Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2.

With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 µM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

Isolation, Cytotoxicity, and In-silico Screening of Coumarins from Psoralea corylifolia Linn.

Psoralea corylifolia (syn. Cullen corylifolium), commonly called bawachi, is a medicinal plant extensively used for skin conditions like leukoderma, vitiligo, and psoriasis. It is notably rich in valuable bioactive compounds, particularly coumarins and furanocoumarins. This study isolated fourteen coumarins from P. corylifolia which were tested for cytotoxicity using the MTT assay, with compound 10 showing good cytotoxicity against A549 cells (IC50 0.9 µM), while compound 1, compound 2, and compound 3 displaying potential cytotoxicity against MDA-MB-231 cells (IC50 0.49 µM, 0.56 µM, and 0.84 µM respectively). Additionally, the compounds' interaction with Epidermal Growth Factor Receptor (EGFR) protein, highly expressed in both cell lines, was investigated through molecular modeling studies, that aligned well with cytotoxicity results. The findings revealed the remarkable cytotoxic potential of four coumarins 1, 2, 3, and 10 against A549 and MDA-MB-231 cell lines.

New monoterpene phenol dimers from the fruits of Psoralea corylifolia.

Three new monoterpene phenol dimers, bisbakuchiols V-X (1-3), and two bakuchiol ethers (4 and 5), along with four known compounds (6-9) were isolated from the fruits of Psoralea corylifolia. Their structures were elucidated based on extensive spectral analysis. The absolute configurations of 1, 2, 4, and 5 were specified by quantum chemical calculations of ECD spectra.

[Pharmacokinetics of 11 active components of Psoraleae Fructus in normal and diabetic rats].

A total of 11 active ingredients including psoralen, isopsoralen, bakuchiol, bavachalcone, bavachinin, corylin, coryfolin, isobavachalcone, neobavaisoflavone, bakuchalcone, and corylifol A from Psoraleae Fructus in the plasma samples of diabetic and normal rats were simultaneously determined by UHPLC-MS/MS. The pharmacokinetic parameters were calculated to elucidate the pharmacokinetic profiles of coumarins, flavonoids, and monoterpene phenols in normal and diabetic rats. The rat model of type 2 diabetes mellitus(T2DM) was induced by a high-sugar and high-fat diet combined with injection of 1% streptozotocin every two days. The plasma samples were collected at different time points after the rats were administrated with Psoraleae Fructus. The proteins in the plasma samples were precipitated by ethyl acetate, and the plasma concentrations of the 11 components of Psoraleae Fructus were determined by UHPLC-MS/MS. The pharmacokinetic parameters were calculated by DAS 3.0. The results showed that the pharmacokinetic beha-viors of 8 components including psoralen, isopsoralen, bakuchiol, and bavachinin from Psoraleae Fructus in both female and male mo-del rats were significantly different from those in normal rats. Among them, the coumarins including psoralen, isopsoralen, and corylin showed lowered levels in the blood of both female and male model rats. The flavonoids(bavachinin, corylifol A, and bakuchalcone) and the monoterpene phenol bakuchiol showed decreased levels in the female model rats but elevated levels in the male model rats. It is suggested that the dosage of Psoraleae Fructus should be reasonably adjusted for the patients of different genders at the time of clinical administration.

Flavonoids dimers from the fruits of Psoralea corylifolia and their cytotoxicity against MCF-7 cells.

