lignans and Inflammation

Inflammation is a major factor affecting human health. Nuclear factor-kappa B (NF-κB) plays a vital role in the development of inflammation, and the promoters of most inflammatory cytokine genes have NF-κB-binding sites. Targeting NF-κB could be an exciting route for the prevention and treatment of inflammatory diseases. As important constituents of natural plants, lignans are proved to have numerous biological functions. There are growing pieces of evidence demonstrate that lignans have the potential anti-inflammatory activities. In this work, the type, structure and source of lignans and the influence on mitigating the inflammation are systematically summarized. This review focuses on the targeting NF-κB signaling pathway in the inflammatory response by different lignans and their molecular mechanisms. Lignans also regulate gut microflora and change gut microbial metabolites, which exert novel pathway to prevent NF-κB activation. Taken together, lignans target NF-κB with various mechanisms to inhibit inflammatory cytokine expressions in the inflammatory response. It will provide a scientific theoretical basis for further research on the anti-inflammatory effects of lignans and the development of functional foods.

Topics: Anti-Inflammatory Agents; Cytokines; Gastrointestinal Microbiome; Humans; Inflammation; Lignans; NF-kappa B

Plant lignans exhibit a wide range of biological activities, which makes them the research objects of potential use as therapeutic agents. They provide diverse naturally-occurring pharmacophores and are available for production by chemical synthesis. A large amount of accumulated data indicates that lignans of different structural groups are apt to demonstrate both anti-inflammatory and antioxidant effects, in many cases, simultaneously. In this review, we summarize the comprehensive knowledge about lignan use as a bioactive agent in disorders associated with oxidative stress and inflammation, pharmacological effects in vitro and in vivo, molecular mechanisms underlying these effects, and chemical synthesis approaches. This article provides an up-to-date overview of the current data in this area, available in PubMed, Scopus, and Web of Science databases, screened from 2000 to 2022.

Topics: Anti-Inflammatory Agents; Antioxidants; Humans; Inflammation; Lignans; Oxidative Stress

Flavonoids, stilbenes, lignans, and phenolic acids, classes of polyphenols found in grape pomace (GP), were investigated as an important alternative source for active substances that could be used in the management of oxidative stress and inflammation. The benefic antioxidant and anti-inflammatory actions of GP are presented in the literature, but they are derived from a large variety of experimental

Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; C-Reactive Protein; Catalase; Dinoprostone; Flavonoids; Glutathione; Glutathione Peroxidase; Inflammation; Interferons; Interleukin-6; Interleukin-8; Lignans; NF-kappa B; Nitric Oxide Synthase Type III; Oxidative Stress; Plant Extracts; Polyphenols; Reactive Oxygen Species; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha; Vitis

Topics: Anti-Inflammatory Agents; Dioxoles; Humans; Immunity; Inflammation; Lignans; Sesamum

Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eye Diseases; Homeostasis; Humans; Hypoglycemic Agents; Inflammation; Lignans; Lipid Metabolism; Magnolia; Mice; Oxidative Stress; Plant Bark; Polyphenols; Treatment Outcome

Matrix metalloproteinases, zinc dependent proteolytic enzymes, have significant implications in extracellular matrix degradation associated with tissue damage in inflammation and Rheumatoid arthritis. Numerous orchestrated pathways affects instigation and blockade of metalloproteinases as well as various factors that increase the expression of MMPs including inflammatory cytokines, hormones and growth factors. Direct inhibition of these proteolytic enzymes or modulation of these pathways can provide protection against tissue destruction in inflammation and rheumatoid arthritis. Inclination towards use of plant derived phytochemicals to prevent tissue damage has been increasing day by day. Diversity of phytochemicals have been known to directly inhibit metalloproteinases. Hence, thorough knowledge of phytochemicals is very important in novel drug discovery.. Present communication evaluates various classes of phytochemicals, in effort to unveil the lead molecules as potential therapeutic agents, for prevention of MMPs mediated tissue damage in inflammation and rheumatoid arthritis. Data have been analyzed through different search engines.. Numerous phytochemicals have been studied for their role as MMPs inhibitors which can be processed further to develop into useful drugs for the treatment of inflammation and rheumatoid arthritis.. In search of new drugs, phytochemicals like flavonoids, glycosides, alkaloids, lignans & terpenes offer a wide canvas to develop into valuable forthcoming medicaments.

Topics: Alkaloids; Arthritis, Rheumatoid; Flavonoids; Glycosides; Humans; Inflammation; Lignans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Phytochemicals; Signal Transduction; Terpenes

Anemia is the main extra-gastrointestinal symptom in inflammatory bowel diseases (IBDs). Interleukin-6 (IL-6) and other cytokines are secreted and act in the microenvironment of the small intestine mucous membrane of IBD patients. Iron is essential for multiple cell functions and its homeostasis is regulated by the hepcidin-ferroportin axis. Hepcidin (HEPC) is mainly produced by the liver in response to iron needs but is also an acute phase protein. During inflammation, hepcidin is upregulated by IL-6 and is responsible for iron compartmentalization within cells, in turn causing anemia of inflammation. Tissues other than liver can produce hepcidin in response to inflammatory stimuli, in order to decrease iron efflux at a local level, then acting in an autocrine-paracrine manner. In IBDs and, in particular, in celiac disease (CeD), IL-6 might trigger the expression, upregulation and secretion of hepcidin in the small intestine, reducing iron efflux and exacerbating defective iron absorption. 7-Hydroxymatairesinol (7-HMR) belongs to the family of lignans, polyphenolic compounds produced by plants, and has nutraceutical antioxidant, anti-inflammatory and estrogenic properties. In this mini-review we revise the role of inflammation in IBDs and in particular in CeD, focusing our attention on the close link among inflammation, anemia and iron metabolism. We also briefly describe the anti-inflammatory and estrogenic activity of 7-HMR contained in foods that are often consumed by CeD patients. Finally, considering that HEPC expression is regulated by iron needs, inflammation and estrogens, we explored the hypothesis that 7-HMR consumption could ameliorate anemia in CeD using Caco-2 cells as bowel model. Further studies are needed to verify the regulation pathway through which 7-HMR may interfere with the local production of HEPC in bowel.

Topics: Anemia; Animals; Anti-Inflammatory Agents; Antioxidants; Caco-2 Cells; Celiac Disease; Cytokines; Edible Grain; Hepcidins; Humans; Inflammation; Inflammatory Bowel Diseases; Iron; Lignans

Flaxseed (Linum usitatissimum) is an oil-based seed that contains high amounts of alpha-linolenic acid, linoleic acid, lignans, fiber and many other bioactive components which is suggested for a healthier life. Nowadays, flaxseed is known as a remarkable functional food with different health benefits for humans and protects against cardiovascular disease, diabetes, dyslipidemia, obesity and altogether metabolic syndrome.. To review the bioactive components of flaxseed and their potential health effects, PubMed and Scopus were searched from commencement to July 2019. Keywords including: "flaxseed", "Linum usitatissimum", "metabolic syndrome", "obesity", "inflammation", "insulin resistance", "diabetes", "hyperlipidemia" and "menopause" were searched in the databases with varying combinations.. Consumption of flaxseed in different forms has valuable effects and protects against cardiovascular disease, hypertension, diabetes, dyslipidemia, inflammation and some other complications. Flaxseed can serve as a promising candidate for the management of metabolic syndrome to control blood lipid levels, fasting blood sugar, insulin resistance, body weight, waist circumference, body mass and blood pressure.

Topics: alpha-Linolenic Acid; Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus; Dietary Fiber; Drug Discovery; Dyslipidemias; Flax; Humans; Inflammation; Insulin Resistance; Lignans; Lipids; Metabolic Syndrome; Obesity; Plant Extracts; Seeds

Functional food-flaxseed and its derivatives (flaxseed oil or lignans) are beneficial for human health, possibly because of their anti-inflammatory effects. C-reactive protein (CRP), a sensitive marker of inflammation was chosen to evaluate the anti-inflammatory effects of flaxseed. We searched randomized controlled trials from PubMed and the Cochrane Library in October 2015 and conducted a meta-analysis to evaluate the effectiveness of flaxseed and its derivatives on CRP. The mean differences (net change) in CRP (mg/L) concentrations were pooled with a random- or a fixed-effects model depending on the results of heterogeneity tests. Overall, flaxseed interventions had no effects on reduction of CRP (p = 0.428). The null effects were consistent in the subgroup analysis with multiple studies and population characteristics. Significant heterogeneity was observed in most of the analyses. Meta-regression identified baseline body mass index (BMI) as a significant source of heterogeneity (P-interaction = 0.032), with a significant reduction in CRP of 0.83 mg/L (95% confidence interval -1.34 to -0.31; p = 0.002) among subjects with a BMI of ≥30 kg/m². In conclusion, our meta-analysis did not find sufficient evidence that flaxseed and its derivatives have a beneficial effect on reducing circulating CRP. However, they may significantly reduce CRP in obese populations.

Topics: Adult; Biomarkers; Body Mass Index; C-Reactive Protein; Diet; Female; Flax; Humans; Inflammation; Inflammation Mediators; Lignans; Linseed Oil; Male; Middle Aged; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Seeds; Treatment Outcome

Schisandra chinensis fruit extract (SCE) has traditionally been used as an oriental medicine for the treatment of various human diseases, including cardiovascular disease. Advances in scientific knowledge and analytical technologies provide opportunities for translational research involving S. chinensis; such research may contribute to future drug discovery. To date, emerging experimental evidence supports the therapeutic effects of the SCE or its bioactive lignan ingredients in cardiovascular disease, unraveling the mechanistic basis for their pharmacological actions. In the present review, we highlight SCE and its lignans as promising resources for the development of safe, effective, and multi-targeted agents against cardiovascular disease. Moreover, we offer novel insight into future challenges and perspective on S. chinensis research to future clinical investigations and healthcare strategies.

Topics: Animals; Apoptosis; Cardiovascular Diseases; Fibrosis; Fruit; Humans; Inflammation; Lignans; Oxidative Stress; Phytotherapy; Plant Extracts; Schisandra; Vasoconstriction

Cancer is a leading cause of death worldwide, and the numbers of new cancer cases are expected to continue to rise. The main goals of cancer therapy include removing the primary tumor, preventing the spread of distant metastases, and improving survival and quality of life for the patients. To attain these goals of cancer therapy, the combination of different chemotherapeutics, as opposed to the conventional single-agent treatment, is an emerging area of research. Given the potential risks of drug toxicity in such treatment, the focus is to have a second compound that increases the anticancer potential of the primary agent but which reduces toxicity. There is an ever growing interest in treatment with natural compounds, such as plant phytoestrogens, as an adjuvant cancer therapy along with conventional cancer therapy. The question remains whether or not adding these compounds to the cancer therapy regimen as a second agent would be beneficial, and if they are safe to be used among cancer patients. The current literature suggests that phytoestrogen treatment is capable of inducing G2/M cell cycle arrest in a number of cancer cell lines, as well as upregulating cell cycle inhibitory molecules. Phytoestrogen therapy has been shown to inhibit inflammation, angiogenesis and metastases in various IN VIVO tumor models, and pronounced benefits have been observed when combined with radiation therapy. The lack of side effects from phase I and II clinical trials of phytoestrogens in cancer therapy points towards their safety, but to further understand their added benefit clinical studies with large sample sizes are required. We have reviewed the recent research studies in these areas in an attempt to find evidence for their role in cancer therapy as well as safety.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Chemotherapy, Adjuvant; Humans; Inflammation; Isoflavones; Lignans; Mice; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Phytoestrogens; Randomized Controlled Trials as Topic

NF-kappaB is a ubiquitous and well-characterised protein responsible for the regulation of complex phenomena, with a pivotal role in controlling cell signalling in the body under certain physiological and pathological conditions. Among other functions, NF-kappaB controls the expression of genes encoding the pro-inflammatory cytokines (e. g., IL-1, IL-2, IL-6, TNF-alpha, etc.), chemokines (e. g., IL-8, MIP-1alpha, MCP1, RANTES, eotaxin, etc.), adhesion molecules (e. g., ICAM, VCAM, E-selectin), inducible enzymes (COX-2 and iNOS), growth factors, some of the acute phase proteins, and immune receptors, all of which play critical roles in controlling most inflammatory processes. Since NF-kappaB represents an important and very attractive therapeutic target for drugs to treat many inflammatory diseases, including arthritis, asthma, and the auto-immune diseases, most attention has been paid in the last decade to the identification of compounds that selectively interfere with this pathway. Recently, a great number of plant-derived substances have been evaluated as possible inhibitors of the NF-kappaB pathway. These include a wide range of compound classess, such as lignans (manassantins, (+)-saucernetin, (-)-saucerneol methyl ether), sesquiterpenes (costunolide, parthenolide, celastrol, celaphanol A), diterpenes (excisanin, kamebakaurin), triterpenes (avicin, oleandrin), polyphenols (resveratrol, epigallocatechin gallate, quercetin), etc. In this mini-review we will discuss the medicinal chemistry of these compounds with regards to the NF-kappaB inhibition.

Topics: Acute-Phase Proteins; Anti-Inflammatory Agents; Biological Products; Cell Adhesion Molecules; Cytokines; Diterpenes; Flavonoids; Gene Expression Regulation; Growth Substances; Humans; Inflammation; Lignans; NF-kappa B; Phenols; Polyphenols; Receptors, Immunologic; Sesquiterpenes; Triterpenes

Inflammation is one of the main characteristics of rheumatoid arthritis. Based on the antiinflammatory properties of sesame, this study was conducted to evaluate the sesamin supplement effects on serum levels of some proteolytic enzymes, inflammatory biomarkers, and clinical indices in women with rheumatoid arthritis. In this randomized, triple-blind, placebo-controlled clinical trial, 44 patients were randomly divided in intervention and control groups. Patients received 200-mg/day sesamin supplement or placebo in the intervention and control group for 6 weeks. Serum levels of proteolytic enzymes (hyaluronidase, aggrecanase, and matrix metalloproteinases-3) and inflammatory biomarkers (hs-CRP, IL-1β, IL-6, TNF-α, and cyclooxygenase-2) were measured with enzyme-linked immunosorbent assay method at the beginning and end of the study. After intervention, serum levels of hyaluronidase and matrix metalloproteinases-3 decreased significantly in sesamin group. Also, serum levels of hs-CRP, TNF-α, and cyclooxygenase-2 in intervention group were significantly decreased in intervention group compared with placebo group. Sesamin supplementation also caused a significant reduction in the number of tender joints and severity of pain in these patients. According to the results, it seems that the sesamin by reducing inflammatory mediators can relieve clinical symptoms and pathological changes that caused by inflammatory impairment in patients with rheumatoid arthritis.

Topics: Antioxidants; Arthritis, Rheumatoid; Biomarkers; Dietary Supplements; Dioxoles; Double-Blind Method; Female; Humans; Inflammation; Lignans; Middle Aged; Peptide Hydrolases

Cystic fibrosis (CF) leads to advanced lung disease despite aggressive care. Persistent inflammation and oxidative stress contribute to exacerbations and disease progression. Flaxseed (FS), a dietary botanical supplement with high fiber, lignan phenolics, and omega-3 fatty acids has anti-inflammatory and antioxidant properties in murine models of acute and chronic lung injury. This pilot study was designed to determine whether CF patients could tolerate FS, evaluate circulating FS metabolites, and study biomarkers of lung damage, as a prelude to studying clinical outcomes.. 10 CF patients and 5 healthy volunteers consumed 40 g of FS daily for 4 weeks with safety and tolerability being assessed. Urine was evaluated for systemic oxidative stress and plasma for FS metabolites (enterolignans) and cytokine levels. Buccal swabs were analyzed for gene expression of Nrf2-regulated antioxidant enzymes including Heme Oxygenase-1 (HO-1) and NAD(P)H Quinone Oxidoreductase 1 (NQO1).. All subjects completed the study without serious adverse events. Plasma levels of enterolignans were detectable in both healthy controls and CF volunteers. CF patients were stratified based on plasma enterolignan levels after 2 weeks of FS administration into high- (174 to 535 nM ED and 232 to 1841 nM EL) and low- (0 to 32 nM ED and 0 to 40 nM EL) plasma lignan cohorts. The low enterolignan level cohort experienced a statistically significant drop in urinary inflammatory IsoP and plasma TNFα levels, while demonstrating higher average NQO1 mRNA levels in buccal epithelium compared to high-lignan patients.. This pilot study demonstrated that FS is tolerated by CF patients. FS metabolites could be detected in the plasma. Future studies will assess appropriate dosing and target populations for FS, while exploring clinical outcomes.. ClinicalTrials.gov identifier: NCT02014181 .

Topics: Adolescent; Adult; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Cystic Fibrosis; Dietary Supplements; Fatty Acids, Omega-3; Female; Flax; Heme Oxygenase-1; Humans; Inflammation; Lignans; Lung; Lung Diseases; Male; Mice; Middle Aged; Oxidative Stress; Phenols; Phytotherapy; Pilot Projects; Plant Extracts; Seeds

Plant lignans are metabolised by the colonic micro-flora to the mammalian lignans enterodiol and enterolactone, which are hypothesized to be cardioprotective. The aim of this study was to investigate the effects of a plant lignan complex isolated from flaxseed, providing 500 mg/d of secoisolariciresinol diglucoside, on inflammatory markers.. Healthy postmenopausal women (n=22) completed a randomised double-blind, placebo-controlled crossover study. Women consumed daily a low-fat muffin, with or without a lignan complex, for 6 weeks, separated by a 6-week washout period. A significant difference of approximately 15% (P=0.028) was observed for C-reactive protein (CRP) concentration between the lignan complex intervention period and placebo period. CRP concentrations (median; 25th, 75th percentiles) were 0.88 (0.63, 2.05) mg/L at baseline and 0.92 (0.59, 1.49) mg/L after the lignan complex intervention period compared with 0.80 (0.62, 1.62) mg/L at baseline and 1.10 (0.72, 1.62) mg/L after placebo. No significant differences in interleukin-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 were found between the lignan complex intervention period and placebo period.. Daily consumption for 6 week of a low-fat muffin enriched with a lignan complex may reduce CRP concentrations compared to a low-fat muffin with no lignans added.

Topics: 4-Butyrolactone; Biomarkers; C-Reactive Protein; Cross-Over Studies; Double-Blind Method; Female; Flax; Humans; Inflammation; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Time Factors

Zhi-Zi-Hou-Po decoction (ZZHPD), as a representative traditional Chinese medicine (TCM) formula for the treatment of depression, has frequently triggered hepatorenal toxicity in recent years. However, its toxic effect, material basis, and underlying mechanisms have not been fully elucidated.. To explore the hepatorenal toxicity-material basis-quality markers (Q-markers) and multiple mechanisms of ZZHPD.. ZZHPD-induced rat model of toxicity was evaluated by behavioral indicators, biochemical parameters, and histopathological sections. Then, UHPLC-Q-Exactive Orbitrap-MS combined with multivariate data analysis was utilized to identify the endogenous differential metabolites and the prototype components of ZZHPD in the plasma. A comprehensive strategy integrating in-house library, diagnostic ions, Compound Discover software, and network databases was constructed to identify the chemical constituents of ZZHPD. Additionally, the differentially absorbed components of ZZHPD were screened out based on the spectrum-effect relationship (toxic state and normal state), feature extraction of exogenous components, and variable influence on projection (VIP). Further, Chinmedomics and network pharmacology oriented by differentially absorbed components were performed to predict toxicity-related Q-markers and core targets, as well as relevant pathways. Finally, the binding ability between components and targets was predicted using molecular docking, and the mRNA expression of core target genes was determined by real-time qPCR experiment.. ZZHPD exerted significant hepatotoxicity and nephrotoxicity in rats accompanied by body weight loss, abnormal biochemical indicators, and pathologic characteristics with mild inflammation and cell damage. The results of plasma metabolomics indicated that 22 differential metabolites interfered by ZZHPD mainly involved in primary bile acid biosynthesis, arginine and proline metabolism, phenylalanine metabolism and biosynthesis, sphingolipid metabolism, pyrimidine and purine metabolism. Firstly, 106 chemical substances of ZZHPD were identified, 44 of them were absorbed into the blood, mainly including 7 iridoid glycosides, 15 flavonoids, 5 lignans, and others. Then, the correlation analysis results suggested that 12 of 19 differentially absorbed constituents were highly correlated with 22 differential metabolites and recognized as potential Q-markers. Finally, 9 toxicity-related Q-markers were predicted and confirmed with better binding ability to 5 core targets (PTGS2, CASP3, TNF, PPARG, HMOX1), including 3 flavonoids (naringin, hesperidin, and neohesperidin), 2 iridoid glycosides (geniposide and genipin-1-β-D-gentiobioside), 2 lignans (honokiol and magnolol), organic acid (chlorogenic acid), and crocin (crocetin). The real-time qPCR results showed that the mRNA levels of CASP3, TNF-α, and PPARG significantly increased in the damaged liver. Combining metabolomics and network pharmacology results, the multiple mechanisms of toxicity might involve in oxidative damage, inflammation, and apoptosis pathways.. Taken together, the toxicity-related Q-markers of ZZHPD screened for the first time in this work were reliable, and the holistic intervention for hepatorenal toxicity further revealed the multi-component, multi-target, and multi-pathway features in TCM. The integrated approach provides a novel perspective for the discovery of toxicity/efficacy-related substances and mechanistic studies in TCM.

Topics: Animals; Caspase 3; Drugs, Chinese Herbal; Flavonoids; Inflammation; Iridoid Glycosides; Lignans; Molecular Docking Simulation; Network Pharmacology; PPAR gamma; Rats; Rats, Sprague-Dawley; RNA, Messenger

Schisandrin B (Scheme B) is the most abundant and active lignan monomer isolated from Schisandra chinensis. At present, most reports focus on its cardioprotective and hepatoprotective effects, however, the related reports on gastrointestinal protective effects are still limited. The study aims to evaluate the protective effect of Scheme B on cisplatin-induced rat intestinal crypt epithelial (IEC-6) cell injury and the possible molecular mechanisms. The results showed that Scheme B at 2.5, 5 and 10 μM could inhibit dose-dependently the reduction of cell activity induced by cisplatin exposure at 1 μM, decrease the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) to alleviate oxidative stress injury in IEC-6 cell lines. Meanwhile, Scheme B could relieve cisplatin-induced apoptosis by regulating PI3K/AKT and the downstream caspase signaling pathway. The results from flow cytometry analysis and mitochondrial membrane potential (MMP) staining also demonstrated the anti-apoptosis effect of Scheme B. Furthermore, Scheme B was found to reduce the inflammation associated with cell damage by evaluating the protein expressions of the nuclear factor-kappa B (NF-κB) signaling pathway. Importantly, Wnt/β-catenin, as a functional signaling pathway that drives intestinal self-recovery, was also in part regulated by Scheme B. In conclusion, Scheme B might alleviate cisplatin-induced IEC-6 cell damage by inhibiting oxidative stress, apoptosis, inflammation, and repairing intestinal barrier function. The present research provides a strong evidence that Scheme B may be a useful modulator in cisplatin-induced intestinal toxicity.

