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Background: Leaky gut symptoms and inflammatory bowel disease (IBD) are associated with damaged intestinal mucosa, intestinal permeability dysfunction by epithelial cell cytoskeleton contraction, disrupted intercellular tight junction (TJ) protein expression, and abnormal immune responses and are intractable diseases., Purpose: We evaluated the effects of schisandrin C, a dibenzocyclooctadiene lignan from Schisandra chinensis, on intestinal inflammation and permeability dysfunction in gut mimetic systems: cultured intestinal cells, intestinal organoids, and a Caenorhabditis elegans model., Methods: Schisandrin C was selected from 9 lignan compounds from S. chinensis based on its anti-inflammatory effects in HT-29 human intestinal cells. IL-1β and Pseudomonas aeruginosa supernatants were used to disrupt intestinal barrier formation in vitro and in C. elegans, respectively. The effects of schisandrin C on transepithelial electrical resistance (TEER) and intestinal permeability were evaluated in intestinal cell monolayers, and its effect on intestinal permeability dysfunction was tested in mouse intestinal organoids and C. elegans by measuring fluorescein isothiocyanate (FITC)-dextran efflux. The effect of schisandrin C on TJ protein expression was investigated by western blotting and fluorescence microscopy. The signaling pathway underlying these effects was also elucidated., Results: Schisandrin C ameliorated intestinal permeability dysfunction in three IBD model systems and enhanced epithelial barrier formation via upregulation of ZO-1 and occludin in intestinal cell monolayers and intestinal organoids. In Caco-2 cells, schisandrin C restored IL-1β-mediated increases in MLCK and p-MLC expression, in turn blocking cytoskeletal contraction and subsequent intestinal permeabilization. Schisandrin C inhibited NF-ĸB and p38 MAPK signaling, which regulates MLCK expression and structural reorganization of the TJ complex in Caco-2 cells. Schisandrin C significantly improved abnormal FITC-dextran permeabilization in both intestinal organoids and C. elegans., Conclusion: Schisandrin C significantly improves abnormal intestinal permeability and regulates the expression of TJ proteins, long MLCK, p-MLC, and inflammation-related proteins, which are closely related to leaky gut symptoms and IBD development. Therefore, schisandrin C is a candidate to treat leaky gut symptoms and IBDs., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The aim of our study is to investigate the molecular mechanism of gomisin J from Schisandra chinensis on the oleic acid (OA)-induced lipid accumulation in HepG2 cells. Gomisin J attenuated lipid accumulation in OA-induced HepG2 cells. It also suppressed the expression of lipogenic enzymes and inflammatory mediators and increased the expression of lipolytic enzymes in OA-induced HepG2 cells. Furthermore, the use of specific inhibitors and fetuin-A siRNA and liver kinase B1 (LKB1) siRNA transfected cells demonstrated that gomisin J regulated lipogenesis and lipolysis via inhibition of fetuin-A and activation of an AMP-activated protein kinase (AMPK)-dependent pathway in HepG2 cells. Our results showed that gomisin J suppressed lipid accumulation by regulating the expression of lipogenic and lipolytic enzymes and inflammatory molecules through activation of AMPK, LKB1, and Ca(2+)/calmodulin-dependent protein kinase II and inhibition of fetuin-A in HepG2 cells. This suggested that gomisin J has potential benefits in treating nonalcoholic fatty liver disease.