Nine new flavonoids dimers, psocorylins R-Z (1-9), were isolated from the fruits of Psoralea corylifolia L. (Psoraleae Fructus), a traditional Chinese medicine. The structures of these compounds were elucidated via multiple spectroscopic techniques and X-ray diffraction. Psocorylins R (1) and S (2) were rare cyclobutane-containing chalcone dimers, and psocorylins T-Z (3-9) were established by CC or COC bond of two flavonoid monomers. The structural-types, flavonoids dimers, were isolated from the plant for the first time, enriching the chemical diversity. The cytotoxicity assay suggested that compounds 1, 2, 4, 5, 6 and 8 exhibited cytotoxic activities against MCF-7 cells. Furthermore, compounds 1 and 8 significantly increased intracellular ROS levels, decreased MMP and induced apoptosis of MCF-7 cells. They markedly upregulated the expression of Bax and cleaved caspase-3, and suppressed Bcl-2 and caspase-3 levels, indicating their mechanism of Bcl-2/Bax/Cleaved caspase-3 pathway. Hence, our findings not only promoted the chemical investigation of Psoraleae Fructus, but also provided potential bioactive natural products for anti-cancer.

Phytochemical and Pharmacological Aspects of Psoralen - A Bioactive Furanocoumarin from Psoralea corylifolia Linn.

Since long ago, medicinal plants have played a vital role in drug discovery. Being blessed and rich in chemovars with diverse scaffolds, they have unique characteristics of evolving based on the need. The World Health Organization also mentions that medicinal plants remain at the center for meeting primary healthcare needs as the population relies on them. The plant-derived natural products have remained an attractive choice for drug development owing to their specific biological functions relevant to human health and also the high degree of potency and specificity they offer. In this context, one such esteemed phytoconstituent with inexplicable biological potential is psoralen, a furanocoumarin. Psoralen was the first constituent isolated from the plant Psoralea corylifolia, commonly known as Bauchi. Despite being a life-saver for psoriasis, vitiligo, and leukoderma, it also showed immense anticancer, anti-inflammatory, and anti-osteoporotic potential. This review brings attention to the possible application of psoralen as an attractive target for rational drug design and medicinal chemistry. It discusses the various methods for the total synthesis of psoralen, its extraction, the pharmacological spectrum of psoralen, and the derivatization done on psoralen.

Psoralidin, a natural compound from Psoralea corylifolia, induces oxidative damage mediated apoptosis in colon cancer cells.

Psoralidin (PSO) is a natural coumarin isolated from the seeds of Psoralea corylifolia Linn. Previous studies have reported that PSO exerts numerous pharmacological bioactivities including antitumor. The present study aimed to investigate its anticancer effect using colon cancer cells. Cultured HT-29 and HCT-116 colon cancer cells were treated with different concentrations of PSO, and the cell viability, the intracellular reactive oxygen species (ROS), the protein expression, and the apoptosis were determined by MTT assay, DCFH2 -DA fluorescence probe, Western blotting, and Annexin V/7-AAD staining, respectively. The activities of caspase 3/7 were determined by a commercial kit. Our study found that PSO effectively induces apoptotic cell death mediated by caspase 3/7 in HT-29 and HCT-116 colon cancer cells. PSO treatment rapidly boosts the ROS generation, which is responsible for the PSO-triggered DNA damage, mitochondria membrane potential decrease and caspase 3/7 activation, and c-Jun N-terminal kinase 1/2 activation. Collectively, these results showed that PSO triggered oxidative damage mediated apoptosis in colon cancer cells.

Total Syntheses and Cytotoxicity Evaluation of Coryaurone A and Representative Analogues.

The first total synthesis of coryaurone A, which was originally obtained from Psoralea corylifolia L., was achieved via an efficient route with the longest linear sequence of six steps from the commercially available 6-hydroxy-2H-benzofuran-3-one in 37% overall yield. A series of representative analogues were synthesized from the same starting material in 4-7 steps with overall yields of 27-56%. The cytotoxicities of these compounds against the leukemia cell line HL-60 and the colon cancer cell line SW480 were determined. Among them, compounds 12, 14, 21, and 27 exhibited different levels of cytotoxic activity, which were greater than the positive control cisplatin.

The Use of Bakuchiol in Dermatology: A Review of In Vitro and In Vivo Evidence.

