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Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethnopharmacological Relevance: Kelisha capsules (KLS) are often used to treat acute diarrhoea, bacillary dysentery, heat stroke, and other diseases. One of its components, Asarum, contains aristolochic acid I which is both nephrotoxic and carcinogenic. However, the aristolochic acid (AA) content in KLS and its toxicity remain unclear., Aim of the Study: The aims of this study were to quantitatively determine the contents of five aristolochic acid analogues (AAAs) in Asarum and KLS, and systematically evaluate the in vivo toxicity of KLS in rats., Materials and Methods: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the content of the five AAAs in Asarum and KLS. Sprague-Dawley rats were administered KLS at 0, 0.75, 1.5, and 3.0 g/kg respectively, and then sacrificed after 4 weeks of administration or after an additional 2 weeks of recovery. The endpoints assessed included body weight measurements, serum biochemistry and haematology indices, and clinical and histopathological observations., Results: The AAAs content in Asarum sieboldii Miq. (HB-ESBJ) were much lower than those of the other Asarums. The contents of AA I, AA IVa, and aristolactam I in KLS were in the ranges of 0.03-0.06 μg/g, 1.89-2.16 μg/g, and 0.55-1.60 μg/g, respectively, whereas AA II and AA IIIa were not detected. None of the rats showed symptoms of toxic reactions and KLS was well tolerated throughout the study. Compared to the control group, the activated partial thromboplastin time values of rats in the 1.5 and 3.0 g/kg groups significantly reduced after administration (P < 0.05). In addition, the serum triglycerides of male rats in the 0.75 and 1.5 g/kg groups after administration, and the 0.75, 1.5, 3.0 g/kg groups after recovery were significantly decreased (P < 0.01 or P < 0.001). No significant drug-related toxicological changes were observed in other serum biochemical indices, haematology, or histopathology., Conclusions: The AA I content in KLS met the limit requirements (<0.001%) of the Chinese Pharmacopoeia. Therefore, it is safe to use KLS in the short-term. However, for safety considerations, attention should be paid to the effects of long-term KLS administration on coagulation function and triglyceride metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Scientific risk assessment of exogenous and endogenous toxic substances in traditional Chinese medicine (TCM) is of great significance. The present review comprises a comprehensive summary of progress in the health risk assessment of harmful exogenous substances in TCMs. Such substances include heavy metals, pesticide residues, biotoxins, and endogenous toxic components involving pyrrolizidine alkaloids. The review also discusses the strengths and weaknesses of various bioaccessibility and bioavailability models, and their applications in risk assessment. Future avenues of risk assessment research are highlighted, including further exploration of risk assessment parameters, innovation of bioaccessibility and bioavailability techniques, enhancement of probabilistic risk assessment combined with bioavailability, improvement of cumulative risk assessment strategies, and formulation of strategies for reducing relative bioavailability (RBA) values in TCMs. Such efforts represent an attempt to develop a risk assessment system that is capable of evaluating the exogenous and endogenous toxic substances in TCMs to ensure its safe use in clinics, and to promote the sustainable development of the TCM industry., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Food and medicinal substances(FAMS) with both edible and medicinal uses have a long history in China, being an important part of China's excellent traditional culture and traditional Chinese medicine(TCM). The legal management of FAMS is in the form of catalogue, which has a history of nearly 40 years. More than 100 substances have been included in the China's FAMS catalogue. According to the Regulation of Food and Medicinal Substances Catalogue, safety assessment is a basis for substances to be included in the catalogue. The safety assessment of FAMS should follow the principles and requirements of food safety risk assessment. However, FAMS is a complex mixture, and the nature and data adequacy of the assessed substance should be comprehensively considered. Different eva-luation models and methods should be selected according to the principle of case analysis. With the development of next-generation technologies such as big data, artificial intelligence, high-throughput and high-content in vitro testing, and computational toxicology and the trend of increasing edible substances with medicinal effects applying for the inclusion in the China's FAMS catalogue, the methods of risk assessment are applied in the management of FAMS, novel food products, and local characteristic food products, playing a scientific role. This paper systematically reviews the methods, challenges, and prospects of safety assessment of FAMS.

As a traditional Chinese medicine (TCM), Cortex Periplocae (CP) has a wide range of pharmacological effects, as well as toxic side effects. The main toxic components of it are cardiac glycosides, which tend to cause cardiotoxicity. Currently, it has also been reported in studies to cause hepatotoxicity, but it is not clear whether the hepatotoxicity is related to the toxicity caused by the reactive metabolites. This study aims to investigate the target components of CP that generate reactive metabolic toxicity. The fluorescent probe method was used to detect glutathione (GSH)-trapped reactive metabolites in a co-incubation system of CP extract with rat liver microsomes. Identification of GSH conjugates was performed by LC-MS/MS and that of the possible precursor components that produce reactive metabolites was conducted by UPLC-Q-TOF/MS. Cell viability assays were performed on HepG2 and L02 cells to determine the cytotoxicity of the target components. The findings of our study demonstrate that the extract derived from CP has the ability to generate metabolites that exhaust the intracellular GSH levels, resulting in the formation of GSH conjugates and subsequent cytotoxic effects. Through the utilization of the UPLC-Q-TOF/MS technique, we were able to accurately determine the molecular weight of the precursor compound in CP to be 355.1023. The primary evidence to determining the GSH conjugetes relies on the appearance of characteristic product ions resulting from central neutral loss (CNL) scanning of 129 Da and product scanning of m/z 660 in the positive MS/MS spectrum. Through analysis, it was ultimately ascertained that the presence of chlorogenic acid (CGA) and its isomers, namely neochlorogenic acid (NCGA) and cryptochlorogenic acid (CCGA), could lead to the production of GSH conjugates, resulting in cytotoxicity at elevated levels. Taking these findings into consideration, the underlying cause for the potential hepatotoxicity of CP was initially determined., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

As a traditional tonic Chinese medicine, Polygonum multiflorum is widely used in clinical practice. However, with the deepening of modern pharmacological research, its drug toxicity, especially hepatotoxicity, has become increasingly prominent. Based on a large number of clinical and experimental evidence, it has been confirmed that Polygonum multiflorum and its main active ingredients such as anthraquinones and diphenylethylene glucoside can cause different degrees of hepatotoxicity. Further studies have shown that the toxicological mechanisms involved in the hepatotoxicity of different extracts and components of Polygonum multiflorum may include oxidative phosphorylation, bile acid excretion, different metabolic pathways, genetic and metabolic factors, immune homeostasis, etc. By sorting out and summarizing the literature related to hepatotoxicity of Polygonum multiflorum in recent years, this paper discussed the hepatotoxicity mechanism of Polygonum multiflorum and its main components and some contradictions in related reports., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Dictamnine(DIC), as the key pharmacological component of the classical Chinese herbal medicine cortex dictamni, possesses multiple pharmacological activities such as anti-microbial, anti-allergic, anti-cancer, and anti-inflammatory activities, however it is also the main toxicant of cortex dictamni induced hepatic damage, yet the underlying molecular mechanisms causing hepatic damage are still largely unknown. With the purpose of explore possibilities hepatotoxicity of dictamnine in zebrafish and to identify the key regulators and metabolites involved in the biological process, we administered zebrafish to dictamnine at a sub-lethal dose (

Background: Radix Aconiti Lateralis (Fuzi), a mono-herbal preparation of Aconitum herbs in the genus Aconitum, is commonly used in traditional Chinese medicine (TCM) to treat critical illnesses. The curative effect of Fuzi is remarkable. However, the toxic effects of Fuzi are still a key clinical focus, and the substances inducing nephrotoxicity are still unclear. Therefore, this study proposes a research model combining "in vitro and in vivo component mining-virtual multi-target screening-active component prediction-literature verification" to screen potential nephrotoxic substances rapidly., Method: The UHPLC-Q-Exactive-Orbitrap MS analysis method was used for the correlation analysis of Fuzi's in vitro-in vivo chemical substance groups. On this basis, the key targets of nephrotoxicity were screened by combining online disease databases and a protein-protein interaction (PPI) network. The computer screening technique was used to verify the binding mode and affinity of Fuzi's components with nephrotoxic targets. Finally, the potential material basis of Fuzi-induced nephrotoxicity was screened., Results: Eighty-one Fuzi components were identified. Among them, 35 components were absorbed into the blood. Based on the network biology method, 21 important chemical components and three potential key targets were screened. Computer virtual screening revealed that mesaconine, benzoylaconine, aconitine, deoxyaconitine, hypaconitine, benzoylhypaconine, benzoylmesaconine, and hypaconitine may be potential nephrotoxic substances of Fuzi., Conclusions: Fuzi may interact with multiple components and targets in the process of inducing nephrotoxicity. In the future, experiments can be designed to explore further. This study provides a reference for screening Fuzi nephrotoxic components and has certain significance for the safe use of Fuzi., (© 2024 John Wiley & Sons Ltd.)