The fruit of Schisandra chinensis is a well-known herbal medicine and dietary supplement due to a variety of biological activities including antihepatotoxic and antihyperlipidemic activities. However, the simultaneous validation methodology and pharmacokinetic investigation of nine lignans of S. chinensis extract in biological samples have not been proved yet. Thus, the present study was undertaken to develop the proper sample preparation method and simultaneous analytical method of schisandrol A, gomisin J, schisandrol B, tigloylgomisin H, angeloylgomisin H, schisandrin A, schisandrin B, gomisin N, and schisandrin C in the hexane-soluble extract of S. chinensis to apply for the pharmacokinetic study in rats. All intra- and interprecisions of nine lignans were below 13.7% and accuracies were 85.1-115% and it is enough to evaluate the pharmacokinetic parameters after both intravenous and oral administration of hexane-soluble extract of S. chinensis to rats., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Here, we report that gomisin J and gomisin N, dibenzocyclooctadiene type lignans isolated from Schisandra chinensis, inhibit Wnt/β-catenin signaling in HCT116 cells. Gomisins J and N appear to inhibit Wnt/β-catenin signaling by disrupting the interaction between β-catenin and its specific target DNA sequences (TCF binding elements, TBE) rather than by altering the expression of the β-catenin protein. Gomisins J and N inhibit HCT116 cell proliferation by arresting the cell cycle at the G0/G1 phase. The G0/G1 phase arrest induced by gomisins J and N appears to be caused by a decrease in the expression of Cyclin D1, a representative target gene of the Wnt/β-catenin signaling pathway, as well as Cdk2, Cdk4, and E2F-1. Therefore, gomisins J and N, the novel Wnt/β-catenin inhibitors discovered in this study, may serve as potential agents for the prevention and treatment of human colorectal cancers., (Copyright © 2012 Elsevier Inc. All rights reserved.)

TGFβ1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Schisandra chinensis (S. chinensis), which is used as an oriental herbal medicine, is effective in the treatment of vascular injuries that cause aberrant TGFβ1 signaling. In this study, we investigated whether S. chinensis extract and its active ingredients inhibit TGFβ1 signaling in A7r5 vascular smooth muscle cells. We found that S. chinensis extract suppressed TGFβ1 signaling via inhibition of Smad2/3 phosphorylation and nuclear translocation. Among the active ingredients of S. chinensis extract, schisandrin B (SchB) most potently inhibited TGFβ1 signaling. SchB inhibited sustained phosphorylation and nuclear translocation of Smad2/3. Moreover, SchB suppressed TGFβ1-induced phosphorylation of p38 and JNK, which contributed to Smad2/3 inactivation. The present study is the first to demonstrate that S. chinensis extract and SchB inhibit TGFβ1 signaling. Our results may help future investigations to understand vascular fibrosis pathogenesis and to develop novel therapeutic strategies for treatment of vascular fibrotic diseases., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The effect of the ethanol extract and active components of the fruit of Schisandra chinensis was evaluated on rabbit penile corpus cavernosum (PCC). PCC, pre-contracted with 10(-5)  m phenylephrine (Phe), was treated with extracts of S. chinensis at five different compositions of ethanol and water (95%, 70%, 50%, 30% and ethanol/water [v/v]) and three fractions (0.1, 0.5, 1 and 2 mg/mL). The effect of the extracts and active lignans (schisandrol A and schisandrol B) from S. chinensis on sildenafil citrate pre-incubated PCC was also evaluated. The PCC relaxation induced by the 95% ethanol extraction and the n-hexane fraction was concentration-dependent and the ethanol extract enhanced sildenafil citrate-induced PCC relaxation. The active components of S. chinensis (schisandrol A and schisandrol B) significantly enhanced sildenafil citrate-induced relaxation >2-fold; schisandrol A had the highest relaxant effect on sildenafil citrate pre-incubated PCC. The lignans, schisandrol A and schisandrol B, isolated from the fruits of S. chinensis enhanced sildenafil citrate-induced relaxation and may have synergistic action in patients who do not completely respond to sildenafil., (Copyright © 2011 John Wiley & Sons, Ltd.)

Arctigenin is a natural plant lignan previously shown to induce G(2)/M arrest in SW480 human colon cancer cells as well as AGS human gastric cancer cells, suggesting its use as a possible cancer chemopreventive agent. Changes in cell and nuclear size often correlate with the functionality of cancer-treating agents. Here, we report that arctigenin induces cell and nuclear enlargement of SW480 cells. Arctigenin clearly induced the formation of giant nuclear shapes in SW480, as demonstrated by fluorescence microscopic observation and quantitative determination of nuclear size. Cell and nuclear size were further assessed by flow cytometric analysis of light scattering and fluorescence pulse width after propidium iodide staining. FSC-H and FL2-W values (parameters referring to cell and nuclear size, respectively) significantly increased after arctigenin treatment; the mean values of FSC-H and FL2-W in arctigenin-treated SW480 cells were 572.6 and 275.1, respectively, whereas those of control cells were 482.0 and 220.7, respectively. Our approach may provide insights into the mechanism behind phytochemical-induced cell and nuclear enlargement as well as functional studies on cancer-treating agents.

