Angelicin: A leading culprit involved in fructus Psoraleae liver injury via inhibition of VKORC1.

ETHNOPHARMACOLOGICAL RELEVANCE: The adverse effects of Fructus Psoraleae (FP), especially liver injury, have attracted wide attention in recent years. AIM OF THE STUDY: To establish a system to explore potential hepatotoxic targets and the chief culprit of liver injury based on clinical experience, network pharmacological method, molecular docking, and in vitro and in vivo experiments. MATERIALS AND METHODS: Clinical applications and adverse reactions to FP were obtained from public literatures. Components absorbed in the blood were selected as candidates to search for potential active targets (PATs) of FP. Subsequently, potential pharmacological core targets (PPCTs) were screened through the "drug targets-disease targets" network. Non-drug active targets (NPATs) were obtained by subtracting the PPCTs from the PATs. The potential hepatotoxic targets (PHTs) of FP were the intersection targets obtained from Venn analysis using NPATs, hepatotoxic targets, and adverse drug reaction (ADR) targets provided by the databases. Then, potential hepatotoxic components and targets were obtained using the "NPATS-component" network relationship. Molecular docking and in vitro and in vivo hepatotoxicity experiments were performed to verify the targets and related components. RESULTS: Overall, 234 NPATs were acquired from our analysis, and 6 targets were identified as PHTs. Results from molecular docking and in vitro and in vivo experiments showed that angelicin is the leading cause of liver injury in FP, and VKORC1 plays an important role. CONCLUSION: The results indicate that six targets, especially VKORC1, are associated with the PHTs of FP, and angelicin is the leading culprit involved in FP liver injury via inhibition of VKORC1.

Exploring quality evaluation markers of Fructus Psoraleae based on chemometric analysis integrated with network pharmacology.

INTRODUCTION: Fructus Psoraleae (FP) is a well-known traditional Chinese medicine for the treatment of osteoporosis. However, major quality differences were witnessed owing to its various origins, thus influencing its safety and efficacy. OBJECTIVES: The study aimed to evaluate the quality of FP from different origins and predict its quality evaluation markers. METHODS: Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was employed for tentative characterisation of the constituents in 10 batches of FP, followed by the utilisation of multivariate statistical analysis methods including principal component analysis and orthogonal partial least squares discriminant analysis for quality evaluation. Network pharmacology approaches were utilised to explore the underlying mechanism of the screened chemotaxonomic markers in treating osteoporosis. RESULTS: Forty-one components in FP including, chalcones, coumarins, coumestans, flavonoids, iso-flavonoids, and phenolics, were characterised based on their fragmentation pathways. Ten batches of FP were basically divided into three categories, and eight chemotaxonomic markers including isopsoralen, calamenene, bakuchiol, psoralen, bavachinin, isoneobavaisoflavone, corylifol C, and neobavaisoflavone were screened. Network pharmacology revealed that the chemotaxonomic markers can act on targets such as AKT1, HSP90AA1, and EGFR and possess effects mainly through glycolysis and wnt/ß-catenin signalling to alleviate osteoporosis. Molecular docking and molecular dynamic simulation confirmed the good binding affinity and stability between proteins and selected markers. So, eight chemotaxonomic markers were all preferentially recommended as quality evaluation markers. CONCLUSION: The study not only provides a reference for the improvement of quality control of FP but also offers a theoretical basis for its further in-depth research in osteoporosis.

Lipidomics reveals the lipid metabolism disorders in Fructus Psoraleae-induced hepatotoxicity in rats with kidney-yin deficiency syndrome.