Polygonum ciliinerve (Nakai) Ohwi is a perennial twining vine plant from the Polygonaceae family, which is a Chinese herbal medicine with great value for development and utilization. The purpose of this paper is to provide a systematic review of the botany, traditional uses, phytochemistry, pharmacology, pharmacokinetics, and toxicology of Polygonum ciliinerve (Nakai) Ohwi, as well as an outlook on the future research directions and development prospects of the plant. Data on Polygonum ciliinerve (Nakai) Ohwi were obtained from different databases, including China National Knowledge Infrastructure, Baidu Academic, Wanfang Database, Google Academic, PubMed, Web of Science, SpringerLink, Wiley; books; standards; and Ph.D. and MSc theses. So far, 86 compounds have been identified from Polygonum ciliinerve (Nakai) Ohwi, including anthraquinones, stilbenes, flavonoids, tannins, chromogenic ketones, organic acids and esters, lignans, isobenzofurans, alkaloids, naphthols, and others. Studies have found that Polygonum ciliinerve (Nakai) Ohwi has a wide range of pharmacological effects, including antiviral, antibacterial, anti-inflammatory and analgesic, antitumor, immunomodulatory, hypoglycemic, and antioxidant effects. Clinically, Polygonum ciliinerve (Nakai) Ohwi is very effective in the treatment of gastritis and chronic gastritis. Based on its traditional use, chemical composition, and pharmacological activity, Polygonum ciliinerve (Nakai) Ohwi is a promising source of natural medicine in drug development., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Jinmao Jiedu granule is a Chinese medicine preparation consisting of Actinidia valvata Dunn, Salvia chinensis Benth, Iphigenia indica Kunth, and chicken gizzard. For many years, it has been employed in adjuvant therapy for cancer, especially liver cancer. However, the potential toxicity of the granule has not been reported. The present study aimed to assess the repeated-dose toxicity of orally administered Jinmao Jiedu granules for Sprague-Dawley (SD) rats. SD rats were orally administered Jinmao Jiedu granules at doses of 2.85, 5.70, and 11.40 g/kg in a 28-day subchronic toxicity study. No adverse clinical signs associated with treatment were noted throughout the experiment. There were no treatment-related toxicity alterations in body weight, hematology, clinical biochemistry, urinalysis, necropsy, and histopathology in rats compared with the control group. The No Observed Adverse Effect Level (NOAEL) of the Jinmao Jiedu granule was higher than 11.40 g/kg/day in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The Dryopteris crassirhizoma Nakai., a commonly used herb, is known as "Guan Zhong" in China, "Oshida" in Japan and "Gwanjung" in Korea. It has long been used for parasitic infestation, hemorrhages and epidemic influenza., Aim of the Review: The present paper aims to provide an up-to-date review at the advancements of the investigations on the traditional use, phytochemistry, pharmacological activity, toxicology and pharmacokinetics of D. crassirhizoma. Besides, possible trends, therapeutic potentials, and perspectives for future research of this plant are also briefly discussed., Materials and Methods: Relevant information on traditional use, phytochemistry, pharmacological activity, toxicology and pharmacokinetics of D. crassirhizoma was collected through published materials and electronic databases, including the Chinese Pharmacopoeia, Flora of China, Web of Science, PubMed, Baidu Scholar, Google Scholar, and China National Knowledge Infrastructure. 109 papers included in the article and we determined that no major information was missing after many checks. All authors participated in the review process for this article and all research paper are from authoritative published materials and electronic databases., Results: 130 chemical components, among which phloroglucinols are the predominant groups, have been isolated and identified from D. crassirhizoma. D. crassirhizoma with its bioactive compounds is possessed of extensive biological activities, including anti-parasite, anti-microbial, anti-viral, anti-cancer, anti-inflammatory, anti-oxidant, anti-diabetic, bone protective, immunomodulatory, anti-platelet and anti-hyperuricemia activity. Besides, D. crassirhizoma has special toxicology and pharmacokinetics characterization., Conclusions: D. crassirhizoma is a traditional Chinese medicine having a long history of application. This review mainly summarized the different chemical components extract from D. crassirhizoma and various reported pharmacological effects. Besides, the toxicology and pharmacokinetics of D. crassirhizoma also be analysed in this review. However, the chemical components of D. crassirhizoma are understudied and require further research to expand its medicinal potential, and it is urgent to design a new extraction scheme, so that the active ingredients can be obtained at a lower cost., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Dichroa febrifuga Lour., a toxic but extensively used traditional Chinese medicine with a remarkable effect, is commonly called "Changshan" in China. It has been used to treat malaria and many other parasitic diseases., Aim of the Review: The study aims to provide a current overview of the progress in the research on traditional use, phytochemistry, pharmacological activities, toxicology, and methods of toxicity reduction of D. febrifuga. Additionally, further research directions and development prospects for the plant were put forward., Materials and Methods: The article uses "Dichroa febrifuga Lour." "D. febrifuga" as the keyword and all relevant information on D. febrifuga was collected from electronic searches (Elsevier, PubMed, ACS, CNKI, Google Scholar, and Baidu Scholar), doctoral and master's dissertations and classic books about Chinese herbs., Results: 30 chemical compounds, including alkaloids, terpenoids, flavonoids and other kinds, were isolated and identified from D. febrifuga. Modern pharmacological studies have shown that these components have a variety of pharmacological activities, including anti-malarial activities, anti-inflammatory activities, anti-tumor activities, anti-parasitic activities and anti-oomycete activities. Meanwhile, alkaloids, as the material basis of its efficacy, are also the source of its toxicity. It can cause multiple organ damage, including liver, kidney and heart, and cause adverse reactions such as nausea and vomiting, abdominal pain and diarrhea. In the current study, the toxicity can be reduced by modifying the structure of the compound, processing and changing the dosage forms., Conclusions: There are few studies on the chemical constituents of D. febrifuga, so the components and their structure characterization contained in it can become the focus of future research. In view of the toxicity of D. febrifuga, there are many methods to reduce it, but the safety and rationality of these methods need further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Ranunculus L. genus contains 413 species, and it is the biggest genus in the family Ranunculaceae Juss. This review is to provide botanical characteristics, traditional uses, phytochemistry, pharmacology, toxicity, and pharmaceutical preparations of the genus Ranunculus., Key Findings: The genus Ranunculus contains flavonoids, organic acids, coumarins, lactones, glycosides, sterols, polysaccharides, and trace elements. These chemical constituents complement the pharmacological actions and work together to exert anti-inflammatory, anticancer, antitubercular, antibacterial, antimalarial, etc. Those traditional Chinese medicine characteristics, like clearing away heat and detoxification, make this genus significant in ethnic medicine. The progress in research and the development of various pharmaceutical preparations made it appear in epidemiological and clinical studies., Summary: The genus Ranunculus has attracted the attention of experts and scholars in many fields due to its unique advantages. However, there are many species that are not scientifically investigated. The toxicity issues are also a huge concern. Fortunately, the toxicity can be overcome via special processes like drying or heating and by choosing a safe extraction solvent, such as water thus ensuring the safety of medication. Pharmaceutical preparations containing the plants from Ranunculus have gratifying clinical value, but they are not promoted sufficiently. Therefore, further research should be carried out to promote the genus for its health benefits to humans., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Emodin-8-O-β-D-glucopyranoside (Em8G) is an active ingredient of traditional Chinese medicine Rhei Radix et Rhizoma and Polygonum multiflorum Thunb.. And it caused hepatotoxicity, while the underlying mechanism was not clear yet., Purpose: We aimed to explore the detrimental effects of Em8G on the zebrafish liver through the metabolome and transcriptome integrated analysis., Study Design and Methods: In this study, zebrafish larvae were used in acute toxicity tests to reveal the hepatotoxicity of Em8G. Adult zebrafish were then used to evaluate the gender differences in hepatotoxicity induced by Em8G. Integration of transcriptomic and metabolomic analysis was used further to explore the molecular mechanisms underlying gender differences in hepatotoxicity., Results: Our results showed that under non-lethal concentration exposure conditions, hepatotoxicity was observed in Em8G-treated zebrafish larvae, including changes in liver transmittance, liver area, hepatocyte apoptosis and hepatocyte vacuolation. Male adult zebrafish displayed a higher Em8G-induced hepatotoxicity than female zebrafish, as demonstrated by the higher mortality and histopathological alterations. The results of transcriptomics combined with metabolomics showed that Em8G mainly affected carbohydrate metabolism (such as TCA cycle) in male zebrafish and amino acid metabolism (such as arginine and proline metabolism) in females, suggesting that the difference of energy metabolism disorder may be the potential mechanism of male and female liver toxicity induced by Em8G., Conclusions: This study provided the direct evidence for the hepatotoxicity of Em8G to zebrafish models in vivo, and brought a new insight into the molecular mechanisms of Em8G hepatotoxicity, which can guide the rational application of this phytotoxin. In addition, our findings revealed gender differences in the hepatotoxicity of Em8G to zebrafish, which is related to energy metabolism and provided a methodological reference for evaluating hepatotoxic drugs with gender differences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Kochiae Fructus (KF) is a traditional Chinese medicine, which has been used to delay aging and treat inflammation, such as rubella, eczema, cutaneous pruritus, etc. In order to fully understand the traditional medicinal value of KF, we evaluated the antioxidant properties and oral safety of its ethanolic extract. Considering flavonoids and phenolics in medicinal plants generally have strong antioxidant activity, we firstly detected the total flavonoids and phenolics contents of KFEE and its fractions. Secondly, we evaluated the antioxidant activities of KFEE and its fractions. Finally, we evaluated the oral safety of KFEE by the acute and 28-day subacute toxicities. The n-butanol fraction (ENBF) possessed the highest phenolics and flavonoids with values of 77.30 ± 3.17 mg gallic acid equivalents/g and 228.81 ± 7.56 mg rutin equivalents/g, respectively. The results of antioxidant tests showed that ENBF possessed potent antioxidant ability. Among them, the high antioxidation capacity observed in ENBF could be attributed to its rich content of flavonoids and phenolics. The results of toxicological studies showed that the LD 50 value of KFEE was 6000 mg/kg BW, and the no observed adverse effect level (NOAEL) of KFEE was 600 mg/kg BW. According to the standards of the American Academy of Sciences for the classification of toxic substances, KFEE can be classified as practically non-toxic substance, which provided valuable evidence for the oral safety of KF as a natural aging delay medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological relevance of Saussurea species for anti-cancer compounds instigated us to develop chemotherapeutic herbal tablets. This study was an ongoing part of our previous research based on the scientific evaluation of Saussurea heteromalla (S. heteromalla) for anti-cancer lead compounds. In the current study, S. heteromalla herbal tablets (500 /800 mg) were designed and evaluated for anti-cancer activity. Arctigenin was found as a bioactive lead molecule with anti-cancer potential for cervical cancer. The in vitro results on the HeLa cell line supported the ethnopharmacological relevance and traditional utilization of S. heteromalla and provided the scientific basis for the management of cervical cancer as proclaimed by traditional practitioners in China. LD50 of the crude extract was established trough oral acute toxicity profiling in mice, wherein the minimum lethal dose was noticed as higher than 1000 mg/kg body weight orally. Chromatographic fingerprint analysis ensured the identity and consistency of S. heteromalla in herbal tablets in terms of standardization of the herbal drug. About 99.15% of the drug (S. heteromalla crude extract) was recovered in herbal tablets (RSD: 0.45%). In vitro drug release profile was found to be more than 87% within 1 h, which was also correlated with different mathematical kinetic models of drug release (r2 = 0.992), indicating that drug release from matrix tablets into the blood is constant throughout the delivery. The dosage form was found stable after an accelerated stability parameters study which may be used for anti-cervical cancer therapy in the future, if it qualifies successful preclinical investigation parameters., Competing Interests: All authors declare that they do not have a conflict of interest relating to conduct of the study or publication of this manuscript., (Copyright: © 2024 Batool et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ethnopharmacological Relevance: Psoraleae Fructus (PF), the dried fruit of Psoralea corylifolia L., is a commonly used traditional medicine that has contributed to the treatment of orthopedic diseases for thousands of years in China. However, recent PF-related liver injury reports have drawn widespread attention regarding its potential hepatotoxicity risks., Aim of the Study: This study was aimed to evaluate the long-term efficacy and chronic toxicity of PF using a 26-week administration experiment on rats in order to simulate the clinical usage situation., Materials and Methods: The PF aqueous extract was consecutively administrated to rats daily at dosages of 0.7, 2.0, and 5.6 g/kg (equivalent to 1-8 times the clinical doses for humans) for as long as 26 weeks. Samples were collected after 13, 26, and 32 weeks (withdrawal for 6 weeks) since the first administration. The chronic toxicity of PF was evaluated by conventional toxicological methods, and the efficacy of PF was evaluated by osteogenic effects in the natural growth process., Results: In our experiments, only the H group (5.6 g/kg) for 26-week PF treatment demonstrated liver or kidney injury, which the injuries were reversible after 6 weeks of withdrawal. Notably, the PF treatment beyond 13 weeks showed significant benefits for bone growth and development in rats, with a higher benefit-risk ratio in female rats., Conclusions: PF displayed a promising benefit-risk ratio in the treatment and prevention of osteoporosis, a disease that lacks effective medicine so far. This is the first study to elucidate the benefit-risk balance associated with clinical dosage and long-term use of PF, thereby providing valuable insights for rational clinical use and risk control of PF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aims to explore the correlation between intestinal toxicity and composition changes of Euphorbia ebracteolata before and after Terminalia chebula soup(TCS) processing. Intragastric administration was performed on the whole animal model. By using fecal water content, inflammatory causes, and pathological damage of different parts of the intestinal tract of mice as indexes, the differences in intestinal toxicity of dichloromethane extraction of raw E. ebracteolata(REDE), dichloromethane extraction of TCS, and dichloromethane extraction of E. ebracteolata after simulated TCS processing(STREDE) were compared, so as to investigate the effect of TCS processing on the intestinal toxicity of E. ebracteolata. At the same time, the component databases of E. ebracteolata and T. chebula were constructed, and the composition changes of diterpenoids, tannins, and phenolic acids in the three extracted parts were analyzed by HPLC-TOF-MS. HPLC was used to compare the content of four diterpenoids including ent-11α-hydroxyabicta-8(14), 13(15)-dien-16, 12-olide(HAO), jolkinolide B(JNB), fischeria A(FA), and jolkinolide E(JNE) in the E. ebracteolata before and after processing and the residue of container wall after processing, so as to investigate the effect of TCS processing on the content and structure of the diterpenoids. The results showed that the REDE group could significantly increase the fecal water content and the release levels of TNF-α and IL-1β from each intestinal segment, and intestinal tissue damage was accompanied by significant infiltration of inflammatory cells. However, compared with the REDE group, the intestinal tissue damage in the STREDE group was alleviated, and the infiltration of inflammatory cells decreased. The intestinal toxicity significantly decreased. Mass spectrometry analysis showed that there was no significant difference in the content of diterpenoids of REDE before and after simulated TCS processing, but a large number of tannins and phenolic acids were added. The results of HPLC showed that the content of four diterpenoids of E. ebracteo-lata decreased to varying degrees after TCS processing, ranging from-0.35% to-19.74%, and the decreased part mainly remained in the container wall, indicating that the structure of toxic diterpenoids of E. ebracteolata was not changed after TCS processing. The antagonistic effect of tannic and phenolic acids in the TCS may be the main reason for the reduced intestinal toxicity of E. ebracteolata after TCS processing. The TCS processing for E. ebracteolata is scientific.

