Aurantio-obtusin is an anthraquinone derived from Cassia obtusifolia (cassiae semen). It is also used as a tool and a detection index for the identification of cassiae semen, as stipulated by the Chinese Pharmacopoeia. Anthraquinones, the main components in cassiae semen, have been reported to show hepatotoxicity. This study investigates the hepatotoxicity of aurantio-obtusin in male Sprague–Dawley rats. We randomly divided the animals into a blank control group and treated three test groups with different doses of aurantio-obtusin: Low dose (4 mg/kg), medium dose (40 mg/kg), and high dose (200 mg/kg). Each group was treated with aurantio-obtusin for 28 days, whereas the control group was administered an equal volume of 0.5% carboxymethyl cellulose sodium salt (CMC-Na) aqueous solution. Subsequently, we conducted biochemical, hematological, and pathological investigations and determined the weight of different organs. We used serum metabolomics to identify possible biomarkers related to hepatotoxicity. The low-dose group showed no significant liver injury, whereas the medium- and high-dose groups manifested obvious liver injury. Compared with the control group, the test groups showed an increase in alanine transaminase, aspartate transaminase, and alkaline phosphatase levels. The liver organ coefficient also significantly increased. Additionally, we found significant changes in the hematological indices. Metabolomics analysis showed that aurantio-obtusin induced 28 endogenous markers related to liver injury. Our data indicate that aurantio-obtusin induces hepatotoxicity in rat liver in a dose-dependent manner and is mediated by pathways involving bile acids, fatty acids, amino acids, and energy metabolism. In particular, changes in bile acid content during treatment with therapeutic agents containing aurantio-obtusin deserve increased attention.
Fructus Psoraleae (FP) is commonly used in the treatment of vitiligo, osteoporosis, and other diseases in clinic. As a result, the toxicity caused by FP is frequently encountered in clinical practice; however, the underlying toxicity mechanism remains unclear. The purpose of this study was to investigate the toxic effect of the ethanol extract of FP (EEFP) in rats and to explore the underlying toxic mechanisms using a metabolomics approach. The toxicity was evaluated by hematological indicators, biochemical indicators, and histological changes. In addition, a serum metabolomic method based on ultra‐performance liquid chromatography coupled with quadrupole time‐of‐flight MS (UPLC–Q‐TOF–MS) had been established to investigate the hepatorenal toxicity of FP. Multivariate statistical approaches, such as partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis, were built to evaluate the toxic effects of FP and find potential biomarkers and metabolic pathways. Ten endogenous metabolites had been identified and the related metabolic pathways were involved in phospholipid metabolism, amino acid metabolism, purine metabolism, and antioxidant system activities. The results showed that long‐term exposure to high‐dose EEFP may cause hepatorenal toxicity in rats. Therefore, serum metabolomics can improve the diagnostic efficiency of FP toxicity and make it more accurate and comprehensive.
Previous studies revealed the hepatotoxic effect of aurantio-obtusin on rats. The aim of this study was to identify potential biomarkers of urine caused by aurantio-obtusin. Sprague–Dawley (SD) rats with body weight of 0, 4, 40, and 200 mg/kg were orally given aurantio-obtusin for 28 days, and urine was collected for 24 h after the last administration. The urine metabolites in the aurantio-obtusin group and the control group were analyzed by ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). Twenty-three metabolites were identified as potential biomarkers, and 10 of them were up-regulated, including xanthosine, hippuric acid, 5-L-glutamyl-taurine, etc. The other 13 biomarkers were down-regulated, including thymidine, 3-methyldioxyindole, cholic acid, etc. The significant changes of these biomarkers indicated that purine metabolism, taurine and hypotaurine metabolism, primary bile acid biosynthesis, pyrimidine metabolism, and tryptophan metabolism played an important role in the hepatotoxicity of aurantio-obtusin in rats. In this paper, the safety and potential risk of aurantio-obtusin were studied for the first time by combining the toxicity of aurantio-obtusin with the results of urine metabolomics, which provided information for the mechanism of liver injury induced by aurantio-obtusin.
Ophiopogonin D (OPD) and Ophiopogonin D ′ (OPD ′ ) are two bioactive ingredients in Ophiopogon japonicus. Previously published studies have often focused on the therapeutic effects related to OPD’s antioxidant capacity but underestimated the cytotoxicity-related side effects of OPD ′ , which may result in unpredictable risks. In this study, we reported another side effect of OPD ′ , hemolysis, and what was unexpected was that this side effect also appeared with OPD. Although hemolysis effects for saponins are familiar to researchers, the hemolytic behavior of OPD or OPD ′ and the interactions between these two isomers are unique. Therefore, we investigated the effects of OPD and OPD ′ alone or in combination on the hemolytic behavior in vitro and in vivo and adopted chemical compatibility and proteomics methods to explain the potential mechanism. Meanwhile, to explain the drug-drug interactions (DDIs), molecular modeling was applied to explore the possible common targets. In this study, we reported that OPD ′ caused hemolysis both in vitro and in vivo, while OPD only caused hemolysis in vivo. We clarified the differences and DDIs in the hemolytic behavior of the two isomers. An analysis of the underlying mechanism governing this phenomenon showed that hemolysis caused by OPD or OPD ′ was related to the destruction of the redox balance of erythrocytes. In vivo, in addition to the redox imbalance, the proteomics data demonstrated that lipid metabolic disorders and mitochondrial energy metabolism are extensively involved by hemolysis. We provided a comprehensive description of the hemolysis of two isomers in Ophiopogon japonicus, and risk warnings related to hemolysis were presented. Our research also provided a positive reference for the development and further research of such bioactive components.
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