Schizandrin A induces non-small cell lung cancer apoptosis by suppressing the epidermal growth factor receptor activation.

OBJECTIVE: The purpose of this study is to explore the biological mechanism of Schizandrin A (SchA) inducing non-small cell lung cancer (NSCLC) apoptosis. METHODS: The reverse molecular docking tool "Swiss Target Prediction" was used to predict the targets of SchA. Protein-protein interaction analysis was performed on potential targets using the String database. Functional enrichment analyses of potential targets were performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The conformation of SchA binding to target was simulated by chemical-protein interactomics and molecular docking. The effect of SchA on the expression and phosphorylation level of EGFR was detected by Western blot. Lipofectamine 3000 and EGFR plasmids were used to overexpress EGFR. Apoptosis was tested with Annexin V-FITC and propidium iodide staining, and cell cycle was detected by propidium iodide staining. RESULTS: The "Swiss Target Prediction" database predicted 112 and 111 targets based on the 2D and 3D structures of SchA, respectively, of which kinases accounted for the most, accounting for 24%. Protein interaction network analyses showed that molecular targets such as ERBB family and SRC were at the center of the network. Functional enrichment analyses indicated that ERBB-related signaling pathways were enriched. Compound-protein interactomics and molecular docking revealed that SchA could bind to the ATP-active pocket of the EGFR tyrosine kinase domain. Laboratory results showed that SchA inhibited the phosphorylation of EGFR. Insulin could counteract the cytotoxic effect of SchA. EGFR overexpression and excess EGF or IGF-1 had limited impacts on the cytotoxicity of SchA. CONCLUSIONS: Network pharmacology analyses suggested that ERBB family members may be the targets of SchA. SchA can inhibit NSCLC at least in part by inhibiting EGFR phosphorylation, and activating the EGFR bypass can neutralize the cytotoxicity of SchA.

A Review of Extraction and Purification, Biological Properties, Structure-Activity Relationships and Future Prospects of Schisandrin C: A Major Active Constituent of Schisandra Chinensis.

Since ancient times, China has used natural medicine as the primary way to combat diseases and has a rich arsenal of natural medicines. With the progress of the times, the extraction of bioactive molecules from natural drugs has become the new development direction for natural medicines. Among the numerous natural drugs, Schisandrin C (Sch C), derived from Schisandra Chinensis (Turcz.) Baill. It has excellent potential for development and has been shown to possess various pharmacological properties, including hepatoprotective, antitumor and anti-inflammatory activities. Based on the biological properties of hepatoprotection, scholars have explored Sch C and its synthetic products in depth; some studies have shown that pentosidine has the effect of improving the symptoms of liver fibrosis and reducing the concentration of alanine transaminase (ALT) and aspartate aminotransferase (AST) in the serum of rats, which is an essential inspiration for the development of anti-liver fibrosis drugs. But more in vivo and ex vivo studies still need to be included. This paper focuses on Sch C's extraction and synthesis, biological activities and drug development progress. The future application prospects of Sch C are discussed to perfect its development work further.

A review: Pharmacology and pharmacokinetics of Schisandrin A.

Schisandrin A (SA) is a bioactive lignan isolated from the traditional Chinese medicine Fructus schisandrae chinensis. In recent years, it has attracted extensive attention because of its multiple pharmacological activities. This review is the first to provide an overview of SA-related pharmacological effects and pharmacokinetic characteristics. The results showed that SA had many pharmacological effects, such as antiinflammation, anticancer, hepatoprotection, antioxidation, neuroprotection, antidiabetes mellitus, and musculoskeletal protection. Among them, NF-κB, Nrf2, MAPK, NLRP3, PI3K/AKT, Wnt, miRNA, P-gp, CYP450, PXR, and other signal transduction pathways are involved. Pharmacokinetic studies showed that SA had good pharmacokinetic characteristics, but these were affected by other factors, such as drugs or hepatic fibrosis. Thus, SA has a variety of pharmacological effects and good pharmacokinetic characteristics, which is worthy of further research and development in the future.