Fructus Psoraleae (FP), one of the important traditional Chinese medicines, is widely used in clinic and has been reported to be hepatotoxic. However, there is no report on the mechanism of FP-induced hepatotoxicity based on the theory of You Gu Wu Yun. In this study, plasma samples of rats with different kidney deficiency syndromes were investigated using a lipidomics approach based on UPLC/Q-TOF-MS technique. Firstly, multivariate statistical analysis, VIP value test, statistical test and other methods were used to find the lipid metabolites in the two syndrome model groups that were different from the normal group. The screening of differential lipid metabolites revealed that there were 12 biomarkers between the blank group and the kidney-yang deficiency model group as well as 16 differential metabolites between the kidney-yin deficiency model group, and finally a total of 17 relevant endogenous metabolites were identified, which could be used as differential lipid metabolites to distinguish between kidney-yin deficiency and kidney-yang deficiency evidence. Secondly, the relative content changes of metabolites in rats after administration of FP decoction were further compared to find the substances associated with toxicity after administration, and the diagnostic ability of the identified biomarkers was evaluated using a receiver operating characteristic curve (ROC). Results a total of 14 potential differential lipid metabolites, including LysoPC(20:0/0:0) and LysoPC(16:0/0:0), which may be related to hepatotoxicity in rats with kidney-yin deficiency syndrome were further screened, namely, the potential active lipid metabolites related to hepatotoxicity in rats induced by FP. Finally, cluster analysis, MetPA analysis and KEGG database were used to analyze metabolic pathways. It was discovered that the metabolism of glycerophospholipid and sphingolipid may be strongly related to the mechanism of hepatotoxicity brought on by FP. Overall, we described the lipidomics changes in rats treated with FP decoction and screened out 14 lipid metabolites related to hepatotoxicity in rats with kidney-yin deficiency, which served as a foundation for the theory of "syndrome differentiation and treatment" in traditional Chinese medicine and a guide for further investigation into the subsequent mechanism.

Unveiling hepatotoxicity distinction of coumarin-related compounds from glycosides to aglycones in Fructus Psoraleae by integrating UPLC-Q-TOF-MS and high content analysis.

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.

Study on the processing chemistry of Fructus Psoraleae by a combination of untargeted and targeted metabolomics.

Fructus Psoralea is widely used to treat osteoporosis and skin inflammatory diseases. Because of the side effects on the liver, renal and cardiovascular systems, it is processed to salt-processed Fructus Psoraleae to meet the requirements of clinical use. However, the mechanisms involved in the transformation of the chemical components are unclear. In this study, ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry was used to analyze the chemical profiles of this herbal medicine and the chemical transformation mechanism involved during the salt processing was studied. A total of 83 compounds were identified. Principal component analysis and orthogonal partial least squares discriminate analysis were used to observe the distribution trend of all samples and visualize the difference. Raw and processed Fructus Psoraleae were clearly clustered into two groups. Furthermore, 17 marker compounds were identified as primary contributors to their differences based on t-test analysis (p < 0.01) and orthogonal partial least squares discriminate analysis (variable importance for the projection > 1). Finally, ultra-high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry was used to evaluate the quality of Fructus Psoraleae by simultaneous analysis of 13 components highly related to efficacy. There were variations in the contents of 13 chemicals of Fructus Psoraleae and salt-processed products. The results of untargeted and targeted metabolomics revealed that salt processing affected the chemical composition of Fructus Psoraleae.

Hepatotoxicity and nephrotoxicity assessment on ethanol extract of Fructus Psoraleae in Sprague Dawley rats using a UPLC-Q-TOF-MS analysis of serum metabolomics.

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.

Bavachinin mitigates DMH induced colon cancer in rats by altering p53/Bcl2/BAX signaling associated with apoptosis.

Bavachinin is a flavanone obtained from the Chinese herb, Fructus Psoraleae. Flavonoids and flavanones are recognized as cancer preventive agents. We investigated the anticancer properties of bavachinin using a model of dimethylhydrazine (DMH and dextran sodium sulfate (DSS) induced rat colon cancer. We investigated aberrant crypt foci (ACF), hyperplastic lesions, catalase (CAT), superoxide dismutase (SOD) and glutathione (GST) levels in Wistar rats. Expression of cancer biomarkers including IL-6, p53, Bcl2 and BAX was investigated. We found that bavachinin administered to rats re-established the colonic crypts that were damaged by DMH and prevented progression of the cancer.

