lignans and phillygenin

Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.

Topics: Antiviral Agents; Benzodioxoles; Biological Products; Biphenyl Compounds; Drug Development; Furans; Lignans; Masoprocol; Plants; Podophyllotoxin

The study investigates the positive effects of phillygenin on intestinal tight junction via the let-7b signaling pathway and the regulation of intestinal microbiota. The expression levels of tight junction proteins are determined through PCR and Western blot. DSS-induced mice colitis is used to verify the protective effects of phillygenin on intestinal barrier and tight junction. Fecal microbiota transplantation is used to verify the role intestinal microbiota. let-7b is detected in the colon tissues of patients with acute stercoral obstruction. Phillygenin could promote the expression of occludin, which might be inhibited by let-7b inhibitor. DSS-induced mice colitis showed that phillygenin could lower the colonic permeability and maintain the tight junction-associated proteins. The effects of phillygenin could be deprived by anti-let-7b and rescued by FMT of normal intestinal microbiota. Clinical samples verified a lower level of let-7b in stercoral obstruction patients. Phillygenin could protect the intestinal barrier from dysfunction via the signaling pathway of let-7b by regulating intestinal microbiota.

Topics: Animals; Colitis; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Lignans; Mice; Signal Transduction

The prevalence of avian infectious bronchitis virus (IBV) is still one of causes inducing severe losses of production in the poultry industry worldwide. Vaccination does not completely prevent IBV infection and spread due to immune failure and viral mutations. ForsythiaeFructus and its compounds have been widely used in a lot of prescriptions of the traditional Chinese medicine for a long history, and it is well-known as safety and efficiency in heat-clearing and detoxifying. This study aims to investigate the anti-IBV activity and mechanism of phillygenin. The results showed that phillygenin inhibited IBV replication by disturbing multiple stages of the virus life cycle, including viral adsorption, invasion, internalization, and release in Vero cells. After being treated with 100, 125 and 150 μg/mL phillygenin, the expression of G3BP1 was significantly increased and the phosphorylation of PKR/eIF2α was activated, which increased stress granule, thereby triggering the antiviral response in Vero cells. The anti-virus activity of PHI was decreased when G3BP1 was interfered by si-RNA, and G3BP1 was down-regulated when PKR/eIF2α was interfered by si-RNA. In conclusion, our findings indicate that phillygenin activates PKR/eIF2α pathway and induces stress granule formation to exert anti-IBV, which holds promise to develop into a novel anti-IBV drug. Further study in vivo is needed to explore phillygenin as a potential and effective drug to prevent IB in poultry.

Topics: Animals; Chlorocebus aethiops; Coronavirus Infections; DNA Helicases; Eukaryotic Initiation Factor-2; Infectious bronchitis virus; Lignans; Poly-ADP-Ribose Binding Proteins; Poultry Diseases; RNA; RNA Helicases; RNA Recognition Motif Proteins; Stress Granules; Vero Cells

Lipophagy is an autophagic process, which delivers the intracellular lipid droplets to the lysosomes for degradation. Recent studies revealed that the impairment of lysosomal biogenesis and autophagic flux led to dysregulation of lipophagy in hepatocytes, which exacerbated the development of nonalcoholic fatty liver disease (NAFLD). Therefore, agents restoring autophagic flux and lipophagy in hepatocytes may have therapeutic potential against this increasingly prevalent disease. Phillygenin (PHI), a lignin extracted from Forsythia suspense, exerts hepatoprotective and anti-inflammatory effects. However, the effect of PHI on NAFLD remains unknown.. This study aimed to investigate the protective effect of PHI on NAFLD and elucidate the underlying mechanism.. The effects of PHI were examined in palmitate (PA)-stimulated AML12 cells and primary hepatocytes, as well as in NAFLD mice induced by a high-fat diet (HFD). We also used transcription factor EB (TFEB) knockdown hepatocytes and hepatocyte-specific TFEB knockout (TFEB. Our results indicated that autophagic flux and lysosome biogenesis in PA-stimulated hepatocytes were impaired. PHI alleviated lipid deposition by increasing lysosomal biogenesis and autophagic flux. It also stimulated the release of endoplasmic reticulum Ca. Despite PHI has been reported to have anti-hepatic fibrosis effects, whether it has a hepatoprotective effects against NAFLD and the underlying molecular mechanism remain unclear. Herein, we found that PHI restored lipophagy and suppressed lipid accumulation and inflammation by regulating the Ca

Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Calcineurin; Hepatocytes; Inflammation; Lignans; Lipids; Lysosomes; Mice; Non-alcoholic Fatty Liver Disease

Forsythiae fructus, the dried fruit of Oleaceae plant Forsythia suspensa (Thunb.) Vahl, is a traditional Chinese medicine widely used in clinical practice and has a variety of pharmacological activities, such as anti-inflammation, antioxidation, and hepatoprotection.. Phillygenin (PHI), an important fingerprint lignan component of Forsythiae fructus, has prominent hepatoprotective, anti-inflammatory and antioxidant effects. Previously, it was shown that PHI could exert anti-fibrotic effects by modulating inflammation and gut microbiota. Therefore, given the important roles of SCFAs and BAs in the development of liver fibrosis, as well as their close links with gut microbiota, we aimed to determine the protective effects of PHI on carbon tetrachloride (CCl. In C57BL/6J mice, liver fibrosis model was established by intraperitoneal injection of olive oil containing 10% CCl. The histological analysis and the determination of relevant biochemical indexes of liver tissues showed that PHI could attenuate CCl. Promoting the production of SCFAs in the gut and restoring the disturbance of BA metabolism may be the potential mechanisms by which PHI alleviated CCl

Topics: Animals; Bile Acids and Salts; Carbon Tetrachloride; Fatty Acids, Volatile; Lignans; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL

Acute lung injury (ALI) is often responsible for the high morbidity of critically ill patients. The present study aimed to investigate whether phillygenin (PHI) can inhibit inflammation and apoptosis of pulmonary epithelial cells by activating peroxisome proliferator‑activated receptor γ (PPARγ) signaling. The

Topics: Acute Lung Injury; Anti-Inflammatory Agents; Apoptosis; Cell Line; Child; Child, Preschool; Epithelial Cells; Female; Humans; Inflammation; Lignans; Male; Matrix Metalloproteinase 8; PPAR gamma

Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Janus Kinase 2; Lignans; Neoplasm Metastasis; Osteosarcoma; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; STAT3 Transcription Factor

Inflammation is a common pathological phenomenon when homeostasis is seriously disturbed. Phillygenin (PHI), a lignin component isolated from Forsythiae Fructus, has shown a good anti-inflammatory effect. However, the mechanisms of PHI on anti-inflammation have not yet been systematically elucidated. In this study, the lipopolysaccharide (LPS) - induced RAW264.7 cell inflammation model was established to investigate mechanisms of PHI on inflammation. The effect of PHI on the release of IL-1β and PGE2 inflammatory factors induced by LPS was detected by ELISA, and the mRNA expressions of IL-1β, IL-6 and TNF-α were detected by RT-qPCR. Proteomics studied the signaling pathways that might be affected by PHI and molecular docking technology was subsequently used to study the possible targets on proteomic screened pathways. Western blot was performed ultimately to detect progressive changes in protein expression on the related pathway. Our research showed that PHI significantly inhibited the robust increase of IL-1β and PGE2 and lowered the transcriptional level of inflammatory genes including IL-6, IL-1β and PGE2 in LPS-stimulated RAW264.7 cells. Proteomics results indicated that PHI was involved in the regulation of multiple signaling pathways. Molecular docking results indicated that PHI had an affinity for most proteins in NF-κB pathway. Western blot analysis proved that PHI inhibited LPS-induced NF-κB pathway activation. On the whole, PHI inhibited the activation of NF-κB pathway, thereby inhibiting the expression of related inflammatory genes and the release of cytokines, and showed a remarkable anti-inflammatory effect.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Dinoprostone; Inflammation; Inflammation Mediators; Lignans; Lipopolysaccharides; Macrophages; Mice; Molecular Docking Simulation; NF-kappa B; Protein Interaction Maps; Proteomics; RAW 264.7 Cells; Signal Transduction