Schisandrin B promotes Foxp3+ regulatory T cell expansion by activating heme oxygenase-1 in dendritic cells and exhibits immunomodulatory effects in Th2-mediated allergic asthma.

Allergic asthma is induced by T helper 2 (Th2) responses and allergen-specific immunoglobulin E (IgE). In asthma, regulatory T (Treg) cells play a crucial role in controlling immune homeostasis, and induction of Treg cells is a good strategy to treat Th2-mediated allergic asthma. Schisandrin B (Sch B), the main component isolated from Schisandra chinensis, reportedly possesses various pharmacological properties, but its immunomodulatory mechanism in allergic asthma remains unclear. In the present study, we explored whether Sch B exerts an antiallergic effect through modifying the function of dendritic cells (DCs) to regulate T-cell polarization and further investigated the immunomodulatory effects of Sch B in allergic asthma. Herein, an in vitro study revealed that 20 µM of Sch B-treated bone-marrow-derived DCs exhibited a semi-mature phenotype that secreted low amounts of proinflammatory cytokines including interleukin (IL)-12, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α, and expressed decreased levels of surface molecules of cluster of differentiation 80 (CD80) and CD86. Compared to fully mature DCs, these Sch B-treated DCs displayed a regulatory ability to promote CD4+Foxp3+ Treg cell generation via upregulation of heme oxygenase (HO)-1 expression. Of note, in a murine model of ovalbumin (OVA)-induced asthma, levels of Th2-type cytokines such as IL-4, IL-5, and IL-13, and C-C motif chemokine 11 (CCL11) were dampened, whereas numbers of forkhead box P3 (Foxp3)-positive Treg cells were augmented in Sch B-treated mice. Moreover, administration of 5 mg/kg of Sch B alleviated the cardinal features of Th2-mediated allergic asthma, namely, serum OVA-specific IgE production, the development of airway hyperresponsiveness (AHR), and airway inflammation. Collectively, these findings indicate that the effectiveness of Sch B treatment against Th2-mediated allergic asthma was at least partially due to enhancement of DC induction of Treg cells, and Sch B can possibly be developed as an immunomodulatory adjuvant to treat allergic asthma.

Schisandrin B suppresses osteosarcoma lung metastasis in vivo by inhibiting the activation of the Wnt/ß­catenin and PI3K/Akt signaling pathways.

Osteosarcoma (OS) is the most common malignant bone tumor worldwide and is associated with a poor prognosis, often being accompanied by lung metastasis at an early stage. At present, there are several side­effects associated with the OS clinical treatment of OS, with the treatment effects often being unsatisfactory. Thus, there is an urgent need for the development of safe and effective novel drugs for the treatment of OS. Schisandrin B (Sch B) has been previously demonstrated to exhibit antitumor properties. The present study was focused on the effects of Sch B on OS cells (143B, MG63, Saos2 and U2OS) in vitro and in vivo, and also on its possible antitumor mechanisms. In cell experiments, it was revealed that Sch B inhibited OS cell proliferation, migration and invasion, and increased OS cell apoptosis. As regards its biosafety, no notable effects of Sch B on the vitality of normal cells were observed. Mechanistically, it was demonstrated that Sch B blocked OS cell proliferation in the G1 phase. Subsequently, by using established animal models, it was revealed that Sch B significantly inhibited OS growth and lung metastasis in vivo. In summary, the results of the present study revealed that Sch B inhibited OS cell proliferation, migration and invasion, and promoted apoptosis via the inhibition of the Wnt/ß­catenin and PI3K/Akt signaling pathways, without causing any noticeable toxic effects on healthy cells at the therapeutic concentrations used. These findings suggest that Sch B has potential for use as a novel agent for the clinical treatment of OS.

Synthesis and biological evaluation of novel schisanhenol derivatives as potential hepatoprotective agents.