Ethnopharmacological Relevance: Aconitum carmichaelii is widely used in traditional Chinese medicine clinics as a bulk medicinal material. It has been used in China for more than two thousand years. Nevertheless, the stems and leaves of this plant are usually discarded as non-medicinal parts, even though they have a large biomass and exhibit therapeutic properties. Thus, it is crucial to investigate metabolites of different parts of Aconitum carmichaelii and explore the relationship between metabolites and toxicity to unleash the utilization potential of the stems and leaves., Aim of the Study: Using plant metabolomics, we aim to correlate different metabolites in various parts of Aconitum carmichaelii with toxicity, thereby screening for toxicity markers. This endeavor seeks to offer valuable insights for the development of Aconitum carmichaelii stem and leaf-based applications., Materials and Methods: UHPLC-Q-Orbitrap MS/MS-based plant metabolomics was employed to analyze metabolites of the different parts of Aconitum carmichaelii. The cardiotoxicity and hepatotoxicity of the extracts from different parts of Aconitum carmichaelii were also investigated using zebrafish as animal model. Toxicity markers were subsequently identified by correlating toxicity with metabolites., Results: A total of 113 alkaloids were identified from the extracts of various parts of Aconitum carmichaelii, with 64 different metabolites in stems and leaves compared to daughter root (Fuzi), and 21 different metabolites in stems and leaves compared to mother root (Wutou). The content of aporphine alkaloids in the stems and leaves of Aconitum carmichaelii is higher than that in the medicinal parts, while the content of the diester-diterpenoid alkaloids is lower. Additionally, the medicinal parts of Aconitum carmichaelii exhibited cardiotoxicity and hepatotoxicity, while the stems and leaves have no obvious toxicity. Finally, through correlation analysis and animal experimental verification, mesaconitine, deoxyaconitine, and hypaconitine were used as toxicity markers., Conclusion: Given the low toxicity of the stems and leaves and the potential efficacy of aporphine alkaloids, the stems and leaves of Aconitum carmichaelii hold promise as a valuable medicinal resource warranting further development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Here, we aimed to optimize the ethanol extraction technology for Yujin powder (YJP) and evaluate its safety. The ultrasonic-assisted ethanol reflux extraction method refluxing was used to extract YJP. The parameters were optimized through a combination of single-factor and response surface methodology (RSM). The comprehensive Y value score calculated using the content of 13 active ingredients in YJP ethanolic extracts (YEEs) and the yield of the dry extract were used as measuring criteria. RSM with a Box-Behnken design using three factors and three levels was adopted to optimize the ethanol extraction technology for YJP. Finally, acute and subchronic toxicity tests were performed to evaluate its safety. The results revealed the best technological parameters: a liquid-material ratio of 24:1, an ethanol concentration of 69%, assistance of ultrasound (40 °C, 50 kHZ, 30 min), reflux time of 53 min, and reflux temperature of 50 °C. In acute toxicity tests, the maximum administration dosage in mice was 28.21 g/kg, which is higher than 10 times the clinical dosage. Adverse effects in the acute and subchronic toxicity tests were not observed. All clinical indexes were normal. In conclusion, the RSM based on AHP-CRITIC weight analysis could be used to optimize the ethanol extraction technology for YJP and YEEs prepared under the above conditions and ensure high safety.

