Through in vitro and in vivo experiments, combined with network pharmacology and molecular docking techniques, this study investigated the mechanism of action of osthole in the treatment of colorectal cancer(CRC). The relevant targets of osthole and CRC were retrieved from the SwissTargetPrediction and SuperPred in drug databases, as well as GeneCards and OMIM in disease databases. Protein-protein interaction(PPI) networks were constructed using the STRING database and Cytoscape 3.8.0 software, and core targets were screened. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed on common targets. Molecular docking validation of core targets with osthole was conducted using AutoDock Vina software. HCT116 cells were treated with different concentrations of osthole, and cell proliferation was detected using the CCK-8 assay and the clonogenic assay. Cell migration ability was assessed using Transwell assay. Western blot and RT-qPCR were performed to detect the expression of caspase-3(CASP3), hypoxia-inducible factor 1 alpha(HIF1A), nuclear factor kappa B subunit 1(NFKB1), glycogen synthase kinase-3 beta(GSK3B), phosphorylated-GSK3B(p-GSK3B), protein kinase B(Akt), phosphorylated-Akt(p-Akt), mammalian target of rapamycin(mTOR), and phosphorylated-mTOR(p-mTOR). A subcutaneous tumor model of HCT116 cells in nude mice was established, and the mice were randomly divided into the model group, low-dose osthole group(20 mg·kg~(-1)), medium-dose osthole group(40 mg·kg~(-1)), and high-dose osthole group(60 mg·kg~(-1)). After 18 days of administration, the growth of tumor xenografts was observed, and the size and weight of tumors were measured after excision. Hematoxylin-eosin(HE) staining was performed to observe the histological changes in tumors in each group. Network pharmacology analysis revealed that osthole treatment of CRC mainly involved 106 treatment targets and 113 treatment pathways, with key pathways including the PI3K/Akt signaling pathway and MAPK signaling pathway. Molecular docking results showed a strong correlation between osthole and core targets. In vitro studies demonstrated that osthole significantly inhibited the proliferation and migration ability of HCT116 cells. Western blot and RT-qPCR experiments showed that compared to those in the model group, the expression of NFKB1, HIF1A, p-Akt, p-mTOR, and GSK3B in the osthole-treated group was significantly decreased, while the expression of CASP3 and p-GSK3B(Ser9) was significantly increased. In vivo studies showed that compared to the model group, osthole-fed animals significantly reduced tumor weight and volume, inhibited tumor growth, and promoted tumor apoptosis, and the results showed a dose-dependent trend. The study suggested that osthole could inhibit the proliferation and migration of HCT116 cells in CRC, and its mechanism may be related to the regulation of the PI3K/Akt signaling pathway and the expression of core targets.
Coumarins/chemistry* ; Humans ; Molecular Docking Simulation ; Colorectal Neoplasms/pathology* ; Animals ; Network Pharmacology ; Mice ; Cell Proliferation/drug effects* ; HCT116 Cells ; Mice, Nude ; Mice, Inbred BALB C ; Proto-Oncogene Proteins c-akt/genetics* ; TOR Serine-Threonine Kinases/genetics* ; Cell Movement/drug effects* ; Apoptosis/drug effects* ; Signal Transduction/drug effects* ; Protein Interaction Maps/drug effects*

Saposhnikovia divaricata (Turcz.) Schischk (S. divaricata, Fangfeng) is a herb in the Apiaceae family, and its root has been used since the Western Han Dynasty (202 B.C.). Chromones and coumarins are the pharmacologically active substances in S. divaricata. Modern phytochemical and pharmacological studies have demonstrated their antipyretic, analgesic, anti-inflammatory, antioxidant, anti-tumor, and anticoagulant activities. Technological and analytical strategy theory advancements have yielded novel results; however, most investigations have been limited to the main active substances-chromones and coumarins. Hence, we reviewed studies related to the chemical composition and pharmacological activity of S. divaricata, analyzed the developing trends and challenges, and proposed that research should focus on components' synergistic effects. We also suggested that, the structure-effect relationship should be prioritized in advanced research.
Drugs, Chinese Herbal/pharmacology* ; Coumarins/pharmacology* ; Apiaceae/chemistry* ; Chromones