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway.

Regulation of cell signaling pathways by Schisandrin in different cancers: Opting for "Swiss Army Knife" instead of "Blunderbuss".

There has been an exponential growth in the field of molecular oncology and cutting-edge research has enabled us to develop a better understanding of therapeutically challenging nature of cancer. Based on the mechanistic insights garnered from decades of research, puzzling mysteries of multifaceted nature of cancer have been solved to a greater extent. Our rapidly evolving knowledge about deregulated oncogenic cell signaling pathways has allowed us to dissect different oncogenic transduction cascades which play critical role in cancer onset, progression and metastasis. Pharmacological targeting of deregulated pathways has attracted greater than ever attention in the recent years. Henceforth, discovery and identification of high-quality biologically active chemicals and products is gaining considerable momentum. There has been an explosion in the dimension of natural product research because of tremendous potential of chemopreventive and pharmaceutical significance of natural products. Schisandrin is mainly obtained from Schisandra chinensis. Schisandrin has been shown to be effective against different cancers because of its ability to inhibit/prevent cancer via modulation of different cell signaling pathways. Importantly, regulation of non-coding RNAs by schisandrin is an exciting area of research that still needs detailed and comprehensive research.   However, we still have unresolved questions about pharmacological properties of schisandrin mainly in context of its regulatory role in TGF/SMAD, SHH/GLI, NOTCH and Hippo pathways.

Schisandrin C Affects Glucose-Stimulated Insulin Secretion in Pancreatic ß-Cells and Glucose Uptake in Skeletal Muscle Cells.

The aim of our study was to investigate the effect of three lignans (schisandrol A, schisandrol B, and schisandrin C) on insulin secretion in rat INS-1 pancreatic ß-cells and glucose uptake in mouse C2C12 skeletal muscle cells. Schisandrol A and schisandrin C enhanced insulin secretion in response to high glucose levels with no toxic effects on INS-1 cells. The effect of schisandrin C was superior to that of gliclazide (positive control), a drug commonly used to treat type 2 diabetes (T2D). In addition, western blot analysis showed that the expression of associated proteins, including peroxisome proliferator-activated receptor γ (PPARγ), pancreatic and duodenal homeobox 1 (PDX-1), phosphatidylinositol 3-kinase (PI3K), Akt, and insulin receptor substrate-2 (IRS-2), was increased in INS-1 cells after treatment with schisandrin C. In addition, insulin secretion effect of schisandrin C were enhanced by the Bay K 8644 (L-type Ca2+ channel agonist) and glibenclamide (K+ channel blocker), were abolished by the nifedipine (L-type Ca2+ channel blocker) and diazoxide (K+ channel activator). Moreover, schisandrin C enhanced glucose uptake with no toxic effects on C2C12 cells. Western blot analysis showed that the expression of associated proteins, including insulin receptor substrate-1 (IRS-1), AMP-activated protein kinase (AMPK), PI3K, Akt, glucose transporter type 4 (GLUT-4), was increased in C2C12 cells after treatment with schisandrin C. Schisandrin C may improve hyperglycemia by enhancing insulin secretion in pancreatic ß-cells and improving glucose uptake into skeletal muscle cells. Our findings may provide evidence that schisandrin C may be beneficial in devising novel anti-T2D strategies.

Thioredoxin-1 mediates neuroprotection of Schisanhenol against MPP+-induced apoptosis via suppression of ASK1-P38-NF-κB pathway in SH-SY5Y cells.

