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.
Animals ; Mice ; Medicine, Tibetan Traditional ; Network Pharmacology ; Molecular Docking Simulation ; Tandem Mass Spectrometry ; Toll-Like Receptor 4 ; Medicine, Chinese Traditional ; Mercury ; Drugs, Chinese Herbal/toxicity*

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.
Animals ; Drugs, Chinese Herbal/toxicity* ; Irritants ; Lectins ; Pinellia ; Rabbits ; Technology, Pharmaceutical/methods*

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.
Drugs, Chinese Herbal/toxicity* ; Evidence-Based Medicine ; Medicine, Chinese Traditional ; Research Design

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.
Drugs, Chinese Herbal/toxicity* ; Fruit/toxicity* ; Liver

To explore the mechanism of ovarian toxicity of Hook. F. (TwHF) by network pharmacology and molecular docking. The candidate toxic compounds and targets of TwHF were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Comparative Toxicogenomics Database (CTD). Then, the potential ovarian toxic targets were obtained from CTD, and the target genes of ovarian toxicity of TwHF were analyzed using the STRING database. The protein-protein interaction (PPI) network was established by Cytoscape and analyzed by the cytoHubba plug-in to identify hub genes. Additionally, the target genes of ovarian toxicity of TwHF were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses by using the R software. Finally, Discovery Studio software was used for molecular docking verification of the core toxic compounds and the hub genes. Nine candidate toxic compounds of TwHF and 56 potential ovarian toxic targets were identified in this study. Further network analysis showed that the core ovarian toxic compounds of TwHF were triptolide, kaempferol and tripterine, and the hub ovarian toxic genes included , , , , , , , , and . Besides, the GO and KEGG analysis indicated that TwHF caused ovarian toxicity through oxidative stress, reproductive system development and function, regulation of cell cycle, response to endogenous hormones and exogenous stimuli, apoptosis regulation and aging. The docking studies suggested that 3 core ovarian toxic compounds of TwHF were able to fit in the binding pocket of the 10 hub genes. TwHF may cause ovarian toxicity by acting on 10 hub genes and 140 signaling pathways.
Drugs, Chinese Herbal/toxicity* ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Network Pharmacology ; Protein Interaction Maps

A total of 33 pesticides have been banned from Chinese medicinal materials and decoction pieces(plants) according to Chinese Pharmacopoeia(2020 edition). According to the chemical structures, they are mainly divided into seven categories: organophosphorus compounds, organochlorines, carbamates, amidines, sulfonylureas, phenylpyrazoles, and ethers. These banned pesticides exhibit neurotoxicity, reproductive toxicity, immune system toxicity, teratogenicity, carcinogenesis, and mutagenesis, seriously damaging human and animal health. They affect not only the quality and safety of traditional Chinese medicines and resulting products, but also their competitiveness in the international market. Due to the numerous varieties of traditional Chinese medicines and their complex substrates, it is necessary to establish a universal and highly sensitive method for pesticide residue detection. This review systematically summarized the residual status, toxicity, and analytical methods of banned pesticides in traditional Chinese medicines, and forecasted the prospects of different analytical techniques, so as to provide reference for further safety and risk assessment of banned pesticide residues in traditional Chinese medicines, thus ensuring the safe production of traditional Chinese medicines.
China ; Drugs, Chinese Herbal/toxicity* ; Humans ; Medicine, Chinese Traditional ; Organophosphorus Compounds ; Pesticide Residues/toxicity* ; Pesticides/analysis*

In this study, the content of five heavy metals(Pb, Cd, As, Hg, and Cu) in 59 batches of Lonicerae Japonicae Flos(LJF) medicinal materials and pieces were determined by inductively coupled plasma mass spectrometry(ICP-MS). The health risk assessment was processed using the maximum estimated daily intake(EDI), target hazard quotients(THQ), and carcinogenic risks(CR) assessment models. With reference to the limit standard for heavy metal content in LJF specified in 2020 edition of Chinese Pharmacopoeia, five batches produced in Hebei were found to contain excessive Pb, and the remaining 54 batches met the specifications, with the unqualified rate of 8.47%. Comparative analysis of heavy metal content in LJF samples from three different producing areas, namely Shandong, Henan, and Hebei showed that the levels of Pb, As, and Hg in LJF from Hebei were significantly higher than those from Henan and Shandong. The samples produced in Shandong contained the highest content of Cd. The samples from Hebei contained the highest content of Cu while those from Shandong had the lowest content of Cu. As demonstrated by health risk assessment based on the EDI, THQ and CR models, these 59 batches of LJF samples did not cause significant health hazards for the exposed population, and there was no potential non-carcinogenic or carcinogenic risk. In conclusion, a few of LJF samples contained excessive heavy metals, so some measures, including controlling production environment, cultivating management mode, and optimizing processing methods, should be taken for ensuring the medication safety of LJF.
Drugs, Chinese Herbal ; Environmental Pollution/analysis* ; Mercury/toxicity* ; Metals, Heavy/toxicity* ; Risk Assessment

