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ObjectiveTo explore the "efficacy-toxicity" association mechanisms of Tripterygium wilfordii polyglycoside tablets （TWPT） by establishing and analyzing an interaction network associated with the clinical efficacy of TWPT in the treatment of rheumatoid arthritis （RA） and TWPT-induced liver injury. MethodOn the basis of the TWPT efficacy-related gene expression profile and TWPT-induced liver injury-related protein expression profile which were both obtained from our clinical cohorts， the "efficacy-toxicity" association network of TWPT was constructed， and the key network targets were identified by calculating the topological values of the nodes， including the degree， closeness and betweenness. After that， the biological functions and pathways of the key network targets were investigated by enrichment analysis. ResultA total of 119 differentially expressed genes （58 up-regulated and 61 down-regulated） between RA patients with TWPT well and weak response were identified as TWPT efficacy-related genes by clinical transcriptomics， and 49 differentially expressed proteins （36 up-regulated and 13 down-regulated） were demonstrated to be TWPT-induced liver injury-related proteins by clinical proteomics. In addition， the clinical symptom enrichment analysis indicated that the TWPT efficacy-related genes were significantly associated with various clinical symptoms of arthralgia in traditional Chinese medicine and clinical phenotypes of modern medicine， and most of the TWPT-induced liver injury-related proteins were involved in digestive system abnormalities. Therefore， the aforementioned multi-omics data represented the main clinical symptoms of TWPT treating RA and inducing liver injury. Mechanically， the "efficacy-toxicity" association network revealed that both TWPT efficacy-related genes and TWPT-induced liver injury-related core proteins were involved in the "immune-inflammatory" imbalance， especially playing an important role in neutrophil degranulation， complement cascade reaction， and immune-inflammatory response mediated by protein post-translational modification. Notably， the above genes and proteins were also enriched in various signaling pathways related to cell proliferation and cell cycle regulation， such as RAS and mitogen-activated protein kinase （MAPK） signaling pathway， and in several liver functional processes， such as glycogen metabolism and redox reaction. ConclusionThis study systematically explained the "efficacy-toxicity" association characteristics and molecular mechanisms of TWPT by applying a research strategy integrating clinical phenomics， transcriptomics and proteomics， laying a good data foundation for exploring the "efficacy enhancing and toxicity-reducing" mechanisms of TWPT.
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Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.
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Aim To explore the efficacy-toxicity of Tripterygium wilfordii Hook.f.in intervention of lupus nephritis by the method of network pharmacology.Methods Firstly, the active components were searched and the action targets of Tripterygium wilfordii Hook.f.were predicted through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).Secondly, the target genes of LN were collected through CoolGeN, OMIM and Gene Cards databases.And then, it was mapped to Tripterygium wilfordii Hook.f.targets and the drug component-disease target interaction network was constructed with Cytoscape software, and STRING database was used to analyze the protein interaction network.Finally, the common targets were analyzed by GO and KEGG pathway enrichment analysis using DAVID database to explore the potential mechanism of Tripterygium wilfordii Hook.f.in the treatment of LN.Results A total of 52 active components of Tripterygium wilfordii Hook.f.and 38 targets for the treatment of LN were screened.Most of the components had potential therapeutic effects on LN, but the effects of triptolide, tripterine, kaempferol and β-sitosterol may not be conducive to the improvement of LN.The results of KEGG analysis showed that efficacy-toxicity mainly involved NOD-like receptor signaling pathway, p53 signaling pathway, Toll-like receptor signal pathway and so on.Conclusions Tripterygium wilfordii Hook.f.plays the efficacy-toxicity effect on LN by regulating immune inflammation, cell proliferation and apoptosis, and its overall intervention effect needs further experimental study.