Oxidative stress-induced dopaminergic neuronal loss and apoptosis play a crucial role in the pathogenesis of Parkinson's disease (PD), and as a vital antioxidant protein, thioredoxin (Trx) exerts neuroprotection against PD. In this study, we investigated the effect of Schisanhenol (Sal), an active component from a traditional Chinese herb Schisandra rubriflora (Franch.), on MPP+-induced apoptosis and its association with thioredoxin-1 (Trx1) in SH-SY5Y cells. The protein levels of Trx1 and apoptosis-related proteins were detected by Western blot, the expression of Trx1 mRNA by real time qPCR, and apoptosis was detected by fluorescence microscopy and flow cytometry. Pretreatment with Sal (1 µM, 10 µM, and 50 µM) dose-dependently ameliorated MPP+-induced neuronal injury, confirmed by the improvement of the viability and morphological changes. Sal decreased the apoptosis rate of cells, suppressed the production of DNA ladder and sub-G1 peak, inhibited the Caspase-3 activity and the expression of apoptosis-related proteins. Sal enhanced the expression of Trx1 both in the protein and mRNA levels. However, the Trx1 inhibitor PX-12 suppressed the protective effects of Sal. In addition, Sal inhibited NF-κB translocation and activation. These results suggest that Sal has a protective effect against MPP+-induced apoptosis in SH-SY5Y cells via up-regulation of Trx1 expression and suppression of ASK1-P38-NF-κB pathway.

Network pharmacology for systematic understanding of Schisandrin B reduces the epithelial cells injury of colitis through regulating pyroptosis by AMPK/Nrf2/NLRP3 inflammasome.

Ulcerative colitis (UC) is a chronic inflammatory disease with increasing incidence and prevalence in many countries. The purpose of this study is to explore the function of Schisandrin B and its underlying molecular mechanisms in colitis. In this study, mice with colitis were induced by giving 2.0% dextran sulfate sodium (DSS, MP) in the drinking water for seven days. Furthermore, TCMSP server and GEO DataSets were used to analyze the mechanism of Schisandrin B in colitis. It was found that Schisandrin B presented colitis in mice model. At the same time, Schisandrin B not only reduced inflammation in vivo and vitro model of colitis, but also suppressed the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome in vivo and vitro model of colitis. In addition, Schisandrin B induced AMP-activated protein kinase (AMPK) / Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in model of colitis, and regulated AMPK protein at 316 sites. The inhibition of AMPK reduced the anti-inflammation effects of Schisandrin B on NLRP3 inflammasome. Apart from that, Schisandrin B decreased reactive oxygen species (ROS)-induced mitochondrial damage and reduced epithelial cells damage of colitis through regulating pyroptosis. Collectively, our novel findings for first time showed that, Schisandrin B suppressed NLRP3 inflammasome activation-mediated interleukin-1beta (IL-1ß) level and pyroptosis in intestinal epithelial cells of colitis model through the activation of AMPK/Nrf2 dependent signaling-ROS-induced mitochondrial damage, which may be a significant therapeutic approach in the treatment of acute colitis.

Schisandrin B Attenuates Colitis-Associated Colorectal Cancer through SIRT1 Linked SMURF2 Signaling.

Colon cancer, a common type of malignant tumor, seriously endangers human health. However, due to the relatively slow progress in diagnosis and treatment, the clinical therapeutic technology of colon cancer has not been substantially improved in the past three decades. The present study was designed to investigate the effects and involved mechanisms of schisandrin B in cell growth and metastasis of colon cancer. C57BL/6 mice received AOM and dextran sulfate sodium. Mice in treatment groups were gavaged with 3.75-30 mg/kg/day of schisandrin B. Transwell chamber migration, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, immunoprecipitation (IP) and immunofluorescence were conducted, and HCT116 cell line was employed in this study. Data showed that schisandrin B inhibited tumor number and tumor size in the AOD+DSS-induced colon cancer mouse model. Schisandrin B also inhibited cell proliferation and metastasis of colon cancer cells. We observed that schisandrin B induced SMURF2 protein expression and affected SIRT1 in vitro and in vivo. SMURF2 interacted with SIRT1 protein, and there was a negative correlation between SIRT1 and SMURF2 expressions in human colorectal cancer. The regulation of SMURF2 was involved in the anticancer effects of schisandrin B in both in vitro and in vivo models. In conclusion, the present study revealed that schisandrin B suppressed SIRT1 protein expression, and SIRT1 is negatively correlated with the induction of SMURF2, which inhibited cell growth and metastasis of colon cancer. Schisandrin B could be a leading compound, which will contribute to finding novel potential agents and therapeutic targets for colon cancer.