We reported the discovery of six novel coumarins, toddasirins A-F (1-6), each endowed with modified isoprenyl or geranyl side chains, derived from the roots of Toddalia asiatica. Comprehensive structural elucidation was achieved through multispectroscopic analyses, single-crystal X-ray diffraction experiments, and advanced quantum mechanical electronic circular dichroism (ECD) calculations. Furthermore, the anti-inflammatory activity of these compounds was assessed. Notably, compounds 1-3 and 6 demonstrated notable inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells, with 50% inhibitory concentration (IC₅₀) values of 3.22, 4.78, 8.90, and 4.31 μmol·L^-1, respectively.
Mice ; Animals ; Coumarins/chemistry* ; Rutaceae/chemistry* ; Anti-Inflammatory Agents/pharmacology* ; Plant Extracts/chemistry* ; RAW 264.7 Cells ; Nitric Oxide ; Molecular Structure

To prepare the herpetolide A nanosuspension lyophilized powder(HPA-NS-LP), in order to investigate its anti-hepatitis B virus(HBV) activity and the dissolution in vitro. Herpetolide A nanosuspension(HPA-NS) was prepared by ultrasonic precipitation method. The formulation and process of HPA-NS were optimized by the single factor experiment. Lyophilized powder(HPA-NS-LP) was prepared by freeze-drying method. Scanning electron microscopy was used to observe morphology of HPA-NS-LP. Paddle method was used to determinate the dissolution of HPT-NS-LP in vitro. The anti-HBV activity of herpetolide A coarse suspension lyophilized powder(HPA-CS-LP) and HPA-NS-LP was evaluated by HepG2.2.15 cell model. The mean particle size of optimized HPA-NS was(173.46±4.36) nm, with a polydispersity index of 0.110±0.012. After redispersion, the mean particle size and the polydispersity index of HPA-NS-LP increased, with changes within a rational range. Scanning electron microscopy showed that HPA-NS-LP was spherical in shape. Cumulative dissolution rate of HPA-NS-LP was more than 90% in 2 hours, which was higher than that of HPA-CS-LP. Both HPA-CS-LP and HPA-NS-LP could effectively inhibit the secretion of HepG2.2.15 cell antigens(HBsAg and HBeAg), and the inhibitory effect of HPA-NS-LP was significantly higher than that of HPA CS-LP(P<0.05). HBV-DNA test showed that high, medium and low-dose HPA-NS-LP(50, 25, 12.5 mg·kg~(-1)) significantly decreased the level of HBV-DNA(P<0.05), and the effect was better than that of the same dose of HPA-CS-LP(P<0.05). The results revealed that HPA-NS-LP exhibited anti-HBV activity in vitro, and its effect was superior to that of HPA-CS-LP.
Coumarins/pharmacology* ; Cucurbitaceae/chemistry* ; Hep G2 Cells ; Hepatitis B virus/drug effects* ; Humans ; Nanoparticles ; Particle Size ; Phytochemicals/pharmacology* ; Solubility ; Suspensions