The plant Psoralea corylfolia contains compounds such as psoralens that are useful for the treatment of psoriasis and vitiligo, and the plant is used in Chinese and Indian traditional medicine for diseases such as psoriasis and leprosy. Bakuchiol, a meroterpene phenol in Psoralea corylfolia, has similar functional properties to topical retinoids, which are commonly used to treat acne, post-inflammatory hyperpigmentation, and wrinkles. Bakuchiol’s anti-inflammatory and anti-proliferative properties also may lead to improvement in psoriasis and skin cancers, yet more clinical evidence is needed to elucidate these effects. Notably, bakuchiol does not cause common adverse effects seen with topical retinoids such as burning and scaling, permitting wider use in patients with sensitive skin. This review will detail the current evidence for bakuchiol as an alternative treatment in dermatologic conditions. J Drugs Dermatol. 2022;21(6):624-629. doi:10.36849/JDD.6740.

Corylin from Psoralea fructus (Psoralea corylifolia L.) protects against UV-induced skin aging by activating Nrf2 defense mechanisms.

Oxidative stress damage can lead to premature skin aging or age-related skin disorders. Therefore, strategies to improve oxidative stress-induced aging are needed to protect the skin and to treat skin diseases. This study aimed to determine whether the flavonoid corylin derived from Psoralea corylifolia can prevent UV-induced skin aging and if so, to explore the potential molecular mechanisms. We found that corylin potently blocked UV-induced skin photoaging in mice by reducing oxidative stress and increasing the nuclear expression of nuclear factor-erythroid factor 2-related factor 2 Nrf2. We also found that corylin stimulated Nrf2 translocation into the nucleus and increased the delivery of its target antioxidant genes together with Kelch-like ECH-associated protein 1 (Keap1) to dissociate Nrf2. These findings indicate that corylin could prevent skin aging by inhibiting oxidative stress via Keap1-Nrf2 in mouse cells. Thus, Nrf2 activation might be a therapeutic target for preventing skin aging or skin diseases caused by aging. Our findings also provided evidence that warrants the further investigation of plant ingredients to facilitate the discovery of novel therapies targeting skin aging.

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to ß-Amyloid Peptide Monomer.

A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer's disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aß42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aß42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aß42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aß42 active site and provide useful information that could benefit the development of new Aß42 accumulation inhibitors.

Exploration of Antimicrobial Ingredients in Psoralea corylifolia L. Seed and Related Mechanism against Methicillin-Resistant Staphylococcus aureus.

With the abuse of antibiotics, bacterial antibiotic resistance is becoming a major public healthcare issue. Natural plants, especially traditional Chinese herbal medicines, which have antibacterial activity, are important sources for discovering potential bacteriostatic agents. This study aimed to develop a fast and reliable method for screening out antimicrobial compounds targeting the MRSA membrane from Psoralea corylifolia Linn. seed. A UPLC-MS/MS method was applied to identify the prenylated flavonoids in major fractions from the extracts of Psoralea corylifolia Linn. seed. The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of different fractions and compounds. The morphological and ultrastructural changes of MRSA were determined by scanning electron microscopy (SEM). The membrane-targeting mechanism of the active ingredients was explored by membrane integrity assays, membrane fluidity assays, membrane potential assays, ATP, and ROS determination. We identified eight prenylated flavonoids in Psoralea corylifolia Linn. seed. The antibacterial activity and mechanism studies showed that this type of compound has a unique destructive effect on MRSA cell membranes and does not result in drug resistance. The results revealed that prenylated flavonoids in Psoralea corylifolia Linn. seeds are promising candidates for the development of novel antibiotic agents to combat MRSA-associated infections.

[Biotransformation of psoralenoside and isopsoralenoside in Psoraleae Fructus incubated with human intestinal bacteria flora in vitro].