The traditional Chinese medicine Forsythiae Fructus is the dried fruit of Forsythia suspensa (Thunb.) Vahl. It is commonly used to clear heat and detoxify, reduce swelling and disperse knot, and evacuate wind and heat.. Inflammation is involved in liver fibrosis. Phillygenin (PHI) is a kind of lignans extracted and separated from Forsythiae Fructus, which has been reported to have a good anti-inflammatory effect. Therefore, we aimed to explore whether PHI has a therapeutic effect on liver fibrosis caused by inflammation.. Firstly, the induction of the LX2 cells inflammatory model and fibrosis model by LPS with different concentrations were studied. Then, high, medium and low doses PHI was given for intervention therapy. The secretion of IL-6, IL-1β and TNF-α inflammatory factors were detected by ELISA kit, and the expression of collagen I and α-SMA was detected by Western blot and RT-qPCR. The possible mechanism of PHI on TLR4/MyD88/NF-κB signal pathway was studied by computer-aided drug design software and the results were further verified by Western blot and RT-qPCR experiments.. The results showed that LPS could promote the expression of IL-6, IL-1β and TNF-α and the expression of collagen I and α-SMA, indicating that LPS could induce inflammation and fibrosis in LX2 cells. PHI could inhibit LX2 cell activation and fibrotic cytokine expression by inhibiting LPS-induced pro-inflammatory reaction. Molecular docking results showed that PHI could successfully dock with TLR4, MyD88, IKKβ, p65, IκBα, and TAK1 proteins. Subsequently, Western blot and qPCR results further proved that PHI could inhibit the proteins expression in TLR4/MyD88/NF-κB signal pathway which were consistent with the molecular docking results.. PHI can inhibit LPS-induced pro-inflammatory reaction and LX2 cell activation through TLR4/MyD88/NF-κB signaling pathway, thereby inhibiting liver fibrosis.

Topics: Actins; Anti-Inflammatory Agents; Cell Line; Collagen Type I; Hepatic Stellate Cells; Hepatitis; Humans; Interleukin-1beta; Interleukin-6; Lignans; Lipopolysaccharides; Liver Cirrhosis; Myeloid Differentiation Factor 88; NF-kappa B; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

BACKGROUND Esophageal cancer causes considerable mortality and is ranked as the 6th most prevalent type of cancer across the world. At present, there is no effective esophageal cancer chemotherapy without adverse effects. Moreover, emergence of drug resistance among cancer is another obstacle in the treatment of esophageal cancer. Novel molecules of plant origin may prove beneficial in the development of chemotherapy for esophageal carcinoma. In this study we examined the anticancer effects of phillygenin against the vindesine-resistant esophageal cancer cell line SH-1-V1. MATERIAL AND METHODS The proliferation rate of SH-1-V1 cells was determined by WST-1 assay. Apoptosis was confirmed by propidium iodide (PI) staining. Cell cycle analysis, ROS, and MMP determination were performed by flow cytometery. Protein expression was assessed by Western blot analysis. RESULTS We found that phillygenin inhibited the growth of SH-1-V1 cells and exhibited an IC50 of 6 µM. Investigation of the underlying mechanism revealed that phillygenin triggered apoptotic cell death of the SH-1-V1 cells, which was also associated with enhancement of Bax expression and decreased expression of Bcl-2. Moreover, the expression of cleaved caspase 3 and 9 also increased upon phillygenin treatment. Phillygenin also caused a significant increase in ROS production, concomitant with decreased MMP levels. Phillygenin also caused arrest of cells in the G2/M phase of the cell cycle. In vivo evaluation of phillygenin revealed that it can inhibit tumor weight and volume, suggesting the anticancer potential of phillygenin. CONCLUSIONS In brief, phillygenin inhibited in vitro and in vivo cancer cell growth in drug-resistant human esophageal cancer cells, and these effects were mediated via apoptosis, ROS generation, mitochondrial membrane potential loss, and activation of the NF-kB signalling pathway.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Esophageal Neoplasms; Humans; Inhibitory Concentration 50; Lignans; Membrane Potential, Mitochondrial; Mitochondria; NF-kappa B; Reactive Oxygen Species; Signal Transduction

This study was aimed to classify the varieties and predict the antioxidant activity of Osmanthus fragrans flowers by UPLC-PDA/QTOF-MS and multivariable analysis. The PLS-DA model successfully classified the four varieties based on both the 21 identified compounds and the effective compounds. For the antioxidant activity prediction, PLS performed well to predict the antioxidant activity of O. fragrans flowers. Furthermore, acteoside, suspensaside A, ligustroside, forsythoside A, phillygenin and caffeic acid were selected as effective compounds by UVE-SPA for prediction. On the basis of effective compounds, PLS, MLR and PCR were applied to establish the calibration models. The UVE-SPA-MLR model was the optimal method to predict the antioxidant activity values with Rp of 0.9200, 0.9010 and 0.8905 for DPPH, ABTS and FRAP assays, respectively. The results revealed that the UPLC-PDA/QTOF-MS combined with chemometrics could be a new method to classify the varieties and predict the antioxidant activity of O. fragrans flowers.