Topics: Animals; Cisplatin; Glutathione; Inflammation; Lignans; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Rats; Schisandra

Topics: Animals; Inflammasomes; Inflammation; Lignans; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Neuroinflammatory Diseases; Neuroprotective Agents; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein

Osteoarthritis (OA) is a now regarded as a worldwide whole joint disease with synovial inflammation, cartilage degeneration, and subchondral sclerosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs for OA treatment which only relieve the symptoms and restrain the progression of OA. However, various severe adverse effects often occur in patients with long-term NSAIDs use, which heavily burdens the healthcare system and impacts the quality of life. Therefore, it is much imperative to identify alternative drugs with increased efficacy. Syringaresinol (Syr), a naturally occurring phytochemical which belonging to the lignan group of polyphenols, shows anti-tumor and anti-oxidant activities, which to benefit human health. Studies has shown Syr can regulate the inflammatory response by modulating the secretion and expression level of cytokines IL-6, IL-8, and tumor necrosis factor (TNF)-α. it also shows the inhibitory effect on NF-κB pathway in mouse cells. In the present study, we aimed to demonstrate the anti-inflammatory effects of Syr in OA. In vitro Syr treatment in IL-1β-activated mouse chondrocytes significantly restrained the expression of NO, PGE2, IL-6, TNF-α, INOS, COX-2 and MMP-13. Moreover, it considerably ameliorated the degradation of aggrecan and collagen II. Furthermore, the phosphorylation of the NF-kB signaling pathway was significantly suppressed by Syr. Moreover, in vivo, the cartilage degeneration was attenuated and the increased Osteoarthritis Research Society International (OARSI) scores were reversed in the DMM + Syr group, comprared to those in the DMM group. In sum, our study demonstrated that Syr can attenuate the inflammation in vitro and further verified its effect on OA in vivo. Thus, Syr might be a potent therapeautic alternative for OA treatment.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Chondrocytes; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lignans; Mice; NF-kappa B; Osteoarthritis; Quality of Life

Sesamin, the major lignan in sesame seeds (Sesamum indicum L.), is known to have several pharmaceutical activities. However, its toxicological profile is still limited, especially regarding embryotoxicity. This study aimed to evaluate the developmental toxicity of sesamin in zebrafish embryos. After 72 h exposure, sesamin did not affect the survival and hatching rates, nor did it cause malformation in zebrafish embryos. Cardiotoxicity was also evaluated by monitoring embryo heartbeats and erythrocyte staining using o-dianisidine. The results showed that sesamin did not affect heart morphology, heart rate, or cardiac output in zebrafish embryos. The present study also evaluated sesamin's anti-angiogenesis, antioxidant and anti-inflammation activities. Sesamin significantly decreased the sub-intestinal vessel plexus as revealed by alkaline phosphatase staining indicating the compound exhibited anti-angiogenesis activity. For the antioxidant and anti-inflammatory assays, oxidative stress and inflammation in zebrafish embryos were induced by hydrogen peroxide and lipopolysaccharide, respectively. The reactive oxygen species (ROS) and nitric oxide (NO) production were detected using a fluorescent dye. Sesamin significantly decreased ROS and NO production in zebrafish embryos. In addition, the transcription examination by qRT-PCR of oxidative- and inflammation-related genes showed that sesamin affected the genes in a manner that correlated with results from the efficacy assays. In conclusion, the present study revealed that sesamin did not cause embryotoxicity and cardiotoxicity in zebrafish embryos. In addition, it exhibited evidence of anti-angiogenesis, antioxidant and anti-inflammatory activities.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cardiotoxicity; Embryo, Nonmammalian; Inflammation; Lignans; Oxidative Stress; Reactive Oxygen Species; Zebrafish

Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Inflammation; Lignans; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin

Salicylic acid has been used as an anti-acne agent with its comedolytic property and antimicrobial activity. However, there is a limit to use for leave-on cosmetics because of the transient skin irritation and low efficacy at neutral pH condition. We prepared a salicylic acid-based ionic pair with. After verifying the structure of IP-BHA, we confirmed anti-acne activities including the regulation of exfoliation, lipogenesis, bacterial growth, and inflammation with IP-BHA and/or magnolol.. The antibacterial activity of IP-BHA and magnolol was evaluated by determining the minimum antibacterial inhibitory concentration. Magnolol showed strong activity against Cutibacterium acnes, which was better than a medical antibiotic acne drug, clindamycin. The combined application with IP-BHA was more effective in antibacterial activity by 2.5 times. It was confirmed that testosterone-induced lipogenesis was significantly inhibited by treatment with IP-BHA and magnolol, while single treatment had no significant inhibitory effect. Interestingly, MMP-1 and VEGF were induced by C. acnes lysate in human keratinocytes. We found that these inflammatory molecules were completely inhibited by combined application of IP-BHA and magnolol. Through ex vivo test, the dose-dependent exfoliation effect of IP-BHA was confirmed at pH 5.5, and the synergic exfoliation effect was shown in the combined application of IP-BHA and magnolol. When topically applied, the emulsion containing IP-BHA and magnolol relieved the sodium dodecyl sulfate-induced erythema and improved inflamed acne with papule and pustule.. Our data demonstrate that the ionic paired salicylic acid with

Topics: Acne Vulgaris; Anti-Bacterial Agents; Carnitine; Humans; Inflammation; Lignans; Lipogenesis; Salicylic Acid

Diabetic retinopathy (DR) is the most common microvascular complication in diabetes and the leading cause of vision loss and blindness globally. Due to the unsatisfied outcome of current therapies, a novel strategy needs to be developed. BV2 microglial cells were treated with 25 natural compounds, respectively, stimulated by high glucose (HG) to screen for a potential candidate drug. Streptozotocin (STZ)-induced diabetic mice were injected with different doses of the candidate sesamin every 2 days for 1 mo. Then, its protective role and possible mechanism were evaluated. Sesamin was selected as the candidate drug due to its inhibition on the secretion of tumor necrosis factor-α (TNFα) in the screen assay. Sesamin also dose-dependently inhibited mRNA levels of HG-induced inflammatory cytokines, including TNFα, interleukin (IL)-1β, and IL-6, activated NF-κB signaling pathway, and reduced oxidative stress by decreasing reactive oxygen species levels and increasing antioxidant enzymes in the BV2 and primary retinal microglia. In addition, sesamin alleviated brain-retinal barrier breakdown by Evans blue leakage assay and reduced inflammation in streptozotocin-induced diabetic mice. In conclusion, sesamin effectively inhibits HG-induced microglial inflammation in the retina both in vivo and in vitro, suggesting that sesamin might serve as a candidate drug for DR treatment.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dioxoles; Inflammation; Lignans; Male; Mice; Microglia

Magnolia officinalis constitutes a traditional Korean medicine used for the treatment of atopic dermatitis, and honokiol is an active diphenyl compound present in Magnolia officinalis.. The aim of the study was to investigate the therapeutic effects of honokiol on atopic dermatitis in vivo.. The therapeutic effects of honokiol were evaluated in a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis model.. Administration of honokiol (10 mg/kg) significantly suppressed mast cell accumulation and inflammation induced by DNCB in skin tissues. Moreover, DNCB-induced increases in serum immunoglobulin E levels were reversed by honokiol treatment. In addition, DNCB-induced elevation of inflammatory cytokines (interleukin (IL)-4, IL-13, IL-17, and interferon-γ) in the skin and lymph nodes was significantly ameliorated by honokiol administration. Furthermore, the increase in lymph nodes sizes induced by DNCB treatment was reduced by honokiol administration.. DNCB-induced atopic responses in the ears and lymph nodes were significantly suppressed by honokiol treatment. These results suggested that honokiol is a potential therapeutic agent for atopic dermatitis.

Topics: Animals; Biphenyl Compounds; Cytokines; Dermatitis, Atopic; Dinitrochlorobenzene; Immunoglobulin E; Inflammation; Lignans; Magnolia; Male; Mast Cells; Mice; Mice, Inbred BALB C

Topics: Animals; Apoptosis; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dioxoles; Humans; Inflammation; Interleukin-4; Lignans; Lung; Mice; Mitochondria; Mitophagy; Protein Kinases; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Arctigenin (ATG) is the active ingredient of the Chinese herbal medicine Arctium lappa, with anti-inflammatory and antioxidant effects. Excessive inflammation and cell apoptosis are important causes of intervertebral disc degeneration (IDD). Hence, this study probed into the possible role of ATG in IDD.. Interleukin (IL)-1β (10 ng/ml) was adopted to induce human nucleus pulposus cells (HNPCs) as a cell model for IDD. The effects of different concentrations of ATG (0, 2, 5, 10, 20, 50 μmol/L) on the viability of HNPCs and effects of ATG (10, 50 μmol/L) on the viability of IL-1β-induced HNPCs were detected by cell counting kit-8 (CCK-8). After IL-1β-induced HNPCs were transfected with miR-483-3p inhibitor and/or treated with ATG, cell viability and apoptosis were determined by CCK-8 and flow cytometry; the expressions of miR-483-3p, extracellular matrix (ECM)-related genes, and inflammation-related genes were measured by quantitative real time polymerase chain reaction (qRT-PCR), and expressions of ECM/apoptosis/NF-κB pathway-related proteins were quantified by Western blot.. ATG had no significant effect on the viability of HNPCs but could promote the viability of IL-1β-induced HNPCs. ATG inhibited apoptosis, ECM degradation, inflammation, and activation of NF-κB pathway in HNPCs induced by IL-1β, but promoted the expression of miR-483-3p. MiR-483-3p inhibitor reversed the above-mentioned regulatory effects of ATG.. Arctigenin suppresses apoptosis, ECM degradation, inflammation, and NF-κB pathway activation in HNPCs by up-regulating miR-483-3p.

Topics: Apoptosis; Cells, Cultured; Extracellular Matrix; Extracellular Matrix Proteins; Furans; Humans; Inflammation; Intervertebral Disc Degeneration; Lignans; MicroRNAs; NF-kappa B; Nucleus Pulposus

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.. 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.. 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.. 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.. 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.

Topics: Animals; Caco-2 Cells; Caenorhabditis elegans; Cyclooctanes; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Lignans; Mice; Myosin-Light-Chain Kinase; Organoids; Permeability; Polycyclic Compounds; Tight Junction Proteins; Tight Junctions

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

Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50 mg/kg per day, i.g.) for 28 days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Abeta (Aβ) generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases.

Topics: Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Arctium; Aspartic Acid Endopeptidases; Cognitive Dysfunction; Furans; Inflammation; Lignans; Lipopolysaccharides; Memory Disorders; Mice; Microglia; Neuroinflammatory Diseases; NF-kappa B; Toll-Like Receptor 4

Lung damage can be caused by fine particulate matter (PM

Topics: Animals; Apoptosis; Autophagy; Dioxoles; Inflammation; Lignans; Lung; Lung Injury; Oxidative Stress; Particulate Matter; Rats; Rats, Sprague-Dawley

Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Chemokine CCL2; Colitis; Cytochrome P-450 CYP2E1; Dioxoles; Endotoxins; Ethanol; Furans; Heme Oxygenase-1; Inflammation; Interleukin-6; Lignans; Malondialdehyde; Mice; Nitric Oxide Synthase Type II; Oxidative Stress; Tight Junction Proteins; Tumor Necrosis Factor-alpha

Non-alcoholic fatty liver disease (NAFLD) is intricately linked to dysregulation of the gut-liver axis, and correlated with intestinal inflammation and barrier disruption.. To investigate the protective effects and possible molecular mechanism of Schisantherin A (Sin A) in a high-fat diet (HFD) induced NAFLD mouse model.. HFD-fed NAFLD mice were treated with the vehicle and 80 mg/kg Sin A every day for 6 weeks. The gut permeability of the NAFLD mice was assessed by intestinal permeability assays. We found that Sin A potently ameliorated HFD-induced hepatic steatosis and inflammation, alleviated gut inflammation, and restored intestinal barrier function. We also observed that Sin A improved gut permeability and reduced the release of lipopolysaccharide (LPS) into circulation and further found that Sin A can suppress LPS-TLR4 signaling to protect against HFD-induced NAFLD. Sin A treatment altered the composition of the microbiome in NAFLD mice compared to vehicle controls.. Sin A is an effective and safe hepatoprotective agent against HFD-induced NAFLD by partly ameliorating gut inflammation, restoring intestinal barrier function, and regulating intestinal microbiota composition.

Topics: Animals; Anti-Bacterial Agents; Cyclooctanes; Dioxoles; Inflammation; Lignans; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; RNA, Ribosomal, 16S; Toll-Like Receptor 4

Lignans are known to exhibit a broad spectrum of biological activities, indicating their potential as constituents of feed supplements. This study investigated two extracts derived from the feed supplements '

Topics: Animal Feed; Animals; Anti-Inflammatory Agents; Antioxidants; Caco-2 Cells; Dietary Supplements; Drosophila melanogaster; Glutathione; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Lignans; Plant Extracts; Reactive Oxygen Species; Superoxide Dismutase; Swine; Tannins; Tumor Necrosis Factor-alpha; Wood

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

Arctigenin, derived from Arctium lappa L., has multiple pharmacological activities, including immunoregulatory, anti-diabetic, anti-tumor, and neuroprotective effects. Nevertheless, the potential therapeutic target of arctigenin in modulating inflammation remains undefined.. In the present study, we identified that arctigenin was a phosphodiesterase-4 (PDE4) selective inhibitor for the first time. Further investigations were performed to fully uncover the effects and mechanism of arctigenin on experimental murine psoriasis model.. Crystal structure determination, PDEs enzyme assay, and isothermal titration calorimetry were included to illustrate the binding specialty, inhibitory effects, and selectivity of arctigenin on PDE4D. The anti-inflammatory effects were conducted in LPS-activated human peripheral blood mononuclear cells (PBMCs) and RAW264.7 cells. Imiquimod-induced murine psoriasis was performed to uncover the therapeutic effects and mechanism of arctigenin. Arctigenin could bind to the catalytic domain of PDE4D via formation of hydrogen bonds as well as π-π stacking interactions between the dibenzyl butyrolactone of arctigenin and several residues of PDE4D. Accordingly, arctigenin showed prominent anti-inflammation in human PBMCs and murine RAW264.7 cells. PDE4 inhibition by arctigenin resulted in elevation of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylation of cAMP-response element binding protein (CREB), which were largely blocked through intervention of protein kinase A (PKA) activity by H89 treatment or reduction of protein expression by siRNA transfection. Moreover, we first identified that a topical application of arctigenin ameliorated experimental psoriatic manifestations in imiquimod-induced murine psoriasis model by decreasing adhesion and chemotaxis of several inflammatory cells. Further proteomics analysis revealed that arctigenin could rectify the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, which might be largely related to the expression of Keratins.. The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Furans; Humans; Inflammation; Leukocytes, Mononuclear; Lignans; Mice

Psoriasis, a chronic inflammatory skin disease, is characterized by the excessive proliferation and impaired differentiation of epidermal keratinocytes and is accompanied by the increased infiltration of inflammatory cells. The condition requires long‑term treatment and has no definitive cure. Hence, supplements and therapeutic agents have been intensely investigated. Gomisin M2 (GM2), a lignan extracted from

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Female; Humans; Imiquimod; Inflammation; Interferon-gamma; Keratinocytes; Lignans; Mice, Inbred C57BL; NF-kappa B; Psoriasis; Signal Transduction; STAT1 Transcription Factor; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha

Neolignans honokiol and 4'-

Topics: Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Fluorine Radioisotopes; Hydrocarbons, Fluorinated; Inflammation; Lignans; Male; Mice; Mice, Inbred C57BL; Radiopharmaceuticals

The mortality of sepsis-induced cardiac dysfunction (SICD) is very high due to the complex pathophysiological mechanism. Syringaresinol (SYR) is a natural abstract which possesses anti-inflammatory property. The present study aims was to identify the protective impact of SYR on sepsis-induced cardiac dysfunction and investigate the specific mechanisms. We found that SYR improved the cardiac function and alleviated myocardial injury in mice that subjected to cecal ligation and puncture, in addition, SIRT1 expression was significantly elevated after SYR treatment compared to sepsis group both in vivo and in vitro, along with suppression of NLRP3 activation and proinflammatory cytokines release. However, SIRT1 inhibitor EX427 abolished the impact of SYR on LPS-induced pyroptosis in cardiomyocytes. Furthermore, molecular docking analysis predicted that there is high affinity between SYR and estrogen receptor (ER), ER inhibitor ICI182780, the specific ERβ inhibitor PHTP and the specific ERαinhibitor AZD9496 were used to examine the role of ER in the protective effect of SYR against SICD, and the results suggested that ER activation was essential for the cardioprotective function of SYR. In conclusion, SYR ameliorates SICD via the ER/SIRT1/NLRP3/GSDMD pathway.

Topics: Animals; Cardiotonic Agents; Cinnamates; Disease Models, Animal; Fulvestrant; Furans; Heart; Heart Diseases; Humans; Indoles; Inflammation; Lignans; Male; Mice; Molecular Docking Simulation; Myocardium; Pyroptosis; Receptors, Estrogen; Sepsis; Sirtuin 1

Honokiol and magnolol are natural components isolated from Magnolia bark that is used in traditional Chinese and Japanese herbal medicine. These two isomers are used as a component of dietary supplements and cosmetic products. In this study, we investigated the antimicrobial effect of honokiol and magnolol on pathogens causing oral diseases, their mechanism of action in biofilm formation and drug resistance of oral pathogens, and inflammatory regulation in mammalian cells.. We determined the minimum inhibitory concentration and minimum bactericidal concentration of honokiol and magnolol, and their stability at different temperatures and pH. We also evaluated their effect on biofilm formation, antibiotic-resistance gene expression in MRSA, and pro-inflammatory gene expression in mammalian cells.. Honokiol showed better antimicrobial activity than magnolol. Both honokiol and magnolol showed stable bacterial inhibitory activity over a wide range of temperature and pH, reduced biofilm formation, and antibiotic resistance in oral pathogens. The biofilm formation- and antibiotic resistance-related gene expression was consistent with the respective phenotypes. Furthermore, these two isomers repressed the expression of pro-inflammatory genes in RAW264.7 cells.. Our study provides evidence of the potential application of honokiol and magnolol in dental medicine to cure or prevent oral diseases.

Topics: Animals; Anti-Bacterial Agents; Biphenyl Compounds; Humans; Inflammation; Lignans; Macrophages

Neuroinflammation and loss of neurotrophic support have key roles in the pathophysiology of diabetes-associated behavioral deficits (DABD). Sesamin (Ses), a major lignan of sesame seed and its oil, shows anti-hyperglycemic, anti-oxidative, and neuroprotective effects. The present study was designed to assess the potential protective effects of Ses against DABD and investigate the roles of inflammatory markers and neurotrophic factors in streptozotocin (STZ)-induced diabetic rats. After confirmation of diabetes, Ses (30 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) was administered to rats for eight consecutive weeks. During the eighth-week period of the study, behavioral functions of the animals were evaluated by employing standard behavioral paradigms. Moreover, inflammation status, neurotrophic factors, and histological changes were assessed in the cerebral cortex and hippocampal regions of the rats. The results of behavioral tests showed that STZ-induced diabetes increased anxiety-/depression-like behaviors, decreased locomotor/exploratory activities, and impaired passive avoidance learning and memory. These DABD were accompanied by neuroinflammation, lack of neurotrophic support, and neuronal loss in both cerebral cortex and hippocampus of the rats. Intriguingly, chronic treatment with Ses improved all the above-mentioned diabetes-related behavioral, biochemical, and histological deficits, and in some cases, it was even more effective than insulin therapy. In conclusion, the results suggest that Ses was capable of improving DABD, which might be ascribed, at least partly, to the reduction of blood glucose level, inhibition of neuroinflammation, and potentiation of neurotrophic factors.

Topics: Animals; Antioxidants; Anxiety; Cerebral Cortex; Depression; Diabetes Mellitus, Experimental; Dioxoles; Disease Models, Animal; Hippocampus; Inflammation; Lignans; Male; Maze Learning; Memory Disorders; Nerve Growth Factors; Neuroprotective Agents; Rats

For Alzheimer's disease (AD), there is still no effective treatment strategy. Pinoresinol diglucoside (PDG) is one of the major lignans isolated from Eucommia ulmoides. It is endowed with multiple pharmacological activities, including anti-inflammatory, antioxidant and anticancer activities. In this study, we investigated the potential neuroprotective functions of PDG in AD. Mice model with AD was established adopting stereotactic hippocampal injection of Aβ1-42 (410 pmol/mouse), and 3 days later, mice were administrated with 5 and 10 mg/kg PDG by intragastric administration every day for 3 weeks. Morris water maze and Y-maze tests demonstrated that PDG treatment could markedly reverse Aβ1-42-induced memory impairment in mice. It is found that PDG restrained the release of proinflammatory cytokines (tumor necrosis factor α and interleukin 1β), reactive oxygen species and malondialdehyde, and promoted the activity of the antioxidant enzyme (superoxide dismutase and catalase) by quantitative real-time-PCR, colorimetric method and ELISA assay. Western blot assay results have shown that PDG could also upregulate the ratio of Bcl-2/Bax and downregulate cytochrome c and cleaved caspase-3 expressions, thereby inhibiting neuronal apoptosis. Furthermore, PDG also significantly reduced the expression of Toll-like receptor 4 (TLR4) and the activation of nuclear factor-κB (NF-κB) p65, and promoted nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expressions. In conclusion, PDG can attenuate neuroinflammation, neuronal apoptosis and oxidative stress through the TLR4/NF-κB and Nrf2/HO-1 pathways, and ameliorate memory dysfunction induced by Aβ1-42 in mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Catalase; Disease Models, Animal; Hippocampus; Inflammation; Injections; Interleukin-1beta; Lignans; Malondialdehyde; Mice; Morris Water Maze Test; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Stereotaxic Techniques; Superoxide Dismutase; Toll-Like Receptor 4; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Periodontal disease and diabetes mellitus (DM) are both chronic inflammatory and highly prevalent diseases. A large amount of evidence suggested that the accumulation of oxidative stress plays a significant role in the deterioration of both diseases. Magnolol has been known to possess anti-inflammatory and anti-oxidant activities in various tissues, but its effects on gingival cells under diabetic conditions have not been fully understood.. We assessed the generation of reactive oxygen species (ROS), Transwell migration, and wound healing ability in response to the advanced glycation end products (AGEs) stimulation with or without Magnolol treatment. Subsequently, we examined the expression of Nrf2 and HO-1 to ascertain whether Magnolol was able to activate the anti-oxidant signaling. We also measured the secretion of IL-6 and IL-8, and conducted a knockdown experiment to elucidate the effect of Mrf2 on their secretion.. The AGEs-induced ROS was dose-dependently downregulated following the Magnolol treatment. Likewise, the reduced Transwell migration and wound healing ability were improved by various concentrations of Magnolol. Results from qRT-PCR indicated that the suppression of Nrf2 and HO-1 following AGEs stimulation was reversed by Magnolol. Also, the AGEs-elicited production of IL-6 and IL-8 was inhibited by Magnolol. Moreover, our results demonstrated that this anti-inflammatory effect was mediated by the upregulation of Nrf2.. These findings showed that excessive AGEs in the gingiva may lead to the accumulation of ROS and pro-inflammatory cytokines. Supplement of Magnolol may be beneficial to improve the impaired wound healing and inflammation by upregulation of Nrf2 signaling for DM patients with periodontal disease.

Topics: Biphenyl Compounds; Diabetes Mellitus; Glycation End Products, Advanced; Humans; Inflammation; Lignans; Oxidative Stress; Periodontitis; Reactive Oxygen Species

Pinoresinol diglucoside (PDG), the active compound extracted from Eucommia ulmoides, Styrax sp. and Forsythia suspensa, plays the roles in regulating hypertension, inflammation and oxidative stress.. Considering that hypertension and inflammation has been proved to contribute to cardiac remodeling, we tested the effects of PDG on cardiac hypertrophy (CM).. Male Sprague Dawley (SD) rats were used to construct hypertrophic rats by partial abdominal aortic constriction (AAC)-surgery. PDG solution (2 mg/ml) was used to treat AAC-induced rats by intraperitoneal injection at low dose (L-PDG, 2.5 mg/kg per day), medium dose (M-PDG, 5 mg/kg per day), and high dose (H-PDG, 7.5 mg/kg per day) for 3 weeks post AAC-surgery. CM was evaluated by the ratio of left ventricular weight to body weight ratio (LVW/BW), left ventricular wall thickness by H&E staining, and collagen content deposit by Masson's staining. Further, isoproterenol (ISO) and phenylephrine (PE) were used to produce cellular models of CM in neonatal rat ventricular cardiomyocytes (NRVMs). PDG pre-treated NRVMs 2 h at low dose (L-PDG, 2.5 μg/ml), medium dose (M-PDG, 5 μg/ml), and high dose (H-PDG, 7.5 μg/ml) for 24 h with or without PE- and ISO-stimulation. CM was evaluated by the expressions of hypertrophic biomarkers. Next, the hypertrophic biomarkers and pro-inflammatory cytokines were measured using quantitative real-time PCR (qRT-PCR), the expressions of protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/transcription factor nuclear factor-kappa B (NF-kB) signaling pathway were determined by Western blotting.. PDG treatment prevented cardiac histomorphology damages, decreased upregulations of hypertrophic biomarkers, and prevented fibrosis and inflammation after pressure overload resulting from AAC-surgery. Consistently, PDG remarkably inhibited the changes of cardiomyocyte hypertrophic biomarkers and inflammatory responses in cellular models of CM. Interestingly, PDG administration inhibited the activation of AKT/mTOR/NF-kB signaling pathway both in vivo and in vitro.. PDG prevents AAC-induced CM in vivo, PE- and ISO-induced CM in vitro. The AKT/mTOR/NF-kB signaling pathway could be the potential therapeutic target involved in the protection of PDG. These findings provide novel evidence that PDG might be a promising therapeutic strategy for CM.

Topics: Animals; Animals, Newborn; Aorta, Abdominal; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Fibrosis; Inflammation; Isoproterenol; Lignans; Male; Myocytes, Cardiac; NF-kappa B; Phenylephrine; Pressure; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Remodeling

Emerging evidence indicates the important role of herbal medicine for neuroinflammation, which is closely associated with neurodegenerative diseases.. To clarify the characteristics and primary mechanisms of action of the traditional herbal medicine Daphne kiusiana var. atrocaulis (Rehd.) F. Maekawa in neuroinflammation by phytochemistry and bioassays using both in vitro and in vivo assays.. The chemical composition of D. kiusiana var. atrocaulis was clarified using multiple chromatography technologies and spectroscopic analysis. The anti-neuroinflammatory effects of the identified components were evaluated in LPS-induced BV-2 cells by monitoring the production of nitric oxide. C57BL/6 mice were used to construct a neuroinflammatory model by injecting LPS into the lateral ventricle of the brain. The most promising component was evaluated in vivo by measuring the number of Iba-1 cells and expression of inflammatory factors. Furthermore, the anti-neuroinflammatory mechanism involved in the activation of the NF-κB pathway was investigated using western blot and immunofluorescence.. Thirty-two constituents (1-32), including five new compounds, were successfully identified from D. kiusiana var. atrocaulis. Compounds 3, 5, 12-15, and 20 (IC. We found that D. kiusiana var. atrocaulis had an inhibitory activity on neuroinflammation. In addition, the main active component (-)-acutissimalignan B (13) showed anti-neuroinflammatory effects in both in vivo and in vitro assays. Its mechanism of action may be associated with the inhibition of the NF-κB signaling pathway. Our current findings provide new information on D. kiusiana var. atrocaulis in the treatment of neuroinflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Daphne; Drug Evaluation, Preclinical; Inflammation; Lignans; Lipopolysaccharides; Male; Mice, Inbred C57BL; Microglia; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type II; Plant Preparations; Signal Transduction

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

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Chorioallantoic Membrane; Disease Models, Animal; Drug Discovery; Electroretinography; Eye Diseases; Inflammation; Intraocular Pressure; Intravitreal Injections; Lignans; Male; Rats; Rats, Wistar; Retinal Pigment Epithelium; Safety; Treatment Outcome; Uveitis

Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. The daily phagocytosis of the photoreceptor outer segment tips by the overlaying RPE provides essential nutrients for the RPE itself and photoreceptors through intricate metabolic synergy. Age-related retinal changes are often characterized by metabolic dysregulation contributing to increased lipid accumulation and peroxidation as well as the release of proinflammatory cytokines. LGM2605 is a synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant and anti-inflammatory properties demonstrated in diverse in vitro and in vivo inflammatory disease models. In these studies, we tested the hypothesis that LGM2605 may be an attractive small-scale therapeutic that protects RPE against inflammation and restores its metabolic capacity under lipid overload. Using an in vitro model in which loss of the autophagy protein, LC3B, results in defective phagosome degradation and metabolic dysregulation, we show that lipid overload results in increased gasdermin cleavage, IL-1 β release, lipid accumulation and decreased oxidative capacity. The addition of LGM2605 resulted in enhanced mitochondrial capacity, decreased lipid accumulation and amelioration of IL-1 β release in a model of defective lipid homeostasis. Collectively, these studies suggest that lipid overload decreases mitochondrial function and increases the inflammatory response, with LGM2605 acting as a protective agent.