Pharmaceutical research has focused on the discovery and development of anticancer drugs. Clinical application of chemotherapy drugs is limited due to their severe side effects. In this regard, new naturally occurring anticancer drugs have gained increasing attention because of their potential effectiveness and safety. Fruits and vegetables are promising sources of anticancer remedy. Clausena (family Rutaceae) is a genus of flowering plants and includes several kinds of edible fruits and vegetables. Phytochemical and pharmacological studies show that carbazole alkaloids and coumarins from Clausena plants exhibit anticancer activity. This review summarizes research progresses made in the anticancer properties of plants belonging to Clausena; in particular, compounds with direct cytotoxicity, cell cycle arrest, apoptosis induction, and immune potentiation effects are discussed. This review reveals the potential use of plants from Clausena in preventing and treating cancer and provides a basis for development of relevant therapeutic agents.
Alkaloids ; chemistry ; pharmacology ; therapeutic use ; Antineoplastic Agents ; chemistry ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Carbazoles ; chemistry ; pharmacology ; therapeutic use ; Cell Cycle Checkpoints ; drug effects ; Clausena ; chemistry ; Coumarins ; chemistry ; pharmacology ; therapeutic use ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; therapeutic use ; Humans ; Plants, Medicinal ; chemistry

There is an increasing interest in phytoestrogens due to their potential medical usage in hormone replacement therapy (HRT). The present study was designed to investigate the in vitro effects of estrogen-like activities of two widespread coumarins, osthole and imperatorin, using the MCF-7 cell proliferation assay and their alkaline phosphatase (ALP) activities in osteoblasts Saos-2 cells. The two compounds were found to strongly stimulate the proliferation of MCF-7 cells. The estrogen receptor-regulated ERα, progesterone receptor (PR) and PS2 mRNA levels were increased by treatment with osthole and imperatorin. All these effects were significantly inhibited by the specific estrogen receptor antagonist ICI182, 780. Cell cycle analysis revealed that their proliferation stimulatory effect was associated with a marked increase in the number of MCF-7 cells in S phase, which was similar to that observed with estradiol. It was also observed that they significantly increased ALP activity, which was reversed by ICI182,780. These results suggested that osthole and imperatorin could stimulate osteoblastic activity by displaying estrogenic properties or through the ER pathway. In conclusion, osthole and imperatorin may represent new pharmacological tools for the treatment of osteoporosis.
Alkaline Phosphatase ; genetics ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cnidium ; chemistry ; Coumarins ; pharmacology ; Drugs, Chinese Herbal ; pharmacology ; Furocoumarins ; pharmacology ; Humans ; MCF-7 Cells ; Osteoblasts ; cytology ; drug effects ; enzymology ; Phytoestrogens ; pharmacology ; Receptors, Estrogen ; genetics ; metabolism

Chemical constituents of Leonurus japonicus were isolated and purified by a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, MCI, and Rp C18. Structures of the isolates were determined by spectroscopic analysis as 10 coumarins: bergapten (1), xanthotoxin (2), isopimpinellin (3), isogosferal (4), imperatorin (5), meransin hydrate(6), isomeranzin(7), murrayone(8) , auraptenol(9), and osthol(10). In addition to compound 9, the others were isolated from the genus Leonurus for the first time. In the in vitro assay, compounds 4 and 8 significantly inhibited the abnormal increase of platelet aggregation induced by ADP.
Blood Platelets ; drug effects ; Coumarins ; chemistry ; pharmacology ; Leonurus ; chemistry ; Platelet Aggregation ; drug effects ; Platelet Aggregation Inhibitors ; chemistry ; pharmacology

Morus alba L. (mulberry) is a well-known deciduous tree, belonging to the genus of Morus of Moraceae famlily. Its leaves, twigs, roots (bark) and fruits are widely used in the traditional Chinese medicine. The active constituents of mulberry contained flavonoids, alkaloids, steroids, coumarins, with the significant hypoglycemic, hypolipidemic, antihypertension, anti-oxidation, anti-inflammatory, anti-bacterial, anti-tumor and immunomodulatory activities. This review summarized the research progress of the major pharmacological activity, pharmacokinetics and drug-drug interaction based on CYPs and transporters of mulberry and its active constituents.
Alkaloids ; pharmacology ; Coumarins ; pharmacology ; Flavonoids ; pharmacology ; Fruit ; chemistry ; Herb-Drug Interactions ; Humans ; Medicine, Chinese Traditional ; Morus ; chemistry ; Plant Extracts ; pharmacology ; Plant Leaves ; chemistry ; Plant Roots ; chemistry ; Steroids ; pharmacology