Effects of psoralen on hepatic bile acid transporters in rats.

Fructus Psoraleae (FP), widely used in traditional medicine, is increasingly reported to cause serious hepatotoxicity in recent years. However, the main toxic constituents responsible for hepatotoxicity and the underlying mechanisms are poorly understood. In the present study, psoralen, a main and quality-control constituent of FP, was intragastrically administered to Sprague-Dawley rats at a dose of 60 mg/kg for 1, 3 and 7 days. Blood and selected tissue samples were collected and analyzed for biochemistry and histopathology to evaluate hepatotoxicity. The results showed that psoralen could induce hepatotoxicity by enhanced liver-to-body weight ratio and alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total cholesterol after administration for 3 days. In addition, histopathological examinations also indicated the hepatotoxicity induced by psoralen. Furthermore, the mRNA and protein levels of hepatic bile acid transporters were significantly changed, in which MRP4, ABCG5 and ABCG8 were repressed, while the protein level of NTCP tended to increase in the rat liver. Taken together, psoralen caused liver injury possibly through affecting bile acid transporters, leading to the disorder of bile acid transport and accumulation in hepatocytes.

Pancreatic lipase inhibitory constituents from Fructus Psoraleae.

Pancreatic lipase (PL), a crucial enzyme in the digestive system of mammals, has been proven as a therapeutic target to prevent and treat obesity. The purpose of this study is to evaluate and characterize the PL inhibition activities of the major constituents from Fructus Psoraleae (FP), one of the most frequently used Chinese herbs with lipid-lowering activity. To this end, a total of eleven major constituents isolated from Fructus Psoraleae have been obtained and their inhibition potentials against PL have been assayed by a fluorescence-based assay. Among all tested compounds, isobavachalcone, bavachalcone and corylifol A displayed strong inhibition on PL (IC50 < 10 µmol·L-1). Inhibition kinetic analyses demonstrated that isobavachalcone, bavachalcone and corylifol A acted as mixed inhibitors against PL-mediated 4-methylumbelliferyl oleate (4-MUO) hydrolysis, with the Ki values of 1.61, 3.77 and 10.16 µmol·L-1, respectively. Furthermore, docking simulations indicated that two chalcones (isobavachalcone and bavachalcone) could interact with the key residues located in the catalytic cavity of PL via hydrogen binding and hydrophobic interactions. Collectively, these finding provided solid evidence to support that Fructus Psoraleae contained bioactive compounds with lipid-lowering effects via targeting PL, and also suggested that the chalcones in Fructus Psoraleae could be used as ideal leading compounds to develop novel PL inhibitors.

Integrative proteomics-metabolomics strategy reveals the mechanism of hepatotoxicity induced by Fructus Psoraleae.

Fructus Psoraleae (FP), one of the significant traditional Chinese medicines, has been reported to cause hepatotoxicity. However, the mechanism remains undetermined and the reported research is limited. In this study, a tandem mass tag (TMT)-based quantitative proteomics and metabolomics were used to reveal a more comprehensive effect caused by FP. The results showed that aqueous extract of FP can induce liver injury in rats. In total, 575 significantly changed proteins were identified by quantitative proteomics analysis, among which 352 proteins were significantly up-regulated and 223 proteins were significantly down-regulated in liver tissues. And we detected 14 biomarkers such as succinic acid, hypoxanthine, l-carnitine, phenylalanine, glutathione, and glycoursodeoxycholic acid. Correlation analysis of altered metabolites and proteins exhibited the aberrant regulation of metabolic pathways including bile secretion, glutathione metabolism, purine metabolism, glycerophospholipid metabolism, TCA cycle and pyruvate metabolism, which indicated the disorder of bile acid metabolism, oxidative stress, energy metabolism and immune system. Notably, the changed proteins including Cyp7a1, FXR, SHP, BSEP, Sult2a1, Nceh1 in bile acid metabolism may play an essential role in the hepatotoxicity induced by aqueous extract of FP. In conclusion, integrative proteomics and metabolomics provide the potential mechanism of hepatotoxicity induced by FP. SIGNIFICANCE: Fructus Psoraleae, a traditional Chinese medicine, is widely used in Asia for the treatment of osteoporosis and vitiligo. Recently, clinical and experimental reports reveal that FP can induce liver injury. However the mechanism of injury induced by FP is still unclear. In this study, we detected 352 significantly up-regulated proteins and 223 significantly down-regulated proteins in liver tissues by TMT-based quantitative proteomics. And 14 important metabolites were identified by metabolomics analysis. Through integrative analysis of the key metabolites and proteins, several metabolism pathways were selected, which implicated in bile acid metabolism, oxidative stress, energy metabolism, immune system. This is the first integrative study of proteomics and metabolomics for FP exposure, the finding clarified the potential mechanism of hepatotoxicity caused by FP and will promote rational use of FP in clinical application.