Topics: Antioxidants; Autophagy; Butylene Glycols; Cell Line; Cytokines; Gene Expression; Glucosides; Humans; Inflammation; Lignans; Lipid Metabolism; Lipids; Mitochondria; Oxidation-Reduction; Oxidative Stress; Phagocytosis; Phagosomes; Retinal Pigment Epithelium; Retinal Pigments

The RNA-binding protein tristetraprolin (TTP) is an anti-inflammatory factor that prompts the mRNA decay of target mRNAs and is involved in inflammatory diseases such as rheumatoid arthritis (RA). TTP is regulated by phosphorylation, and protein phosphatase 2A (PP2A) can dephosphorylate TTP to activate its mRNA-degrading function. Some small molecules can enhance PP2A activation. Short interfering RNA (siRNA) targeting TTP expression or PP2A agonist (Arctigenin) was administered to monosodium urate (MSU) crystal-induced J774A.1 cells, and the expression of inflammatory related genes was detected by RT-PCR and Western blot assays. The effects of Arctigenin in mouse models of acute inflammation induced by MSU crystals, including peritonitis and arthritis, were evaluated. The data indicated that TTP expression levels and endogenous PP2A activity were increased in MSU-crystal treated J774A.1 cells. TTP knockdown exacerbated inflammation-related genes expression and NLRP3 inflammasome activation. However, PP2A agonist treatment (Arctigenin) suppressed MSU crystal-induced inflammation in J774A.1 cells. Arctigenin also relieved mitochondrial reactive oxygen species (mtROS) production and improved lysosomal membrane permeability in MSU crystal-treated J774A.1 cells. Moreover, TTP knockdown reversed the anti-inflammatory and antioxidant effects of Arctigenin. Oral administration of Arctigenin significantly alleviated foot pad swelling, the number of inflammatory cells in peritoneal lavage fluids and the production of IL-1β in the mouse model of inflammation induced by MSU crystals. Collectively, these data imply that targeting TTP expression or functional activity may provide a potential therapeutic strategy for inflammation caused by MSU crystals.

Topics: Animals; Anti-Inflammatory Agents; Autophagy; Caspase 1; Cell Culture Techniques; Cytokines; Furans; Inflammation; Lignans; Lysosomes; Mice; Mice, Inbred C57BL; Mitochondria; Protein Phosphatase 2; Reactive Oxygen Species; RNA, Small Interfering; Tristetraprolin; Uric Acid

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms.. Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-β)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed.. Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-β/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-β/SMAD/MAPK signaling pathways.. The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-β/SMAD/MAPK signaling pathways.

Topics: Actins; Animals; Biphenyl Compounds; Concanavalin A; Hydroxyproline; Inflammation; Lignans; Liver Cirrhosis; Male; Mitogen-Activated Protein Kinases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Survival Analysis; Transforming Growth Factor beta

In this study, we screened potential natural compounds for the treatment of myocardial infarction (MI) and explored the underlying mechanisms. We built three machine learning models to screen the potential compounds. qPCR, flow cytometry, immunohistochemistry, and immunofluorescence analyses were applied to analyze the pharmacological effects of the compounds on macrophages/monocytes in vivo and in vitro. Arctigenin (AG) was selected as a candidate, and echocardiography, Masson's trichrome staining, and TUNEL staining were utilized to detect the effect of AG on MI in vivo. Transcriptome analysis and subsequent bioinformatics analyses were performed to predict the target of the selected compound. Western blot and luciferase reporter assays were used to confirm the target and mechanism of AG. The reversibility of the effects of AG were verified through overexpression of NFAT5. The results showed that AG can improve cardiac injury after MI by reducing infarct size, improving heart function, and inhibiting cardiac death. In addition, AG suppresses inflammatory macrophages/monocytes and proinflammatory cytokines in vivo and in vitro. Transcriptomic and biological experiments revealed that AG modulates macrophage polarization via the NFAT5-induced signaling pathway. Therefore, our data suggest that AG can improve MI by inhibiting the inflammatory phenotype of macrophages/monocytes through targeting of NFAT5.

Topics: Animals; Furans; Heart; Inflammation; Lignans; Macrophages; Male; Mice; Mice, Inbred C57BL; Monocytes; Myocardial Infarction; Myocardium; RAW 264.7 Cells; Signal Transduction; Transcription Factors

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway.

Topics: Animals; Biphenyl Compounds; Cell Line; Disease Models, Animal; Fibrosis; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Kidney Diseases; Lignans; Mice; Mitochondrial Dynamics; NF-kappa B; Signal Transduction; Sirtuin 3; Smad Proteins; Transforming Growth Factor beta1

This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Apolipoproteins E; Biphenyl Compounds; Caenorhabditis elegans; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Lignans; Microglia; NF-kappa B; Phagocytosis; PPAR gamma

Avian pathogenic Escherichia coli (APEC) is a kind of highly pathogenic parenteral bacteria, which adheres to chicken type II pneumocytes through pili, causing inflammatory damage of chicken type II pneumocytes. Without affecting the growth of bacteria, anti-adhesion to achieve anti-inflammatory effect is considered to be a new method for the treatment of multi-drug-resistant bacterial infections. In this study, the anti-APEC activity of schizandrin was studied in vitro. By establishing the model of chicken type II pneumocytes infected with APEC-O78, the adhesion number, the expression of virulence genes, the release of lactate dehydrogenase (LDH), levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were detected. The results showed that schizandrin reduced the release of LDH and the adherence of APEC on chicken type II pneumocytes. Moreover, schizandrin markedly decreased the levels of IL-1β, IL-8, IL-6, and TNF-α, the mechanism responsible for these effects was attributed to the inhibitory effect of schizandrin on NF-κB and MAPK signaling activation. In conclusion, our findings revealed that schizandrin could reduce the inflammatory injury of chicken type II pneumocytes by reducing the adhesion of APEC-O78 to chicken type II pneumocytes. The results indicate that schizandrin can be a potential agent to treat inflammation caused by avian colibacillosis.

Topics: Alveolar Epithelial Cells; Animals; Anti-Inflammatory Agents; Bacterial Adhesion; Cells, Cultured; Chickens; Cyclooctanes; Cytokines; Escherichia coli; Escherichia coli Infections; Extracellular Signal-Regulated MAP Kinases; Inflammation; Inflammation Mediators; L-Lactate Dehydrogenase; Lignans; NF-kappa B; Polycyclic Compounds; Poultry Diseases; Signal Transduction

Schisandrin A (Sch A) is a lignin extracted from the fruit of Schisandra chinensis, which has potential anti-inflammatory properties and is used for treating various inflammatory diseases. In this study, we aimed to evaluate the anti-inflammatory effects of Sch A and the underlying mechanisms in animal models of acute inflammation. First, the anti-inflammatory effects of Sch A were evaluated preliminarily in an animal model of xylene-induced ear edema. Sch A pretreatment significantly decreased the degree of edema and inhibited telangiectasia in the ear. Second, a mouse model of paw edema was used to investigate the anti-inflammatory effects and mechanisms of Sch A. Pretreatment with Sch A significantly inhibited carrageenan-induced paw edema in mice. Hematoxylin-eosin (HE) staining of paw tissues demonstrated that Sch A inhibited the infiltration of inflammatory cells in the mouse model of paw edema. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of inflammatory factors decreased. The western blot and immunohistochemical assay results revealed that the toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-κB) pathway could play a role in the anti-inflammatory functions of Sch A. The findings demonstrated that Sch A exerts anti-inflammatory effects and may provide possible strategies for the treatment of inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooctanes; Disease Models, Animal; Edema; Inflammation; Inflammation Mediators; Lignans; Male; Mice; NF-kappa B; Polycyclic Compounds; Signal Transduction; Toll-Like Receptor 4; Xylenes

Osteoarthritis (OA), which is principally featured by progressive joint metabolic imbalance and subsequent degeneration of articular cartilage, is a common chronic joint disease. Arctigenin (ATG), a dietary phyto-oestrogen, has been described to have potent anti-inflammatory effects. Nevertheless, its protective effects on OA have not been clearly established. The target of our following study is to evaluate the protective effects of ATG on IL-1β-induced human OA chondrocytes and mouse OA model. Our results revealed that the ATG pre-treatment effectively decreases the level of pro-inflammatory mediators, such as prostaglandin E2 (PGE2), nitrous oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-6 and tumour necrosis factor alpha (TNF-α) in IL-1β-induced human chondrocytes. In addition, ATG protects against the degradation of extracellular matrix (ECM) under the stimulation of IL-1β and the possible mechanism might be connected with the inactivation of phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor-kappa B (NF-κB) axis. Furthermore, a powerful binding capacity between ATG and PI3K was also uncovered in our molecular docking research. Meanwhile, ATG may act as a protector on the mouse OA model. Collectively, all these findings suggest that ATG could be utilized as a promising therapeutic agent for the treatment of OA.

Topics: Animals; Cartilage, Articular; Chondrocytes; Dinoprostone; Disease Models, Animal; Disease Progression; Furans; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lignans; Mice; Molecular Docking Simulation; NF-kappa B; Nitric Oxide Synthase Type II; Nitrous Oxide; Osteoarthritis; Phosphatidylinositol 3-Kinases; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Signal Transduction

Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens elderly health. Schisandrin (SCH) and nootkatone (NKT) are two core components derived from Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP), a traditional Chinese medicine formulation. Previous studies demonstrated that the combination of NKT and SCH exerted a neuroprotective effect in AD mouse models. The present study was undertaken to investigate whether there was a synergistic effect between NKT and SCH and the possible mechanism in Aβ1-42 induced PC12 cells. SCH (50 μM) and NKT (10 μM) had the most notable inhibitory effect on the level of Aβ secreted by cells. Treatment with NKT + SCH activated the PI3K/AKT/Gsk-3β/mTOR pathway. Inflammation related proteins such as NF-κB, IKK, IL-1β, IL-6 and TNF-α were decreased. The levels of cleaved-Caspase3 and LC3-II were reduced, indicating that apoptosis and autophagy were inhibited. These results revealed that NKT + SCH exerted a neuroprotective effect via the PI3K/AKT pathway, inhibiting inflammation, apoptosis and autophagy.

Topics: Alzheimer Disease; Animals; Apoptosis; Autophagy; Cyclooctanes; Disease Models, Animal; Drug Synergism; Inflammation; Lignans; Mice; Neuroprotective Agents; PC12 Cells; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Polycyclic Sesquiterpenes; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; tau Proteins

Ischemia-reperfusion injury (IRI) refers to tissue damage that occurs when blood supply returns to tissue after a period of ischemia, anoxia or hypoxia. It occurs frequently during shock, organ transplantation and heart failure. It can cause impairment or even renal failure. Macelignan is a lignin isolated from the seeds of Myristica fragrans. It has been reported to inhibit neuroinflammation and oxidative toxicity. The preventive or therapeutic effects of macelignan on renal IRI has not been reported. The present study investigated the effects of macelignan on renal IRI in rats, and the underlying mechanism(s). Healthy adult male Sprague Dawley rats (n = 50) aged 7 - 9 weeks (mean weight = 220 ± 20 g) were used in this study. The rats were randomly assigned to five groups of 10 rats each: sham   treated group, IRI group and 40 mg macelignan/kg body weight (bwt) group, 80 mg macelignan/kg bwt group, and 160 mg macelignan/kg bwt group. Ischemia-reperfusion injury was induced in the rats using standard procedure. The results showed that serum levels of creatinine, blood urea nitrogen (BUN), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and gamma interferon (IFN-γ) were significantly higher in IRI group than in sham treated group, but were significantly and dose-dependently reduced after treatment with macelignan (p < 0.05). The activities of catalase and superoxide dismutase (SOD), and reduced glutathione (GSH) level were significantly reduced in IRI group, when compared with sham treated group, but were significantly and dose-dependently increased after treatment with macelignan (p < 0.05). However, the level of malondialdehyde (MDA) was significantly higher in IRI group than in sham treated group, but treatment with macelignan reduced it significantly and dose-dependently (p < 0.05). Macelignan also significantly and dose-dependently inhibited IRI-induced apoptosis in epithelial cells of renal tubules (p < 0.05). The results of Western blotting showed that IRI significantly upregulated the expressions of bax and caspase-3, and down-regulated the expression of bcl-2 in epithelial cells of renal tubules (p < 0.05). However, treatment with macelignan significantly and dose-dependently down-regulated the expressions of bax and caspase-3 in these cells, but significantly and dose-dependently upregulated the expression of bcl-2. These results show that macelignan confers protection on renal IRI via mechanisms involving inhibition of infla

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Blood Urea Nitrogen; Caspase 3; Catalase; Creatinine; Epithelial Cells; Glutathione; Inflammation; Interferon-gamma; Interleukin-6; Kidney; Lignans; Male; Malondialdehyde; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Topics: Animals; Atherosclerosis; Biphenyl Compounds; Carotid Arteries; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Inflammation; Lignans; Male; Mice; Oxidative Stress; Plaque, Atherosclerotic; Signal Transduction

Ultraviolet (UV) irradiation induces detrimental changes in human skin which result in photoaging. UV-induced intracellular changes cause degradation of extracellular matrix (ECM). UV-stimulated cleavage of collagen in ECM occurs via matrix metalloproteinases (MMPs). (±)-syringaresinol (SYR), a phytochemical which belongs to the lignan group of polyphenols, was investigated for its ability to reverse the UVA-induced changes in human HaCaT keratinocytes and dermal fibroblasts (HDFs) in vitro. Effect of SYR on UVA-induced changes was investigated by production and activation of MMPs and its transcriptional upstream effectors; mitogen-activated protein kinases (MAPKs) and pro-inflammatory mediators. Levels of expression were determined using ELISA, RT-PCR and immunoblotting. UVA irradiation stimulated the production of MMP-1 and inhibited collagen production. SYR treatment suppressed MMP-1 and enhanced collagen production in UVA-irradiated HaCaT keratinocytes and HDFs. SYR repressed the UV-induced phosphorylation of p38, ERK and JNK MAPKs in HaCaT keratinocytes while only suppressing JNK phosphorylation in HDFs. In addition, SYR was able to inhibit UVA-induced production of inflammatory cytokines; TNF-α, COX-2, IL-1β and IL-6. Moreover, SYR suppressed the activator protein-1 (AP-1), a heterodimer of phosphorylated transcription factors c-Jun and c-Fos. SYR-treatment decreased nuclear levels of activated c-Fos and c-Jun as a mechanism to inhibit UVA-induced transcriptional activities leading to MMP-1 production. In conclusion, current results demonstrated that SYR could inhibit UVA-induced upregulation of MMP-1 by suppressing MAPK/AP-1 signaling in HaCaT keratinocytes and HDFs. Therefore, SYR was suggested as a potential compound with antiphotoaging properties against UVA-induced skin aging.

Topics: Collagen; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Furans; HaCaT Cells; Humans; Inflammation; Keratinocytes; Lignans; MAP Kinase Signaling System; Matrix Metalloproteinase 1; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Skin; Skin Aging; Transcription Factor AP-1; Ultraviolet Rays

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cytokines; Dinoprostone; Extracellular Signal-Regulated MAP Kinases; Inflammation; Inflammation Mediators; Janus Kinases; JNK Mitogen-Activated Protein Kinases; Lignans; Lipopolysaccharides; Macrophages; Mice; NF-kappa B p50 Subunit; Nitric Oxide; Nitric Oxide Synthase Type II; Patrinia; RAW 264.7 Cells; Signal Transduction; STAT Transcription Factors; Transcription Factor AP-1

Tubulointerstitial inflammation is recognized as a key determinant of progressive sepsis-induced acute kidney injury (AKI). Schisantherin A (SchA) has been shown to be capable of regulating inflammatory processes. In the present study, we explored the possibility of SchA in preventing lipopolysaccharide (LPS)-induced kidney inflammation and injury.. AKI was induced by a single intraperitoneal injection of LPS in CD1 mice, administration of SchA was used for treatment. The protective effect of SchA on renal function and inflammation were analyzed respectively; the NRK-52E cell line was employed for the in vitro study and relative molecular mechanism was explored.. Administration with SchA markedly attenuated LPS-induced damage on renal function and histopathological changes of the kidney. Additionally, pretreatment with SchA could inhibit the expression of inflammatory factors in the kidneys. In NRK-52E cells, SchA treatment significantly inhibited LPS-induced NF-κB activation and pro-inflammatory cytokine expression. Moreover, SchA could promote NRF2 pathway activation, and further blockade of NRF2 activation reversed the SchA-induced inhibition of NF-κB activation.. These presented results indicated that SchA may have great potential for protecting against sepsis-induced AKI.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Cell Line; Cyclooctanes; Dioxoles; Inflammation; Kidney; Lignans; Male; Mice; NF-E2-Related Factor 2; Rats; Sepsis; Signal Transduction

Schisandrin B (SchB) is the highest content of biphenyl cyclooctene lignans in Schisandra chinensis. It has been reported to have a variety of pharmacological effects, including anti-inflammatory, anti-oxidant, anti-cancer, heart protection, liver protection. In this study, we found that SchB can promote the proliferation of MC3T3-E1 subclone 14 cells. Meanwhile, we found that SchB can regulate the BMP2-SMADs signaling pathway by increasing gene and protein expression of those relative biomolecules. Furthermore, SchB can raise the RUNX2 and SP7 expression in both mRNA and protein levels. Since the role of BMP2-SMADs-RUNX2-SP7 signaling axis in osteoblast proliferation and differentiation has been well documented. The present experimental findings indicate that SchB could promote the proliferation and differentiation of osteoblasts through BMP2-SMADs-RUNX2-SP7 signaling axis.

Topics: 3T3 Cells; Animals; Bone Morphogenetic Protein 2; Cell Differentiation; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Cyclooctanes; Heart; Inflammation; Lignans; Liver; Mice; Osteoblasts; Polycyclic Compounds; Schisandra; Signal Transduction; Smad Proteins; Sp7 Transcription Factor

Sepsis is currently one of the leading causes of death in intensive care units (ICUs). Sesamin was previously reported to inhibit inflammation. However, no studies have revealed the impact of sesamin on sepsis.. We studied the mechanism underlying the effect of sesamin on the pathophysiology of sepsis through the HMGB1/TLR4/IL-33 signalling pathway.. We found mice in the sepsis group survived for only 4 days, while those treated with sesamin survived for 6-7 days. In addition, sesamin significantly relieved the increase in the levels of MPO (21%, 33.3%), MDA (40.5% and 31.6%), DAO (1.24-fold and 2.31-fold), and pro-inflammatory cytokines such as TNF-α (75% and 79%) and IL-6 (1-fold and 1.67-fold) 24 and 48 h after sepsis induction and downregulated the expression of HMGB1, TLR4, and IL-33 while upregulating the expression of ZO-1 and occludin.. Sesamin improved the 7-day survival rate of septic mice, suppressed the inflammatory response in sepsis through the HMGB-1/TLR4/IL-33 signalling pathway, and further alleviated intestinal injury.

Topics: Animals; Bacteria; Cell Line; Cytokines; Dioxoles; Disease Models, Animal; Epithelial Cells; HMGB1 Protein; Humans; Inflammation; Interleukin-33; Intestinal Mucosa; Lignans; Male; Mice; Mice, Inbred BALB C; Occludin; Sepsis; Signal Transduction; Toll-Like Receptor 4; Zonula Occludens-1 Protein

Hypertrophic scars (HSs) are a progressive fibroproliferation disorder caused by abnormal tissue repair after deep skin injury, and are characterized by continuous activation of fibroblasts and excessive deposition of extracellular matrix. Arctigenin (ATG), a phytomedicine derived from certain plants, displays antifibrotic effects in certain diseases, such as oral submucous fibrosis and peritoneal fibrosis. In the present study, to determine the antifibrotic potential of ATG in HS, a bleomycin (BLM)‑induced skin fibrosis murine model was established. C57BL/6 mice were randomly divided into Control group, BLM group and BLM+ATG group. At 1 day post‑bleomycin induction, the BLM+ATG group was intraperitoneally injected with 3 mg/kg/day ATG for 28 consecutive days. Pathological changes in the skin tissues were observed by hematoxylin and eosin staining. Collagen content was determined using a Sircol Collagen assay kit. Immunofluorescence staining was performed to detect the expression of TGF‑β1 and α‑SMA. The expression changes of various factors were detected by reverse transcription‑quantitative PCR, western blotting and ELISA. Compared with the BLM group, ATG treatment significantly alleviated skin fibrosis by reducing dermal thickness, collagen content and expression levels of extracellular matrix‑related genes (collagen type I α1 chain, collagen type I α2 chain, connective tissue growth factor and plasminogen activator inhibitor‑1) in BLM‑induced fibrotic skin. ATG also inhibited the transformation of fibroblasts into myofibroblasts in vivo and decreased the expression of TGF‑β1 in BLM‑induced fibrotic skin. Furthermore, the contents of proinflammatory cytokines, including IL‑1β, IL‑4, IL‑6, TNF‑α and monocyte chemoattractant protein‑1, were significantly decreased in the BLM+ATG group compared with the BLM group. Redox imbalance and oxidative stress were also reversed by ATG in BLM‑induced fibrotic skin, as demonstrated by the upregulation of antioxidants (glutathione and superoxide dismutase) and downregulation of oxidants (malondialdehyde) in the BLM+ATG group compared with the BLM group. Moreover, the results indicated that the antioxidant effect of ATG may occur via activation of the nuclear factor erythroid‑2‑related factor 2/heme oxygenase‑1 signaling pathway. Collectively, the present study indicated that ATG could ameliorate skin fibrosis in a murine model of HS, which was partly mediated by reducing inflammation and oxidative stress. Therefore,

Topics: Animals; Antioxidants; Bleomycin; Cicatrix, Hypertrophic; Cytokines; Disease Models, Animal; Extracellular Matrix; Female; Fibroblasts; Fibrosis; Furans; Inflammation; Lignans; Malondialdehyde; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Pulmonary Fibrosis; Superoxide Dismutase; Transforming Growth Factor beta1

Sesamin is a major component in lignans of sesame seeds, has been described to possess a lot of biological activity. The main objective of our study was to investigate the inhibitory effect and novel molecular mechanisms of sesamin on carrageenan-induced lung inflammation in rats. Here we showed that sesamin can obviously reduce polymorphonuclear neutrophils infiltration and exudate volume. Further studies exhibited sesamin can inhibit cytokines release, polymorphonuclear neutrophils markers production and the degree of lung tissues injury. Western blot analysis revealed that sesamin can inhibit the TRAF6 expression and NF-κB pathway activation in lung tissue. We found that sesamin can increase the expression of A20 and TAX1BP1 in lung tissues, and the interaction between the two molecules. In conclusion, all these results demonstrated that sesamin can attenuate carrageenan-induced lung inflammation, the mechanisms that may be related to upregulation of the novel target A20 and TAX1BP1 which can negative regulation for NF-κB pathway. Importantly, this is the first evidence showing that TAX1BP1 can be as a novel regulatory target to attenuate the lung inflammation.

Topics: Animals; Antioxidants; Apoptosis Regulatory Proteins; Biomarkers; Carrageenan; Dioxoles; Gene Expression Regulation; Inflammation; Lignans; Lung Diseases; Neoplasm Proteins; Neutrophils; NF-kappa B; Pleural Effusion; Rats; Tumor Necrosis Factor alpha-Induced Protein 3; Up-Regulation

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Biological Availability; Biphenyl Compounds; Computer Simulation; Disease Models, Animal; Granulocytes; Inflammation; Lignans; Linear Models; Male; Mice, Inbred BALB C; Phenyl Ethers; Respiratory Function Tests; Respiratory Hypersensitivity

Acute pancreatitis (AP) is a severe inflammatory condition of the pancreas, with no specific treatment available. We have previously reported that Nardostachys jatamansi (NJ) ameliorates cerulein-induced AP. However, the specific compound responsible for this inhibitory effect has not been identified. Therefore, in the present study, we focused on a single compound, 8α-hydroxypinoresinol (HP), from NJ. The aim of this study was to determine the effect of HP on the development of pancreatitis in mice and to explore the underlying mechanism(s). AP was induced by the injection of cerulein (50 μg/kg/h) for 6 h. HP (0.5, 5 or 10 mg/kg, i.p.) was administered 1 h prior to and 1, 3 or 5 h after the first cerulein injection, with vehicle- and DMSO-treated groups as controls. Blood samples were collected to determine serum levels of amylase, lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) assays, cytokine assays, and assessment of nuclear factor (NF)-κB activation. The lungs were removed for morphological examination and MPO assays. Administration of HP dramatically improved pancreatic damage and pancreatitis-associated lung damage and also reduced amylase and lipase activities in serum. Moreover, administration of HP reduced the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the pancreas and serum during AP. In addition, the administration of HP inhibited degradation of inhibitory κ-Bα (Iκ-Bα), NF-κB p65 translocation into nucleus and NF-κB binding activity in the pancreas. Our results suggest that HP exerted therapeutic effects on pancreatitis and these beneficial effects may be due to the inhibition of NF-κB activation.

Topics: Animals; Ceruletide; Cytokines; Female; Furans; Inflammation; Lignans; Lung; Mice; Mice, Inbred C57BL; Nardostachys; Pancreas; Pancreatitis; Signal Transduction; Tumor Necrosis Factor-alpha

Extensive research has revealed the association of continued oxidative stress with chronic inflammation, which could subsequently affect many different chronic diseases. The mycotoxin deoxynivalenol (DON) frequently contaminates cereals crops worldwide, and are a public health concern since DON ingestion may result in persistent intestinal inflammation. There has also been considerable attention over the potential of DON to provoke oxidative stress. In this study, the cytoprotective effect of Schisandrin A (Sch A), one of the most abundant active dibenzocyclooctadiene lignans in the fruit of Schisandra chinensis (Turcz.) Baill (also known as Chinese magnolia-vine), was investigated in HT-29 cells against DON-induced cytotoxicity, oxidative stress and inflammation. Sch A appeared to protect against DON-induced cytotoxicity in HT-29 cells, and significantly lessened the DON-stimulated intracellular reactive oxygen species and nitrogen oxidative species production. Furthermore, Sch A lowered DON-induced catalase, superoxide dismutase and glutathione peroxidase antioxidant enzyme activities but maintains glutathione S transferase activity and glutathione levels. Mechanistic studies suggest that Sch A reduced DON-induced oxidative stress by down-regulating heme oxygenase-1 expression via nuclear factor (erythroid-derived 2)-like 2 signalling pathway. In addition, Sch A decreased the DON-induced cyclooxygenase-2 expression and prostaglandin E2 production and pro-inflammatory cytokine interleukin 8 expression and secretion. This may be mediated by preventing DON-induced translocation of nuclear factor-κB, as well as activation of mitogen-activated protein kinases pathways. In the light of these findings, we concluded that Sch A exerted a cytoprotective role in DON-induced toxicity in vitro, and it would be valuable to examine in vivo effects.