Schiandra chinensis is a well-known Chinese traditional medicine for the treatment of hepatic disease. In this study, we investigated whether the nine major compounds of Schiandra chinensis could be applied to suppress lipopolysaccharide (LPS)-induced inflammatory responses in murine macrophages (Raw 264.7 cells). Among the nine lignans, three, gomisin J, gomisin N, and schisandrin C, were found to reduce nitric oxide (NO) production from LPS-stimulated Raw 264.7 cells. These three lignans showed low cytotoxic effects in Raw 264.7 cells. Pre-treatment of Raw 264.7 cells with gomisin J, gomisin N, or schisandrin C reduced the expression of mRNA and the secretion of pro-inflammatory cytokines. These inhibitory effects were found to be caused by blockage of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and c-Jun N-terminal kinase (JNK) phosphorylation.

The upregulation of phase II detoxification genes is believed to play an important role in cancer prevention. The molecular mechanism underlying the changes in gene expression that accompany cancer prevention involves activation of the transcription factor, NF-E2-related factor 2 (Nrf2). In traditional medicine, the fruit of Schisandra chinensis Baill is used as a tonic, an anti-tussive and an anti-aging drug. In the current study, nine lignans were isolated from S. chinensis and tested for their ability to induce quinone reductase (QR) activity in Hepa1c1c7 mouse hepatocarcinoma cells. Tigloylgomisin H (TGH) and angeloylgomisin H (AGH) significantly induced QR activity and exhibited a relatively high chemoprevention index (CI) (10.80 and 4.59, respectively) as compared to control. TGH also induced QR activity in BPrc1 mouse hepatocarcinoma cells as well, which are defective in aryl hydrocarbon nuclear translocator (Arnt). In HepG2 human hepatocarcinoma cells, TGH significantly activated gene expression mediated by the antioxidant response element (ARE), a key regulatory region in the promoters of detoxification enzymes, through the nuclear accumulation of Nrf2. The results of the current study suggest that TGH functions as a novel monofunctional inducer that specifically upregulates phase II enzymes through the Nrf2-ARE pathway. TGH thus represents a potential liver cancer prevention agent., (Georg Thieme Verlag KG Stuttgart, New York.)

Abstract: As aberrant activation of Wnt/β-catenin signaling is one of the major mechanisms of carcinogenesis in colon cancer, identification of inhibitors of this pathway may aid in colon cancer prevention. We investigated the ability of the lignans arctiin, matairesinol and arctigenin from Saussurea salicifolia to inhibit Wnt/β-catenin signaling in SW480 human colon cancer cells. The lignans inhibited SW480 cell growth. In addition, the transcriptional activity of a reporter construct containing the TCF binding element (TBE) was decreased after the treatment with all three lignans. Although arctiin, matairesinol and arctigenin have similar structures, arctigenin affected Wnt/β-catenin signaling most significantly. Further, arctigenin reduced the level of β-catenin by inducing its phosphorylation and thus its degradation. Arctigenin also decreased expression of the β-catenin/TCF downstream genes CCND1, survivin and CTNNB1, and induced apoptosis. These results suggest that arctigenin, an aglycone with a methoxyl group, potently inhibits the growth of human colon cancer cells via the Wnt/β-catenin signaling pathway. [Copyright &y& Elsevier]

Abstract: The pressurized liquid extraction and HPLC-DAD was developed for extraction and determination of bioactive lignans in Schisandra chinensis. The efficient PLE conditions employed methanol as extraction solvent, 125°C of extraction temperature, 5min of static extraction time and only one cycle. A rapid HPLC-DAD method was described for simultaneous determination of nine lignans, including schisandrol A, gomisin J, schisandrol B, tigloylgomisin H, angeloylgomisin H, schisandrin A, γ-schisandrin, gomisin N and schisandrin C. The extraction efficiency of PLE was observed to be comparable with reflux and sonication. In addition, the contents of nine lignans in S. chinensis from different regions were analysed by PLE and HPLC-DAD method. [Copyright &y& Elsevier]