Quantitative proteomics analysis of Fructus Psoraleae-induced hepatotoxicity in rats.

Fructus Psoraleae, which is commonly consumed for the treatment of osteoporosis, bone fracture, and leucoderma, induces liver injury. This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae (EEFP)-induced liver injury in rats. EEFP (1.35, 1.80, and 2.25 g·kg-1) was administrated to Sprague Dawley (SD) rats for 30 d. We measured liver chemistries, histopathology, and quantitative isobaric tags for relative and absolute quantitation (iTRAQ)-based protein profiling. EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion, bile flow rate, and liver histopathology. iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats. Among these proteins, 81 were upregulated and 32 were downregulated in the treatment group. KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450, glutathione metabolism, glycerolipid metabolism, and bile secretion were enriched with differentially expressed proteins. The expression of key proteins related to the farnesoid X receptor (FXR), i.e., the peroxisome proliferators-activated receptor alpha (PPAR-α), were downregulated, and multidrug resistance-associated protein 3 (MRP3) was upregulated in the EEFP-treated rats. Our results provide evidence that EEFP may induce hepatotoxicity through various pathways. Furthermore, our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.

CYPs-mediated drug-drug interactions on psoralidin, isobavachalcone, neobavaisoflavone and daidzein in rats liver microsomes.

The incubation system of CYP2E1 and CYP3A4 enzymes in rat liver microsomes was established to investigate the effects of psoralidin, isobavachalcone, neobavaisoflavone and daidzein from Fructus Psoraleae in vitro. The relevant metabolites were measured by the method of high performance liquid chromatography (HPLC), after probe substrates of 4-nitrophenol, testosterone and the drugs at different concentrations were added to the incubation systems. In addition, real-time RT-PCR was performed to determine the effect of psoralidin, neobavaisoflavone and daidzein on the mRNA expression of CYP3A4 in rat liver. The results suggested that psoralidin, isobavachalcone and neobavaisoflavone were Medium-intensity inhibitors of CYP2E1 with Ki values of 2.58, 1.28 and 19.07 µM, respectively, which could inhibit the increase of CYP2E1 and reduce diseases caused by lipid peroxidation. Isobavachalcone (Ki = 37.52 µM) showed a weak competitive inhibition on CYP3A4. Psoralidin and neobavaisoflavone showed obvious induction effects on CYP3A4 in the expression level of mRNA, which could accelerate the effects of drug metabolism and lead to the risk of inducing DDIs and serious adverse reactions. The results could be used for guideline of Fructus Psoraleae in clinic, which aimed to calculate the drug toxicity by studying the drug-drug interactions caused by the induction and inhibition of CYP450.

Fructus Psoraleae-Induced Severe Liver Injury and Treatment With Two Artificial Liver Support Systems: A Case Series Study.