Ethnopharmacological Relevance: Fructus Psoraleae (FP), the dried and ripe fruit of Cullen corylifolium (L.) Medik., is widely used due to its various clinical pharmacological effects, but its hepatotoxicity restricts its clinical application. So far, its hepatotoxic components and their underlying mechanism have not been systematically elucidated., Aim of the Study: This study was undertaken to reveal the hepatotoxicity distinction of coumarin-related compounds from glycosides to aglycones in FP and elucidate their potential mechanism., Methods: Rats were administrated with the aqueous extract of Fructus Psoraleae (AEFP), in which eight coumarin-related compounds were focused. Subsequently, compounds exposed in rats' livers were detected by UPLC-Q-TOF-MS, and the identified hepatotoxic compounds were evaluated to elaborate their possible mechanism by the aid of high content analysis (HCA)., Results: Eight coumarin-related compounds were identified, among which psoralenoside (PO), isopsoralenoside (IPO), psoralen (P), and isopsoralen (IP) were the principally exposed compounds in rats' livers. Furocoumarinic acid glucoside (FAG), (E)-3-(4-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy) benzofuran-5-yl) acrylic acid (isofurocoumarinic acid glucoside, IFAG), furocoumarinic acid (FA), and (E)-3-(4-hydroxybenzofuran-5-yl) acrylic acid (isofurocoumarinic acid, IFA) were also detected in low abundance. P, IP, FA, and IFA were identified as the hepatotoxic compounds, while their glycosides were almost non-hepatotoxic. The HCA's results showed that hepatotoxic compounds disrupted the balance in reactive oxygen species (ROS), nuclear area, and mitochondrial membrane potential of HepG2 cells, leading to the occurrence of hepatotoxicity., Conclusions: P, IP, FA, and IFA were identified as hepatotoxic compounds, from which P and IP were proposed as the important risk components for hepatotoxicity. The conversion from glycosides to aglycones played an essential role in FP-induced hepatotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Pharbitidis Semen (the seeds of Ipomoea nil (L.) Roth or Ipomoea purpurea (L.) Roth), a popular traditional Chinese medicine, is also known as "Heichou" or "Baichou" (Chinese: , ). It can purge the bowels, promote diuresis, remove stagnated accumulation, and kill worms. It can be used for treating anasarca with constipation and oliguria; dyspnea and cough caused by retained fluid; abdominal pain because of intestinal parasitosis; ascariasis; and taeniasis., Aims: This review discusses the botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicology, and quality control of Pharbitidis Semen, to obtain a complete understanding of its effects and provide a basis for further research and the development of new drugs., Materials and Methods: The literature on Pharbitidis Semen is mainly obtained from pharmacopoeias of different countries, masterpieces of traditional Chinese medicine, Master's and Ph.D. theses, and published articles obtained from literature retrieval websites, such as CNKI, PubMed, SciFinder, WanFang data, Web of Science, Springer, ScienceDirect, Wiley, ACS Publications, Taylor & Francis, J-STAGE, and Google Scholar. Its botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicology, and quality control are discussed to understand its effects and provide a basis for further research., Results: Pharbitidis semen has been used ethnomedically in many tropical and subtropical countries as deobstruents, diuretics, and anthelmintics. About 170 chemical compounds, including terpenoids, phenylpropanoids, resin glycosides, fatty acids and other compounds, have been isolated. It has been reported to have different effects, including laxative, renal-protective, neuroprotective, insecticidal, antitumor, anti-inflammatory, and antioxidant. Moreover, a brief introduction to processing, toxicity, and quality control is provided., Conclusions: The traditional efficacy of Pharbitidis Semen in diarrhea has been confirmed, but its bioactive and toxic ingredients are not entirely clear. It is necessary to strengthen the research and identification of effective parts or natural active components of Pharbitidis Semen, clarify the molecular mechanism of its toxicity and change rule of endogenous substances to make Pharbitidis Semen better used in clinical practice. Additionally, the imperfect quality standard is also a challenge that must be solved urgently. The study of modern pharmacology has broadened the application of Pharbitidis Semen and provided ideas for better utilization of this resource., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Adverse reactions to traditional Chinese medicine have hindered the healthy development and internationalization process of the traditional Chinese medicine industry. The critical issue that needs to be solved urgently is to evaluate the safety of traditional Chinese medicine systematically and effectively. Podophyllotoxin (PPT) is a highly active compound extracted from plants of the genus Podophyllum such as Dysosma versipellis (DV). However, its high toxicity and toxicity to multiple target organs affect the clinical application, such as the liver and kidney. Based on the concurrent effects of PPT's medicinal activity and toxicity, it would be a good example to conduct a systematic review of its safety. Therefore, this study revolves around the Toxicological Evidence Chain (TEC) concept. Based on PPT as the main toxic constituent in DV, observe the objective toxicity impairment phenotype of animals. Evaluate the serum biochemical indicators and pathological tissue sections for substantial toxic damage results. Using metabolomics, lipidomics, and network toxicology to evaluate the nephrotoxicity of PPT from multiple perspectives systematically. The results showed that PPT-induced nephrotoxicity manifested as renal tubular damage, mainly affecting metabolic pathways such as glycerophospholipid metabolism and sphingolipid metabolism. PPT inhibits the autophagy process of kidney cells through the PI3K/Akt/mTOR and Nrf2/HO1 pathways and induces the activation of oxidative stress in the body, thereby causing nephrotoxic injury. This study fully verified the feasibility of the TEC concept for the safety and toxicity evaluation of traditional Chinese medicine. Provide a research template for systematically evaluating the safety of traditional Chinese medicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Spatholobus suberectus vine stem (SSVS) is the dried lianoid stem of the leguminous plant, Spatholobus suberectus Dunn, which is mainly distributed in China and some Southeast Asian countries. Due to its notable effects of promoting blood circulation and tonifying blood, regulating menstruation and relieving pain, this phytomedicine has been used in traditional Chinese medicine for hundreds of years., Aim of the Study: This review is designed to provide a comprehensive profile of SSVS concerning its botany, traditional uses, phytochemistry, quality control, pharmacology, pharmacokinetics, and toxicology and attempts to provide a scientific basis and future directions for further research and development., Materials and Methods: Related document information was collected with the help of databases such as the Web of Science, Science Direct, PubMed, China National Knowledge Infrastructure (CNKI) and Flora of China., Results: SSVS is reported to be traditionally used to treat rheumatic arthralgia, numbness and paralysis, blood deficiency, irregular menstruation and other gynecological diseases. Botanical studies have revealed that there are some confusable varieties in some specific locations with a long history. Additionally, 145 chemical constituents have been isolated and identified from SSVS, including flavonoids, organic acids, terpenoids, lignans, and phenolic glycosides. Pharmacological studies have shown that SSVS has a variety of effects, such as nervous system regulation, and antioxidative, antitumor, antiviral, antidiabetic, and anti-inflammatory effects. However, in regard to the absorption-distribution-metabolism-elimination-toxicity (ADMET) of SSVS, few studies have been carried out, and few articles have been published., Conclusion: With a long history of traditional uses, a variety of bioactive phytochemicals and a wide range of definite pharmacological activities, SSVS is believed to have great potential in clinical applications and further research, development and exploitation. The precise action mechanisms, rational quality control and quality markers, and explicit ADMET routes should be highlighted in the future, which might provide effective help to safely, effectively and sustainably use this herbal medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The occurrence of severe liver injury by the herbal medicine Polygoni Multiflori Radix (PMR) has drawn significant attention. The fact that processing attenuates PMR-induced hepatotoxicity has been well accepted, but the mechanisms are still ambiguous., Purpose: This study aimed to illuminate the mechanism of processing-based attenuation of PMR hepatotoxicity., Methods: The contents of emodin-8-O-β-d-glucoside (EG) and emodin (EMD) in raw and processed PMR were quantified. The difference in toxicokinetic behaviors of EG and EMD was determined in vivo, and the disposition properties of EG were investigated in vitro and in vivo., Results: Decreased EG content was found in processed (black bean) PMR. Processed PMR showed reduced adverse effects relative to raw PMR. In addition, less hepatic protein adduction derived from EMD was produced in mice after exposure to processed PMR than that in animals receiving raw PMR. Glucose transporters SGLT1 and GLUT2 participated in the absorption of EG, and effective hydrolysis of EG to EMD took place in the intestinal epithelial cells during the process of absorption. Cytosolic broad-specificity β-glucosidase and lactase phlorizin hydrolase, as well as intestinal flora, participated in the hydrolysis of EG. The circulated EMD resulting from the deglycosylation of EG executed the hepatotoxic action., Conclusion: EG is a pre-toxin and can be metabolically activated to EMD participating in the hepatotoxic event. The reduction of EG content due to processing is a key mechanistic factor that initiates the detoxification of PMR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier GmbH.)