Topics: Catalase; Cell Cycle Checkpoints; Cell Death; Cell Nucleus; Cell Survival; Cyclooctanes; Cyclooxygenase 2; Cytoprotection; Dinoprostone; Enterocytes; Gene Expression Regulation; Glutathione Peroxidase; Heme Oxygenase-1; HT29 Cells; Humans; Inflammation; Inflammation Mediators; Interleukin-8; Lignans; Lipid Peroxidation; MAP Kinase Signaling System; Models, Biological; NF-E2-Related Factor 2; NF-kappa B; Nitrites; Oxidative Stress; Polycyclic Compounds; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase; Trichothecenes

Topics: Amyloid beta-Peptides; Animals; Cytokines; Inflammation; Lignans; MAP Kinase Signaling System; Microglia; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide; Peptide Fragments; Phosphorylation; Plant Stems; Rats, Sprague-Dawley; Schisandra; Signal Transduction

Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia-induced cognitive decline in mice.. Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia and HNK or SIRT3 inhibitor (3-TYP) treatment. Cognitive function and locomotor activity of mice were evaluated using fear conditioning test and open field test on postoperative 1 and 3 days. Neuronal apoptosis in CA1 and CA3 area of hippocampus was examined using TUNEL assay. And Western blot was applied to measure the expression of pro-inflammatory cytokines and SIRT3/SOD2 signaling-associated proteins in hippocampus. Meanwhile, SIRT3 positive cells were calculated by immunohistochemistry. The mitochondrial membrane potential, malondialdehyde (MDA), and mitochondrial radical oxygen species (mtROS) were detected using standard methods.. Honokiol attenuated surgery-induced memory loss and neuronal apoptosis, decreased neuroinflammatory response, and ameliorated oxidative damage in hippocampus. Notably, surgery/anesthesia induced an obviously decrease in hippocampal SIRT3 expression, whereas the HNK increased SIRT3 expression and thus decreased the acetylation of superoxide dismutase 2 (SOD2). However, 3-TYP treatment inhibited the HNK's rescuing effects.. These results suggested that activation of SIRT3 by honokiol may attenuate surgery/anesthesia-induced cognitive impairment in mice through regulation of oxidative stress and neuroinflammatory in hippocampus.

Topics: Anesthesia; Anesthetics, Inhalation; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Cognitive Dysfunction; Female; Hippocampus; Inflammation; Laparotomy; Lignans; Mice, Inbred C57BL; Nootropic Agents; Oxidative Stress; Postoperative Complications; Random Allocation; Sevoflurane; Sirtuin 3

Depression is a mood disorder that is related to neuroinflammation and cognition loss. This study is aimed to determine the potential antidepressant effects of (+)-sesamin, a lignan component of sesame, in a mild stress-induced depression mouse model. CD-1 mice were treated with chronic unpredictable mild stress (CUMS) process and orally administrated with sesamin (50 mg/kg/d) for 6 weeks. Behavioral tests including forced swimming test, tail suspension test, open field test, and elevated plus maze test demonstrated that sesamin treatment inhibited CUMS-induced mice depressant-like behaviors and anxiety, without changing immobility. It was found that sesamin prevented stress-induced decease levels of 5-HT and NE in striatum and serum. Cognitive deficits were assessed using Y-maze and Morris water maze test. Sesamin treatment also prevented stressed-induced memory impairments and neuronal damages. Consistently, sesamin also enhanced synapse ultrastructure and improved expressions of PSD-95 in stressed mice hippocampus with improving neurotrophic factors expression including BDNF and NT3. Moreover, sesamin treatment significantly prevented CUMS-induced neuroinflammation by inhibiting over-activation of microglia and expressions of inflammatory mediators including iNOS, COX-2, TNF-α and IL-1β in stressed mice hippocampus and cortex. These results illustrated that sesamin markedly improved CUMS-induced depression and memory loss via inhibiting neuroinflammation, which indicate that as food component, sesamin might be also a novel potential therapeutic for depression.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Cytokines; Depression; Dietary Supplements; Dioxoles; Disease Models, Animal; Inflammation; Lignans; Male; Maze Learning; Memory Disorders; Mice, Inbred Strains; Nerve Tissue Proteins; Norepinephrine; Serotonin

Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients, with inflammation and oxidative stress implicated as crucial pathogenic factors. There is an urgent need to develop effective therapeutic drug. Natural medicines are rich resources for active lead compounds. They would provide new opportunities for the treatment of DN. The present study was designed to investigate the protective effects of Schisandrin B (SchB) on DN and to delineate the underlying mechanism. Oral administration of SchB in the diabetic mouse model significantly alleviated hyperglycemia-induced renal injury, which was accompanied by maintenance of urine creatinine and albumin levels at similar to those of control non-diabetic mice. Histological examination of renal tissue indicated that both development of fibrosis and renal cell apoptosis were dramatically inhibited by SchB. The protective effect of SchB on DN associated with suppression of inflammatory response and oxidative stress. These results strongly suggested that SchB could be a potential therapeutic agent for treatment of DN. Moreover, our findings provided a fuller understanding of the regulatory role of NF-κB and Nrf2 in DN, indicating that they could be important therapeutic targets.

Topics: Animals; Cyclooctanes; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Inflammation; Lignans; Mice; Mice, Inbred C57BL; Molecular Conformation; Oxidative Stress; Polycyclic Compounds; Reactive Oxygen Species; Streptozocin

Magnolol is a natural extract and the main bioactive component from Chinese medicine-Magnolia. We speculate that it's functional action might be associated with the anti-inflammatory effects of magnolol. Herein, the main purpose was to elucidate the phagocytic immune function and anti-inflammatory activities associated. The toxicity of magnolol on U937 and LO-2 cells was assayed by MTT, flow cytometry and laser scanning confocal microscope was utilized to detect the phagocytosis effect on U937 cells, C57BL/6 mice and the follow-up hematoxylin-eosin staining methods were used to evaluate its bioactivity in vivo. The results showed that magnolol had dose dependent effects on enhancement of phagocytosis ability and significantly inhibited the NO production at the concentration range from10 to 40 μM. Furthermore, Magnolol significantly reduced the gene expression and protein release of IL-1β and TNF-α. However, the p-ERK1/2 in MAPK signaling pathway was not significantly affected by magnolol, whereas p-JNK and p-P38 were down-regulated. Magnolol also inhibited the expression of p-IκBα and p-P65 of NF-κB signaling pathways. The loss of body weight and the shorter length of colon were significantly improved in DSS-treated colitis C57BL/6 mice after the administration of magnolol. The cytokines of pro-inflammatory factors TNF-α, IL-6 and IL-1β attenuated significantly in a concentration dependent manner. The histopathological manifestations of 5-20 mg/kg after the treatment magnolol were markedly improved in the DSS-treated mice. These findings showed that magnolol exerted an anti-inflammatory effect through immunoregulatory phagocytosis, MAPK and NF-κB signaling pathways. Our results provide experimental evidence and theory basis for research on anti-inflammatory effects for magnolol as a potentially anti-inflammatory drug candidate.

Topics: Animals; Biphenyl Compounds; Cytokines; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inflammation; Lignans; MAP Kinase Signaling System; Mice; NF-kappa B; Phagocytosis; U937 Cells

To investigate the mechanism of Schisandrin B (Sch B) on the inflammation in LPS-induced sepsis. Sepsis mouse model was established by injecting LPS. qRT-PCR and western blot were used to measure the expression of miR-17-5p and TLR4. ELISA was used to test the concentrations of IL-1β and TNF-α. Sch B could increase miR-17-5p expression, promote inflammation, and decrease TLR4 expression in sepsis mice and LPS-induced macrophages. Moreover, miR-17-5p could negatively regulate TLR4. Overexpression of miR-17-5p suppressed the concentrations of inflammatory factors (IL-1β and TNF-α) in LPS induced-macrophages, while pcDNA-TLR4 could change the inhibition effect. Additionally, miR-17-5p inhibitor changed the inhibitory effects of Sch B on TLR4 expression and the concentrations of IL-1β and TNF-α in LPS induced-macrophages. Sch B could attenuate inflammation in LPS-induced sepsis through miR-17-5p downregulating TLR4.

Topics: Animals; Anti-Inflammatory Agents; Cyclooctanes; Down-Regulation; Inflammation; Interleukin-1beta; Lignans; Lipopolysaccharides; Macrophages; Mice; MicroRNAs; Polycyclic Compounds; Sepsis; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Intracerebral haemorrhage (ICH) induces inflammation, which can cause severe secondary injury. Recent evidence has suggested that magnolol (MG) has a protective effect against ischaemic stroke through the inhibition of inflammation. However, the anti-inflammatory effect of MG in intracerebral haemorrhage (ICH) remains unclear. Here, we report that the protective effect of MG in a rat model of ICH can be achieved by anti-inflammatory processes. We found that MG administration significantly reduced the brain water content, restored the blood-brain barrier (BBB) and subsequently attenuated neurological deficits via decreasing the activation of glial cells, decreasing the infiltration of neutrophils and reducing the production of pro-inflammation factors (IL-1β, TNF-α and MMP-9) in a rat model of ICH. These results suggest that MG reduced inflammatory injury and improved neurological outcomes in ICH model.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Biphenyl Compounds; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Inflammation; Lignans; Male; Neuroglia; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke

Acute kidney injury (AKI) is one of the most common complications of sepsis, which largely contributes to the high mortality rate of sepsis. Honokiol, a natural polyphenol from the traditional Chinese herb Magnolia officinalis, is known to possess anti-inflammatory and antioxidant activity. Here, the underlying mechanism of honokiol-induced amelioration of sepsis-associated AKI was analyzed. The expression patterns of oxidative stress moleculars and TLRs-mediated inflammation pathway were examined to identify the response of NRK-52E cells incubated with septic rats' serum to honokiol. The levels of iNOS, NO, and myeloperoxidase in NRK-52E cells were increased during sepsis, which could be reversed by honokiol. The production of GSH and SOD as in vivo antioxidant was increased after honokiol treatment. The administration of honokiol significantly inhibited TLR2/4/MyD88 signaling pathway in AKI-induced NRK-52E cells. Furthermore, ZnPPIX, the HO-1 inhibitor, weakened honokiol-mediated morphological amelioration, and the reduced level of TNF-α, IL-1β, and IL-6 in kidneys of rats subjected to CLP. Finally, Honokiol was shown to connect with the Nrf2-Keap1 dimensionally. These findings suggest that honokiol plays its protective role on sepsis-associated AKI against oxidative stress and inflammatory signals.

Topics: Acute Kidney Injury; Animals; Anti-Infective Agents; Biphenyl Compounds; Cell Line; Inflammation; Lignans; Oxidative Stress; Rats; Sepsis

Anti-oestrogens such as tamoxifen, decrease the risk of breast cancer but are unsuitable for prevention because of their side-effects. Diet modifications may be a breast cancer prevention strategy. Here, we investigated if a diet addition of flaxseed, which can be converted to the phytoestrogen enterolactone by the gut microbiota, exhibited similar effects as tamoxifen on normal human breast tissue in vivo, with special emphasis on inflammatory mediators implicated in cancer progression.. A total of 28 postmenopausal women were included. Thirteen women added 25 g of ground flaxseed per day and 15 were treated with tamoxifen as an adjuvant for early breast cancer for 6 weeks. Microdialysis of normal breast tissue and, as a control, in subcutaneous abdominal fat was performed for sampling of extracellular proteins in vivo before and after exposures.. Enterolactone levels increased significantly after flaxseed. IL-1Ra and IL-1Ra/IL-1β ratio in the breast increased in a similar fashion after the two different treatments. Flaxseed also increased breast specific levels of IL-1RT2, IL-18 and sST2 and an overall increase of MMP-9. These changes correlated significantly with enterolactone levels. Tamoxifen decreased breast tissue levels of IL-8 and IL-18. None of the treatments induced any changes of IL-1β, IL-1RT1, IL-18BP, IL-33, IL-6, IL-6RA, MMP-1, MMP-2 and MMP-3.. We conclude that dietary flaxseed and tamoxifen exert both similar and different effects, as listed above, on normal breast tissue in vivo and that a relatively modest diet change can induce significant effects on the breast microenvironment.

Topics: 4-Butyrolactone; Breast; Breast Neoplasms; Diet; Estrogen Antagonists; Female; Flax; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-18; Interleukin-1beta; Interleukin-8; Lignans; Matrix Metalloproteinase 9; Microdialysis; Middle Aged; Postmenopause; Seeds; Tamoxifen; Tumor Microenvironment

Although 4-

Topics: Animals; Biphenyl Compounds; Cardiovascular System; Disease Models, Animal; Embryo, Nonmammalian; Herbal Medicine; Inflammation; Lignans; Magnolia; Male; Oryzias; Random Allocation; Signal Transduction

The aim of this study was to assess the effects of enterolactone (ENL) on lipid fractions fatty acids composition affecting hepatocyte inflammation development.. The experiments were conducted in HepG2 cells incubated with ENL and/or palmitic acid (16 h). Intracellular contents of free fatty acids (FFA), di- (DAG) and tri- (TAG) acylglycerol as well as their fatty acids compositions were assessed by Gas-Liquid Chromatography. Moreover, the ω-6/ω-3 ratios in the above mentioned lipids fractions were estimated. The expression of proteins involved in eicosanoids and prostanoids production (COX-2, 15-LOX), inflammatory process (TNFα), as well as the proteins participating in the desaturation (SCD 1) and elongation (Elovl 3, Elovl 6) of fatty acids were evaluated by Western Blot.. Enterolactone modified fatty acids composition in FFA, DAG and TAG fractions. In conjunction with lipid overload, it increased the content of ω-6 more than ω-3 PUFA. Moreover, it enhanced the expressions of Elovl 3, Elovl 6, COX-2 and TNFα, whereas it had no influence on SCD 1 and 15-LOX level.. Our study revealed that the supplementation with ENL affected intracellular hepatic composition of saturated as well as unsaturated fatty acids in each of the investigated lipid fractions. Based on the shift in the ω-6/ω-3 balance towards ω-6, as well as the increase in COX-2 and TNFα protein expressions, we may postulate a pro-inflammatory nature of the examined polyphenol. Moreover, our findings could prove to be useful in the future research in the topic of widespread diseases such as NASH.

Topics: 4-Butyrolactone; Eicosanoids; Fatty Acids; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Lignans; Lipid Metabolism; Lipids; Liver; Palmitic Acid; Prostaglandins; Triglycerides

To address the molecular mechanism of the anti-inflammation effects of schisandrin B (Sch B) in atherosclerosis, we examined injured HMEC-1, HBMEC, and HUVEC-12 cells induced by high glucose (HG).. Western blot was performed to detect the levels of the proteins Hsp27, Noxa, TLR5, p-IκBα, and p-p65 in HG-induced cells, while ELISA was used to analyze the inflammatory cytokines TNF-α, IL-6, MCP-1, and IL-1β in cells with Hsp27 or Noxa stable expression.. Overexpression of Hsp27 upregulated the inflammatory cytokines and the release of IκBα, promoted transportation of p65 into the nucleus, and lastly, affected the inflammation process, while Sch B counteracted the upregulation. In addition, the effect of Noxa overexpression, which is different from Hsp27 overexpression, was consistent with that of Sch B treatment.. Sch B may inhibit the inflammatory cascade and alleviate the injury to HMEC-1, HBMEC, and HUEVC-12 cells caused by HG by regulating the Noxa/Hsp27/NF-κB signaling pathway.

Topics: Anti-Inflammatory Agents; Cell Survival; Cells, Cultured; Cyclooctanes; Endothelial Cells; Glucose; HSP27 Heat-Shock Proteins; Humans; Inflammation; Lignans; NF-kappa B; Polycyclic Compounds; Proto-Oncogene Proteins c-bcl-2; Signal Transduction

Burn pain is one of the worst imaginable pain, associated with considerable morbidity and mortality worldwide. The management of pain made significant progress; however, more research is needed for burn pain. In the present study, the antinociceptive effect of honokiol extracted from Magnolia officinalis was assessed for 3 consecutive days. The third-degree burns were induced by the hot water method. The honokiol both by intraperitoneal (i.p) and intra plantar (i.pl) route and in combination with tramadol (i.p) was found to be effective in significantly reducing the mechanical allodynia, hyperalgesia, thermal hyperalgesia and paw edema. Honokiol also succeeded in reducing weight loss and spontaneous pain behavior in mice. Honokiol treatment both i.p and ipl decrease significantly the loss of total protein (3.3 and 3.4 g/dl of total protein) and albumin (2.2 and 2.6 g/dl of total albumin) respectively. It also significantly recovers the normal balance of blood electrolytes and normalizes blood profile. Effect of honokiol on cytokines and mRNA expression levels of TRPV1 and P2Y were also assessed. Honokiol significantly decreases the expression of TNF-α, IL-1β and IL-6 and decreases expression level of TRPV1 and P2Y. Additionally, TRPV1 and P2Y proteins expression levels were also assessed by Western blot in paw skin tissue, sciatic nerve and spinal cord which were remarkably down-regulated by honokiol. Histological analysis of vehicle control and drug-treated paws were also performed through hematoxylin and eosin (H&E) staining which exhibited that honokiol significantly reduced the dermal layers distortion and inflammation associated with the burn. The antioxidant enzymes and nitric oxide (NO) were also determined through ELISA. Honokiol treatment also potentiates the expression of reduced glutathione and glutathione S-transferase, and catalase levels and reduced significantly the nitric oxide (NO) as compared to the burn-induced group. It can be concluded on the base of the results that honokiol has a significant analgesic activity through its action on cytokines and by downregulating TRPV1 and P2Y receptors. It also has a protective role against burn damage by upregulation of antioxidants.

Topics: Analgesics; Animals; Biphenyl Compounds; Burns; Cytokines; Edema; Hyperalgesia; Inflammation; Inflammation Mediators; Interleukin-1beta; Lignans; Magnolia; Male; Mice; Mice, Inbred BALB C; Pain; Receptors, Purinergic P2Y; Signal Transduction; Spinal Cord; TRPV Cation Channels; Tumor Necrosis Factor-alpha; Up-Regulation

Recently, our research team reported the anti-amnesic potential of desalted-hydroethanolic extracts of Salicornia europaea L. (SE-EE). In this study, we performed bioactivity-guided isolation and identification of Acanthoside B (Aca.B), from SE-EE, as the potential bioactive candidate and examined anti-amnesic activity with its potential mechanism of action using an in vivo model. S7-L3-3 purified from SE-EE showed enhanced in vitro acetylcholinesterase (AChE) inhibitory activity. The isolated S7-L3-3 was identified and characterized as Aca.B using varied spectral analyses, i.e., Nuclear magnetic resonance (NMR), Ultraviolet-visible (UV-Vis), and Electrospray ionization-mass spectrometry (ESI-MS). In the in vitro studies, Aca.B exhibited negligible toxicity and showed a dose-dependent nitric oxide inhibitory potential in Lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. In the in vivo studies, the oral administration of Aca.B to mice showed enhanced bioavailability and dose-dependent repression of the behavioral/cognitive impairment by regulating the cholinergic function, restoring the antioxidant status, attenuating the inflammatory cytokines/mediators and actively enriching neurotropic proteins in the hippocampal regions of the scopolamine-administered mice.

Topics: Amnesia; Animals; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Furans; Glucosides; Inflammation; Lignans; Membrane Glycoproteins; Mice; Oxidation-Reduction; Protein-Tyrosine Kinases; Receptors, Cholinergic; Scopolamine

Angiotensin II (Ang II)-induced chronic inflammation and oxidative stress often leads to irreversible vascular injury, in which the endothelial to mesenchymal transition (EndMT) in the endothelial layers are involved. Schisandrin B (Sch B), a natural product isolated from traditional Schisandra chinensis, has been reported to exert vascular protective properties with unclear mechanism.. This study investigated the protective effects and mechanism of Sch B against Ang II-induced vascular injury.. C57BL/6 mice were subcutaneous injected of Ang II for 4 weeks to induce irreversible vascular injury. In vitro, Ang II-induced HUVECs injury was used to study the underlying mechanism. The markers of EndMT, inflammation and oxidative stress were studied both in vitro and in vivo.. Pre-administration of Sch B effectively attenuated phenotypes of vascular EndMT and fibrosis in Ang II-treated animals, accompanied with decreased inflammatory cytokine and ROS. The in vitro data from HUVECs suggest that Sch B directly targets NF-κB activation to suppress Ang II-induced EndMT and vascular injury. The activation of EndMT in the presence of Ang II is regulated by the NF-κB, a common player in inflammation and oxidative stress. Ang II-induced inflammation and oxidative stress also contributed to vascular EndMT development and Sch B inhibited inflammation/ROS-mediated EndMT by suppressing NF-κB.. EndMT contributes to vascular injury in Ang II-treated mice, and it can be prevented via suppressing NF-κB activation by Sch B treatment. These results also imply that NF-κB might be a promising target to attenuate vascular remodeling induced by inflammation and oxidative stress through an EndMT mechanism.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents; Cells, Cultured; Cyclooctanes; Cytokines; Disease Models, Animal; Endothelium, Vascular; Fibrosis; Gene Expression Regulation; Inflammation; Lignans; Male; Mice; Mice, Inbred C57BL; NF-kappa B p50 Subunit; Oxidative Stress; Phenotype; Polycyclic Compounds; Signal Transduction; Vascular Remodeling

Diabetic cardiomyopathy (DCM) is characterized by increased left ventricular mass and wall thickness, decreased systolic function, reduced ejection fraction (EF) and ultimately heart failure. The 4-O-methylhonokiol (MH) has been isolated mainly from the bark of the root and stem of Magnolia species. In this study, we aimed to elucidate whether MH can effectively prevent DCM in type 2 diabetic (T2D) mice and, if so, whether the protective response of MH is associated with its activation of AMPK-mediated inhibition of lipid accumulation and inflammation. A total number of 40 mice were divided into four groups: Ctrl, Ctrl + MH, T2D, T2D + MH. Five mice from each group were sacrificed after 3-month MH treatment. The remaining animals in each group were kept for additional 3 months without further MH treatment. In T2D mice, the typical DCM symptoms were induced as expected, reflected by decreased ejection fraction and lipotoxic effects inducing lipid accumulation, oxidative stress, inflammatory reactions, and final fibrosis. However, these typical DCM changes were significantly prevented by the MH treatment immediately or 3 months after the 3-month MH treatment, suggesting MH-induced cardiac protection from T2D had a memory effect. Mechanistically, MH cardiac protection from DCM may be associated with its lipid metabolism improvement by the activation of AMPK/CPT1-mediated fatty acid oxidation. In addition, the MH treatment of DCM mice significantly improved their insulin resistance levels by activation of GSK-3β. These results indicate that the treatment of T2D with MH effectively prevents DCM probably via AMPK-dependent improvement of the lipid metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Lignans; Lipid Metabolism; Male; Mice, Inbred C57BL; Models, Biological; Oxidative Stress

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4'-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4'-alkylated derivative.

Topics: Alkylation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Humans; Inflammation; Lignans; Lipopolysaccharides; Mice; Molecular Structure; Nitric Oxide; RAW 264.7 Cells; Stereoisomerism

Vascular dementia (VaD) is caused by chronic decreases in brain blood flow and accounts for 15-20% of dementia cases worldwide. In contrast to Alzheimer's disease (AD), no effective drug treatments are currently available for VaD. Previous studies have suggested that oxidative stress and neuroinflammation in the brain play important roles in the pathogenesis of VaD. Honokiol (HKL) is a well-known bioactive and nutraceutical compound that can act as an antioxidant and anti-inflammatory molecule. HKL can protect against memory impairments in AD mouse models. In this study, we explored whether the application of HKL was also protective against the insult of chronic cerebral hypoperfusion (CCH) in rats. We found that HKL supplementation prevented the memory impairments in the inhibitory avoidance step-down and Morris water maze tasks in CCH rats. HKL also suppressed the levels of oxidative stress and inflammation in CCH rats. Moreover, HKL prevented dendritic spines abnormalities in CCH rats. We also found that HKL inhibited the activity of GSK-3β, which may be critical for the neuroprotective activity of HKL. Thus, our study demonstrated the protective role of HKL in VaD.

Topics: Animals; Biphenyl Compounds; Brain; Dementia, Vascular; Disease Models, Animal; Enzyme Activation; Glycogen Synthase Kinase 3 beta; Inflammation; Lignans; Maze Learning; Memory Disorders; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar

To examine the properties of Schisandrin C as an anti-inflammatory and antioxidant compound, and whether its characteristics promote mitochondrial biogenesis in human dental pulp cells (HDPCs).. HDPCs were extracted from fresh third molars and cultured for experiments. Reactive oxidative stress (ROS) and nitric oxide (NO) formation were analysed by a Muse cell analyser. Western blotting and gelatin zymography were used to identify the presence of antioxidants, as well as anti-inflammatory and mitochondrial biogenesis with specific antibody. An unpaired Student's t-test was used for statistical analysis.. Schisandrin C inhibited lipopolysaccharide-stimulated inflammatory molecules; interleukin 1 beta, tumour necrosis factor alpha, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, matrix metalloproteinase-2 and -9, NO production, ROS formation, nuclear factor kappa B translocation (P < 0.05) through the mitogen-activated protein kinase pathway. Schisandrin C increased the expression of superoxide dismutase enzymes as well as haem oxygenase-1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha through the phosphorylated-protein kinase B (p-Akt) and nuclear factor erythroid 2-related factor-2 pathways (P < 0.05). The anti-inflammatory and antioxidant properties of Schisandrin C promoted mitochondrial biogenesis.. Schisandrin C has the potential to reduce inflammation and oxidation and to promote mitochondrial biogenesis. Therefore, Schisandrin C may be considered for use as an anti-inflammatory compound for oral inflammation through mitochondrial biogenesis.

Topics: Anti-Inflammatory Agents; Antioxidants; Cyclooctanes; Dental Pulp; Gelatin; Heme Oxygenase (Decyclizing); Humans; Inflammation; Interleukin-1beta; Lignans; Lipopolysaccharides; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitochondria; Mitogen-Activated Protein Kinases; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide; Organelle Biogenesis; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polycyclic Compounds; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Transcription Factors; Tumor Necrosis Factor-alpha

Honokiol is a biphenolic isolate extracted from the bark of the magnolia tree that has been used in traditional Chinese and Japanese medicine, and has more recently been investigated for its anti-inflammatory and antibacterial properties. Honokiol has previously been demonstrated to improve survival in sepsis models that have rapid 100% lethality. The purpose of this study was to determine the impact of Honokiol on the host response in a model of sepsis that more closely approximates human disease. Male and female C57BL/6 mice underwent cecal ligation and puncture to induce polymicrobial intra-abdominal sepsis. Mice were then randomized to receive an injection of either Honokiol (120 mg/kg/day) or vehicle and were sacrificed after 24 h for functional studies or followed 7 days for survival. Honokiol treatment after sepsis increased the frequency of CD4 T cells and increased activation of CD4 T cells as measured by the activation marker CD69. Honokiol also increased splenic dendritic cells. Honokiol simultaneously decreased frequency and number of CD8 T cells. Honokiol decreased systemic tumor necrosis factor without impacting other systemic cytokines. Honokiol did not have a detectable effect on kidney function, lung physiology, liver function, or intestinal integrity. In contrast to prior studies of Honokiol in a lethal model of sepsis, Honokiol did not alter survival at 7 days (70% mortality for Honokiol vs. 60% mortality for vehicle). Honokiol is thus effective in modulating the host immune response and inflammation following a clinically relevant model of sepsis but is not sufficient to alter survival.