Schizandrin A can inhibit non­small cell lung cancer cell proliferation by inducing cell cycle arrest, apoptosis and autophagy.

Schizandrin A (SchA) can be extracted from the vine plant Schisandra chinensis and has been reported to confer various biologically active properties. However, its potential biological effects on non­small cell lung cancer (NSCLC) remain unknown. Therefore, the present study aims to address this issue. NSCLC and normal lung epithelial cell lines were first treated with SchA. Cell viability and proliferation were measured using CellTiter­Glo Assay and colony formation assays, respectively. PI staining was used to measure cell cycle distribution. Cell cycle­related proteins p53, p21, cyclin D1, CDK4, CDK6, cyclin E1, cyclin E2, CDK2 and DNA damage­related protein SOX4 were detected by western blot analysis. Annexin V­FITC/PI staining, DNA electrophoresis and Hoechst 33342/PI dual staining were used to detect apoptosis. JC­1 and DCFH­DA fluorescent dyes were used to measure the mitochondrial membrane potential and reactive oxygen species concentrations, respectively. Apoptosis­related proteins caspase­3, cleaved caspase­3, poly(ADP­ribose) polymerase (PARP), cleaved PARP, BimEL, BimL, BimS, Bcl2, Bax, caspase­9 and cleaved caspas­9 were measured by western blot analysis. Dansylcadaverine was used to detect the presence of the acidic lysosomal vesicles. The expression levels of the autophagy­related proteins LC3­I/II, p62/SQSTM and AMPKα activation were measured using western blot analysis. In addition, the autophagy inhibitor 3­methyladenine was used to inhibit autophagy. SchA treatment was found to reduce NSCLC cell viability whilst inhibiting cell proliferation. Low concentrations of SchA (10­20 µM) mainly induced G1/S­phase cell cycle arrest. By contrast, as the concentration of SchA used increases (20­50 µM), cells underwent apoptosis and G2/M­phase cell cycle a13rrest. As the treatment concentration of SchA increased from 0 to 50 µM, the expression of p53 and SOX4 protein also concomitantly increased, but the expression of p21 protein was increased by 10 µM SchA and decreased by higher concentrations (20­50 µM). In addition, the mRNA and protein expression levels of Bcl­like 11 (Bim)EL, BimL and BimS increased following SchA application. SchA induced the accumulation of acidic vesicles and induced a marked increase in the expression of LC3­II protein, suggsting that SchA activated the autophagy pathway. However, the expression of the p62 protein was found to be increased by SchA, suggesting that p62 was not degraded during the autophagic flux. The 3­methyladenine exerted no notable effects on SchA­induced apoptosis. Taken together, results from the present study suggest that SchA exerted inhibitory effects on NSCLC physiology by inducing cell cycle arrest and apoptosis. In addition, SchA partially induced autophagy, which did not result in any cytoprotective effects.

Schisandrin B promotes TH1 cell differentiation by targeting STAT1.

Schisandrin B (Sch B) is the major active ingredient of the traditional Chinese medicine Schisandra chinensis and has antitumor activity, anti-inflammatory activity. CD4+ Th subsets orchestrate immune responses to plenty of pathogen infections and participate in the pathogenesis of many immune-related diseases. However, little is known about the relationship between Sch B and T cell differentiation. Here, we showed that Sch B might participate in T cell receptor signaling pathway by using the TCMIO database. Importantly, Sch B promoted TH1 cell differentiation. Furthermore, Sch B did not affect TH2 cell and Treg differentiation. Mechanismly, Sch B increased the level of IFN-γ of CD4+ T cells by upregulating the phosphorylation of STAT1 protein. Then, STAT1 promoted T-bet expression in CD4+ T cells. In conclusion, Sch B modulates the differentiation of naïve CD4+ T cells into TH1 subset by STAT1/T-bet signaling, which may have the potential for the treatment of T cell-mediated-immune diseases.

