the keyword analysis in Phase II and for review articles, the immune activity of AAs and their derivatives acting as snake venom inhibitors is an important research field in Phase II. According to Chinese medicine theory, herbs containing AA often have the effect of heat-clearing and detoxifying. The immune activity of AA may provide an explanation for this theory. (3) Scholars should make a thorough overview on the discovery of naturally occurring AAs owing to their toxicity and wide distribution in various plants. (4) More efforts should be directed toward exploring the correlation between the mutational signature of AA and various cancers, because the existence of such connections has not yet reached a definite conclusion. In contrast, there is insufficient epidemiological and animal experimental evidence to support a direct correlation between the mutational signature of AA and cancer; however, it is not yet known whether there are other factors contributing to the mutational signature of AA. (5) Further efforts should be devoted to the research and review work in the theme of analytical chemistry. Additional and better rapid detection technologies are needed. The detection techniques for AA in plant samples and AA adducts for biological samples have yet to be improved.




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