With the availability of public databases that store compound-target/compound-toxicity information, and Traditional Chinese medicine (TCM) databases, in silico approaches are used in toxicity studies of TCM herbal medicine. Here, three in silico approaches for toxicity studies were reviewed, which include machine learning, network toxicology and molecular docking. For each method, its application and implementation e.g., single classifier vs. multiple classifier, single compound vs. multiple compounds, validation vs. screening, were explored. While these methods provide data-driven toxicity prediction that is validated in vitro and/or in vivo, it is still limited to single compound analysis. In addition, these methods are limited to several types of toxicity, with hepatotoxicity being the most dominant. Future studies involving the testing of combination of compounds on the front end i.e., to generate data for in silico modeling, and back end i.e., validate findings from prediction models will advance the in silico toxicity modeling of TCM compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aconiti Lateralis Radix Praeparata is one of the most famous traditional Chinese medicines possessing a variety of pharmacological activities on top of the toxicities. Due to the heterogeneity and non-standardization of the processing procedures, the subtypes and contents of the differential compounds between different processed products still remained indistinct, causing great risk in their proper use. In order to achieve the comparison and quality evaluation of different processed products of Aconiti Lateralis Radix Praeparata and develop new processed products with less toxicity, a quantification and pseudotargeted metabolomics method was developed based on the dynamic MRM mode of triple quadrupole (QqQ) mass spectrometry, and multivariate statistical analysis methods were applied to compare different processed products. Method validation results indicated good specificity, linearity, repeatability, precision, stability and recovery of the established quantification method and good linearity, precision and stability of the pseudotargeted metabolomics method. Differential compounds of different processed products were screened out and further confirmed by the quantification results. At last, the processing procedures were optimized to obtain new processed products of "Heishunpian" (black slices) with less toxicity, in which the contents of the toxic diester-type diterpenoid alkaloids were reduced from 106.98 μg/g to 0.85-12.96 μg/g. This study provided a valuable reference for the establishment of comprehensive quality evaluation methods of herbal medicines and a scientific basis for the optimization of processing procedures of Aconiti Lateralis Radix Praeparata., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

As arsenic widely exists in nature and has been used in the pharmaceutical preparations, the traditional Chinese medicine(TCM) with arsenic include realgar(As&#95;2S&#95;2 or As&#95;4S&#95;4), orpiment(As&#95;2S&#95;3), and white arsenic(As&#95;2O&#95;3). Among the above representative medicine, the TCM compound formulas with realgar are utilized extensively. Just in Chinese Pharmacopoeia(2020 edition), there are 37 Chinese patent medicines including realgar. The traditional element analysis focuses on the detection of the total amount of elements, which neglects the study on the speciation and valence of elements. The activity, toxicity, bioavailability, and metabolic pathways of arsenic in vivo are closely related to the existence of its form, and different forms of arsenic have different effects on organisms. Therefore, the study on the speciation and valence of arsenic is of great importance for arsenic-containing TCMs and their compound formulas. This paper reviewed four aspects of the speciation and valence of arsenic, including property, absorption and metabolism, toxicity, and analytical assay.

To explore the mechanism of the active ingredients of Qishiwei Zhenzhu Pills in inhibiting the hepatorenal toxicity of the zogta component based on serum pharmacochemistry and network pharmacology, thereby providing references for the clinical safety application of Qishiwei Zhenzhu Pills. The small molecular compounds in the serum containing Qishiwei Zhenzhu Pills of mice were identified by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS). Then, by comprehensively using Traditional Chinese Medicines Systems Pharmacology(TCMSP), High-throughput Experiment-and Reference-guided Database(HERB), PubChem, GeneCards, SuperPred, and other databases, the active compounds in the serum containing Qishiwei Zhenzhu Pills were retrieved and their action targets were predicted. The predicted targets were compared with the targets of liver and kidney injury related to mercury toxicity retrieved from the database, and the action targets of Qishiwei Zhenzhu Pills to inhibit the potential mercury toxicity of zogta were screened out. Cytoscape was used to construct the active ingredient in Qishiwei Zhenzhu Pills-containing serum-action target network, and STRING database was used to construct the protein-protein interaction(PPI) network of intersection targets. The Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were carried out on the target genes by the DAVID database. The active ingredient-target-pathway network was constructed, and the key ingredients and targets were screened out for molecular docking verification. The results showed that 44 active compounds were identified from the serum containing Qishiwei Zhenzhu Pills, including 13 possible prototype drug ingredients, and 70 potential targets for mercury toxicity in liver and kidney were identified. Through PPI network topology analysis, 12 key target genes(HSP90AA1, MAPK3, STAT3, EGFR, MAPK1, APP, MMP9, NOS3, PRKCA, TLR4, PTGS2, and PARP1) and 6 subnetworks were obtained. Through GO and KEGG analysis of 4 subnetworks containing key target genes, the interaction network diagram of active ingredient-action target-key pathway was constructed and verified by molecular docking. It was found that taurodeoxycholic acid, N-acetyl-L-leucine, D-pantothenic acid hemicalcium, and other active ingredients may regulate biological functions and pathways related to metabolism, immunity, inflammation, and oxidative stress by acting on major targets such as MAPK1, STAT3, and TLR4, so as to inhibit the potential mercury toxicity of zogta in Qishiwei Zhenzhu Pills. In conclusion, the active ingredients of Qishiwei Zhenzhu Pills may have a certain detoxification effect, thus inhibiting the potential mercury toxicity of zogta and playing a role of reducing toxicity and enhancing effect.