AIM: To investigate the chemical and bioactive constituents from the stems and leaves of Micromelum integerrimum. METHOD: The chemical constituents were isolated and purified by silica gel, Sephadex LH-20, and HPLC. Their structures were mainly elucidated on the basis of extensive 1D- and 2D-NMR spectroscopy and mass spectrometry. Their cytotoxicity and antimicrobial activities were tested by the SRB and turbidimetric methods, respectively. RESULTS: Two new phenylpropanoids and two known coumarins were obtained, and their structures were identified as microintegerrin A (1), microintegerrin B (2), scopoletin (3), and scopolin (4). All of the compounds were tested for their cytotoxicity against three cancer cell lines (HeLa, A549, and BGC-823) and for antimicrobial activity against the fungus Candida albicans and the bacterium Staphylococcus aureus. CONCLUSION Two new phenylpropanoids 1 and 2 were isolated and identified from the stems and leaves of M. intgerrimum. None of the compounds showed cytotoxic or antimicrobial activity at the tested concentration of 20 μg·mL(-1).
Candida albicans ; drug effects ; Coumarins ; isolation & purification ; pharmacology ; Glucosides ; isolation & purification ; pharmacology ; HeLa Cells ; Humans ; Molecular Structure ; Phenylpropionates ; chemistry ; isolation & purification ; pharmacology ; Plant Extracts ; chemistry ; pharmacology ; Plant Leaves ; Plant Stems ; Rutaceae ; chemistry ; Scopoletin ; isolation & purification ; pharmacology ; Staphylococcus aureus ; drug effects

OBJECTIVETo study the transport mechanism of baicalin of Scutellariae Radix extracts and the effect of Angelica dahurica extracts on the intestinal absorption of baicalin by using Caco-2 cell monolayer model, in order to analyze the effect mechanism of Angelica dahurica extracts on the intestinal absorption of baicalin.

METHODThe Caco-2 cell monolayer model was established with human colonic adenocarcinoma cells, and used to study the effect of pH, time, drug concentration and temperature on the transport of baicalin in Scutellariae Radix extracts, the effect of P-gp and MRP protein-dedicated inhibitors on the bidirectional transport of baicalin in Caco-2 cell model, and the effect of angelica root extracts on baicalin absorption and transport.

RESULTBaicalin was absorbed well at 37 degrees C and under pH 7.4 condition and concentration dependent. Its proteins became inactive at 4 degrees C, with a low transport. The bi-drectional transfer PDR was 0. 54. After P-gp inhibitor verapamil and MRP inhibitor probenecid were added, the value of PappBL-AP of baicalin decreased, but without any difference in PDR. The transport of baicalin was improved by 2.34, 3.31 and 3.13 times, after A. dahurica extract coumarin, volatile oil, and mixture of coumarin and volatile oil.

CONCLUSIONThe transport mechanism of baicalin is mainly passive transfer and supplemented with efflux proteins involved. A. dahurica extracts can enhance the absorption of baicalin, which may be related to the passive transfer merchanism of baicalin. A. dahurica extracts' effect in opening the close junction among cells may be related to its expression or function in inhibiting efflux proteins.

ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; metabolism ; Angelica ; chemistry ; Biological Transport ; drug effects ; Caco-2 Cells ; Cell Line, Tumor ; Coumarins ; chemistry ; pharmacology ; Drug Interactions ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Flavonoids ; pharmacokinetics ; Humans ; Intestinal Absorption ; drug effects ; physiology ; Oils, Volatile ; chemistry ; pharmacology ; Plant Extracts ; chemistry ; pharmacology ; Plant Roots ; chemistry ; Probenecid ; pharmacology ; Scutellaria baicalensis ; chemistry ; Verapamil ; pharmacology