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Objective: To explore the “efficacy-toxicity” targets, pathways, and mechanism of Xiaochaihu Decoction in the treatment of hepatitis based on the ADR information excavating of drug-induced liver injury in the treatment of hepatitis with Xiaochaihu Decoction. Methods: Taking Xiaochaihu Decoction as the research object, the integrated pharmacology platform was used to analyze and predict key targets and pathways. Cytoscape software was used to collate and analyze key targets and pathways to obtain co-participation pathways and mechanisms of “efficacy-toxicity”. Results: The analysis of the effect of Xiaochaihu Decoction for liver injury in the treatment of hepatitis showed that there were 40 common targets such as HADHA, HADH, NSDHL, ADH1A, ALDH 3A2, and GCK among the top 100 candidate targets with degree value. The chemical components jointly participated in the network of “effect-toxicity” which belonged to Xiaochaihu Decoction including 27 components in Bupleuri Radix, 74 components in Ginseng Radix, 13 components in Pinelliae Rhizoma, 8 components in Zingiberis Rhizoma, 32 components in Glycyrrhizae Radix et Rhizoma, 39 components in Jujubae Fructus, and 33 components in Scutellaria baicalensis. A total of 226 components were involved in the “effect-toxicity” process through endocrine and metabolic diseases, non-alcoholic fatty liver disease (NAFLD), estrogen signaling pathway, neurodegenerative diseases, nervous system, chemokine signaling pathway, and endocrine system. Conclusion: The “efficacy-toxicity” effect of Xiaochaihu Decoction on liver injury in the treatment of hepatitis may be closely related to Ras/Raf/MEK/ERK, NF-B, and PI3K/AKT signal transduction pathway. It plays a role by regulating cell proliferation, cell apoptosis and the expression of inflammatory factors, which provides a theoretical basis for further pharmacological and toxicological verification and chemical separation research. It plays a role by regulating cell proliferation, cell apoptosis and the expression of inflammatory factors.
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Based on the relation of efficacy and toxicity, this study mined the dosage rules and characteristics of Aconitum herbs in oral prescriptions from 48 traditional ancient books from Eastern Han dynasty to Qing dynasty, to provide the basis for strengthening the clinical risk pharmacovigilance. In the 48 traditional ancient books, 4 521 prescriptions with clear daily oral dosage were included to establish a database. SPSS 20.0 software was used for statistics and analysis of the daily dosage characteristics with different kinds of herbs, indications, dose forms, processing, use in special population, and other aspects. The results showed that 67% prescriptions contained Aconitum carmichaeli(Fuzi), and 90% of them was less than 14.87 g·d⁻¹; The dosage of A. carmichaeli(Chuanwu) and A. kusnezoffii(Caowu) were less than 3.14 g·d⁻¹. In the prescriptions for treating typhoid, epidemic, edema and phlegm, the dosage of Aconitum was larger. There dosage in the decoction and vinum was significantly higher than that in the pill and powder. With the dynastic evolution, the dosage of Aconitum herbal medicines prescriptions and the application percentage of superposition drug also had decreased. For the special populations that with different metabolism process, such as old people, children, pregnant and lactating women, the application of Aconitum was not only with relatively small ratio, but also with lower dose. Therefore, based on the data-mining of ancient books, the dosage of Aconitum should not exceed the limit prescribed by the current China Pharmacopoeia, and also should be strictly controlled by considering various factors, which will ensure the balance of efficacy and toxicity.
Subject(s)
Humans , Aconitum , Chemistry , Toxicity , China , Data Mining , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Toxicity , Medicine, Chinese TraditionalABSTRACT
To evaluate the efficacy and safety associated with anti-hypoxia effect and establish the quality standard for Brassicea Radix extract, the investigations of acute toxicity and subacute toxicity were carried out to preliminarily appraise the toxicity, and the models of normal pressure hypoxia, acute cerebral ischemia and sodium nitrite poisoning in mice were used to evaluate the effect of enhancing anoxia endurance. Then according to the methods described in the Appendix of Chinese Pharmacopoeia (2010 edition), the sulfuric acid-phenol method was applied to determine the content of polysaccharide, and the water, ash and insoluble matter in water inspections were carried out and the control medicinal herb was identified with the samples by qualitative TLC. The results indicated that ① the toxic effects (LD₅₀) of mice was 56.73 g•kg⁻¹ by oral administration of Brassicea Radix extract, while Dm and Dn were respective 86.80 g•kg•d⁻¹ and 35.55 g•kg•d⁻¹;②the determined effective dosage of Brassicea Radix extract which could enhance anoxia endurance was 0.388 g•kg⁻¹•d⁻¹; ③ the methods of TLC and the content of polysaccharide were established. The method of quality control has been recorded in Sichuan Province Standard for Tibetan Medicine, which is reliable, accurate and simple, with good reproducibility. Meanwhile, given the prominent effect on anti-hypoxia and good safety, it provided important basis for clinic safe and effective usage and the development of health products.