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Biphenyl Compounds; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Disease Models, Animal; Female; Inflammation; Lectins, C-Type; Lignans; Lymphocyte Activation; Lymphocyte Count; Male; Mice; Random Allocation; Sepsis; Tumor Necrosis Factor-alpha

Schisandrin A is a bioactive lignan occurring in the fruits of plants of the Schisandra genus that have traditionally been used in Korea for treating various inflammatory diseases. Although the anti-inflammatory and antioxidant effects of lignan analogues similar to schisandrin A have been reported, the underlying molecular mechanisms have remained elusive. In the present study, schisandrin A significantly suppressed the lipopolysaccharide (LPS)-induced production of the key pro-inflammatory mediators nitric oxide (NO) and prostaglandin E2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2 at the mRNA and protein levels in RAW 264.7 macrophages. Furthermore, schisandrin A was demonstrated to reduce the LPS-induced secretion of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β; this was accompanied by a simultaneous decrease in the respective mRNA and protein levels in the macrophages. In addition, the LPS- induced translocation of nuclear factor-κB (NF-κB), as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol‑3 kinase (PI3K)/Akt pathways were inhibited by schisandrin A. Furthermore, schisandrin A significantly diminished the LPS-stimulated accumulation of intracellular reactive oxygen species, and effectively enhanced the expression of NF erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These results suggested that schisandrin A has a protective effect against LPS-induced inflammatory and oxidative responses in RAW 264.7 cells by inhibiting the NF-κB, MAPK and PI3K/Akt pathways; these effects are mediated, at least in part, by the activation of the Nrf2/HO-1 pathway. Based on these results, it is concluded that schisandrin A may have therapeutic potential for treating inflammatory and oxidative disorders caused by over-activation of macrophages.

Topics: Animals; Cyclooctanes; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Inflammation; Lignans; Lipopolysaccharides; Membrane Proteins; Mice; Mitogen-Activated Protein Kinase Kinases; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Polycyclic Compounds; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Signal Transduction

Magnolol, the main and active ingredient of the Magnolia officinalis, has been widely used in traditional prescription to the human disorders. Magnolol has been proved to have several pharmacological properties including anti-bacterial, anti-oxidant and anti-inflammatory activities. However, the effects of magnolol on ulcerative colitis (UC) have not been reported. The aim of this study was to investigate the protective effects and mechanisms of magnolol on dextran sulphate sodium (DSS)-induced colitis in mice. The results showed that magnolol significantly alleviated DSS-induced body weight loss, disease activities index (DAI), colon length shortening and colonic pathological damage. In addition, magnolol restrained the expression of TNF-α, IL-1β and IL-12 via the regulation of nuclear factor-κB (NF-κB) and Peroxisome proliferator-activated receptor-γ (PPAR-γ) pathways. Magnolol also enhanced the expression of ZO-1 and occludin in DSS-induced mice colonic tissues. These results showed that magnolol played protective effects on DSS-induced colitis and may be an alternative therapeutic reagent for colitis treatment.

Topics: Animals; Biphenyl Compounds; Cecum; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Gastrointestinal Agents; Inflammation; Inflammation Mediators; Intestinal Mucosa; Lignans; Male; Mice; Mice, Inbred C57BL; Occludin; PPAR gamma; Weight Loss

Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A

Topics: Animals; Anti-Asthmatic Agents; Antibodies, Neutralizing; Asthma; Cyclic Nucleotide Phosphodiesterases, Type 4; Dioxolanes; Disease Models, Animal; Female; Inflammation; Justicia; Lignans; Mice, Inbred BALB C; Plant Extracts; Protective Agents; Receptor, Adenosine A3; Receptors, Immunologic; Th2 Cells

Arctigenin (ATG), a lignin extracted from Arctium lappa (L.), exerts antioxidant and anti-inflammatory effects. We hypothesized that ATG exerts a protective effect on hepatocytes by preventing nonalcoholic fatty liver disease (NAFLD) progression associated with lipid oxidation-associated lipotoxicity and inflammation. We established an in vitro NAFLD cell model by using normal WRL68 hepatocytes to investigate oleic acid (OA) accumulation and the potential bioactive role of ATG. The results revealed that ATG inhibited OA-induced lipid accumulation, lipid peroxidation, and inflammation in WRL68 hepatocytes, as determined using Oil Red O staining, thiobarbituric acid reactive substance assay, and inflammation antibody array assays. Quantitative RT-PCR analysis demonstrated that ATG significantly mitigated the expression of acetylcoenzyme A carboxylase 1 and sterol regulatory element-binding protein-1 and significantly increased the expression of carnitine palmitoyltransferase 1 and peroxisome proliferator-activated receptor alpha. The 40 targets of the Human Inflammation Antibody Array indicated that ATG significantly inhibited the elevation of the U937 lymphocyte chemoattractant, ICAM-1, IL-1β, IL-6, IL-6sR, IL-7, and IL-8. ATG could activate the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK) pathways and could increase the phosphorylation levels of Akt and AMPK to mediate cell survival, lipid metabolism, oxidation stress, and inflammation. Thus, we demonstrated that ATG could inhibit NAFLD progression associated with lipid oxidation-associated lipotoxicity and inflammation, and we provided insights into the underlying mechanisms and revealed potential targets to enable a thorough understanding of NAFLD progression.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Arctium; Carnitine O-Palmitoyltransferase; Fatty Liver; Furans; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukins; Lignans; Liver; Non-alcoholic Fatty Liver Disease; Oleic Acid; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phytotherapy; Plant Extracts; PPAR alpha; Proto-Oncogene Proteins c-akt; Signal Transduction; Sterol Regulatory Element Binding Protein 1

As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression.

Topics: Acute Disease; Animals; CD4-Positive T-Lymphocytes; Concanavalin A; Furans; Hepatitis; Inflammation; Inflammation Mediators; Interleukin-10; Lignans; Liver; Macrophages; Male; Mice; Mice, Inbred BALB C; Natural Killer T-Cells; Protective Agents; RAW 264.7 Cells

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Furans; Inflammation; Kidney; Lignans; Male; Mice, Inbred C57BL; Oxidative Stress; Reperfusion Injury

Osteoarthritis (OA) is the most prevalent joint disorder in the elderly population, and inflammatory mediators like IL-1β were thought to play central roles in its development. Schisandrin B, the main active component derived from. In the present study, the protective effect and the underlying mechanism of Schisan-drin B on OA was investigated in vivo and in vitro.. The results showed that Schisandrin B decreased IL-1β-induced upregulation of matrix metalloproteinase 3 (MMP3), MMP13, IL-6, and inducible nitric oxide synthase (iNOS) and increased IL-1β-induced downregulation of collagen II, aggrecan, and sox9 as well. Schisandrin B significantly decreased IL-1β-induced p65 phosphorylation and nuclear translocation of p65 in rat chondrocytes. Mitogen-activated protein kinase (MAPK) activation was also inhibited by Schisandrin B, as evidenced by the reduction of p38, extracellular signal-regulated kinase (Erk), and c-Jun amino-terminal kinase (Jnk) phosphorylation. In addition, Schisandrin B prevented cartilage degeneration in rat OA model with significantly lower Mankin's score than the control group.. Our study demonstrated that Schisandrin B ameliorated chondrocytes inflammation and OA via suppression of nuclear factor-κB (NF-κB) and MAPK signal pathways, indicating a therapeutic potential in OA treatment.

Topics: Animals; Anti-Inflammatory Agents; Cell Survival; Cells, Cultured; Chondrocytes; Cyclooctanes; Dose-Response Relationship, Drug; Inflammation; Lignans; MAP Kinase Signaling System; Matrix Metalloproteinases; NF-kappa B; Osteoarthritis; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Schisandra; Structure-Activity Relationship

In the present study, we investigated whether schisantherin A (StA) had anti-inflammatory effects under neuroinflammatory conditions.. The effects of StA and its underlying mechanisms were examined in lipopolysaccharide (LPS)-activated BV-2 microglial cells by ELISA, qPCR, EMSA, Western blot, and IHC.. Firstly, we found that StA inhibited the inflammatory response in LPS-activated BV-2 microglia. Secondly, we found that StA suppressed LPS-induced activation of NF-κB via interfering with degradation of IκB and phosphorylation of IκB, IKK, PI3K/Akt, JNK, and p38 MAPK. Thirdly, StA conferred indirect antioxidative effects via quenching ROS and promoted expression of antioxidant enzymes, including HO-1 and NQO-1, via stimulating activation of Nrf2 pathways. Finally, we demonstrated that anti-neuroinflammatory actions of StA were dependent on ERK phosphorylation-mediated Nrf2 activation.. StA induced ERK phosphorylation-mediated Nrf2 activation, which contributed to its anti-inflammation and anti-oxidation. The anti-neuroinflammatory and anti-oxidative effects of StA may show preventive therapeutic potential for various neuroinflammatory disorders.

Topics: Animals; Cell Line, Transformed; Cyclooctanes; Dioxoles; Inflammation; Lignans; MAP Kinase Signaling System; Mice; Microglia; NF-E2-Related Factor 2; Phosphorylation

Higher lignan exposure has been associated with lower all-cause mortality (ACM) and breast cancer-specific mortality (BCSM) for postmenopausal breast cancer patients. However, the biological mechanisms underpinning these associations are still unclear. We investigated for the first time whether and to what extent the association between enterolactone (ENL), the major lignan metabolite, and postmenopausal breast cancer prognosis is mediated by inflammatory biomarkers. Circulating concentrations of ENL and inflammatory markers were measured in a population-based prospective cohort of 1,743 breast cancer patients recruited between 2002 and 2005 and followed-up until 2009. Hazard ratios (HR) and 95% CIs were estimated using multivariable Cox regression. Mediation analysis was performed to estimate the percentage association between ENL (log2) and ACM, BCSM and distant disease-free survival (DDFS), which is mediated by C-reactive protein (CRP) (log2), as the strongest potential mediator, and also interleukin (IL)-10. Median serum/plasma ENL and CRP concentrations for all patients, including 180 deceased patients, were 23.2 and 17.5 nmol/L, and 3.2 and 6.5 mg/l, respectively. ENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 [0.87, 0.99], 0.91 [0.84, 0.99] and 0.92 [0.87, 0.99]), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL-10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone-independent mechanisms.

Topics: 4-Butyrolactone; Aged; Biomarkers; Breast Neoplasms; Case-Control Studies; Disease-Free Survival; Female; Humans; Inflammation; Lignans; Middle Aged; Postmenopause; Prognosis; Proportional Hazards Models; Prospective Studies

Allergic asthma is a disease that pathologically characterized by eosinophilia infiltration, airway inflammation and hyper responsiveness. In this study, we evaluated the anti-inflammatory and anti-allergy possibilities of honokiol, a bi-phenolic compound obtained from species of the genus Magnolia, which has long been involved in traditional Chinese prescriptions for asthma-related lung diseases, in an ovalbumin-induced mouse model of allergic asthma. We found honokiol significantly inhibited the eosinophilia infiltration, reduced the airway inflammation and suppressed the production of inflammatory cytokines) as well as the IgE in serum. Moreover, MMP-9 and? (IL-4 and IFN- NF-κB were found to be involved in the honokiol induced biological process. These results suggested that honokiol may be a possible candidate in the treatment of lung asthma related diseases.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Asthma; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Immunoglobulin E; Inflammation; Lignans; Mice, Inbred BALB C; Respiratory System

Endotoxin shock is a life-threatening response caused by a disordered immune response to an infection. MDSCs are accumulated and play a protective role in the pathogenesis of endotoxin shock. However, the regulation of MDSCs by small molecule remains unrevealed. Here, we report that arctigenin, a small molecule extracted from Arctium lappa, induces accumulation of functional MDSCs. Arctigenin was able to ameliorate LPS-induced inflammation through accumulating MDSCs, especially granulocytic MDSCs (G-MDSCs), and enhancing the immunosuppressive function of MDSCs in vivo and in vitro. Mechanistically, arctigenin promoted the accumulation of MDSCs through upregulating miR-127-5p which targets the 3'UTR of interferon regulatory factor-8 (IRF8) mRNA. In addition, arctigenin enhanced the immunosuppressive activity of MDSCs on M1 macrophage polarization by elevating the expression of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS). Our study provides new insights into the regulation of functional MDSCs by arctigenin in exerting immune responses and pathogenesis of inflammatory diseases.

Topics: Animals; Arginase; Furans; Inflammation; Interferon Regulatory Factors; Lignans; Lipopolysaccharides; Mice; MicroRNAs; Myeloid-Derived Suppressor Cells; Nitric Oxide Synthase Type II; RNA, Messenger; Shock, Septic

Phyllanthin, a lignan from Phyllanthus species, has been reported to possess potent immunosuppressive properties on immune cells and on adaptive and innate immune responses in animal models. Herein, we investigated the inhibitory effects of phyllanthin isolated from Phyllanthus amarus on nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and PI3K-Akt signal transducing pathways in LPS-activated U937 cells. The lipopolysaccharide-stimulated excess production of prostaglandin was significantly suppressed by phyllanthin via the mechanisms linked to the modulatory effects of cyclooxygenase 2 protein and gene expression. Phyllanthin also significantly inhibited the release and mRNA expression of proinflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha). Phyllanthin also significantly downregulated the phosphorylation of IκBα, NF-κB (p65), and IKKα/β and suppressed the activation of JNK, ERK, p38MAPK, and Akt in a concentration-dependent manner. Additionally, phyllanthin downregulated the expression of upstream signaling molecules including MyD88 and toll-like receptor 4 that are essential for the activation of NF-κB, MAPKs, and PI3K-Akt signal transducing pathways. Based on these observations, phyllanthin may exert their suppressive effects on inflammatory process by mediating the release of inflammatory signaling molecules via the NF-κB, MAPKs, and PI3K-Akt signal transducing pathways. Thus, phyllanthin holds a great promise as a potential anti-inflammatory agent to treat various inflammatory diseases.

Topics: Anti-Inflammatory Agents; Down-Regulation; Humans; Inflammation; Lignans; Lipopolysaccharides; Macrophages; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphatidylinositol 3-Kinases; Phyllanthus; Proto-Oncogene Proteins c-akt; Signal Transduction; U937 Cells

Acute kidney injury (AKI) is considered a major public health concern in today's world. Sepsis-induced AKI is large as a result of exposure to lipopolysaccharide (LPS) that is the major outer membrane component of Gram-negative bacteria. Sesamin is the main lignan of sesame seeds with multiple protective effects.. In this research, we tried to demonstrate the protective effect of sesamin pretreatment in LPS-induced mouse model of AKI.. LPS was injected at a single dose of 10 mg/kg (i.p.) and sesamin was given p.o. at doses of 25, 50, or 100 mg/kg, one hour prior to LPS.. Treatment of LPS-challenged mice with sesamin reduced serum level of creatinine and blood urea nitrogen (BUN) and returned back renal oxidative stress-related parameters including glutathione (GSH), malondialdehyde (MDA), and activity of catalase and superoxide dismutase (SOD). Moreover, sesamin alleviated inappropriate changes of renal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-6, DNA fragmentation (an apoptotic index), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, sesamin diminished magnitude of kidney tissue damage due to LPS.. In summary, sesamin could dose-dependently abrogate LPS-induced AKI via attenuation of renal oxidative stress, inflammation, and apoptosis.

Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Cytokines; Dioxoles; Disease Models, Animal; Inflammation; Kidney Function Tests; Lignans; Lipopolysaccharides; Male; Mice, Inbred C57BL; Oxidative Stress

Ultraviolet (UV) radiation exposure induces immunosuppression, which contributes to the development of cutaneous malignancies. We investigated the effects of honokiol, a phytochemical found in plants of the genus Magnolia, on UVB-induced immunosuppression using contact hypersensitivity (CHS) as a model in C3H/HeN mice. Topical application of honokiol (0.5 and 1.0 mg/cm

Topics: Animals; Biphenyl Compounds; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dermatitis, Contact; DNA Methylation; Female; Immunosuppression Therapy; Inflammation; Inflammation Mediators; Lignans; Methyltransferases; Mice; Models, Biological; Protective Agents; Proto-Oncogene Proteins; Skin; Ultraviolet Rays

Silent information regulator 1 (SIRT1), a histone deacetylase, plays a protective role in ischemic brain injury. Previous studies have shown that magnolol has a beneficial effect on ischemic stroke; however, the role of SIRT1 in the protective effect of magnolol against cerebral ischemia has not been investigated.. We used a middle cerebral artery occlusion model of stroke in rats. Before stroke induction, the rats received intraperitoneal injections of magnolol with or without the SIRT1 inhibitor, EX527. Brain water content, neurological score, and infarct volume were measured. Moreover, the levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. Western blot analysis was performed to detect Ac-FOXO1, SIRT1, bax, and Bcl-2 expression.. Magnolol exerted a beneficial effect on cerebral ischemia, as indicated by reduced brain edema, decreased infarct volume, and improved neurological score. Magnolol had an anti-inflammatory effect mediated by a decrease in the expression of IL-1β and TNF-α in the brain tissue. Additionally, magnolol down-regulated bax and Ac-FOXO1 expression and up-regulated Bcl-2 and SIRT1 expression. This effect of magnolol was abolished by EX527 treatment.. In conclusion, our data clearly indicate that magnolol modulates brain injury caused by ischemic stroke by inhibiting inflammatory cytokines and apoptosis through SIRT1 activation.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Gene Expression Regulation; Hypoxia, Brain; Inflammation; Lignans; Nerve Tissue Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Sirtuin 1; Stroke

Schisandrin B (SchB), an active ingredient extracted from Schisandra chinensis (Turcz.) Baill, has been known to have anti-oxidant and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effects and mechanism of SchB in LPS-stimulated human umbilical vein endothelial cells (HUVECs). The effects of SchB on VCAM-1, ICAM-1, NF-κB and Nrf2 expression were detected by western blot analysis. The effects of SchB on TNF-α and IL-8 production were detected by ELISA. The results showed that SchB strongly suppressed the production of TNF-α and IL-8 in HUVECs stimulated with LPS. SchB also inhibited LPS-induced VCAM-1 and ICAM-1 expression. Furthermore, SchB blocked the activation of NF-κB induced by LPS. In addition, SchB increased the expression of Nrf2 and HO-1 in a concentration-dependent manner. And the inhibition of TNF-α and IL-8 production by SchB was blocked by transfection with Nrf2 siRNA. Our findings showed that SchB inhibited LPS-induced inflammation in HUVECs by activating Nrf2 signaling pathway.

Topics: Anti-Inflammatory Agents; Cyclooctanes; Endothelium, Vascular; Heme Oxygenase-1; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Lignans; Lipopolysaccharides; NF-E2-Related Factor 2; NF-kappa B; Polycyclic Compounds; RNA, Small Interfering; Schisandra; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

The goal of this study was to test the effects of bioactive phenylpropanoid dibenzylbutyrolactone lignan arctigenin (ATG) in vascular tone. Human bypass graft vessel, from a saphenous vein (SV), were set up in organ bath system and contracted with potassium chloride (KCl, 40mM). Two concentration-response curves of noradrenaline (NE) (10nM-100μM) separated with an incubation period of 30min without (Control) or with ATG (3-100μM) were established. Inhibitors of nitric oxide, prostaglandins, K

Topics: Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Furans; Humans; Inflammation; Inflammation Mediators; Lignans; Saphenous Vein; Vascular Resistance; Vasodilation

Toll-like receptor 4 (TLR4) and C5aR1 (CD88) have been recognized as potential therapeutic targets for the reduction of inflammation and secondary damage and improvement of outcome after ischemia and reperfusion (I/R). The inflammatory responses which induce cell apoptosis and necrosis after I/R brain injury lead to a limited process of neural repair. To further comprehend how these targets function in I/R state, we investigated the pathological changes and TLR4 and C5aR1 signaling pathways in vitro and in vivo models of I/R brain injury in this study. Meanwhile, we explored the roles of schisantherin A on I/R brain injury, and whether it exerted neuroprotective effects by regulating the TLR4 and C5aR1 signaling pathways or not. The results showed that schisantherin A significantly reduced the neuronal apoptosis induced by oxygen and glucose deprivation and reperfusion (OGD/R) injury in primary culture of rat cortical neurons. Also, schisantherin A alleviated neurological deficits, reduced infarct volume, attenuated oxidation stress, inflammation and apoptosis in ischemic parietal cortex of rats after middle cerebral artery occlusion and reperfusion (MCAO/R) injury. Moreover, the activated TLR4 and C5aR1 signaling pathways were inhibited by schisantherin A treatment. In conclusion, TLR4 and C5aR1 played a vital role during I/R brain injury in rats, and schisantherin A exhibited neuroprotective effects by TLR4 and C5aR1 signaling pathways. These findings also provided new insights that would aid in elucidating the effect of schisantherin A against cerebral I/R and support the development of schisantherin A as a potential treatment for ischemic stroke.

Topics: Animals; Apoptosis; Brain Ischemia; Cell Survival; Cerebral Cortex; Cyclooctanes; Dioxoles; Inflammation; Lignans; Necrosis; Neurons; Neuroprotective Agents; Oxidative Stress; Parietal Lobe; Primary Cell Culture; Rats, Sprague-Dawley; Receptor, Anaphylatoxin C5a; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4

Endothelial inflammation is an increasingly prevalent condition in the pathogenesis of many cardiovascular diseases. (-)-7(S)-hydroxymatairesinol (7-HMR), a naturally occurring plant lignan, possesses both antioxidant and anti-cancer properties and therefore would be a good strategy to suppress tumor necrosis factor-α (TNF-α)-mediated inflammation in vascular endothelial cells (VECs).. The objective of this study is to evaluate for its anti-inflammatory effect on TNF-α-stimulated VECs and underling mechanisms.. The effect of the 7-HMR on suppression of TNF-α-induced inflammation mediators in VECs were determined by qRT-PCR and Western blot. MAPKs and phosphorylation of Akt, HO-1 and NF-κB p65 were examined using Western blot. Nuclear localisation of NF-κB was also examined using Western blot and immunofluorescence.. Here we found that 7-HMR could suppress TNF-α-induced inflammatory mediators, such as vascularcelladhesion molecule-1, interleukin-6 and inducible nitric oxide synthase expression both in mRNA and protein levels, and concentration-dependently attenuated reactive oxidase species generation. We further identified that 7-HMR remarkably induced superoxide dismutase and heme oxygenase-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (keap1) and up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, 7-HMR time- and concentration-dependently attenuated TNF-α-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) and Akt, but not p38, or c-Jun N-terminal kinase 1/2. Moreover, 7-HMR significantly suppressed TNF-α-mediated nuclear factor-κB (NF-κB) activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65.. Our results demonstrated that 7-HMR inhibited TNF-α-stimulated endothelial inflammation, at least in part, through inhibition of NF-κB activation and upregulation of Nrf2-antioxidant response element signaling pathway, suggesting 7-HMR might be used as a promising vascular protective drug.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidant Response Elements; Endothelial Cells; Endothelium, Vascular; Extracellular Signal-Regulated MAP Kinases; Heme Oxygenase-1; Inflammation; Inflammation Mediators; Interleukin-6; Lignans; Male; NF-E2-Related Factor 2; NF-kappa B; Phosphorylation; Rats; Tumor Necrosis Factor-alpha

Cartilage degradation is the significant pathological process in osteoarthritis (OA). Inflammatory cytokines, such as interleukin-1β (IL-1β), activate various downstream mediators contributing to OA pathology. Recently, stem cell-based cartilage repair emerges as a potential therapeutic strategy that being widely studied, whereas, the outcome is still far from clinical application. In this study, we focused on an anti-inflammatory agent, honokiol, which is isolated from an herb, investigated the potential effects on human umbilical cord derived mesenchymal stem cells (hUC-MSCs) in IL-1β stimulation.. Second passage hUC-MSCs were cultured for multi-differentiation. Flow cytometry, qRT-PCR, von Kossa stain, alcian blue stain and oil red O stain were used for characterization and multi-differentiation determination. Honokiol (5, 10, 25, 50 μM) and IL-1β (10 ng/ml) were applied in hUC-MSCs during chondrogenesis. Analysis was performed by MTT, cell apoptosis evaluation, ELISA assay, qRT-PCR and western blot.. hUC-MSC was positive for CD73, CD90 and CD105, but lack of CD34 and CD45. Remarkable osteogenesis, chondrogenesis and adipogenesis were detected in hUC-MSCs. IL-1β enhanced cell apoptosis and necrosis and activated the expression of caspase-3, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-1, -9, 13 in hUC-MSCs. Moreover, the expression of SRY-related high-mobility group box 9 (SOX-9), aggrecan and col2α1 was suppressed. Honokiol relieved these negative impacts induced by IL-1β and suppressed Nuclear factor-κB (NF-κB) pathway by downregulating expression of p-IKKα/β, p-IκBα and p-p65 in dose-dependent and time-dependent manner.. Honokiol improved cell survival and chondrogenesis of hUC-MSCs and inhibited IL-1β-induced inflammatory response, which suggested that combination of anti-inflammation and stem cell can be a novel strategy for better cartilage repair.

Topics: Anti-Inflammatory Agents; Apoptosis; Biphenyl Compounds; Caspase 3; Cell Differentiation; Cell Survival; Cells, Cultured; Chondrogenesis; Collagenases; Cyclooxygenase 2; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Lignans; Mesenchymal Stem Cells; NF-kappa B; Signal Transduction

Inflammatory responses induced by Propionibacterium acnes are a major etiological factor in the pathogenesis of acne vulgaris. Schisandrin A, schisandrin B, and schisandrin C are the representative lignans of Schisandra chinensis (Turcz.) Baill. extract. Although anti-inflammatory effects of the lignans have been shown, their effects on acne-related inflammation caused by P. acnes have not been investigated and compared. We pretreated THP-1 human monocytic cells with 5, 10, and 20 μM schisandrin A, B, and C, and stimulated the cells with P. acnes. Schisandrin B and C inhibited the release of inflammatory cytokines at a concentration of 5 μM, while schisandrin A required a concentration of 10 μM to exert the effects. All of the schisandrins decreased the levels of toll-like receptor 2, and schisandrin B and C reduced the intracellular mRNA expression of the receptor gene. We also studied the influence of schisandrins on the MAPK signaling pathway. Schisandrin A suppressed the P. acnes-induced activation of JNK, while exerting only a weak effect on ERK and p38. Schisandrin B exerted a strong effect on p38, a lesser effect on ERK, and almost no effect on JNK. Schisandrin C inhibited the phosphorylation of all three proteins, especially ERK. Furthermore, the three lignans also prevented the nuclear translocation of NF-κB. These results contribute to our understanding of the mechanisms underlying the effects of the three lignans on P. acnes-induced inflammation and suggest that schisandrins might be developed as pharmacological agents for acne therapy.