Inhibition of amyloid formation of amyloid ß (1-42), amylin and insulin by 1,5-diazacyclooctanes, a spermine-acrolein conjugate.

Amyloid aggregates of proteins are known to be involved in various diseases such as Alzheimer's disease (AD). It is therefore speculated that the inhibition of amyloid formation can play an important role in the prevention of various diseases involving amyloids. Recently, we have found that acrolein reacts with polyamines, such as spermine, and produces 1,5-diazacyclooctane, such as cyclic spermine (cSPM). cSPM could suppress the aggregation of amyloid ß 1-40 (Aß40), one of the causative proteins of AD. This result suggests the potential inhibitory effect of cSPM against Aß 1-42 (Aß42) and other amyloid protein aggregation which are the main pathological features of AD and other diseases. However, the effect on the aggregation of such proteins remains unclear. In this study, the effect of cSPM on the amyloid formation of Aß42, amylin, and insulin was investigated. These three amyloidogenic proteins forming amyloids under physiological conditions (pH 7.4 and 37℃) served as model and are thought to be the causative proteins of AD, type 2 diabetes, and insulin-derived amyloidosis, respectively. Our results indicate that cSPM can suppress the amyloid aggregation of these proteins and reduce cytotoxicity. This study contributes to a better understanding of means to potentially counteract diseases by the means of polyamine and acrolein.

Schizandrin A induces the apoptosis and suppresses the proliferation, invasion and migration of gastric cancer cells by activating endoplasmic reticulum stress.

Apart from its basic antioxidant and anti­inflammatory properties, schizandrin A (SchA), which is isolated from Fructus schisandra, can exert anticancer effects on multiple cancer types. However, to the best of our knowledge, there has been no study identifying the impacts of SchA on gastric cancer (GC). Therefore, the aim of the present study was to identify how SchA functioned to affect the progression of GC. To investigate the role of SchA in GC development, Cell Counting Kit­8, colony formation, wound healing and Transwell assays were conducted to assess the viability, proliferation, migration and invasion of AGS cells, respectively. Then, the apoptosis rate and apoptosis­ and endoplasmic reticulum (ER) stress­related protein expression levels in AGS cells exposed to SchA were detected via TUNEL assays and western blotting, respectively. Subsequently, the aforementioned functional assays were performed again in AGS cells exposed to both SchA and the ER stress inhibitor 4­phenylbutyric acid (4­PBA) for the confirmation of the effect of SchA on ER stress in GC. It was found that SchA markedly decreased the viability, proliferation, migration and invasion, while it induced the apoptosis of AGS cells. Moreover, the markers of ER stress were elevated by SchA treatment in AGS cells. Nevertheless, 4­PBA reversed the effects of SchA on the viability, proliferation, migration, invasion and apoptosis of AGS cells, accompanied by decreased expression of ER stress markers. In conclusion, the present study demonstrated that SchA induced the apoptosis and suppressed the proliferation, invasion and migration of GC cells by activating ER stress, which provides a theoretical basis for the use of SchA in the treatment of GC.

Protective effects of Schisandrin B against D-GalN-induced cell apoptosis in human hepatocyte (L02) cells via modulating Bcl-2 and Bax.