Absorption is crucial to the resultant efficacy of oral drugs where the intestinal bacteria flora functions as one of the first-pass effects.The present study investigated the biotransformation of psoralenoside and isopsoralenoside in Chinese medicine Psoraleae Fructus(the dried fruit of Psoralea corylifolia) with the internationally recognized human intestinal bacteria flora model in vitro.Pso-ralenoside and isopsoralenoside were anaerobically incubated with human intestinal bacteria flora at 37 ℃, respectively, and biotransformation products were analyzed and identified using high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS) and comparison with reference standards.The main biotransformation products of psoralenoside were psoralen and a small amount of 6,7-furano-hydrocoumaric acid, and the main biotransformation products of isopsoralenoside were isopsoralen and a small amount of 5,6-furano-hydrocoumaric acid.

[Comparison on distribution of 8 components from ethanol extract of Psoraleae Fructus between normal and lipopolysaccharide-induced model rats].

UPLC-TQ/MS was employed to determine the content of 8 main components(psoralen, isopsoralen, psoralenoside, isopsoralenoside, bavachin, psoralidin, corylin, and neobavaisoflavone) in tissues of normal and lipopolysaccharide(LPS)-induced model rats 0.5, 1, 2, 6, and 12 h after intragastric administration of 3.6 g·kg~(-1) ethanol extract of Psoraleae Fructus. The distribution characteristics of the 8 main components in the different tissues(liver, kidney, spleen, heart, and lung) were studied and compared. The results showed that the distribution behaviors of the components varied among different tissues. At different time points, the components presented wide and uneven distribution in the body. Liver and kidney had higher content of the components, followed by spleen, heart, and lung. In both normal and LPS-induced model rats, the content of the 8 main components was higher in liver and kidney and varied significantly among different tissues. The content of psoralen in the tissues of LPS-induced model rat was significantly higher than that of the normal group 12 h after administration. The reason may be that the modeling slowed down the absorption and distribution of psoralen. The LPS-induced model rats had higher content of psoralenoside and isopsoralenoside in the liver tissue than the normal rats, which indicated that the modeling increased the absorption and distribution of psoralenoside and isopsoralenoside in the liver tissue. Further, it is hypothesized that psoralenoside and isopsoralenoside may be toxic substances of Psoraleae Fructus-induced liver injury.

[Hypoglycemic mechanism of Psoraleae Fructus and its main chemical constituents].

With the rise of incidence, fatality rate, and number of young cases, diabetes mellitus has been one of the seven major diseases threatening human health. Although many antidiabetic drugs(oral or for injection) are available, the majority have serious side effects during the long-term use. Thus, it is of particularly vital to develop new drugs with low risk and definite effect. Psoraleae Fructus, a traditional medicinal widely used in the folk, has hypoglycemic, anti-osteoporosis, antitumor, estrogen-like, and anti-inflammatory effects. Thus, it has great clinical application potential. Chinese medicine and the active ingredients, characterized by multiple targets, multiple pathways, and multiple effects in the treatment of diabetes mellitus, have distinct advantages in clinical application. However, the safety of Chinese medicine remains to be a challenge, and one of keys is to clarifying the mechanism of a single Chinese medicinal and its active ingredients. With the method of literature research, this study summarized and analyzed the hypoglycemic mechanisms of Psoraleae Fructus and its main active ingredients over the last decade: regulating glucose metabolism, improving insulin resistance, and directly acting on pancreatic ß-cells. The result is expected to serve as a reference for further research on the effects of Psoraleae Fructus and its main chemical constituents in lowering blood glucose and preventing diabetes mellitus and the clinical application.

[Quality evaluation of Psoraleae Fructus based on QAMS method and TLC identification].

The present study established a determination method of Psoraleae Fructus by quantitative analysis of multi-components by the single marker(QAMS) and further improved the thin-layer chromatography(TLC) method. The QAMS method was established by UPLC with psoralen as the internal marker, and the content of psoralenoside, isopsoralenoside, psoralen, and isopsoralen was simultaneously determined. As revealed by the comparison with results of the external standard method, the QAMS method was accurate and feasible. According to the current quality standards of Psoraleae Fructus, the TLC method was further optimized and improved, and bakuchiol was added for identification based on the original TLC method with psoralen and isopsoralen as indicators. This study provides a reference for improving the quality control method of Psoraleae Fructus.