Topics: Acne Vulgaris; Anti-Inflammatory Agents; Cyclooctanes; Humans; Inflammation; Lignans; MAP Kinase Signaling System; Polycyclic Compounds; Propionibacterium acnes; THP-1 Cells

The novel target products were synthesized in the formation of a triazine ring from berberine, magnolol, and metformin catalyzed by sodium methylate. The structures of products

Topics: Anti-Inflammatory Agents; Berberine; Biphenyl Compounds; Cyclization; Humans; Inflammation; Insulin Resistance; Lignans; Metformin; Molecular Structure; Sodium; Structure-Activity Relationship; Triazines

Cardiac remodeling is associated with oxidative stress. Sesamin, a well-known antioxidant from sesamin seeds, have been used extensively as traditional health foods. However, there is little known about the effect of sesamin on cardiac remodeling. Therefore, the present study aimed to determine whether sesamin could protect against cardiac remodeling and to clarify potential molecular mechanisms.. The mice were subjected to either transverse aortic constriction (TAC) or sham surgery (control group). Beginning one week after surgery, the mice were oral gavage treated with sesamin (100mg·kg-1·day-1) or vehicle for 3 weeks. Cardiac hypertrophy was assessed by echocardiographic parameters, histological analyses and hypertrophic markers.. Sesamin alleviated cardiac hypertrophy, inhibited fibrosis and attenuated the inflammatory response. The increased production of reactive oxygen species, the activation of ERK1/2-dependent nuclear factor-κB and the increased level of Smad2 phosphorylation were observed in cardiac remolding model that were treated with sesamin. Furthermore, TAC induced alteration of Sirt3 and SOD2 was normalized by sesamin treatment. Finally, a selective Sirt3 inhibitor 3-TYP blocks all the protective role of sesamin, suggesting that a Sirt3-dependent effect of sesamin on cardiac remodeling.. Sesamin improves cardiac function and prevents the development of cardiac hypertrophy via Sirt3/ROS pathway. Our results suggest the protective effect of sesamin on cardiac remolding.

Topics: Animals; Antioxidants; Cardiomegaly; Dioxoles; Fibrosis; Heart; Inflammation; Lignans; Male; MAP Kinase Signaling System; Mice; Myocardium; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Sirtuin 3

This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8. The expression of IL-1β, caspase-1 in the supernatant and the expression of pro-caspase-1, pro-IL-1β, ASC, NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L(−1)) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25–400 μmol·L(−1). Deoxyschizandrin (25, 50, 100, and 200 μmol·L(−1)) could inhibit the activation of NLRP3 inflammasome caused by nigericin and ATP, and inhibit the secretion of IL-1β, which was associated with inhibiting the cleavage of pro-caspase-1. The results of immunofluorescence and Western blot also suggest that the inhibitory activity of deoxyschizandrin on NLRP3 inflammasome was not dependent on NF-κB pathway and protein expression of NLRP3, ASC, pro-caspase-1 and pro-IL-1β mediated by NF-κB. Our results confirmed that deoxyschizandrin could suppress the cleavage of pro-caspase-1 and inhibit the activity of NLRP3 inflammasome at 25–200 μmol·L−1 to reduce the inflammation response.This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family,pyrin domain containing 3) inflammasome.Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8.The expression of IL-1β,caspase-1 in the supernatant and the expression of pro-caspase-1,pro-IL-1β,ASC,NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L(-1)) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25-400 μmol·L(-1). Deoxyschizandrin (25, 50, 100,and 200 μmol·L(-1)) could inhibit the activation of NLRP3 infla

Topics: Caspase 1; Cells, Cultured; Cyclooctanes; Humans; Inflammasomes; Inflammation; Interleukin-1beta; Lignans; Macrophages; NLR Family, Pyrin Domain-Containing 3 Protein; Polycyclic Compounds; Transcription Factor RelA

Fargesin is a lignan from Magnolia fargesii, an oriental medicine used in the treatment of nasal congestion and sinusitis. The anti-inflammatory properties of this compound have not been fully elucidated yet.. This study focused on assessing the anti-inflammatory effects of fargesin on phorbal ester (PMA)-stimulated THP-1 human monocytes, and the molecular mechanisms underlying them.. Cell viability was evaluated by MTS assay. Protein expression levels of inflammatory mediators were analyzed by Western blotting, ELISA, Immunofluorescence assay. mRNA levels were measured by Real-time PCR. Promoter activities were elucidated by Luciferase assay.. It was found that pre-treatment with fargesin attenuated significantly the expression of two major inflammatory mediators, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Fargesin also inhibited the production of pro-inflammation cytokines (IL-1β, TNF-α) and chemokine (CCL-5). Besides, nuclear translocation of transcription factors nuclear factor-kappa B (NF-ĸB) and activator protein-1 (AP-1), which regulate multiple pro-inflammatory genes, was suppressed by fargesin in a PKC-dependent manner. Furthermore, among the mitogen-activated protein kinases (MAPKs), only c-Jun N-terminal kinase (JNK) was downregulated by fargesin in a PKC-dependent manner, and this reduction was involved in PMA-induced AP-1 and NF-ĸB nuclear translocation attenuation, demonstrated using a specific JNK inhibitor.. Taken together, our results found that fargesin exhibits anti-inflammation effects on THP-1 cells via suppression of PKC pathway including downstream JNK, nuclear factors AP-1 and NF-ĸB. These results suggest that fargesin has anti-inflammatory properties with potential applications in drug development against inflammatory disorders.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Humans; Inflammation; Lignans; Magnolia; Mice; Monocytes; Phytotherapy; Plant Extracts; Signal Transduction

Pollution, especially cigarette smoke, is a major cause of skin damage.. To assess the effects of the small molecule polyphenol, honokiol, on reversing cigarette smoke-induced damage in vitro to relevant skin cells.. Keratinocytes (HaCat) cultures were exposed to cigarette smoke and, after 48 hours, IL-1α and IL-8 were measured in cell supernatants. Moreover, TIMP-2 production, apoptosis rate, and senescence β-galactosidase expression were evaluated in primary human foreskin fibroblasts (HFF-1) cultures.. Honokiol at 10 μm reduced IL-1α production by 3.4 folds (P < 0.05) and at 10 and 20 μm reduced IL-8 by 23.9% and 53.1% (P < 0.001), respectively, in HaCat keratinocytes. In HFF-1, honokiol restored TIMP-2 production by 96.9% and 91.9% (P < 0.001), respectively, at 10 and 20 μm, as well as reduced apoptosis by 47.1% (P < 0.001) and 41.3% (P < 0.01), respectively. Finally, honokiol reduced senescence-associated β-galactosidase expression in HFF-1.. Honokiol protects both HFF-1 and HaCat against cigarette smoke-induced inflammation, collagenolysis, apoptosis, and senescence.

Topics: Antioxidants; Apoptosis; beta-Galactosidase; Biphenyl Compounds; Cells, Cultured; Cellular Senescence; Fibroblasts; Humans; Inflammation; Interleukin-1alpha; Interleukin-8; Lignans; Tissue Inhibitor of Metalloproteinase-2; Tobacco Smoke Pollution

Two new secolignans, urticin A (1) and urticin B (2), were isolated from the ethanol extract of Urtica fissa rhizomes. Their structures were elucidated on the basis of extensive spectroscopic evidence (UV, IR, HR-ESI-MS, and NMR). Urticin A and urticin B possessed in vitro anti-inflammatory activities, which significantly inhibited the TNF-α and NO release induced by LPS in RAW 264.7 cells.

Topics: Animals; Anti-Inflammatory Agents; Inflammation; Lignans; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Mice; Nitric Oxide; Plant Extracts; RAW 264.7 Cells; Rhizome; Tumor Necrosis Factor-alpha; Urticaceae

To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis.. Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloe-emodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated.. The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (. DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

Topics: Acute Disease; Alanine Transaminase; Animals; Anthraquinones; Aspartate Aminotransferases; Biphenyl Compounds; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Emodin; Flavanones; Hesperidin; Inflammation; Lignans; Liver; Male; Pancreatitis; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Schisandrin B (Sch B), a dibenzocyclooctadiene lignan isolated from Schisandra chinensis (Turcz.) Baill, has been shown to have anti-inflammatory effect. The purpose of this study was to evaluate the effect of Sch B on LPS-induced inflammation in microglia and to investigate the molecular targets of Sch B. BV2 cells were stimulated by LPS in the presence or absence of Sch B. The results showed that the levels of TNF-α, IL-6, IL-1β, and PGE

Topics: Anti-Inflammatory Agents; Cell Line; Cyclooctanes; Enzyme Activation; Humans; Inflammation; Lignans; Lipopolysaccharides; Microglia; Polycyclic Compounds; PPAR gamma

The association of polyphenol content of human diet with low-grade inflammation is not yet fully understood. It was the objective of this study to evaluate the association of flavonoid and lignan intake with frequently used and easily applicable in clinical practice low-grade inflammation biomarkers, in a novel holistic approach. A total of 5,948 women and 5,965 men (aged ≥ 35 years) were analysed from the Moli-sani cohort, randomly recruited from the general population. The EPIC-FFQ was used for dietary assessment. Flavonol, flavone, flavanone, flavanol, anthocyanin, isoflavone and lignan intakes were calculated using Eurofir eBASIS and the polyphenol antioxidant content (PAC)-score was constructed to assess the total content of diet in these nutrients. CRP levels, WBC and PLT count and granulocyte to lymphocyte ratio were conceived as low-grade inflammation biomarkers. INFLA-score was constructed summarizing synergistic effects of these biomarkers. The INFLA-score was negatively associated with PAC-score in different levels of adjustment, in both genders (for all β-coef<0, P<0.05). 10 units increase in PAC-score was associated with 5-8% decrease in the likelihood of higher low-grade inflammation status (i.e. higher quartile of INFLA-score) in men and women (odds ratio [ORs] 0.92 to 0.95, p<0.05). The total variation of INFLA-score that was explained by PAC-score was estimated to be 16.7% in women and 9.1% in men (%R²=16.7 and 9.1). In conclusion, polyphenol content of diet evaluated in a holistic approach was negatively associated with a score of low-grade inflammation biomarkers in a large population based study. For the first time low-grade inflammation was evaluated in a holistic way through INFLA-score and was associated with polyphenol content of diet.

Topics: Adult; Aged; Antioxidants; Biomarkers; Cohort Studies; Diet; Female; Flavonoids; Granulocytes; Humans; Inflammation; Italy; Lignans; Male; Middle Aged; Odds Ratio; Polyphenols; Risk Factors; Sex Factors; Surveys and Questionnaires

In 2009, swine flu (H1N1) had spread significantly to levels that threatened pandemic influenza. There have been many treatments that have arisen for patients since the WHO first reported the disease. Although some progress in controlling influenza has taken place during the last few years, the disease is not yet under control. The development of new and less expensive anti-influenza drugs is still needed. Here, we show that sesamin from the seeds of the Thai medicinal plant Sesamum indicum has anti-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) induced by 2009 influenza virus type A H1N1. In this study, the combinatorial screening method combined with the computational approach was applied to investigate the new molecular binding structures of sesamin against the 2009 influenza virus type A H1N1 (p09N1) crystallized structure. Experimental methods were applied to propose the mechanisms of sesamin against cytokine production from H1N1-induced human PBMC model. The molecular dynamics simulation of sesamin binding with the p09N1 crystallized structure showed new molecular binding structures at ARG118, ILE222, ARG224, and TYR406, and it has been proposed that sesamin could potentially be used to produce anti-H1N1 compounds. Furthermore, the mechanisms of sesamin against cytokine production from influenza type A H1N1-induced PBMCs by ELISA and signaling transduction showed that sesamin exhibits the ability to inhibit proinflammatory cytokines, IL-1β and TNF-α, and to enhance the activity of the immune cell cytokine IL-2 via downregulating the phosphorylated JNK, p38, and ERK1/2 MAPK signaling pathways. This information might very well be useful in the prevention and treatment of immune-induced inflammatory disorders.

Topics: Animals; Crystallography, X-Ray; Dioxoles; Humans; Inflammation; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-1beta; Interleukin-2; Leukocytes, Mononuclear; Lignans; Models, Molecular; Molecular Dynamics Simulation; Orthomyxoviridae Infections; Signal Transduction; Swine; Swine Diseases; Tumor Necrosis Factor-alpha

Honokiol is the predominant active ingredient in the commonly used traditional Chinese medicine, Magnolia, which has been confirmed in previous studies to exhibit anti-oxidation, antimicrobial, antitumor and other pharmacological effects. However, its effects on renal ischemia/reperfusion injury (IRI) remain to be elucidated. The present study aimed to examine the effects of honokiol on renal IRI, and to investigate its potential protective mechanisms in the heart. Male adult Wistar albino rats were induced into a renal IRI model. Subsequently, the levels of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), and the levels of serum nitrite and the kidney nitrite were examined in the IRI group. The levels of oxidative stress, inducible nitric oxide synthase (iNOS), inflammatory factors and caspase-3 were evaluated using a series of commercially available kits. The levels of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and the protein expression levels of STAT3 were determined using western blotting. Pretreatment with honokiol significantly reduced the levels of serum creatinine, BUN, ALT, AST and ALP, and the level of nitrite in the kidney of the IRI group, compared with the control group. The levels of malondialdehyde, the activity of myeloperoxidase, and the gene expression and activity of iNOS were reduced in the IRI rats, compared with the sham-operated rats, whereas the levels of superoxide dismutase and catalase were increased following treatment with honokiol in the IRI rats. In addition, the expression levels of tumor necrosis factor-α and interleukin-6 in the IRI rats were increased by honokiol. Treatment with honokiol suppressed the protein expression levels of p-STAT3 and caspase-3 in the IRI rats. These findings indicated that honokiol protects against renal IRI via the suppression of oxidative stress, iNOS, inflammation and STAT3 in the rat.

Topics: Animals; Biphenyl Compounds; Gene Expression Regulation; Humans; Inflammation; Kidney; Lignans; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Reperfusion Injury; STAT3 Transcription Factor

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2(+/mu) mice. Mice (n = 16-17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.

Topics: Animals; Antioxidants; Asbestos, Crocidolite; Butylene Glycols; Chromatography, Liquid; Diet; Dietary Supplements; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flax; Glucosides; Inflammation; Lignans; Mesothelioma; Mice; Mice, Mutant Strains; Oxidative Stress; Peritoneal Lavage; Peritoneum; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; Seeds; Tandem Mass Spectrometry; Transcriptome

Microglial-mediated neuroinflammation has been established as playing a vital role in pathogenesis of neurodegenerative disorders. Thus, rational regulation of microglia functions to inhibit inflammation injury may be a logical and promising approach to neurodegenerative disease therapy. The purposes of the present study were to explore the neuroprotective effects and potential molecular mechanism of Schizandrin A (Sch A), a lignin compound isolated from Schisandra chinesnesis. Our observations showed that Sch A could significantly down-regulate the increased production of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-6 induced by lipopolysaccharide (LPS) both in BV-2 cells and primary microglia cells. Moreover, Sch A exerted obvious neuroprotective effects against inflammatory injury in neurons when exposed to microglia-conditioned medium. Investigations of the mechanism showed the anti-inflammatory effect of Sch A involved the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression levels and inhibition of the LPS-induced TRAF6-IKKβ-NF-κB pathway. Furthermore, inhibition of Jak2-Stat3 pathway activation and Stat3 nuclear translocation also was observed. In conclusion, SchA can exert anti-inflammatory and neuroprotective effects by alleviating microglia-mediated neuroinflammation injury through inhibiting the TRAF6-IKKβ-NF-κB and Jak2-Stat3 signaling pathways.

Topics: Animals; Animals, Newborn; Brain; Cells, Cultured; Cyclooctanes; Down-Regulation; Inflammation; Inflammation Mediators; Janus Kinase 2; Lignans; Lipopolysaccharides; Mice; Mice, Inbred ICR; Microglia; Neuroprotection; NF-kappa B; Polycyclic Compounds; RAW 264.7 Cells; Signal Transduction; STAT3 Transcription Factor; TNF Receptor-Associated Factor 6

(7R, 8S)-9-Acetyl-dehydrodiconiferyl alcohol (ADDA), a novel lignan compound isolated from Clematis armandii Franch (Ranunculaceae) stems, has been found to exert potential anti-inflammatory activities in vitro.. To investigate the pharmacological effects and molecular mechanisms of ADDA on lipopolysaccharide (LPS)-induced activation and migration of macrophages.. Macrophages were stimulated with LPS in the presence or absence of ADDA. Expression of inflammatory mediators, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) were measured by Western blot and commercial NO detection kit. Cellular viability and chemotactic properties of macrophages were investigated using MTT and transwell migration assays. The activation and expression of mitogen activated protein kinases, nuclear factor-κB (NF-κB), protein kinase B (Akt), Src, and focal adhesion kinase (FAK) were analyzed by Western blot.. Non-toxic concentrations (12.5-50 µM) of ADDA concentration-dependently inhibited expression/release of inflammatory mediators (COX-2, iNOS, and NO), suppressed Akt and c-jun N-terminal kinase 1/2 (JNK) phosphorylation, and NF-κB activation in LPS-stimulated macrophages. In addition, ADDA blocked LPS-mediated macrophage migration and this was associated with inhibition of LPS-induced Src and FAK phosphorylation as well as Src expression in a concentration dependent manner. Notably, the inhibitory effects of ADDA on iNOS, NO, and Src could be mimicked by a Src inhibitor PP2 or an iNOS inhibitor l-NMMA.. Our results suggested that ADDA attenuated LPS-induced inflammatory responses in macrophages and cell migration, at least in part, through inhibition of NF-κB activation and modulation of iNOS/Src/FAK axis.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Clematis; Cyclooxygenase 2; Inflammation; Lignans; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Plant Stems; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells

Intervertebral disc (IVD) degeneration contributes to most spinal degenerative diseases, while treatment inhibiting IVD degeneration is still in the experimental stage. Sesamin, a bioactive component extracted from sesame, has been reported to exert chondroprotective and anti-inflammatory effects. Here, we analyzed the anti-inflammatory and anti-catabolic effects of sesamin on rat IVD in vitro and ex vivo. Results show that sesamin significantly inhibits the lipopolysaccharide (LPS)-induced expression of catabolic enzymes (MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5) and inflammation factors (IL-1β, TNF-α, iNOS, NO, COX-2, PGE2) in a dose-dependent manner in vitro. It is also proven that migration of macrophages induced by LPS can be inhibited by treatment with sesamin. Organ culture experiments demonstrate that sesamin protects the IVD from LPS-induced depletion of the extracellular matrix ex vivo. Moreover, sesamin suppresses LPS-induced activation of the mitogen-activated protein kinase (MAPK) pathway through inhibiting phosphorylation of JNK, the common downstream signaling pathway of LPS and IL-1β, which may be the potential mechanism of the effects of sesamin. In light of our results, sesamin protects the IVD from inflammation and extracellular matrix catabolism, presenting positive prospects in the treatment of IVD degenerative diseases.

Topics: Animals; Cell Movement; Cell Survival; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Dioxoles; Enzyme Activation; Extracellular Matrix; Inflammation; Interleukin-1beta; Intervertebral Disc; Intervertebral Disc Degeneration; JNK Mitogen-Activated Protein Kinases; Lignans; Lipopolysaccharides; Macrophages; MAP Kinase Signaling System; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Nucleus Pulposus; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Schisandrin A (Sch A) and schisandrin B (Sch B) are active components of Schisandrae Fructus. We compared the biochemical mechanism underlying the anti-inflammatory action of Sch A and Sch B, using cultured lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and concanavalin (ConA)-stimulated mouse splenocytes. Pre-incubation with Sch A or Sch B produced an anti-inflammatory action in LPS-stimulated RAW264.7 cells, as evidenced by the inhibition of the pro-inflammatory c-Jun N-terminal kinases/p38 kinase/nuclear factor-κB signaling pathway as well as the suppression of various pro-inflammatory cytokines and effectors, with the extent of inhibition by Sch A being more pronounced. The greater activity of Sch A in anti-inflammatory response was associated with a greater decrease in cellular reduced glutathione (GSH) level and a greater increase in glutathione S-transferase activity than corresponding changes produced by Sch B. However, upon incubation, only Sch B resulted in the activation of the nuclear factor (erythroid-derived 2)-like factor 2 and the induction of a significant increase in the expression of thioredoxin (TRX) in RAW264.7 cells. The Sch B-induced increase in TRX expression was associated with the suppression of pro-inflammatory cytokines and effectors in LPS-stimulated macrophages. Studies in a mouse model of inflammation (carrageenan-induced paw edema) indicated that while long-term treatment with either Sch A or Sch B suppressed the extent of paw edema, only acute treatment with Sch A produced a significant degree of inhibition on the inflammatory response. Although only Sch A decreased the cellular GSH level and suppressed the release of pro-inflammatory cytokines and cell proliferation in ConA-simulated splenocytes in vitro, both Sch A and Sch B treatments, while not altering cellular GSH levels, suppressed ConA-stimulated splenocyte proliferation ex vivo. These results suggest that Sch A and Sch B may act differentially on activating GST/ depleting cellular GSH and inducing an antioxidant response involved in their anti-inflammatory actions.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Antioxidants; Concanavalin A; Cyclooctanes; Cytokines; Edema; Enzyme-Linked Immunosorbent Assay; Female; Glutathione; Glutathione Transferase; Inflammation; Lignans; Lipopolysaccharides; Mice; Mice, Inbred ICR; Polycyclic Compounds; RAW 264.7 Cells

The present investigation of the chemical constituents of the stem barks of Ailanthus altissima has resulted in the isolation of six canthinone-type alkaloids, including a new compound, (R)-5-(1-hydroxyethyl)-canthine-6-one (1), and five known compounds (2-6). Moreover, four phenyl propanoids (7-10), two lignans (11 and 12), two triterpenoids (13 and 14) and a fatty acid (15) having previously known chemical structures were isolated during the same course of this study. The structure of the new compound was elucidated by physical (m.p., [α]D) and spectroscopic data (¹H-NMR, (13)C-NMR, 2D NMR, and HR-DART-MS) interpretation and its absolute configuration was determined by electronic circular dichroism (ECD) data and quantum chemical calculations. The inflammatory activities of the isolates were screened on lipopolysaccharide (LPS)-induced nitric oxide (NO), a proinflammatory mediator, in RAW 264.7 cells. Among these isolated compounds, six compounds exhibited significant inhibition of NO production, with IC50 values in the range of 5.92 ± 0.9 to 15.09 ± 1.8 μM.

Topics: Ailanthus; Alkaloids; Animals; Inflammation; Lignans; Magnetic Resonance Spectroscopy; Mice; Plant Bark; Plant Extracts; Propanols; RAW 264.7 Cells; Triterpenes

Nonalcoholic fatty liver disease (NAFLD) is defined by a nonalcohol relevant pathological accumulation of fat in the liver. Previous studies have shown that sesamin exerts antioxidant effects and improves lipid metabolism of the fatty liver. In this study, we hypothesized that sesamin improves lipid homeostasis of Sprague-Dawley rats fed a high-fat diet (HFD) by regulating the expression of genes related to de novo lipogenesis and β-oxidation. We induced NAFLD in rats with HFD and examined the effect of sesamin in vivo. The results showed that HFD rats accumulated total cholesterol and triacylglycerols in the liver and developed inflammation, as evidenced by the elevation of interleukin-6 and tumor necrosis factor-α in the liver and serum. Sesamin attenuated the disease progression by improving the blood lipid profile in a dose-dependent manner. Sesamin reduced the serum levels of total cholesterol, triacylglycerols, low-density lipoprotein cholesterol, and free fatty acid, whereas it increased the level of high-density lipoprotein cholesterol. Meanwhile, sesamin increased the activities of hepatic glutathione peroxidase and superoxide dismutase while reducing the level of malonaldehyde and cytochrome P450 2E1. Furthermore, higher doses of sesamin reduced the expression of liver X receptor α and its downstream target genes, whereas it upregulated the peroxisome proliferator-activated receptor α-mediated signaling. These findings suggest that sesamin attenuates diet-induced dyslipidemia and inflammation of NAFLD in rats via mechanisms regulated by liver X receptor α and peroxisome proliferator-activated receptor α.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytochrome P-450 CYP2E1; Diet, High-Fat; Dioxoles; Dyslipidemias; Hypolipidemic Agents; Inflammation; Interleukin-6; Lignans; Lipid Metabolism; Lipids; Lipogenesis; Liver; Liver X Receptors; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phytotherapy; Plant Extracts; PPAR alpha; Rats, Sprague-Dawley; Sesamum; Tumor Necrosis Factor-alpha

Emotional impairments such as depressive symptoms often develop in patients with sustained and systemic immune activation. The objective of this study is to investigate the effect of gomisin N, a dibenzocyclooctadiene lignan isolated from the dried fruits of Schisandra chinensis (Turcz.) Baill., which exhibited inhibitory effects of the bacterial endotoxin lipopolysaccharide (LPS)-induced NO production in a screening assay, on inflammation-induced depressive symptoms. We examined the effects of gomisin N on inflammation induced by LPS in murine microglial BV-2 cells and on LPS-induced behavioral changes in mice. Gomisin N inhibited LPS-induced expression of mRNAs for inflammation-related genes (inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α) in BV-2 cells. Administration of gomisin N attenuated LPS-induced expression of mRNAs for inflammation-related genes, increases in the number of c-Fos immunopositive cells in the hypothalamus and amygdala, depressive-like behavior in the forced swim test and exploratory behavior deficits 24 h after LPS administration in mice. These results suggest that gomisin N might ameliorate LPS-induced depressive-like behaviors through inhibition of inflammatory responses and neural activation in the hypothalamus and amygdala.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Central Amygdaloid Nucleus; Cyclooctanes; Depression; Dose-Response Relationship, Drug; Inflammation; Inflammation Mediators; Lignans; Lipopolysaccharides; Male; Mice; Paraventricular Hypothalamic Nucleus; Plant Extracts; Polycyclic Compounds; Schisandra

Phyllanthin found in many Phyllanthus species has various biochemical and pharmacological properties especially on its hepatoprotective effects. However, its effect on the immune system has not been well documented.. In the present study, phyllanthin isolated from Phyllanthus amarus was investigated for its immunosuppressive effects on various cellular and humoral immune responses in Balb/C mice.. Male mice were treated daily at 20, 40 and 100mg/kg of phyllanthin for 14 days by oral gavage. The effects of phyllanthin on cellular immune responses in treated /non treated mice were determined by measuring CD 11b/CD 18 integrin expression, phagocytosis, nitric oxide (NO) production, myeloperoxidase activity (MPO), T and B cells proliferation, lymphocyte phenotyping, serum cytokines production by activated T-cells and delayed type hypersensitivity (DTH). Its effects on humoral immune responses were evaluated by determining the serum levels of lysozyme and ceruloplasmin, and immunoglobulins (IgG and IgM).. The strong inhibitory effects of phyllanthin on the cellular and humoral immune responses suggest that phyllanthin may be a good candidate for development into an effective immunosuppressive agent.