Schisandrin B is a dibenzocyclooctadiene derivative extracted fromSchisandra chinensis (Turcz.) Baill., that exhibits anti-oxidation, anti-inflammation, anti-tumor and hepatoprotective activities. To understand the hepatoprotective mechanism of schisandrin B, this study investigated the efficacy of schisandrin B on L02 cells after treatment with D-GalN. Following pretreatment with 40 µM schisandrin B, L02 cells were stimulated with 40 mM D-GalN. Cell viability, apoptosis, the expression levels of genes associated with apoptosis, and the intracellular oxidative stress indexes were measured. The viability of L02 cells was determined using MTT assay, and the Annexin V-FITC/PI assay kit was utilized for the assessment of apoptosis. The activities of GSH-Px and SOD, the level of MDA were assessed, separately, using relative detection kits. Moreover, RT-PCR as well as Western blot was applied to measure the mRNA and protein expression of Bax and Bcl-2. The results indicated that schisandrin B significantly prevented D-GalN­induced oxidative damage in L02 cells (P<0.05), decreased GSH-Px and SOD activities (P<0.05), increased MDA content (P<0.05). Furthermore, schisandrin B inhibited D-GalN-induced apoptosis in L02 cells (P<0.05), regulated the expression of Bax and Bcl-2 (P<0.05). The results indicated that schisandrin B decreased the D-GalN-induced intracellular oxidative stress indexes generation, and inhibited the down-regulation of Bcl-2 and up-regulation of Bax induced by D-GalN. In conclusion, schisandrin B was shown to exert protective effect against oxidative damage of L02 cells, which, in part, was achieved by regulating the mRNA and protein levels of Bax and Bcl-2.

Gomisin M2 Ameliorates Atopic Dermatitis-like Skin Lesions via Inhibition of STAT1 and NF-κB Activation in 2,4-Dinitrochlorobenzene/Dermatophagoides farinae Extract-Induced BALB/c Mice.

The extracts of Schisandra chinensis (Turcz.) Baill. (Schisandraceae) have various therapeutic effects, including inflammation and allergy. In this study, gomisin M2 (GM2) was isolated from S. chinensis and its beneficial effects were assessed against atopic dermatitis (AD). We evaluated the therapeutic effects of GM2 on 2,4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae extract (DFE)-induced AD-like skin lesions with BALB/c mice ears and within the tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated keratinocytes. The oral administration of GM2 resulted in reduced epidermal and dermal thickness, infiltration of tissue eosinophils, mast cells, and helper T cells in AD-like lesions. GM2 suppressed the expression of IL-1ß, IL-4, IL-5, IL-6, IL-12a, and TSLP in ear tissue and the expression of IFN-γ, IL-4, and IL-17A in auricular lymph nodes. GM2 also inhibited STAT1 and NF-κB phosphorylation in DNCB/DFE-induced AD-like lesions. The oral administration of GM2 reduced levels of IgE (DFE-specific and total) and IgG2a in the mice sera, as well as protein levels of IL-4, IL-6, and TSLP in ear tissues. In TNF-α/IFN-γ-stimulated keratinocytes, GM2 significantly inhibited IL-1ß, IL-6, CXCL8, and CCL22 through the suppression of STAT1 phosphorylation and the nuclear translocation of NF-κB. Taken together, these results indicate that GM2 is a biologically active compound that exhibits inhibitory effects on skin inflammation and suggests that GM2 might serve as a remedy in inflammatory skin diseases, specifically on AD.

Dibenzocyclooctadiene lignans from Kadsura coccinea alleviate APAP-induced hepatotoxicity via oxidative stress inhibition and activating the Nrf2 pathway in vitro.

Phytochemical investigation on the roots of Kadsura coccinea led to the isolation five previously unknown dibenzocyclooctadiene lignans, named heilaohusuins A-E (1-5). Their structures determined by NMR spectroscopy, HR-ESI-MS, and ECD spectra. Hepatoprotection effects of a series of dibenzocyclooctadiene derivatives (1-68) were investigated against acetaminophen (APAP) induced HepG2 cells. Compounds 2, 10, 13, 21, 32, 41, 46, and 49 showed remarkable protective effects, increasing the viabilities to > 52.2% (bicyclol, 52.1 ± 1.3%) at 10 µM. The structure-activity relationships (SAR) for hepatoprotective activity were summarized, according to the activity results of dibenzocyclooctadiene derivatives. Furthermore, we found that one new dibenzocyclooctadiene lignan heilaohusuin B attenuates hepatotoxicity, the mechanism might be closely correlated with oxidative stress inhibition via activating the Nrf2 pathway.