Ethnopharmacological Relevance: Various toxic medicinal materials have been used by different ethnic minorities in China for thousands of years because of their extraordinary pharmacological activities. However, the improper use and complex toxicity-efficacy relationship could cause poisoning and even death. Therefore, the study of toxicity-attenuating methods and mechanisms is necessary., Aim of the Study: This review aims to summarize commonly used toxic ethnomedicines and their processing methods as well as the underlying mechanisms to potentially reduce toxicity and even enhance or preserve efficacy. Prospective for possible future investigations is also discussed., Materials and Methods: Processing methods and mechanisms are investigated mainly through literature review., Results: Processing methods with heating (boiling, stir frying, and steaming, etc.) and without heating (soaking) are usually used by Chinese ethnic minorities to attenuate the toxicity of ethnomedicines. Wheat bran, vinegar, wine, and herbal decoction are commonly used processing excipients. The mechanisms of detoxification by processing can be briefly summarized into three major categories: (1) direct elimination of impurities or reduction of toxic constituents' contents of ethnomedicines by cutting, washing, soaking or frosting; (2) chemical structure transformation of toxic constituents, such as alkaloids, glycosides, toxic proteins, animal toxicants, and mineral components, during heating and/or soaking; and (3) biological synergism or antagonism effects between the chemical constituents of processing excipients and ethnomedicines in vivo, to reduce toxicity and protect target organs., Conclusion: Toxic ethnomedicines have long been used in China, and detoxification by processing is the prerequisite for their safe clinical application. However, understanding on the special processing methods and detoxification mechanisms of ethnomedicines in China remains insufficient. Investigations on quality control of toxic ethnomedicines, as well as evaluation of processing methods and studies of the corresponding mechanisms should be further strengthened for safe and effective clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The present study aimed to evaluate the effect of a mouthwash containing a novel compound Chinese herbal medicine (artemisia capillaris, chrysanthemum, honeysuckle, angelica dahurica and asarum sieboldii) on oral ulcers and analyze sub chronic oral toxicity in rats. For efficacy study, mouthwash was administered on the ulcer area twice daily. Compared with the control group, healing time in the test group was shorter and the ulcer area was smaller. Histological analysis showed less inflammatory cell infiltration in the test group. For sub chronic oral toxicity, mouthwash was administered by oral gavage for 93 consecutive days. There were no significant differences in body weight, food consumption or organ coefficients between the test and control groups. Some parameters of haematology and serum chemistry were statistically different but within normal physiological ranges. No obvious abnormalities were found in the necropsies and histopathological observations. In conclusion, the compound Chinese herbal medicine mouthwash promoted oral ulcer healing in rats with no obvious sub chronic toxicity, providing a potential alternative therapeutic strategy for oral ulcers.

Over the years, the safety of traditional Chinese medicine (TCM) has received widespread attention, especially the central nervous system-related adverse reactions. Indeed, the complexity of TCM has limited the widespread application of TCM. The article summarizes the main components associated with neurotoxicity, including alkaloids, terpenes, flavonoids, saponins, proteins, and heavy metals, by reviewing the literature on the neurotoxicity of TCM. It has been established that the neurotoxicity mechanisms mainly include mitochondrial damage, oxidative damage, inhibition of cell proliferation (including transcriptional and DNA damage), changes in cell membrane permeability, and apoptosis. By reviewing the latest literature, this paper provides the foothold for follow-up studies and can assist clinicians in preventing neurotoxicity via rational and safe TCM drug use., (© 2022 John Wiley & Sons Ltd.)

Ethnopharmacological Relevance: As a traditional Chinese medicine, Euodiae Fructus (EF) has been used to treat stomachache, belching, and emesis for more than a thousand years. Ancient records and modern research have shown that EF has mild toxicity, which needs to be processed with licorice juice to reduce its toxicity. Research suggested that the toxicity of EF can be caused by in vivo metabolism, but whether its metabolites are related to hepatotoxicity and whether licorice can affect the metabolism of EF have not been reported, which needed an effective strategy to clarify the correlation between metabolites and toxicity and the attenuation mechanism of licorice processing., Aim of the Study: The poisonous substances and metabolic pathways were clarified by comparing the mechanism in vivo process of the main alkaloids of EF in normal rats and rats treated with dexamethasone (DXMS), ketoconazole (KTC), and EF processed with licorice (EFP)., Materials and Methods: Rats were given EF and EFP by oral administration, respectively. The EF + DXMS and EF + KTC groups were pretreated with DXMS and KTC, respectively, by i. p. for seven days, and their toxicity differences were compared. The comprehensive strategy based on UPLC-Q-Exactive-MS and Orthogonal Partial Least Squares Discriminant Analysis was developed to compare the types and contents of metabolites and clarify the metabolic pathways of alkaloids among EF, EFP, EF + KTC, and EF + DXMS groups., Results: EF + DXMS group significantly increased the hepatotoxicity, whereas the EF + KTC and EFP groups reduced the hepatotoxicity compared with the EF group. One hundred and thirty-five metabolites were detected, and the metabolic pathways of the main alkaloid components related to toxicity were inferred in the plasma, urine, feces, and bile of rats. KTC and licorice similarly inhibited the production of toxic metabolites, changed metabolism in vivo, and produced many new II and a few phases I metabolites, while the contents of toxic metabolites increased in the DXMS group., Conclusion: Licorice and KTC could inhibit the production of metabolites of EF related to toxicity, increase the production of other metabolites and promote the excretion of alkaloids, which may be why licorice and KTC can minimize EF toxicity., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Houttuynia cordata (H. cordata) is the most common herb as a food and traditional Chinese medicine. Currently, studies on its toxicity have mainly focused on hepatotoxicity. However, its potential embryotoxicity by long-term exposure is often overlooked. Objective: To investigate the effects of H. cordata on embryonic development and its toxicity mechanism by combining network pharmacology, molecular docking, and in vitro experimental methods. Methods: The effects of H. cordata on embryos were evaluated. Zebrafish embryos and embryoid bodies were administered to observe the effects of H. cordata on embryonic development. Based on network pharmacological analysis, it was found that the main active agents producing toxicity in H. cordata were oleanolic acid, lignan, and aristolactam AII. H. cordata can affect PI3K-Akt, MAPK, and Ras signaling pathways by regulating targets, such as AKT1, EGFR, CASP3, and IGF-1. RT-PCR and immunohistochemistry results showed that the expression of AKT1 and PI3K in the embryoid body was significantly reduced after drug administration (p < 0.05). Conclusions: The results of network pharmacology and in vitro experiments suggest that H. cordata may affect embryonic development by influencing the PI3K-Akt signaling pathway.

According to Provisions for Drug Registration and Categories and Requirements of Application Dossiers for Traditional Chinese Medicine(TCM), non-clinical safety research/toxicology research should be conducted for classical compound Chinese medicine prescriptions(Categories 3.1 and 3.2), and the data should be submitted at the application for the marketing authorization. Based on the requirements of toxicology research in Categories and Requirements of Application Dossiers for Traditional Chinese Medicine, this study further refined and clarified the requirements of toxicology research on classical compound Chinese medicine preparations(Categories 3.1 and 3.2).

Psoraleae Fructus (PF) is an important traditional herbal medicine with a long history of clinical application. It is widely used to treat various diseases, such as osteoporosis, leucoderma and diarrhea. As a traditional nontoxic herb, it has aroused worldwide concern about the potential risks due to increasing adverse reaction events. This article reviews the botany, ancient records of medical uses, adverse reactions, toxicological research advance and detoxification methods of PF. According to clinical studies, liver injury is the most predominant in PF-related adverse reactions. The underlying mechanisms include bile acid metabolism and transport disorders, oxidative stress, mitochondrial damage, inhibition of liver cell regeneration and inflammatory reactions. Furthermore, the potential toxins of PF are summarized. Traditional methods of processing and compatibility will provide reference for reducing the toxicity of PF, which requires further research. In sum, this work systematically summarizes the reserach progress on the safety of PF, which will provide comprehensive insights into the toxicity of PF and facilitate its safe use and future development., (Copyright © 2022 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

With the increasing application of traditional Chinese medicine (TCM), TCM-induced reproductive toxicity has gradually aroused people's concern. Various TCM, such as Tripterygium wilfordii Hook. f., Radix Aconiti lateralis Preparata and Rhizoma Pinelliae, are currently reported to cause reproductive toxicity in humans and animals. However, a summary of the material bases, mechanisms and biological markers of TCM-induced reproductive toxicity is still lacking. This review filled the gap by searching and summarising relevant studies and articles published on PubMed, CNKI and Web of Science databases from January 2000 to November 2021. The risk ingredients involved in TCM-induced reproductive toxicity were divided into glycosides, alkaloids, phenols, terpenoids, anthraquinones, lactones, plant toxin proteins, animal toxins and so forth. Potential mechanisms underlying TCM-induced reproductive toxicity, including steroidogenic toxicity, lipids metabolism abnormity, energy insufficiency, oxidative stress and apoptosis, were illustrated. We also outlined possible biomarkers, especially biomarkers of effect involved in TCM-induced reproductive toxicity, including anti-oxidant enzymes, signalling pathways, genes and growth factors., (© 2022 John Wiley & Sons, Ltd.)