Topics: Animals; CD4-CD8 Ratio; Cytokines; Down-Regulation; Erythrocytes; Escherichia coli; Hypersensitivity, Delayed; Immunity, Cellular; Immunity, Humoral; Immunoglobulins; Inflammation; Lignans; Lymphocyte Activation; Male; Mice, Inbred BALB C; Phyllanthus; Plant Extracts; Sheep

Deoxyschizandrin as one of the most important component of Schisandra chinensis (Turcz.) Baill plays an immunomodulatory role in a variety of diseases, yet its role in ulcerative colitis remains to be elucidated. We aimed to investigate the role of deoxyschizandrin in DSS-induced ulcerative colitis in mice.. In the present study, an inflammation model of cells was constructed to confirm the anti-inflammatory effect of deoxyschizandrin. Then a mouse model with Dextran sulfate sodium sulfate (DSS)-induced ulcerative colitis was constructed, and the effects of deoxyschizandrin on mouse colon inflammation, apoptosis, and CD4 T lymphocyte infiltration in ulcerative colitis were examined.. Deoxyschizandrin could improve the symptoms of ulcerative colitis, determined by hematoxylin-eosin (HE) staining and histopathological scores. Moreover, deoxyschizandrin reduced the levels of inflammatory cytokines, suppressed CD4 T cell infiltration, and effectively inhibited apoptosis in the colon of DSS-induced ulcerative colitis mice.. In summary, deoxyschizandrin can effectively rescue the symptoms of DSS-induced ulcerative colitis in mice by inhibiting inflammation. T cell infiltration and apoptosis in the colon, suggesting that deoxyschizandrin could be a potential drug in treating ulcerative colitis.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; CD4-Positive T-Lymphocytes; Cell Line; Colitis, Ulcerative; Cyclooctanes; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Gene Expression Regulation; Inflammation; Lignans; Mice; Mice, Inbred C57BL; Polycyclic Compounds

4-O-methylhonokiol (MH) is known to inhibit inflammation by partially understood mechanisms. Here, the anti-inflammatory mechanisms of MH were examined using enzymatic, cellular, and animal assays. In enzymatic assays, MH inhibited COX-2 activity with an IC50 of 0.062 μM, and also COX-1 with an IC50 of 2.4 μM. In cellular assays, MH was immunotoxic above 10 μM. At non-toxic concentrations (below 3 μM), MH strongly inhibited COX-2-mediated prostaglandin production with an IC50 of 0.1 μM, whereas did not or slightly affect other functions of B cells, T cells, dendritic cells, and macrophages. In an animal model, MH inhibited the increase in footpad thickness and popliteal lymph node weight in zymosan-injected mice. When analyzed the draining pLNs of zymosan-injected mice on day 5, MH inhibited the overall inflammatory responses. However, MH inhibited cyclooxygenase (COX)-2-mediated prostaglandin production without affecting tumor necrosis factor-α production in inflamed tissues within 6 h after zymosan injection. In summary, our data suggest that COX-2 may be a direct anti-inflammatory target of MH in vitro and in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Inflammation; Lignans; Macrophages; Mice; Mice, Inbred C57BL; Zymosan

Mastitis comprises an inflammation of the mammary gland, which is almost always linked with bacterial infection. The treatment of mastitis concerns antimicrobial substances, but not very successful. On the other hand, anti-inflammatory therapy with Chinese traditional medicine becomes an effective way for treating mastitis. Magnolol is a polyphenolic binaphthalene compound extracted from the stem bark of Magnolia sp., which has been shown to exert a potential for anti-inflammatory activity. The purpose of this study was to investigate the protective effects of magnolol on inflammation in lipopolysaccharide (LPS)-induced mastitis mouse model in vivo and the mechanism of this protective effects in LPS-stimulated mouse mammary epithelial cells (MMECs) in vitro. The damage of tissues was determined by histopathology and myeloperoxidase (MPO) assay. The expression of pro-inflammatory cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and Toll-like receptor 4 (TLR4) were determined by Western blot. The results showed that magnolol significantly inhibit the LPS-induced TNF-α, IL-6, and IL-1β production both in vivo and vitro. Magnolol declined the phosphorylation of IκBα, p65, p38, ERK, and JNK in LPS-stimulated MMECs. Furthermore, magnolol inhibited the expression of TLR4 in LPS-stimulated MMECs. In vivo study, it was also observed that magnolol attenuated the damage of mastitis tissues in the mouse models. These findings demonstrated that magnolol attenuate LPS-stimulated inflammatory response by suppressing TLR4/NF-κB/mitogen-activated protein kinase (MAPK) signaling system. Thereby, magnolol may be a therapeutic agent against mastitis.

Topics: Animals; Biphenyl Compounds; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Inflammation; Lignans; Male; Mammary Glands, Animal; Mastitis; Mice; Mice, Inbred BALB C

Preventing pathologic tissue inflammation is key to treating obesity-induced insulin resistance and type 2 diabetes. Previously, we synthesized a series of methylhonokiol analogs and reported that compounds with a carbamate structure had inhibitory function against cyclooxygenase-2 in a cell-free enzyme assay. However, whether these compounds could inhibit the expression of inflammatory genes in macrophages has not been investigated. Here, we found that a new 4-O-methylhonokiol analog, 3',5-diallyl-4'-methoxy-[1,1'-biphenyl]-2-yl morpholine-4-carboxylate (GS12021) inhibited LPS- or TNFα-stimulated inflammation in macrophages and adipocytes, respectively. LPS-induced phosphorylation of nuclear factor-kappa B (NF-κB)/p65 was significantly decreased, whereas NF-κB luciferase activities were slightly inhibited, by GS12021 treatment in RAW 264.7 cells. Either mitogen-activated protein kinase phosphorylation or AP-1 luciferase activity was not altered by GS12021. GS12021 increased the phosphorylation of AMP-activated protein kinase (AMPK) α and the expression of sirtuin (SIRT) 1. Inhibition of mRNA expression of inflammatory genes by GS12021 was abolished in AMPKα1-knockdown cells, but not in SIRT1 knockout cells, demonstrating that GS12021 exerts anti-inflammatory effects through AMPKα activation. The transwell migration assay results showed that GS12021 treatment of macrophages prevented the cell migration promoted by incubation with conditioned medium obtained from adipocytes. GS12021 suppression of p65 phosphorylation and macrophage chemotaxis were preserved in AMPKα1-knockdown cells, indicating AMPK is not required for these functions of GS12021. Identification of this novel methylhonokiol analog could enable studies of the structure-activity relationship of this class of compounds and further evaluation of its in vivo potential for the treatment of insulin-resistant states and other chronic inflammatory diseases.

Topics: Adenylate Kinase; Animals; Biphenyl Compounds; Cell Line; Chemotaxis; Cyclooxygenase 2; Enzyme Activation; Inflammation; Lignans; Lipopolysaccharides; Macrophages; Mice; Morpholines; Nitric Oxide Synthase Type II

Randomized experimental study.. To investigate the neuroprotective effect of honokiol (HNK) on rats subjected to traumatic spinal cord injury (SCI) and the molecular mechanisms.. Inflammation contributes to the secondary injury to the spinal cord. Honokiol has been used as a neuroprotective agent because of its strong antioxidant and anti-inflammatory properties. Kruppel-like factor 4 (Klf4) is a newly identified critical target for the anti-inflammatory effect of HNK. Whether HNK can inhibit inflammatory response in rat model of SCI through mediating the expression of Klf4 has yet to be elucidated.. Eighty-four adult female Sprague-Dawley rats were randomly divided into 4 groups as sham, SCI, SCI + Vehicle (0.1% propylene glycol in saline, intraperitoneally), and SCI + HNK (20 mg/kg, intraperitoneally) groups. The influences of HNK on the proinflammatory cytokines, microglial activation, neutrophil infiltration, histological changes, and improvement in motor function were assessed.. In the SCI group, proinflammatory cytokines, microglial activation, neutrophil infiltration, and Klf4 expression levels were increased compared with the sham group (P < 0.001). HNK intervention downregulated the expression of Klf4, reduced the production of proinflammatory cytokines, inhibited microglial activation, and neutrophil infiltration (P < 0.05). Furthermore, HNK also reduced histopathology and improved functional outcome after traumatic SCI.. HNK reduces secondary tissue damage and improves locomotor function recovery after SCI through suppressing inflammatory response, and can be used as a potential therapeutic agent for SCI.. NA.

Topics: Animals; Antioxidants; Biphenyl Compounds; Cytokines; Down-Regulation; Female; Inflammation; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lignans; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries

Inflammatory events involving activated microglia have been recognized to play an important role in pathogenesis of various neurodegenerative disorders including Parkinson disease. Compounds regulating activation profiles of microglia may provide therapeutic benefits for Parkinson disease characterized by degeneration of midbrain dopaminergic neurons. Here we examined the effect of macelignan, a compound derived from nutmeg, on inflammatory degeneration of midbrain dopaminergic neurons. Treatment of midbrain slice cultures with interferon (IFN)-γ and lipopolysaccharide (LPS) caused a substantial decrease in viable dopaminergic neurons and an increase in nitric oxide (NO) production indicated by extracellular nitrite accumulation. Application of macelignan (10 μM) concomitantly with LPS prevented the loss of dopaminergic neurons. Besides nitrite accumulation, up-regulation of inducible NO synthase protein expression in response to IFN-γ/LPS was confirmed by Western blotting, and immunohistochemical examination revealed expression of inducible NO synthase in a subpopulation of Iba-1-poitive microglia. However, macelignan did not affect any of these NO-related parameters. On the other hand, macelignan promoted expression of arginase-1 in midbrain slice cultures irrespective of the presence or the absence of IFN-γ/LPS treatment. Arginase-1 expression was mainly localized in a subpopulation of Iba-1-positive cells. Importantly, the neuroprotective effect of macelignan was antagonized by N(ω)-hydroxy-nor-L-arginine, a specific arginase inhibitor. The neuroprotective effect of macelignan was also prevented by GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Overall, these results indicate that macelignan, a compound with PPARγ agonist activity, can provide neuroprotective effect on dopaminergic neurons in an arginase-dependent but NO-independent manner.

Topics: Animals; Animals, Newborn; Arginase; Dopaminergic Neurons; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Inflammation; Lignans; Mesencephalon; Microglia; Nerve Degeneration; Neuroprotective Agents; Organ Culture Techniques; Rats; Rats, Wistar

Transforming growth factor-β1 (TGF-β1) induces expression of the proinflammatory and profibrotic cytokine monocyte chemoattractant protein-1 (MCP-1) in tubular epithelial cells (TECs) and thereby contributes to the tubular epithelial-mesenchymal transition (EMT), which in turn leads to the progression of tubulointerstitial inflammation into tubulointerstitial fibrosis. Exactly how TGF-β1 causes MCP-1 overexpression and subsequent EMT is not well understood. Using human tubular epithelial cultures, we found that TGF-β1 upregulated the expression of reduced nicotinamide adenine dinucleotide phosphate oxidases 2 and 4 and their regulatory subunits, inducing the production of reactive oxygen species. These reactive species activated a signaling pathway mediated by extracellular signal-regulated kinase (ERK1/2) and nuclear factor-κB (NF-κB), which upregulated expression of MCP-1. Incubating cultures with TGF-β1 was sufficient to induce hallmarks of EMT, such as downregulation of epithelial marker proteins (E-cadherin and zonula occludens-1), induction of mesenchymal marker proteins (α-smooth muscle actin, fibronectin, and vimentin), and elevated cell migration and invasion in an EMT-like manner. Overexpressing MCP-1 in cells exposed to TGF-β1 exacerbated these EMT-like changes. Pretreating cells with the antioxidant and anti-inflammatory compound arctigenin (ATG) protected them against these TGF-β1-induced EMT-like changes; the compound worked by inhibiting the ROS/ERK1/2/NF-κB pathway to decrease MCP-1 upregulation. These findings suggest ATG as a new therapeutic candidate to inhibit or even reverse tubular EMT-like changes during progression to tubulointerstitial fibrosis, and they provide the first clues to how ATG may work.

Topics: Antigens, CD; Antioxidants; Cadherins; Cell Movement; Chemokine CCL2; Epithelial Cells; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Furans; Gene Expression Regulation; Humans; Inflammation; Kidney Tubules; Lignans; Membrane Glycoproteins; Microscopy, Fluorescence; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; NF-kappa B; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta1; Zonula Occludens-1 Protein

The current study was aimed at evaluating the antihyperalgesic effects of lignans (phyllanthin and hypophyllanthin) and tannin (corilagin) rich three standardized extracts of Phyllanthus amarus in a model of chronic musculoskeletal inflammatory pain. Three percent carrageenan injected in the gastrocnemius muscle produced hyperalgesia to mechanical and heat stimuli ipsilaterally, which spreads to the contralateral side within 7 to 9 days. To investigate the effects on chronic thermal and mechanical hypersensitivity, three extracts of P. amarus in three doses (100, 200, and 400 mg/kg) were administered to animals intraperitoneally from 14th day to 22nd day after intramuscular injection of carrageenan. It was observed that intraperitoneal administrations of Phyllanthus extracts showed antihyperalgesic activity, as they elevated thermal and mechanical threshold, which was supported by histopathological observations along with reduction in prostaglandin E2 (PGE2) concentration. In conclusion, we strongly suggest that the observed antihyperalgesic and antiinflammatory effects of P. amarus in current pain model are mediated via spinal or supraspinal neuronal mechanisms, mainly by inhibition of PGE2. Modulation of chronic muscular inflammation may be due to presence of phytoconstituents like phyllanthin, hypophyllanthin, and corilagin, which offers a promising means for treatment of chronic muscle pain.

Topics: Animals; Carrageenan; Dinoprostone; Disease Models, Animal; Glucosides; Hydrolyzable Tannins; Hyperalgesia; Inflammation; Lignans; Male; Muscle, Skeletal; Musculoskeletal Pain; Pain; Phyllanthus; Rats, Wistar

A new γ-alkylated-γ-butyrolactone, named melongenolide A (1), along with nine known compounds were obtained from the roots of Solanum melongena, and their structures were identified as melongenolide A (1), (+)-syringaresinol (2), (+)-lyoniresinol (3), 5,5'-dimethoxy lariciresinol (4), (+)-(7R,8R)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneoligna-7, 9-diol-7'-aldehyde (5), kaempferol-3-O-(2″,6″-di-O-p-trans-coumaroyl)-β-glucoside (6), arjunolic acid (7), vanillic acid (8), scoparone (9), and β-sitosterol (10). Compounds 2, 6, and 7 showed potent inhibitory effects on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages, with IC50 values being 5.62 ± 0.86, 11.47 ± 0.98, and 27.75 ± 1.26 μmol·L(-1), respectively.

Topics: 4-Butyrolactone; Animals; Furans; Inflammation; Inhibitory Concentration 50; Kaempferols; Lignans; Macrophages; Mice; Nitric Oxide; Plant Extracts; Plant Roots; RAW 264.7 Cells; Solanum melongena; Triterpenes

Three sulfated phenolic compounds, juglanin B (11R)-O-sulfate (1), myricetin 3´-O-sulfate (2), and ampelopsin 3´-O-sulfate (3), were isolated from the leaves of Myrica rubra. Compound 1 was a new sulfated lignan, 2 was a new sulfated flavone, and 3 was a known sulfated flavone. The structures of the new compounds (1 and 2) were determined by acid hydrolysis and spectroscopic methods, including IR, FAB-MS, 1D and 2D NMR. The inhibitory activities of compounds 1-3 and their hydrolysates (1a-3a) against LPS-induced cytokine (TNF-α, IL-1β, and IL-6) production in macrophage RAW 264.7 cells were evaluated. The 2 new compounds (1 and 2) and their aglycones (1a and 2a) significantly reduced LPS-induced expression of iNOS and COX-2 proteins.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cytokines; Flavones; Inflammation; Inflammation Mediators; Interleukins; Lignans; Lipopolysaccharides; Macrophages; Mice; Molecular Structure; Myrica; Nitric Oxide Synthase Type II; Phytotherapy; Plant Extracts; Plant Leaves; Sulfuric Acid Esters; Tumor Necrosis Factor-alpha

Chronic inflammation has been implicated in the etiology of various chronic diseases. We previously found that certain urinary isoflavones are associated with markers of inflammation. In the present study, we examined the associations of serum C-reactive protein (CRP) and white blood cell (WBC) count with lignans, which are more frequent in the Western diet than isoflavones.. Our analysis included 2,028 participants of NHANES 2005-2008 and 2,628 participants of NHANES 1999-2004 aged 18 years and older. The exposures of interest were urinary mammalian lignans (enterodiol and enterolactone). Outcome variables were two inflammatory markers (CRP [≤10 mg/L] and WBC [≥3.0 and ≤11.7 (1,000 cells/μL)]). Log-transformed CRP concentration and WBC count by log-transformed creatinine-standardized concentrations of mammalian lignans were used for linear regression.. Statistically significant inverse associations of urinary lignan, enterodiol, and enterolactone concentrations with circulating CRP and WBC counts were observed in the multivariate-adjusted models: In NHANES 2005-2008, per one-percent increase in lignan concentrations in the urine, CRP concentrations and WBC counts decreased by 8.1 % (95 % CI -11.5, -4.5) and 1.9 % (95 % CI -2.7; -1.2), respectively. Per one-percent increase in enterodiol and enterolactone, WBC counts decreased by 2.1 % (95 % CI -2.8, -1.3) and 1.3 % (95 % CI -1.9, -0.6), respectively. In NHANES 1999-2004, analogous results were 3.0 % (95 % CI -5.6, -0.3), 1.2 % (95 % CI -2.0; -0.4), 1.0 % (95 % CI -1.8, -0.2), and 0.8 % (95 % CI -1.4, 0.2).. Mammalian lignans were inversely associated with markers of chronic inflammation. Due to the cross-sectional design, our findings require confirmation in prospective studies.

Topics: 4-Butyrolactone; Adult; Aged; Biomarkers; C-Reactive Protein; Chronic Disease; Cross-Sectional Studies; Female; Humans; Inflammation; Leukocyte Count; Lignans; Male; Middle Aged; Nutrition Surveys; United States

Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the high mortality rate of sepsis. Honokiol, a natural product isolated from Magnolia officinalis (Houpo), has been shown to exhibit anti-inflammatory and antioxidant properties. Here, we investigated the effects of honokiol on sepsis-associated AKI in rats subjected to cecal ligation and puncture (CLP). We found that the administration of honokiol improved the survival of septic rats. Periodic acid-Schiff stain revealed that the morphological changes of kidney tissues in CLP rats were restored after honokiol treatment. Furthermore, honokiol reduced CLP-induced oxidative stress and inflammatory cytokine production. The levels of nitric oxide (NO) and inducible NO synthetase (iNOS) were attenuated by honokiol in septic rats. Finally, honokiol inhibited CLP-induced activation of NF-κB signaling in CLP rats. Our findings suggest that honokiol might be used as a potential therapeutic agent for complications of sepsis, especially for sepsis-induced AKI.

Topics: Acute Kidney Injury; Animals; Antioxidants; Biphenyl Compounds; Cytokines; Disease Models, Animal; Inflammation; Kidney; Lignans; Male; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sepsis; Signal Transduction

This study was designed to investigate the effect of w007B, a newly synthesized derivative of honokiol, on MCAO reperfusion, and its therapeutic time window and related mechanisms in rats. Neurological deficit scores, infarct size and brain water content were measured after 24 h reperfusion following 2 h ischemia. The results showed that w007B (10 and 50 μg/kg, IV immediately after reperfusion) markedly decreased neurological deficit scores, reduced infarct size and alleviated brain water content, and then 50 μg/kg w007B given within 3 h after reperfusion (5 h after ischemia) significantly attenuated ischemia-induced brain injury. Additionally, no sign of toxicity was observed when a single dose of 50mg/kg w007B (1000 times of the highest effective dose, IP) was administered. To explore the underlying mechanisms, the expression level of apoptosis, inflammation and autophagy-related markers in brain tissue were detected with kits or by western blot. It was observed that w007B rapidly and significantly reduced caspase-3 activity and NO production in the injured semi-brain, and also lowered the level of the p65 subunit of NF-κB in the nucleus. Besides, it also reduced the expression of Beclin-1 and LC3B-II, and increased the level of p62, the autophagy-related proteins in I/R-injured hemisphere. In conclusion, w007B exerts neuroprotective effect on cerebral ischemia-reperfusion injury with wider therapeutic time window and better safety; its mechanisms may be associated with its anti-inflammation, anti-apoptosis and anti-autophagy action. These results suggest that w007B shows strong potential as a clinical neuroprotective candidate for the treatment of ischemic stroke.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Body Weight; Cerebrovascular Circulation; Disease Models, Animal; Female; Inflammation; Lignans; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; NF-kappa B; Nitric Oxide; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sex Factors; Time Factors

The seeds of Vitex negundo L. (Verbenaceae) have been commonly used as a folk remedy for the treatment of rheumatism and joint inflammation in Traditional Chinese Medicine. This study aimed to evaluate the anti-arthritic activity of the extract of V. negundo seeds (EVNS) using Freund's complete adjuvant (CFA) induced arthritis (AA) in rat model. As a result, EVNS, with abundant phenylnaphthalene-type lignans, significantly inhibited the paw edema, decreased the arthritis score and spleen index, and reversed the weight loss of CFA-injected rats. Histopathological studies showed a marked decrease of synovial inflammatory infiltration and synovial lining hyperplasia in the joints of EVNS-treated animals. The remarkable decrement of serum inflammatory factors (TNF-α, IL-1β and IL-6) were observed in EVNS-treated rats, whereas, IL-10, an anti-inflammatory cytokine, was found to be significantly increased by EVNS. The expressions of COX-2 and 5-LOX in PBMC were also inhibited by administration of EVNS. Our results demonstrated that V. negundo seeds possessed potential therapeutic effect on adjuvant induced arthritis in rats by decreasing the levels of TNF-α, IL-1β and IL-6 and increasing that of IL-10 in serum as well as down-regulating the levels of COX-2 and 5-LOX, and therefore may be an effective cure for the treatment of human rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Cyclooxygenase 2; Down-Regulation; Edema; Freund's Adjuvant; Inflammation; Inflammation Mediators; Interleukins; Joints; Leukocytes, Mononuclear; Lignans; Lipoxygenases; Male; Naphthalenes; Phytotherapy; Plant Extracts; Rats, Wistar; Seeds; Synovial Membrane; Tumor Necrosis Factor-alpha; Vitex; Weight Loss

Since the increasing smoking rate among women has resulted in higher rates of embryonic malformations, it is important to search for an efficient and inexpensive agent that can help reduce the rate of serious fetal anomalies caused by maternal cigarette smoking. In this study, the bioavailability of 4-O-methylhonokiol isolated from Magnolia officinalis was first demonstrated in the mouse embryos exposed to nicotine using a whole embryo culture system.. Mouse embryos on embryonic day 8.5 were cultured with 1 mM nicotine and/or 4-O-methylhonokiol (1 × 10(-4) or 1 × 10(-3) μM) for 48 hr and were analyzed on the viewpoints of embryo developmental changes, oxidative damages, and apoptotic and inflammatory changes.. Embryos exposed to 1 mM nicotine developed not only severe morphological anomalies, increased expressions of tumor necrosis factor-α, interleukin-1β, and caspase 3 mRNAs; and elevated levels of lipid peroxidation, but also decreased levels of cytoplasmic superoxide dismutase, cytosolic glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, hypoxia inducible factor-1α, and B-cell lymphoma-extra large mRNAs, and reduced superoxide dismutase activity. However, these parameters were significantly improved when embryos exposed to the nicotine were concurrently treated with 4-O-methylhonokiol (1 × 10(-4) or 1 × 10(-3) μM).. These findings indicate that 4-O-methylhonokiol reduces serious embryo anomalies caused by nicotine in mouse embryos via the modulations of oxidative stress, apoptosis, and inflammation, suggesting that 4-O-methylhonokiol may be a preventive and therapeutic agent against the dysmorphology induced by maternal smoking during pregnancy.

Topics: Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Embryo Culture Techniques; Female; Glutathione Peroxidase; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-1beta; Lignans; Lipid Peroxidation; Lymphoma, B-Cell; Male; Mice; Mice, Inbred ICR; Nicotine; Organogenesis; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Sesame oil is widely consumed as nutritious food, cooking oil, and in pharmaceuticals and food. In this study, the antinociceptive and anti-inflammatory properties of the sesame oil and sesamin were investigated. The sesame oil and sesamin reduced the number of abdominal contortions at the doses 100, 200, or 400 mg/kg. The first and second phases of the time paw licking were inhibited by sesame oil and sesamin (100, 200, or 400 mg/kg). After 90 min of treatment, sesame oil and sesamin increased the reaction time on a hot plate (200 or 400 mg/kg). Considering the tail-immersion assay, the sesame oil and sesamin produced significant effect after 60 min at the doses of 100, 200, or 400 mg/kg. After 4 h of application of the carrageenan, the sesame oil and sesamin were effective against the paw edema. The exudate volume and leucocyte migration were also reduced by sesame oil and sesamin. These results suggest that sesamin is one of the active compounds found in sesame oil and justify the antinociceptive and anti-inflammatory properties of this product.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Dioxoles; Edema; Formaldehyde; Inflammation; Lignans; Male; Mice; Nociception; Pain; Pleurisy; Rats; Rats, Wistar; Sesame Oil; Toxicity Tests, Acute

Obesity is caused by a combination of both genetic and environmental risks. Disruption in energy balance is one of these risk factors. In the present study, the preventive effect on high-fat diet- (HFD-) induced obesity and insulin resistance in mice by Magnolia bioactive constituent 4-O-methylhonokiol (MH) was compared with Magnolia officinalis extract BL153. C57BL/6J mice were fed by normal diet or by HFD with gavage-administered vehicle, BL153, low-dose MH, and high-dose MH simultaneously for 24 weeks, respectively. Either MH or BL153 slightly inhibited body-weight gain of mice by HFD feeding although the food intake had no obvious difference. Body fat mass and the epididymal white adipose tissue weight were also mildly decreased by MH or BL153. Moreover, MH significantly lowered HFD-induced plasma triglyceride, cholesterol levels and activity of alanine transaminase (ALT), liver weight and hepatic triglyceride level, and ameliorated hepatic steatosis. BL153 only significantly reduced ALT and liver triglyceride level. Concurrently, low-dose MH improved HFD-induced hyperinsulinemia and insulin resistance. Furthermore, the infiltration of mast cells in adipose tissue was decreased in MH or in BL153 treatment. These results suggested that Magnolia bioactive constituent MH might exhibit potential benefits for HFD-induced obesity by improvement of lipid metabolism and insulin resistance.