Schisantherin A ameliorates liver fibrosis through TGF-ß1mediated activation of TAK1/MAPK and NF-κB pathways in vitro and in vivo.

BACKGROUD: Schisandra chinensis, a traditional Chinese medicine for liver protection, can significantly improve liver fibrosis. However, it is still unclear which active components in Schisandra chinensis play an anti-fibrosis role. PURPOSE: The purpose of present study was to observe the anti-fibrosis effect of schisantherin A (SCA) on liver fibrosis and explore its underlying mechanism. METHODS: The liver fibrosis model of mice was constructed by the progressive intraperitoneal injection of thioacetamide (TAA), and SCA (1, 2, and 4 mg/kg) was administered by gavage for 5 weeks. The biochemical indicators and inflammatory cytokines were measured, changes in the pathology of the mice liver were observed by hematoxylin & eosin (H&E) and Masson stainings for studying the anti-fibrosis effect of SCA. A hepatic stellate cell (HSCs) activation model induced by transforming growth factor-ß1 (TGF-ß1) was established, and the effect of SCA on the HSCs proliferation was observed by MTT assay. The expressions of target proteins related to transforming growth factor-ß-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated by western blotting, immunohistochemistry or immunofluorescence analysis, to explore the potential mechanism of SCA. RESULTS: SCA could significantly ameliorate the pathological changes of liver tissue induced by TAA, and reduce the serum transaminase level, the hydroxyproline level and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 (COL1A1) proteins in the liver tissue. SCA could significantly lower the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the serum and liver tissue, and down-regulate the expression of target proteins related to TAK1/MAPK and NF-κB pathways in the liver tissue. The in vitro studies demonstrated that SCA significantly inhibited the proliferation and activation of HCS-T6 cells induced by TGF-ß1, decreased TNF-α and IL-6 levels, and inhibited the TAK1 activation induced by TGF-ß1 and then the expression of MAPK and NF-κB signaling pathway-related proteins. CONCLUSION: Together, SCA can ameliorate the liver fibrosis induced by TAA and the HSC-T6 cell activation induced by TGF-ß1 in mice, and its mechanism may be to inhibit the HSCs activation and inflammatory response by inhibiting TGF-ß1 mediated TAK1/MAPK and signal pathways.

Ameliorative effects of Schisandrin B on Schistosoma mansoni-induced hepatic fibrosis in vivo.

Schistosomiasis is second only to malaria as the most devastating parasitic disease in the world. It is caused by the helminths Schistosoma mansoni (S. mansoni), S. haematobium, or S. japonicum. Typically, patients with schistosomiasis suffer from symptoms of liver fibrosis and hepatosplenomegaly. Currently, patients were treated with praziquantel. Although praziquantel effectively kills the worm, it cannot prevent re-infection or resolve liver fibrosis. Also, current treatment options are not ample to completely cure liver fibrosis and splenic damages. Moreover, resistance of praziquantel has been reported in vivo and in vitro studies. Therefore, finding new effective treatment agents is urgently needed. Schisandrin B (Sch B) of Schisandra chinensis has been shown to protect against different liver injuries including fatty liver disease, hepatotoxicity, fibrosis, and hepatoma. We herein investigate the potential of using Sch B to treat S. mansoni-induced liver fibrosis. Results from the present study demonstrate that Sch B is beneficial in treating S. mansoni-induced liver fibrosis and splenic damages, through inhibition of inflammasome activation and apoptosis; and aside from that regulates host immune responses. Besides, Sch B treatment damages male adult worm in the mice, consequently helps to reduce egg production and lessen the parasite burden.