Ethnopharmacological Relevance: Tripterygium wilfordii polyglycosides (TWP) are extracted from Tripterygium wilfordii Hook. f., which has the significant effects of anti-inflammation and immunosuppression and has been widely used to treat autoimmune diseases in traditional Chinese medicine., Aim of Study: In Chinese clinical dermatology, TWP was generally used for the treatment of autoimmune skin diseases including psoriasis (PSO), systemic lupus erythematosus (SLE) and pemphigus (PEM). However, the potential hepatotoxicity (HPT) induced by TWP was also existing with the long-term use of TWP. This study aims to explore the potential shared therapeutic mechanism of TWP treating PSO, SLE, PEM and the possible hepatotoxic mechanism induced by TWP., Materials and Methods: Network pharmacology was used to predict the potential targets and pathways in this study. The main bioactive compounds in TWP was screened according to TCMSP, PubChem, ChEMBL databases and Lipinski's Rule of Five. The potential targets of these chemical constituents were obtained from PharmMapper, SEA and SIB databases. The related targets of PSO, SLE, PEM and HPT were collected from GeneCards, DrugBank, DisGeNET and CTD databases. The target network construction was performed through STRING database and Cytoscape. GO enrichment, KEGG enrichment and molecular docking were then performed, respectively. In particular, imiquimod (IMQ)-induced PSO model was selected as the representative for the experimental verification of effects and shared therapeutic mechanisms of TWP., Results: 41 targets were considered as the potential shared targets of TWP treating PSO, SLE and PEM. KEGG enrichment indicated that IL-17 signaling pathway and Th17 cell differentiation were significant in the potential shared therapeutic mechanism of TWP. The animal experimental verification demonstrated that TWP could notably ameliorate skin lesions (P˂0.001), decrease inflammatory response (P˂0.05, P˂0.01, P˂0.001) and inhibit the differentiation of Th1/Th17 cells (P˂0.05, P˂0.01) compared to PSO model group. The molecular docking and qPCR validation then showed that TWP could effectively act on MAPK14, IL-2, IL-6 and suppress Th17 cell differentiation and IL-17 signaling pathway. The possible hepatotoxic mechanism of TWP indicated that there were 145 hepatotoxic targets and it was also associated with IL-17 signaling pathway and Th17 cell differentiation, especially for the key role of ALB, CASP3 and HSP90AA1. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP showed that 28 targets were shared by therapeutic and hepatotoxic mechanisms such as IL-6, IL-2, MAPK14, MMP9, ALB, CASP3 and HSP90AA1. These significant relevant targets were also involved in IL-17 signaling pathway and Th17 cell differentiation., Conclusions: There were shared disease targets in PSO, SLE and PEM, and TWP could treat them by potential shared therapeutic mechanisms of suppressing IL-17 signaling pathway and Th17 cell differentiation. The possible hepatotoxicity induced by TWP was also significantly associated with the regulation of IL-17 signaling pathway and Th17 cell differentiation. Meanwhile, the potential correlations between efficacy and hepatotoxicity of TWP also mainly focused on IL-17 signaling pathway and Th17 cell differentiation, which provided a potential direction for the study of the mechanism of "You Gu Wu Yun" theory of TWP treating autoimmune skin diseases in the future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The present study aims to investigate the correlation between irritant toxicity variation and lectin content variation during the processing of Pinelliae Rhizoma products and to explore the feasibility of Western blot as a method for the detection of lectin. We processed Pinelliae Rhizoma Praeparatum Cum Alumine, Pinelliae Rhizoma Praeparatum, and Pinelliae Rhizoma Praeparatumcum Zingibere et Alumine to different degrees and then analyzed their irritant toxicity via Draize rabbit eye test. Western blot was employed to determine the lectin content in Pinelliae Rhizoma products processed with different methods. The correlation between toxicity variation and lectin content variation was then analyzed. Different decoction pieces of Pinelliae Rhizoma were collected for the determination of lectin content. The three processed products of Pinelliae Rhizoma showed gradually decreased toxicity and lectin content as the processing continued. The decreasing trend of lectin content was consistent with that of irritant toxicity during processing, which indicated that the change in lectin content could reflect the trend of irritant toxicity. No band of lectin appeared in the Western blot of processed products of Pinelliae Rhizoma, which suggested that western blotting can be used for the detection of toxic lectin in the processed products of Pinelliae Rhizoma. Lectin should not be detected in the Pinelliae Rhizoma products processed according to the methods in the Chinese Pharmacopoeia.

Advances in science and technology promote the rapid development of toxicological detection technologies. However, there is still a lack of decision-making tools for toxicological risk assessment, such as the lack of transparent schemes to evaluate current toxicological research and practice and the lag of toxicological testing tools to evaluate toxicity, resulting in difficulties in toxicity verification and hindering the transformation of toxicological research paradigm. Some scholars have proposed to integrate the concept of evidence-based medicine with the toxicological practice to improve the technical methods of toxicological research concept and risk assessment decision-making. With the promotion of relevant scholars and academic organizations, the concept and connotation of evidence-based toxicology have gradually become clear and a framework for research and practice has been initially formed. Although there are still many challenges, it also provides a new idea for the toxicity risk assessment and safe medication decision-making of traditional Chinese medicine(TCM). The era of digital intelligence has brought new opportunities and broad space for the development of TCM evidence-based toxicology. The exploration of TCM evidence-based toxicology from concept to method is an important embodiment of the development of TCM evidence-based toxicology, and will also promote the continuous enrichment and improvement of the research and practice system of TCM evidence-based toxicology.

Background: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms., Methods: Sprague-Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms., Results: Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female)., Conclusions: TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF., (© 2022. The Author(s).)

Ethnopharmacological Relevance: Houttuynia cordata Thunb., a plant belonging to the family of Saururaceae, has been used as a traditional Chinese medicine for more than 1500 years. Because of its various pharmacological activities, it was widely used as antipyretic, detoxification, anti-inflammatory drugs. Houttuynia cordata (HC) injection was prepared using contemporary methods to extract effective components from H. cordata Thunb. However, the adverse event reports of HC injection are accumulating remarkably with the HC injection clinical applications increased. Previous studies demonstrated that the major side effects of HC injection were anaphylactoid reactions. Our work might shed the light on the role of Mas-related G-protein coupled receptor-X2 (MRGPRX2) in modulating drug-induced anaphylactoid reactions., Aim of the Study: We aimed to investigate the role of the mouse Mas-related G-protein coupled receptor B2 (Mrgprb2) (the orthologous gene of human MRGPRX2) in anaphylactoid reactions induced by HC injection., Materials and Methods: Mrgprb2 related anaphylactoid reactions induced by HC injection were investigated by histamine/β-hexosaminidase releasing, mast cell degranulation, and hind paw swelling assays by using a Mrgprb2 knockout mouse model. Furthermore, the transcriptomic profiles of the anaphylactoid reaction induced by HC injection was analyzed by RNA sequencing., Results: Mice without Mrgprb2 exhibited significantly decreasing in mast cell degranulation, serum histamine release, and hind paw swelling degrees. The RNA sequencing results indicated that Mrgprb2 could play a pivotal role in HC injection induced anaphylactoid reaction mediated by mTOR/AMPK pathway. Intriguingly, our results showed that Mrgprb2 might involve in Compound 48/80 induced anaphylactoid reactions mediated by Reelin/E-cadherin axis, which suggested different roles of Mrgprb2 in anaphylactoid reactions induced by HC injection and C48/80., Conclusion: Our studies reported effects and underlying mechanisms of Mrgprb2 in the anaphylactoid reaction induced by HC injection., (Copyright © 2022 Elsevier B.V. All rights reserved.)

To evaluate the detoxification effect of a combination of Radix Glycyrrhizae (GU) and Semen Strychni (SN) from toxicokinetics and drug tissue distribution perspectives, decoctions of processed SN and codecoction of SN and GU (SGN) were prepared, and an HPLC-ESI-MS/MS method was developed to monitor the severe exposure level in 1-month toxicokinetics and tissue distribution experiments to detect brucine and strychnine in rats. The toxicokinetic characteristics and tissue distribution before and after the addition of GU were analyzed. The method was successfully applied to evaluate the toxicokinetics and tissue distribution before and after the combination of SN and GU. The results show that GU decreased the blood concentration of toxic components in SN, and a double peak was observed in the drug time curve. The results of tissue distribution show that a combination of GU and SN significantly decreased the accumulation of toxic substances in metabolic organs and accelerated the clearance of toxic substances in the brain. These results provide a reference for the toxicity reduction mechanism of GU combined with SN., (© 2022 John Wiley & Sons, Ltd.)