Topics: Caffeic Acids; Flowers; Glucosides; Lignans; Mass Spectrometry; Models, Theoretical; Oleaceae; Phenols

The research group has been dedicated to the study of Fructus Forsythiae which was used widely in traditional Chinese medicines. And some research results have been accepted in Chinese Pharmacopeia. In a recent study, phillygenin was found to be a potential "metabolite" of phillyrin and the effective material of phillyrin may be changed according to the in vivo pharmacokinetic process. Therefore, a sensitive, specific, accurate, and reproducible reversed phase HPLC method for the determination of phillygenin in rat plasma was developed. Separation was achieved on a Hypersil ODS C18 column with UV detection at 277 nm. The good linear calibration curves ranged from 0.039 to 20 μg/mL with the limit of quantification estimated as 0.026 μg/mL. The intra- and inter-day precisions were in the range of 98-103 %. The average recoveries of phillygenin were 90.54, 92.47, and 92.15 % for phillygenin of 0.156, 1.25, and 10.0 μg/mL. And the Ruggedness of HPLC method was evaluated. The analytical method was also successfully applied to the pharmacokinetic study of phillygenin in rat for the first time. A rapid distribution was observed from the plasma concentration-time curves, and was followed by a quick elimination for phillygenin. The mean t 1/2z was 6.02, 5.62, and 5.79 min for 1.4, 2.8, and 5.6 mg/kg, respectively. The AUC (0-t) increased linearly from 166.29 to 332.48 mg/L min. All results indicated that, in the range of the doses examined, the pharmacokinetics of phillygenin in rat was based on first-order kinetics.

Topics: Animals; Chromatography, High Pressure Liquid; Lignans; Male; Rats; Rats, Sprague-Dawley

In this paper, the interaction of human serum albumin (HSA) with phillygenin was investigated by fluorescence, circular dichroism (CD), UV-vis spectroscopic and molecular docking methods under physiological conditions. The Stern-Volmer analysis indicated that the fluorescence quenching of HSA by phillygenin resulted from static mechanism, and the binding constants were 1.71×10(5), 1.61×10(5) and 1.47×10(4) at 300, 305 and 310K, respectively. The results of UV-vis spectra show that the secondary structure of the protein has been changed in the presence of phillygenin. The CD spectra showed that HSA conformation was altered by phillygenin with a major reduction of α-helix and an increase in β-sheet and random coil structures, indicating a partial protein unfolding. The distance between donor (HSA) and acceptor (phillygenin) was calculated to be 3.52nm and the results of synchronous fluorescence spectra showed that binding of phillygenin to HSA can induce conformational changes in HSA. Molecular docking experiments found that phillygenin binds with HSA at IIIA domain of hydrophobic pocket with hydrogen bond interactions. The ionic bonds were formed with the O (4), O (5) and O (6) of phillygenin with nitrogen of ASN109, ARG186 and LEU115, respectively. The hydrogen bonds are formed between O (2) of phillygenin and SER419. In the presence of copper (II), iron (III) and alcohol, the apparent association constant K(A) and the number of binding sites of phillygenin on HSA were both decreased in the range of 88.84-91.97% and 16.09-18.85%, respectively. In view of the evidence presented, it is expected to enrich our knowledge of the interaction dynamics of phillygenin to the important plasma protein HSA, and it is also expected to provide important information of designs of new inspired drugs.

Topics: Binding Sites; Circular Dichroism; Humans; Lignans; Models, Molecular; Oleaceae; Protein Binding; Protein Structure, Secondary; Serum Albumin; Spectrometry, Fluorescence; Spectrophotometry

Forsythia suspensa extract has been proved as a potential antioxidant in the recent years. The present study was undertaken to obtain the optimal antioxidant fraction in vitro and examine its antioxidative potential against diquat-induced oxidative stress in male Sprague Dawley rats in vivo. In vitro, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiment indicated that the CH2Cl2 fraction of F. suspensa (FSC) exerted the strongest scavenging activities; forsythoside A, forythialan A and phillygenin from it might be the major antioxidant constituents. In vivo, pretreatment of rats with different doses of FSC (25, 50 and 100 mg/kg bw) and vitamin C (100 mg/kg bw, positive control) for 15 days significantly lowered the tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in plasma compared to the negative control group. Also, FSC significantly increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of glutathione (GSH) in plasma, liver and kidney whereas it decreased the levels of malondialdehyde (MDA) in plasma and kidney. Moreover, the protective effect of FSC (100 mg/kg bw) was better than vitamin C. These results revealed that FSC exerted a protective effect against diquat-induced oxidative stress and is worthy of becoming a potential dietary antioxidant.