In this study, the toxicological/pharmacological research method of "quantity-weight-evidence" network was first proposed and practiced to supplement the existing methodology of network toxicology. We transformed the traditional qualitative network into a quantitative network in this study by attributing weights to toxic component content and target frequency, which improved the reliability of data and provided a research idea for the systematic safety evaluation and toxicological research of Chinese medicinal herbs. Firstly, 50% ethanol extract of Dysosma versipellis(DV) was administrated to rats via gavage and the potential hepatotoxic components were identified by serum pharmacochemistry. Then, the component targets were obtained from SwissTargetPrediction, PharmMapper and other online databases, and the target weights were given according to the relative content of components and target fishing frequency. Meanwhile, the targets of hepatotoxicity were predicted from online databases such as Comparative Toxicology Database(CTD) and GeneCards. Subsequently, protein-protein interaction analysis and KEGG pathway enrichment were performed with the STRING database. Finally, the quantitative network of "toxic components-weighted targets-pathways" was constructed. Eleven potential toxic compounds were predicted, including podophyllotoxin, podophyllotoxone, deoxypodophyllotoxin, and 6-methoxypodophyllotoxin. A total of 106 hepatotoxic targets and 65 weighted targets(e.g., Cdk2, Egfr, and Cyp2 c9) were identified. The results of Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment showed that these targets could act on PI3 K-AKT, MAPK, and Ras signaling pathways to play a role in inflammatory response and oxidative stress. However, traditional network toxicology showed that 51 targets such as AKT1, Alb, and Stat3 may lead to hepatotoxicity by mediating inflammation and cell proliferation. In conclusion, we proposed "quantity-weight-evidence" network toxicology in this study and used it to study the mechanism of DV-induced hepatotoxicity in rats. This study confirms the feasibility of this new methodology in toxicological evaluation and further improves the systematic evaluation of the safety of Chinese medicinal herbs.
Animals ; Chemical and Drug Induced Liver Injury/etiology* ; Drugs, Chinese Herbal/toxicity* ; Ethanol ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Rats ; Reproducibility of Results

This study systematically searched CNKI and Web of Science(WoS) for the research papers on the toxicity of Tripterygium wilfordii included from database inception to August 31, 2021, and visually displayed the authors, research institutions, keywords, and other contents using bibliometrics and CiteSpace 5.8.3. Furthermore, the current situation and research progress on T. wilfordii safety were also analyzed based on information extraction to find the research hotspot, evolution path, and development trend, and to provide references for future research. A total of 1 876 Chinese papers and 243 English papers were included in the study. The analysis of authors showed that WANG Qi and ZHANG Luyong had the most publications in Chinese and English papers, respectively. According to the analysis of research institutions, National Institutes for Food and Drug Control and China Pharmaceutical University possessed the largest number of Chinese and English papers, respectively, but there was less cooperation between them. The analysis of keywords in Chinese and English papers showed that the research contents of the safety of T. wilfordii mainly focused on clinical monitoring, mechanism, dosage form improvement, quality standard, component analysis, monomer research, efficiency and toxicity reduction, etc. Metabonomics, tripterine, and the underlying mechanism of toxicity were the research hotspots in the future. At present, the research on the toxicity of T. wilfordii is still under development. It is necessary to highlight the in-depth research and strengthen the inter-group and inter-region cooperation of authors or institutions to provide references for the research on the toxicity of T. wilfordii.
Bibliometrics ; China ; Drugs, Chinese Herbal/toxicity* ; Humans ; Tripterygium

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 "molecular-cellular-organ-overall" levels, unclear interaction of multiple medicinals and multiple substances, the "toxicity-efficacy-compatibility-syndrome" correlation, and the "dosage-time-toxicity-efficacy" conversion law. Therefore, following the principle of "starting from the clinical practice, verifying via the theoretical basis, and finally applying in clinical practice", we verified the toxicity at "molecular-cellular-organ-overall" levels, revealed the interaction of multiple medicinals and substances, collected evidence at multiple levels, clarified the "dosage-time-toxicity-efficacy" 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 "dosage-time-toxicity-efficacy" 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.
Drugs, Chinese Herbal/toxicity* ; Medicine, Chinese Traditional ; Research Design