To describe the clinical features and outcomes of patients with suspected Fructus Psoraleae (FP)-induced severe liver injury who underwent treatment with two artificial liver support systems (ALSSs). The cases of 12 patients with severe liver injury by FP were enrolled. We evaluated the tolerability of, and changes in biochemical parameters after treatment with plasma exchange combined with hemofiltration and double plasma molecular absorption system, and 6-month follow-up information were collected. The median age of the 12 patients was 60 years and nine (75%) patients were females. All patients had jaundice as the initial symptom. Two ALSS types were used to treat the patients. The group that underwent plasma exchange combined with hemofiltration showed remarkable improvements in ALT, AST, total bilirubin (TB), GGT and international normalized ratio levels (AST, TB, international normalized ratio, P < 0.01; ALT, GGT, P < 0.05), and the levels of AST, ALP, TB, and total bile acid decreased significantly in the double plasma molecular absorption system group after treatment (TB, P < 0.01; AST, ALP, total bile acid P < 0.05). During 6 months of follow-up, two patients died, two became chronic, and eight recovered to normal. FP can cause clinically severe liver injury, characterized by gastrointestinal symptoms and jaundice, which can lead to death or become chronic. Both ALSSs were safe and well tolerated in drug-induced liver injury patients. After ALSS treatment, the levels of biochemical indicators of liver function improved significantly, indicating that ALSS might be beneficial for patients with severe drug-induced liver injury.

Long-Term Exposure of Psoralen and Isopsoralen Induced Hepatotoxicity and Serum Metabolites Profiles Changes in Female Rats.

:Pre-clinical safety evaluation of traditional medicines is imperative because of the universality of drug-induced adverse reactions. Psoralen and isopsoralen are the major active molecules and quality-control components of a traditional herbal medicine which is popularly used in Asia, Fructus Psoraleae. The purpose of this study is to assess the long-term effects of psoralen and isopsoralen with low levels on the biochemical parameters and metabolic profiles of rats. Three doses (14, 28, and 56 mg/kg) of psoralen and one dose (28 mg/kg) of isopsoralen were administered to rats over 12 weeks. Blood and selected tissue samples were collected and analyzed for hematology, serum biochemistry, and histopathology. Metabolic changes in serum samples were detected via proton nuclear magnetic resonance (1H-NMR) spectroscopy. We found that psoralen significantly changed the visceral coefficients, blood biochemical parameters, and histopathology, and isopsoralen extra influenced the hematological index. Moreover, psoralen induced remarkable elevations of forvaline, isoleucine, isobutyrate, alanine, acetone, pyruvate, glutamine, citrate, unsaturated lipids, choline, creatine, phenylalanine, and 4-hydroxybenzoate, and significant reductions of ethanol and dimethyl sulfone. Isopsoralen only induced a few remarkable changes of metabolites. These results suggest that chronic exposure to low-level of psoralen causes a disturbance in alanine metabolism, glutamate metabolism, urea cycle, glucose-alanine cycle, ammonia recycling, glycine, and serine metabolism pathways. Psoralen and isopsoralen showed different toxicity characteristics to the rats.

Effects of Bakuchiol on chondrocyte proliferation via the PI3K-Akt and ERK1/2 pathways mediated by the estrogen receptor for promotion of the regeneration of knee articular cartilage defects.

OBJECTIVES: Cartilaginous tissue degradation occurs because of the lack of survival of chondrocytes. Here, we ascertained whether bakuchiol (BAK) has the capability of activating chondrocyte proliferation. MATERIALS AND METHODS: The effect of BAK on the proliferation of rat chondrocytes at a concentration of 10 and 20 µmol/L was investigated. The molecular mechanisms involving target binding and signalling pathways were elucidated by RNA-sequencing, qPCR, molecular docking and Western blotting. Matrigel mixed with bakuchiol was implanted locally into rat knee articular cartilage defects to verify the activation of chondrocytes due to bakuchiol in vivo. RESULTS: Bakuchiol implantation resulted in the activation of rat chondrocyte proliferation in a dose-dependent manner. RNA-sequencing revealed 107 differentially expressed genes (DEGs) with 75 that were up-regulated and 32 that were down-regulated, indicating increased activation of the PI3K-Akt and cell cycle pathways. Activation of the phosphorylation of Akt, ERK1/2 and their inhibitors blocked the proliferative effect of bakuchiol treatment, confirming its direct involvement in these signal transduction pathways. Molecular docking and siRNA silencing revealed that estrogen receptor-α (ERα) was the target of bakuchiol in terms of its cell proliferative effect via PI3K activation. Two weeks after implantation of bakuchiol, the appearance and physiological structure of the articular cartilage was more integrated with abundant chondrocytes and cartilage matrix compared to that of the control. CONCLUSIONS: Bakuchiol demonstrated significant bioactivity towards chondrocyte proliferation via the PI3K-Akt and ERK1/2 pathways mediated by estrogen receptor activation and exhibited enhanced promotion of the remodelling of injured cartilage.