Topics: Animals; Antioxidants; Ascorbic Acid; Biphenyl Compounds; Cytokines; Diquat; Forsythia; Free Radicals; Fruit; Glycosides; Herbicides; Indicators and Reagents; Kidney; Lignans; Liver; Male; Oxidative Stress; Oxidoreductases; Picrates; Rats; Rats, Sprague-Dawley

To study the chemical constituents from Radix Ranunculi Ternate.. The compounds were isolated by silica gel, Sephadex LH-20, and ODS column chromatography, and their structures were elucidated by means of spectral analysis.. Eight compounds were isolated and identified as phillygenin (I), bis-(2-ethylhexyl) phthalate (DEHP, II), henicosanoic acid methyl ester (III), 5-hydroxymethyl-furfural (IV), mixture of stigmasterol and sitosterol (V and VI), daucosterol (VII).. Compounds I-III are isolated from the genus for the first time.

Topics: Diethylhexyl Phthalate; Furaldehyde; Lignans; Magnetic Resonance Spectroscopy; Plant Roots; Plants, Medicinal; Ranunculus; Sitosterols; Stigmasterol

There is mounting evidence that peroxynitrite (ONOO(-)) is closely related to the pathogenesis of various diseases. As a pharmacological strategy aimed at preventing ONOO(-)-mediated toxicity, the protective activity of Forsythia suspensa (Thunb.) Vahl (Oleaceae) against ONOO(-)-induced cellular damage was investigated and its active components identified. After bioactivity-guided fractionation of its methylene chloride fraction, two tetrahydrofurofuran lignans were isolated, namely phillygenin and 8-hydroxypinoresinol. The protective effects of these lignans against ONOO(-)-induced cell death were evaluated using renal epithelial cell LLC-PK1. Phillygenin and 8-hydroxypinoresinol significantly reduced the cell injury by 3-morpholinosydnonimine (SIN-1), a ONOO(-) generator. The hydroxy substituents on the phenyl moieties may contribute to the antioxidant activities of these lignans. These results suggest that phillygenin and 8-hydroxypinoresinol may be useful for the therapeutic or preventive applications in treating ONOO(-)-related diseases.

Topics: Animals; Cytoprotection; Forsythia; Lignans; LLC-PK1 Cells; Molecular Structure; Molsidomine; Peroxynitrous Acid; Plant Extracts; Swine

A simple and reproducible HPLC-photodiode array detector method has been described for evaluating and controlling quality of Forsythia suspensa extract (FSE). First, by analysis of chromatographic fingerprints, the similarities of chromatograms of FSE samples from the same pharmaceutical company exceeded 0.999, 0.997 and 0.960, respectively, although they were much lower from different pharmaceutical companies. Second, by further comparing many batches of extract chromatograph charts with the corresponding reference herb materials, the "common peaks" 3, 5, 7 and 10 were defined as "marker peaks", which were identified as (+)-pinoresinol-beta-D-glucoside, forsythiaside, phillyrin and phillygenin, respectively. Third, four "marker peaks" were simultaneously determined based on fingerprint chromatogram for further controlling the quality of FSE quantitatively. Namely, the newly developed method was successfully applied to analyze 38 batches of FSE samples supplied by three pharmaceutical factories, which showed acceptable linearity, intra-day precision (RSD<2.76%), inter-day precision (RSD<3.43%) and the average recovery rates in the range of (95.38+/-2.96)% to (101.60+/-3.08)%. At last, hierarchical clustering analysis and Bayes discriminant analysis statistical methods were used to classify and differentiate the 38 FSE samples to provide the basis for guiding reasonable use of FSE and controlling its quality better.

Topics: Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Forsythia; Glucosides; Glycosides; Lignans; Magnetic Resonance Spectroscopy; Plant Extracts; Plants, Medicinal; Quality Control