Traditional Chinese medicine(TCM) has made outstanding contributions to disease prevention and treatment, survival, and reproduction of the Chinese nation. Currently, the inheritance and innovative development of TCM have become a national strategy. However, in recent years, adverse reactions/events of Chinese medicine frequently occurred. In particular, in terms of the safety problem of newly discovered &quot;toxic&quot; Chinese medicine, it is often difficult to answer the question scientifically and develop effective solutions. When facing international public opinions and public questioning, they are often &quot;passively criticized&quot;. To solve the difficult problem about the safety of Chinese medicine, we urgently need to make breakthroughs in the cognition of toxicity of Chinese medicine and prevention and control of risks. This research team has been committed to the research on the safety of Chinese medicine for the long term. In particular, in terms of safety evaluation and risk prevention and control of newly discovered &quot;toxic&quot; Chinese medicine, they have made a series of original discoveries. On the basis of the discoveries, they innovated the cognition theory and methods of the toxicity of Chinese medicine, opened up a new field of research on the idiosyncratic toxicity and indirect toxicity of Chinese medicine, and proposed and established the disease-syndrome-based toxicology(DSBT), the model and method of safety evaluation of Chinese medicine related to diseases and syndromes. In light of the theory and methods of DSBT which have been applied to the objective eva-luation and analysis of the mechanism of the hepatotoxicity of Chinese medicine such as Polygoni Multiflori Radix, the mechanism hypothesis of &quot;toxicity due to three causes&quot; of idiosyncratic hepatotoxicity of Chinese medicine was proposed and confirmed. The findings revealed that the substances that induced idiosyncratic or indirect toxicity in Chinese medicine often did not possess definite direct toxi-city. Therefore, this research team proposed the concept of toxicity-related substances(TRS) in Chinese medicine. Based on the mo-dern scientific cognition of toxicity of Chinese medicine, the team proposed the strategy and method of Chinese medicine compatibility to reduce the toxicity based on the component-effect-target interaction to underpin the demonstration of the scientific connotation of toxicity and side effects of &quot;toxic&quot; Chinese medicine and establishment of scientific and effective risk prevention and control strategies. In light of the innovative development of toxicity cognition of Chinese medicine, this study is expected to provide important theoretical guidance and methodological support for scientific evaluation and precise prevention and control of the safety risk of &quot;toxic&quot; Chinese medicine.

Ethnopharmacological Relevance: Sanren decoction (SRD) is a well-known traditional Chinese medicine prescription containing eight kinds of materials. SRD has been used mainly in China for more than 200 years for the treatment of respiratory disorders that co-occur with a bad fever after midday., Aim of the Study: To evaluate the acute and 28-day subacute toxicity of an aqueous extract of SRD using in vivo methods., Materials and Methods: To determine acute toxicity, SRD was administered by gavage at a dosage of 58.5 g/kg/day to male and female mice for 7 days. To determine subacute toxicity, SRD was administered at 3.3, 6.5, or 13 g/kg/day to male and female rats for 28 days. The general behavior, body weight, biochemical and hematological parameters, organ coefficients and pathological morphology of the treated animals were analyzed., Results: Neither acute nor subacute concentrations of SRD caused significant changes in the body weights, general behavior, hematology and biochemical parameters, organ weights, or histopathological appearances of the liver, kidney, spleen, brain, lung or heart in mice or rats., Conclusions: The administration of SRD can be considered safe within the conditions of this study., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Toxicity-attenuating compatibility is an effective measure to ensure the safety of Chinese medicine. Involving the origin, processing method, compatibility mode, and dosage, it faces multiple challenges, such as the uncertainty of toxic substances, toxicity latency, indefinite safe dose, complex toxicity-efficacy relationship, and individual difference. As a result, research on clinical safety of Chinese medicine is limited by the consistency at &quot;molecular-cellular-organ-overall&quot; levels, unclear interaction of multiple medicinals and multiple substances, the &quot;toxicity-efficacy-compatibility-syndrome&quot; correlation, and the &quot;dosage-time-toxicity-efficacy&quot; conversion law. Therefore, following the principle of &quot;starting from the clinical practice, verifying via the theoretical basis, and finally applying in clinical practice&quot;, we verified the toxicity at &quot;molecular-cellular-organ-overall&quot; levels, revealed the interaction of multiple medicinals and substances, collected evidence at multiple levels, clarified the &quot;dosage-time-toxicity-efficacy&quot; relationship, and tested the consistency between basic and clinical biomarkers. On this basis, we studied the toxicity-alleviating and efficacy-enhancing(preserving) compatibility characteristics, the fate of one medicinal and multiple medicinals in vivo, the molecular mechanism of toxicity, the &quot;dosage-time-toxicity-efficacy&quot; conversion law, and the clinical characteristics of toxic traditional Chinese medicine based on disease and syndrome. The three mechanisms of toxicity-attenuating compatibility reflect the seven-reaction theory in Chinese medicine compatibility. Finally, the strategies for safe use of Chinese medicine were proposed.

Plasmodium falciparum, the most virulent human malaria parasite, causes serious diseases among the infected patients in the world and is particularly important in African regions. Although artemisinin combination therapy is recommended by the WHO for treatment of P. falciparum-malaria, the emergence of artemisinin-resistant parasites has become a serious issue which underscores the importance of sustained efforts to obtain novel chemotherapeutic agents against malaria. As a part of such efforts, thirty-nine herbal extracts from traditional Chinese medicine (TCM) were assayed for their anti-malarial activity using 3D7 strain of P. falciparum. Three herbal supplements appeared to possess higher specific anti-malarial activity than the others. One of them (D3) was separated by two sequential fractionations with reverse-phase (the first step) and normal-phase (the second step) liquid chromatography, in which some fractions resulted in higher specific activities than those of D3 or the previous fractions. Cell toxicity assay was performed with the fractions of the first fractionation and demonstrated no obvious cell toxicity. These results suggest that structure determination of the major compound for the anti-malarial activity in D3 may help the development of more potent chemicals in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this study, the inhibitory effect of components from Chinese Herb Medicine (CHMs) with potential hepatotoxicity was assessed by human bile salt export pump (hBSEP) vesicles with and without S9 metabolism. Sixty-three compounds from 22 hepatoxicity CHMs were selected as the test articles. In hBSEP vesicles, eighteen of them were found to have moderate or strong inhibitory effect towards BSEP. Further studies were performed to determine the IC 50 values of strong inhibitors. For the compounds belong to CHMs reported to cause cholestasis and strong inhibitors defined in hBSEP vesicles, their relative transport activities of Taurocholic acid (TCA) were evaluated in hBSEP vesicles as well as hBSEP vesicles with S9 system (S9/hBSEP vesicles). The differences of their relative transport activities of TCA between the above two system were compared to reveal the net effect of metabolism on BSEP's activity. It was found that the inhibitory effect of Saikogenin A (SGA), Saikogenin D (SGD), Diosbulbin B (DB) and rhein were significantly increased; while the inhibitory effect of isobavachalcone, saikosaponin d and saikosaponin b2 were significantly decreased after S9 metabolizing. Identification of metabolic pathways suggested that CYP3A4 was responsible for aggravating inhibitory effect of SGA and SGD against BSEP., (Copyright © 2022. Published by Elsevier Ltd.)

This study aims to explore the toxicity mechanism of Rhododendri Mollis Flos(RMF) based on serum metabolomics and network toxicology. The toxic effect of RMF on normal rats was evaluated according to the symptoms, serum biochemical indexes, and histopathology. Serum metabolomics was combined with multivariate statistical analysis to search endogenous differential metabolites and related metabolic pathways. The toxic components, targets, and signaling pathways of RMF were screened by network toxicology technique, and the component-target-metabolite-metabolic pathway network was established with the help of serum metabolomics. The result suggested the neurotoxicity, hepatotoxicity, and cardiotoxicity of RMF. A total of 31 differential metabolites and 10 main metabolic pathways were identified by serum metabolomics, and 11 toxic components, 332 related target genes and 141 main signaling pathways were screened out by network toxicology. Further analysis yielded 7 key toxic components: grayanotoxin Ⅲ,grayanotoxinⅠ, rhodojaponin Ⅱ, rhodojaponin Ⅴ, rhodojaponin Ⅵ, rhodojaponin Ⅶ, and kalmanol, which acted on the following 12 key targets: androgen receptor(AR), albumin(ALB), estrogen receptor β(ESR2), sex-hormone binding globulin(SHBG), type 11 hydroxysteroid(17-beta) dehydrogenase(HSD17 B11), estrogen receptor α(ESR1), retinoic X receptor-gamma(RXRG), lactate dehydrogenase type C(LDHC), Aldo-keto reductase(AKR) 1 C family member 3(AKR1 C3), ATP binding cassette subfamily B member 1(ABCB1), UDP-glucuronosyltransferase 2 B7(UGT2 B7), and glutamate-ammonia ligase(GLUL). These targets interfered with the metabolism of gamma-aminobutyric acid, estriol, testosterone, retinoic acid, 2-oxobutyric acid, and affected 4 key metabolic pathways of alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism, steroid hormone biosynthesis, and retinol metabolism. RMF exerts toxic effect on multiple systems through multiple components, targets, and pathways. Through the analysis of key toxic components, target genes, metabolites, and metabolic pathways, this study unveiled the mechanism of potential neurotoxicity, cardiotoxicity, and hepatotoxicity of RMF, which is expected to provide a clue for the basic research on toxic Chinese medicinals.