Acute liver failure associated with Fructus Psoraleae: a case report and literature review.

BACKGROUND: Fructus Psoraleae is the seed of Psoralea corylifolia Linn. Fructus Psoraleae has been shown to be effective in treating some skin diseases, such as vitiligo. As a main ingredient in five types of herbs in the Qubaibabuqi tablet formula, Fructus Psoraleae plays an important role in the treatment of vitiligo. Fructus Psoraleae has potential hepatotoxicity, thus Qubaibabuqi tablets also have potential liver toxicity. CASE PRESENTATION: A 53-year-old woman who was diagnosed with vitiligo in September 2017 was treated with Qubaibabuqi tablets. After approximately 7 months of treatment, the patient developed a severe, diffuse yellow staining of the skin and sclera in March 2018. On admission, she was diagnosed with acute cholestatic hepatitis associated with Fructus Psoraleae. Despite receiving active treatment, her condition rapidly deteriorated and she died 5 days later due to acute liver failure and multiple organ dysfunction. To the best of our knowledge, there are only six reported cases of liver injury associated with Fructus Psoraleae described in the English language literature; however, cases of acute liver failure associated with the use of Fructus Psoraleae have not been described. CONCLUSION: As a main ingredient in the Qubaibabuqi tablet formula, Fructus Psoraleae has potential hepatotoxicity. This potentially fatal adverse effect should be considered when physicians prescribe Qubaibabuqi tablets.

Multiorgan toxicity induced by EtOH extract of Fructus Psoraleae in Wistar rats.

BACKGROUND: The fruits of Psoralea corylifolia L. (Fructus Psoraleae, FP) has a long history and a wide range of applications in the treatment of osteoporosis and leukoderma. Although it is well known that FP could cause hepatotoxicity and reproductive toxicity, less is known about its potential toxicity on multiple organs. PURPOSE: This study aims to determine the multiorgan toxicity of EtOH extract of FP (EEFP) and to investigate the underlying mechanisms through a systematic evaluation in Wistar rats. STUDY DESIGN AND METHODS: Wistar rats were orally administered with the EEFP at doses of 1.5, 1.0 and 0.5 g/kg for 28 days. Histopathologic and clinicopathologic analyses were performed, and the hormone levels in serum and the mRNA levels of enzymes related to the production of steroid hormones in adrenal glands were detected. The area of each band of adrenal glands and the steroid levels in the adrenal glands were also measured. RESULTS: After the treatment, both the histopathologic and clinicopathologic examination showed that EEFP caused liver, prostate, seminal vesicle and adrenal gland damage. Among the enzymes involved in the regulation of adrenal steroid hormone production, NET, VMAT2, and CYP11B1 were upregulated, while CYP17A1 was downregulated. Among the adrenal steroid hormones, COR and NE were upregulated, while levels of DHT and serum ACRH and CRH decreased. CONCLUSION: Our results indicated that adrenal gland, prostate, and seminal vesicles could also be the target organs of FP-induced toxicity. Abnormal enzyme and hormone production related to the hypothalamic pituitary adrenal (HPA) axis caused by the EEFP may be the potential toxic mechanism for changes in the adrenal gland and secondary sex organs of male rats.

Isopsoralen induces different subchronic toxicities and metabolomic outcomes between male and female Wistar rats.