Corylin, a flavonoid derived from Psoralea Fructus, induces osteoblastic differentiation via estrogen and Wnt/ß-catenin signaling pathways.

Corylin is a naturally occurring flavonoid isolated from the fruit of Psoralea corylifolia L. (Fabaceae), which is a Chinese medicinal herb in treating osteoporosis. Although a variety of pharmacological activities of corylin have been reported, its osteogenic action and the underlying mechanism in bone development remain unclear. In the present study, the involvement of bone-specific genes in corylininduced differentiated osteoblasts was analyzed by RT-PCR, promoter-reporter assay, and Western blotting. In cultured osteoblasts, corylin-induced cell differentiation and mineralization, as well as increased the expressions of vital biological markers for osteogenesis, such as Runx2, Osterix, Col1, and ALP. Corylin was proposed to have dual pathways in triggering the osteoblastic differentiation. First, the osteogenic function of corylin acted through the activation of Wnt/ß-catenin signaling. The nuclear translocation of ß-catenin of cultured osteoblasts, as determined by flow cytometry and confocal microscopy, was triggered by applied corylin, and which was blocked by DKK-1, an inhibitor of Wnt/ß-catenin signaling. Second, the application of corylin-induced estrogenic response in a dose-dependent manner, and which was blocked by ICI 182 780, an antagonist of estrogen receptor. Furthermore, the activation of Runx2 promoter by corylin was abolished by both DKK-1 and ICI 182,780, indicating that the corylin exhibited its osteogenic effect via estrogen and Wnt/ß-catenin signaling pathways. In addition, corylin regulated the metabolic profiles, as well as the membrane potential of mitochondria, in cultured osteoblasts. Corylin also stimulated the osteogenesis in bone micromass derived from mesenchymal progenitor cells. This study demonstrated the osteogenic activities of corylin in osteoblasts and micromass, suggesting that corylin has the potential to be developed as a novel pro-osteogenic agent in targeting for the treatment of osteoblast-mediated osteoporosis.

Pharmacological review of isobavachalcone, a naturally occurring chalcone.

Isobavachalcone (IBC), a naturally occurring chalcone, is mainly isolated from the seeds of Psoralea corylifolia Linn. IBC demonstrates multiple pharmacological activities, including anti-cancer, anti-microbial, anti-inflammatory, antioxidative, neuroprotective, and among others. Several potential targets of IBC, such as AKT, dihydroorotate dehydrogenase (DHODH), have been identified. The pharmacokinetic profiles of IBC have been reported as well. In this review, the pharmacological activities, the underlying mechanisms, the potential targets, and the pharmacokinetic profiles of IBC were summarized. IBC might be a promising lead compound for drug discovery.

Bioactive monoterpene phenol dimers from the fruits of Psoralea corylifolia L.

Nine undescribed monoterpene phenol dimers, bisbakuchiols D-L (1-9), were isolated from the fruits of Psoralea corylifolia L. Their structures were elucidated based on extensive spectral analysis. The absolute configurations of 1-9 were specified by experimental and quantum chemical calculations of ECD spectra, and that of 1 was further established by X-ray diffraction analysis using Cu Kα radiation. Bisbakuchiols (1-4) were composed of two bakuchiols, one of which was cyclized via a C-7'/ C-12' single bond to form a six-member ring, and connect to each other by C-4-O-C-13' bonds. Bisbakuchiols (7-9) had a pyran ring by linkage of C-8-O-C-12. In the enzyme assay, compounds 5 and 9 exhibited significant PTP1B inhibitory activities with IC50 values of 0.69 and 0.73 µM, and compounds 1 and 3 showed moderate PTP1B inhibitory activities. Furthermore, a molecular docking simulation of PTP1B and active compounds 5 and 9 showed that these active compounds possess low binding affinities ranging from -6.9 to -7.1 kcal/mol.

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.