Isopsoralen is a major active and quality-control component of Fructus Psoraleae, but lacks a full safety evaluation. We evaluated the oral toxicity of isopsoralen in Wistar rats treated for 3 months at doses of 0, 3.5, 7.0, and 14 mg/kg. Additionally, the plasma metabolomics of isopsoralen in male and female rats treated for 3 months at doses of 0 and 14 mg/kg were investigated by gas chromatography-mass spectrometry. Many abnormalities were observed in the isopsoralen-treated rats, including suppression of body weight gain, and changes in serum biochemical parameters and visceral coefficients. Histopathological changes in liver, pancreatic, and reproductive system tissues were also observed in the isopsoralen-treated rats. The metabolomic analyses showed alterations in many metabolites (19 in female rats; 28 in male rats) after isopsoralen administration. The significant changes in these metabolites revealed metabolomic alterations in the isopsoralen-treated rats, especially in amino acid metabolism regardless of sex, including phenylalanine, tyrosine, and tryptophan biosynthesis and glycine, serine, and threonine metabolism. Furthermore, fatty acid metabolism comprised the main affected pathways in female rats, while lipid metabolism and energy metabolism were the main affected pathways in male rats.

General survey of Fructus Psoraleae from the different origins and chemical identification of the roasted from raw Fructus Psoraleae.

Fructus Psoraleae, a traditional Chinese medicine, is widely used for preventing and treating various diseases such as vitiligo, osteoporosis and psoriasis. Coumarin, such as psoralenoside, isopsoralenoside, psoralen and isopsoralen, are important compounds in Fructus Psoraleae. In our study, ultra performance liquid chromatography coupled with diode array detector was employed for an excellent method validation for simultaneous quantification of psoralenoside, isopsoralenoside, psoralen and isopsoralen, which was further applied in performing general survey of Fructus Psoraleae from the different origins and chemical identification of the roasted from raw Fructus Psoraleae in the light of illuminating the transformed rule of psoralenoside and isopsoralenoside. There is a reciprocal relationship between (iso)psoralenoside and (iso)psoralen, and the total content remains balance in Fructus Psoraleae from the different origins. In addition, we found that (iso)psoralenoside in the powder of the raw Fructus Psoraleae could be easily transformed into (iso)psoralen in methanol aqueous solution, especially above 50% water, rather than the roasted one. Thus, we proposed a hypothesis that transformation between (iso)psoralenoside and (iso)psoralen was hindered by inactivation of ß-glucosidase in the process of roasting Fructus Psoraleae, which was further verified by observing transformation of (iso)psoralenoside under the different conditions, such as temperature, pH and ß-glucosidase. Therefore, we developed a feasible method to distinguish the roasted from raw Fructus Psoraleae by observing conversion from (iso)psoralenoside to (iso)psoralen in 50% methanol aqueous solution. In summary, these results pave the way for elevating quality standard for Fructus Psoraleae and distinguishing the salt-processed from raw Fructus Psoraleae.

Polymeric monolith column composited with multiwalled carbon nanotubes-ß-cyclodextrin for the selective extraction of psoralen and isopsoralen.

A polymeric column that contains multiwalled carbon nanotubes-ß-cyclodextrin composite was developed. The composite was wrapped into the poly(butyl methacrylate-ethylene dimethacrylate) monolith column (0.76 mm id and 10 cm in length). The column was then applied for the online solid-phase microextraction of psoralen and isopsoralen from Fructus Psoraleae. Following microextraction, the coumarins were quantified by high-performance liquid chromatography with C18 separation column and UV detection. The effects of sample flow rate, sample volume, and pH value were optimized. The method showed low limits of detection (20 pg/mL, S/N = 3) for both psoralen and isopsoralen. Finally the method was successfully applied to the determination of psoralen and isopsoralen in spiked herb extracts and rat plasma where it gave recoveries that ranged between 93.2 and 102.1%. The empty hydrophobic cavities of ß-cyclodextrin and the hydrophobicity of multiwalled carbon nanotubes provided specific extraction capability for psoralen and isopsoralen.