Topics: Adipose Tissue; Adiposity; Animals; Biphenyl Compounds; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Fatty Liver; Feeding Behavior; Glucose Tolerance Test; Inflammation; Insulin; Insulin Resistance; Lignans; Lipid Metabolism; Magnolia; Male; Mice, Inbred C57BL; Obesity; Protective Agents; Triglycerides

Depression is an inflammatory, commonly occurring and lethal psychiatric disorder having high lifetime prevalence. Preclinical and clinical studies suggest that activation of immuno-inflammatory and oxido-nitrosative stress pathways play major role in the pathophysiology of depression. Honokiol (HNK) is a biphenolic neolignan possessing multiple biological activities including antioxidant, anti-inflammatory, anxiolytic, antidepressant and neuroprotective. The present study investigated the effect of HNK (2.5 and 5 mg/kg, i.p.) pretreatment (30 min prior to LPS) on lipopolysaccharide (LPS) (0.83 mg/kg, i.p.) induced depressive like behavior, neuroinflammation, and oxido-nitrosative stress in mice. HNK pretreatment at both the doses significantly attenuated LPS induced depressive-like behavior by reducing the immobility time in forced swim and tail suspension test, and by improving the anhedonic behavior observed in sucrose preference test. HNK pretreatment ameliorated LPS induced neuroinflammation by reducing IL-1β, IL-6 and TNF-α level in hippocampus (HC) and prefrontal cortex (PFC). HNK pretreatment prevented LPS evoked oxidative/nitrosative stress via improving reduced glutathione level along with reduction in the lipid peroxidation and nitrite level in HC and PFC. Pretreatment with HNK also prevented the increase in plasma corticosterone (CORT) and decrease in hippocampal BDNF level in LPS challenged mice. In conclusion, current investigation suggested that HNK pretreatment provided protection against LPS-induced depressive like behavior which may be mediated by repression of pro-inflammatory cytokines as well as oxido-nitrosative stress in HC and PFC. Our results strongly speculated that HNK could be a therapeutic approach for the treatment of depression and other pathophysiological conditions which are closely associated with neuroinflammation and oxido-nitrosative stress.

Topics: Animals; Antidepressive Agents; Biphenyl Compounds; Brain-Derived Neurotrophic Factor; Corticosterone; Depression; Disease Models, Animal; Glutathione; Hippocampus; Inflammation; Interleukin-1beta; Interleukin-6; Lignans; Lipid Peroxidation; Lipopolysaccharides; Mice; Nitrites; Oxidative Stress; Prefrontal Cortex; Tumor Necrosis Factor-alpha

In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders, cognitive deficits, chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C. In this article we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting a potential application in the treatment of both cannabis dependence and cannabis-related disorders.

Topics: Animals; Biphenyl Compounds; Cannabis; Humans; Inflammation; Lignans; Magnolia; Marijuana Abuse; Plant Bark; Plant Extracts; Polyphenols; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, G-Protein-Coupled

Endometritis is an inflammation of the uterine lining that is commonly initiated at parturition. The uterine epithelial cells play an important role in defending against invading pathogens. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been shown to have anti-inflammatory effects. The aim of this study was to investigate the anti-inflammatory effect of magnolol in modifying lipopolysaccharide (LPS)-induced signal pathways in mouse uterine epithelial cells. We found that magnolol inhibited TNF-α and IL-6 production in LPS-stimulated mouse uterine epithelial cells. We also found that magnolol inhibited LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK, and P38. Furthermore, magnolol could significantly inhibit the expression of TLR4 stimulating by LPS. These results suggest that magnolol exerts an anti-inflammatory property by downregulating the expression of TLR4 upregulated by LPS, thereby attenuating TLR4-mediated NF-κB and MAPK signaling and the release of pro-inflammatory cytokines. These findings suggest that magnolol may be a therapeutic agent against endometritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Survival; Cells, Cultured; Down-Regulation; Endometritis; Enzyme Activation; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; I-kappa B Proteins; Inflammation; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lignans; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Uterus

One alkyl glycoside, saussurostelloside A (1), two phenolic glycosides, saussurostellosides B1 (2) and B2 (3), and 27 known compounds, including eleven flavonoids, seven phenolics, six lignans, one neolignan, one phenethyl glucoside and one fatty acid, were isolated from an ethanol extract of Saussurea stella (Asteraceae). Their structures were elucidated by NMR, MS, UV, and IR spectroscopic analysis. Of the known compounds, (+)-medioresinol-di-O-β-D-glucoside (7), picraquassioside C (10), and diosmetin-3'-O-β-D-glucoside (27) were isolated from the Asteraceae family for the first time, while (+)-pinoresinol-di-O-β-D-glucoside (6), di-O-methylcrenatin (11), protocatechuic acid (14), 1,5-di-O-caffeoylquinic acid (17), formononetin (28), and phenethyl glucoside (29) were isolated from the Saussurea genus for the first time. The anti-inflammatory activities of three new compounds (1-3), five lignans ((-)-arctiin (4), (+)-pinoresinol-4-O-β-D-glucoside (5), (+)-pinoresinol-di-O-β-D-glucoside (6), (+)-medioresinol-di-O-β-D-glucoside (7) and (+)-syringaresinol-4-O-β-D-glucoside (8)), one neolignan (picraquassioside C (10)), and one phenolic glycoside (di-O-methylcrenatin (11)) were evaluated by testing their inhibition of the release of β-glucuronidase from PAF-stimulated neutrophils. Only compound 5 showed moderate inhibition of the release of β-glucuronidase, with an inhibition ratio of 39.1%.

Topics: Animals; Anti-Inflammatory Agents; Coumaric Acids; Disaccharides; Female; Flavonoids; Furans; Glucosides; Glucuronidase; Glycosides; Hydroxybenzoates; Inflammation; Isoflavones; Lignans; Male; Molecular Structure; Neutrophils; Phytotherapy; Plant Extracts; Platelet Activating Factor; Quinic Acid; Rats, Wistar; Saussurea

This study aims to clarify out the anti-inflammatory mechanism of Qingfei Xiaoyan Wan. Chemical constituents of Qingfei Xiaoyan Wan identified by UPLC Q-TOF, were submit to Molinspiration, PharmMapper and KEGG bioinformatics softwares for predicting their absorption parameters, target proteins and related pathways respectively; and the gene chip and real time-PCR were carried out to investigate the expression of inflammatory genes on lung tissue of guinea pigs or human bronchial epithelial cell lines. The predicted results showed that 19 of the 24 absorbable constituents affected at 9 inflammation-related pathways through 11 protein targets; Qingfei Xiaoyan Wan treatment can significantly reduce the infiltration of cytokines through ERK1 gene and 5 inflammatory pathways (Focal adhesion, Fc epsilon RI, Toll-like receptors, NK cell-mediated cytotoxic, and ERK/MAPK). The results of real time-PCR further confirmed that the anti-inflammatory effects of Qingfei Xiaoyan Wan were due to active ingredients such as arctigenin, cholic acid and sinapic acid intervened focal adhesion, Fc epsilon RI signaling and ERK/MAPK pathways. The novel approach of 'drug-target-pathway' will present an effective strategy for the study of traditional Chinese medicines.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Cell Line; Cholic Acid; Coumaric Acids; Cytokines; Drug Combinations; Drugs, Chinese Herbal; Epithelial Cells; Female; Furans; Guinea Pigs; Humans; Inflammation; Lignans; Lung; Male; MAP Kinase Signaling System; Random Allocation; Receptors, IgE; Toll-Like Receptors

This study investigated the effect of honokiol (HON) and magnolol (MAG), phenolic compounds in Magnolia plants, on adiposity and adiposity-related metabolic disturbances in mice fed high-fat diet (HFD), and the potential underlying mechanisms focusing on the lipid metabolism and inflammatory response.. C57BL/6J mice were fed HFD (45 kcal% fat) with or without HON (0.02%, w/w) or MAG (0.02%, w/w) for 16 wk. Despite no changes in body weight, food intake, and hepatic fat accumulation, HON and MAG significantly lowered the weight of white adipose tissue (WAT) as well as adipocyte size and protected against insulin resistance induced by HFD. These effects were associated with increases in energy expenditure and adipose fatty acid oxidation and decreases in fatty acid synthase activity and expression of genes related to fatty acid synthesis, desaturation, and uptake, as well as adipocyte differentiation in WAT. Moreover, HON and MAG significantly lowered the expression of proinflammatory genes in WAT and elevated the plasma IL-10 level. Particularly, HON significantly decreased the plasma resistin level and increased the plasma adiponectin level compared to the control group.. HON and MAG have potential as novel agents for amelioration of adiposity and associated insulin resistance and inflammation.

Topics: Adipogenesis; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Biphenyl Compounds; Blood Glucose; Body Weight; Chemokine CCL2; Cholesterol; Diet, High-Fat; Dietary Supplements; Energy Metabolism; Glucose Tolerance Test; Inflammation; Insulin Resistance; Interleukin-10; Interleukin-6; Lignans; Liver; Male; Mice; Mice, Inbred C57BL; Triglycerides; Tumor Necrosis Factor-alpha

Three new neolignans, named 9-methoxyobovatol (6), magnobovatol (7), and 2-hydroxyobovaaldehyde (9), along with six known ones, magnolol (1), honokiol (2), isomagnolol (3), obovatol (4), obovatal (5), and obovaaldehyde (8), were isolated from the fruits of Magnolia obovata using silica gel and ODS column chromatography. From the results of spectroscopic data including EIMS, IR, 1H- and 13C-NMR, DEPT, and 2D-NMR (gCOSY, gHSQC, gHMBC), the chemical structures were determined. All isolated compounds were evaluated for inhibition activity on nitric oxide production in LPS-induced RAW 264.7 cells, and compounds 1-4, 6, 7, and 9 showed significant activity with IC50 values of 15.8 ± 0.3, 3.3 ± 1.2, 14.1 ± 0.9, 6.2 ± 1.2, 14.8 ± 2.3, 14.2 ± 1.2, and 14.8 ± 3.2 µM, respectively, without any visible toxic effect.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Fruit; Inflammation; Lignans; Lipopolysaccharides; Macrophages; Magnolia; Mice; Molecular Structure; Nitric Oxide; Plant Extracts

Microglial activation has been associated with neurodegenerative diseases by inducing the neuroinflammatory mediators such as nitric oxide (NO), TNF-α and IL-1β. (-)-Nyasol, a norlignan isolated from a medicinal plant Anemarrhena asphodeloides, showed anti-inflammatory potential in lipopolysaccharide (LPS)-activated BV-2 microglial cells. (-)-Nyasol inhibited the production of NO and prostaglandin E2 (PGE2) and also the expression of inducible nitric oxide synthase and cyclooxygenase-2, which are responsible for the respective production of NO and PGE2. It also suppressed the mRNA levels of TNF-α and IL-1β in activated microglial cells. These effects of (-)-nyasol were correlated with the inactivation of p38 MAPK and the suppression of LPS-induced I-κBα degradation. Taken together, these results suggest that (-)-nyasol can be a modulator in neuroinflammatory conditions induced by microglial activation.

Topics: Anemarrhena; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; I-kappa B Proteins; Inflammation; Lignans; Lipopolysaccharides; Mice; Microglia; Molecular Structure; Phenols; Stereoisomerism

Obesity and its associated health risks still demand for effective therapeutic strategies. Drugs and compositions derived from Oriental medicine such as green tea polyphenols attract growing attention. Previously, an extract from the Japanese spice bush Lindera obtusiloba (L. obtusiloba) traditionally used for treatment of inflammation and prevention of liver damage was shown to inhibit adipogenesis. Aiming for the active principle of this extract (+)-episesamin was identified, isolated and applied in adipogenic research using 3T3-L1 (pre)adipocytes, an established cell line for studying adipogenesis. With an IC50 of 10μM (+)-episesamin effectively reduced the growth of 3T3-L1 preadipocytes and decreased hormone-induced 3T3-L1 differentiation as shown by reduced accumulation of intracellular lipid droplets and diminished protein expression of GLUT-4 and vascular endothelial growth factor. Mechanistically, the presence of (+)-episesamin during hormone-induced differentiation provoked a reduced phosphorylation of ERK1/2 and β-catenin along with a reduced protein expression of peroxisome proliferator-activated receptor γ and a strongly increased protein expression of iNOS. Treatment of mature adipocytes with (+)-episesamin resulted in a reduction of intracellular stored lipid droplets and induced the proapoptotic enzymes caspases-3/-7. Besides interfering with adipogenesis, (+)-episesamin showed anti-inflammatory activity by counteracting the lipopolysaccharide- and tumor necrosis factor α-induced secretion of interleukin 6 by 3T3-L1 preadipocytes. In conclusion, (+)-episesamin seems to be the active drug in the L. obtusiloba extract being responsible for the inhibition of adipogenesis and, thus, should be evaluated as a novel potential complementary treatment for obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Anti-Inflammatory Agents; beta Catenin; Caspase 3; Caspase 7; Cell Differentiation; Dioxoles; Down-Regulation; Glucose Transporter Type 4; Inflammation; Interleukin-6; Lignans; Lindera; Lipid Metabolism; Liver; Mice; Nitric Oxide Synthase Type II; Obesity; Phosphorylation; Plant Extracts; PPAR gamma; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway

Magnolia officinalis as a traditional Chinese herb has long been used for the treatment of anxiety, cough, headache and allergic diseases, and also have been used in traditional Chinese medicine to treat a variety of mental disorders including depression.. Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to have anti-inflammatory properties. However, the underlying molecular mechanisms are not well understood. The aim of this study was to investigate the molecular mechanism of magnolol in modifying lipopolysaccharide (LPS)-induced signal pathways in RAW264.7 cells.. The purity of magnolol was determined by high performance liquid chromatography. RAW264.7 cells were stimulated with LPS in the presence or absence of magnolol. The expression of proinflammatory cytokines were determined by ELISA and reverse transcription-PCR. Nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and Toll-like receptor 4 (TLR4) were determined by Western blot. Further analyses were performed on mTLR4 and mMD2 co-transfected HEK293 cells.. The result showed that the purity of magnolol used in this study was 100%. Magnolol inhibited the expression of TNF-α, IL-6 and IL-1β in LPS-stimulated RAW264.7 cells in a dose-dependent manner. Western blot analysis showed that magnolol suppressed LPS-induced NF-κB activation, IκBα degradation, phosphorylation of ERK, JNK and P38. Magnolol could significantly down-regulated the expression of TLR4 stimulating by LPS. Furthermore, magnolol suppressed LPS-induced IL-8 production in HEK293-mTLR4/MD-2 cells.. Our results suggest that magnolol exerts an anti-inflammatory property by down-regulated the expression of TLR4 up-regulated by LPS, thereby attenuating TLR4 mediated the activation of NF-κB and MAPK signaling and the release of pro-inflammatory cytokines. These findings suggest that magnolol may be a therapeutic agent against inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Cell Survival; Cells, Cultured; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Interleukin-8; Lignans; Lipopolysaccharides; MAP Kinase Signaling System; Mice; NF-kappa B; Signal Transduction; Toll-Like Receptor 4; Transfection

This study was designed to investigate the effects of honokiol, a neuroprotective agent, on cerebral edema in cerebral ischemia reperfusion (IR) mice and its mechanism of anti-inflammation. Honokiol (0.7-70μg/kg) significantly reduced brain water contents and decreased the exudation of Evans blue dye from brain capillaries in cerebral IR mice. Honokiol (0.1-10μM) significantly reduced the p65 subunit level of NF-κB in the nucleus of primary culture-microglia. It (0.01-10μM) evidently reduced nitric oxide (NO) level in the microglia culture medium and in the microglia and astrocytes coculture medium. Honokiol (0.01-10μM) significantly decreased the level of TNF-α in the microglia medium or coculture cell medium. Honokiol (10μM) decreased the level of Regulated upon Activation Normal T-cell Expressed and Secreted (RANTES/CCL5) protein in medium of microglia or astrocytes. In conclusion, Honokiol has a potent anti-inflammatory effect in cerebral ischemia-reperfusion mice and this effect might be attributed to its inhibition ability on the NF-κB activation, consequently blocking the production of inflammatory factors including: NO, tumor necrosis factor-α (TNF-α) and RANTES/CCL5 in glial cells. These results provide evidence for the anti-inflammatory effect of honokiol for the potential treatment of ischemic stroke.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Biphenyl Compounds; Brain Edema; Brain Ischemia; Capillary Permeability; Chemokine CCL5; Coculture Techniques; Cytokines; Drugs, Chinese Herbal; Female; Inflammation; Lignans; Male; Mice; Microglia; Neuroglia; NF-kappa B; Nitric Oxide; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

The bark of magnolia has been used in Oriental medicine to treat a variety of remedies, including some neurological disorders. Magnolol (Mag) and honokiol (Hon) are isomers of polyphenolic compounds from the bark of Magnolia officinalis, and have been identified as major active components exhibiting anti-oxidative, anti-inflammatory, and neuroprotective effects. In this study, we investigate the ability of these isomers to suppress oxidative stress in neurons stimulated by the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) and oxidative and inflammatory responses in microglial cells activated by interferon-γ (IFNγ) and lipopolysaccharide (LPS). We also attempt to elucidate the mechanism and signaling pathways involved in cytokine-induced production of reactive oxygen species (ROS) in microglial cells.. Dihydroethidium (DHE) was used to assay superoxide production in neurons, while CM-H2DCF-DA was used to test for ROS production in murine (BV-2) and rat (HAPI) immortalized microglial cells. NADPH oxidase inhibitors (for example, diphenyleneiodonium (DPI), AEBSF, and apocynin) and immunocytochemistry targeting p47phox and gp91phox were used to assess the involvement of NADPH oxidase. Western blotting was used to assess iNOS and ERK1/2 expression, and the Griess reaction protocol was employed to determine nitric oxide (NO) concentration.. Exposure of Hon and Mag (1-10 μM) to neurons for 24 h did not alter neuronal viability, but both compounds (10 μM) inhibited NMDA-stimulated superoxide production, a pathway known to involve NADPH oxidase. In microglial cells, Hon and Mag inhibited IFNγ±LPS-induced iNOS expression, NO, and ROS production. Studies with inhibitors and immunocytochemical assay further demonstrated the important role of IFNγ activating the NADPH oxidase through the p-ERK-dependent pathway. Hon and, to a lesser extent, Mag inhibited IFNγ-induced p-ERK1/2 and its downstream pathway for ROS and NO production.. This study highlights the important role of NADPH oxidase in mediating oxidative stress in neurons and microglial cells and has unveiled the role of IFNγ in stimulating the MAPK/ERK1/2 signaling pathway for activation of NADPH oxidase in microglial cells. Hon and Mag offer anti-oxidative or anti-inflammatory effects, at least in part, through suppressing IFNγ-induced p-ERK1/2 and its downstream pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Cell Line, Transformed; Cells, Cultured; Inflammation; Inflammation Mediators; Lignans; Magnolia; Mice; Microglia; Neurons; Oxidative Stress; Polyphenols; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Myrislignan is a new kind of lignan isolated from Myristica fragrans Houtt. Its antiinflammatory effects have not yet been reported. In the present study, the antiinflammatory effects and the underlying mechanisms of myrislignan in lipopolysaccharide (LPS)-induced inflammation in murine RAW 264.7 macrophage cells were investigated. Myrislignan significantly inhibited LPS-induced production of nitric oxide (NO) in a dose-dependent manner. It inhibited mRNA expression and release of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). This compound significantly inhibited mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) dose-dependently in LPS-stimulated macrophage cells. Further study showed that myrislignan decreased the cytoplasmic loss of inhibitor κB-α (IκB-α) protein and the translocation of NF-κB from cytoplasm to the nucleus. Our results suggest that myrislignan may exert its antiinflammatory effects in LPS-stimulated macrophages cells by inhibiting the NF-κB signalling pathway activation.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cyclooxygenase 2; I-kappa B Proteins; Inflammation; Interleukin-6; Lignans; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide; Nitric Oxide Synthase Type II; Signal Transduction; Tumor Necrosis Factor-alpha

Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-O-methylhonokiol, a constituent of Magnolia officinalis, on memory deficiency caused by LPS, along with the underlying mechanisms.. We investigated whether 4-O-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-O-methylhonkiol (0.5, 1 and 2 μM).. Oral administration of 4-O-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-O-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In in vitro study, we also found that 4-O-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-O-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-O-methylhonokiol inhibited LPS-induced Aβ1-42 generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.. These results suggest that 4-O-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-O-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Anti-Inflammatory Agents; Aspartic Acid Endopeptidases; Astrocytes; Avoidance Learning; Biphenyl Compounds; Brain; Cell Line, Transformed; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Lignans; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Microglia; NF-kappa B; Nitric Oxide; Peptide Fragments

The cannabinoid type-2 G protein-coupled (CB₂) receptor is an emerging therapeutic target for pain management and immune system modulation. In a mouse model of Alzheimer's disease (AD) the orally administered natural product 4'-O-methylhonokiol (MH) has been shown to prevent amyloidogenesis and progression of AD by inhibiting neuroinflammation. In this commentary we discuss an intriguing link between the recently found CB₂ receptor-mediated molecular mechanisms of MH and its anti-inflammatory and protective effects in AD animal models. We argue that the novel cannabimimetic MH may exert its beneficial effects via modulation of CB₂ receptors expressed in microglial cells and astrocytes. The recent findings provide further evidence for a potential role of CB₂ receptors in the pathophysiology of AD, spurring target validation and drug discovery.

Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Humans; Inflammation; Lignans; Plants, Medicinal; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid

Magnolia officinalis has been widely used in traditional Chinese medicine. Magnolol, an active component isolated from Magnolia officinalis, is known to be a cardiovascular protector since 1994. The multiplex mechanisms of magnolol on cardiovascular protection depends on cell types and dosages, and will be reviewed and discussed in this article. Magnolol under low and moderate dosage possesses the ability to protect heart from ischemic/reperfusion injury, reduces atherosclerotic change, protects endothelial cell against apoptosis and inhibits neutrophil-endothelial adhesion. The moderate to high concentration of magnolol mainly acts on smooth muscle cells and platelets. Magnolol induces apoptosis in vascular smooth muscle cells at moderate concentration and inhibits proliferation at moderate and high concentration. High concentration of magnolol also abrogates platelet activation, aggregation and thrombus formation. Magnolol also serves as an smooth muscle relaxant only upon the high concentration. Oral intake of magnolol to reach the therapeutic level for cardiovascular protection is applicable, thus makes magnolol an agent of great potential for preventing cardiovascular diseases in high-risk patients.

Topics: Apoptosis; Biphenyl Compounds; Cardiovascular System; Drugs, Chinese Herbal; Humans; Inflammation; Lignans; Magnolia; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle

A growing body of evidence indicates that the majority of Parkinson's disease (PD) cases are associated with microglia activation with resultant elevation of various inflammatory mediators and neuroinflammation. In this study, we investigated the effects of 2 natural molecules, quercetin and sesamin, on neuroinflammation induced by the Parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP(+)) in a glial-neuronal system. We first established that quercetin and sesamin defend microglial cells against MPP(+)-induced increases in the mRNA or protein levels of 3 pro-inflammatory cytokines (interleukin-6, IL-1β and tumor necrosis factor-alpha), as revealed by real time-quantitative polymerase chain reaction and enzyme-linked immunoabsorbent assay, respectively. Quercetin and sesamin also decrease MPP(+)-induced oxidative stress in microglial cells by reducing inducible nitric oxide synthase protein expression as well as mitochondrial superoxide radicals. We then measured neuronal cell death and apoptosis after MPP(+) activation of microglia, in a microglial (N9)-neuronal (PC12) coculture system. Our results revealed that quercetin and sesamin rescued neuronal PC12 cells from apoptotic death induced by MPP(+) activation of microglial cells. Altogether, our data demonstrate that the phytoestrogen quercetin and the lignan sesamin diminish MPP(+)-evoked microglial activation and suggest that both these molecules may be regarded as potent, natural, anti-inflammatory compounds.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Apoptosis; Coculture Techniques; Cytokines; Cytoprotection; Dioxoles; Dopaminergic Neurons; Gene Expression Regulation; Inflammation; Kinetics; Lignans; Mice; Microglia; Mitochondria; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type II; Oxidative Stress; PC12 Cells; Quercetin; Rats; RNA, Messenger; Superoxides

Fruits of Schisandra have been traditionally used in East Asia for the treatment of dyspnea, cough, dysentery, insomnia, tonic-clonic seizures, and amnesia. Schisandrin B, a dibenzocyclooctadiene derivative isolated from Fructus Schisandrae, has been shown to produce antioxidant effect on rodent liver and heart. In the present study, we investigated the neuroprotective effects of Schisandrin B, a constituent drug of the fruit of Schisandra, against focal cerebral ischemia in rats. Schisandrin B (10, 30 mg/kg, i.p.) was twice administered 30 min before the onset of ischemia and 2h after reperfusion. Schisandrin B 10 and 30 mg/kg treated groups showed infarct volumes reduced by 25.7% and 53.4%, respectively, 2h after occlusion. Also, Schisandrin B treated animal treatment abrogated protein expression of TNF-α and IL-1β and degradation of MMP-2 and MMP-9 in ischemic hemispheres. These results suggest that Schisandrin B treatment provides a neuroprotective effect to rats after transient focal cerebral ischemia by inhibiting inflammation and by protecting against metalloproteinase degradation.

Topics: Animals; Antioxidants; Cerebral Infarction; Cyclooctanes; Drugs, Chinese Herbal; Inflammation; Interleukin-1beta; Ischemic Attack, Transient; Lignans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neuroprotective Agents; Plant Extracts; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Reperfusion; Schisandra; Tumor Necrosis Factor-alpha

Stroke is the third leading cause of death in industrialized countries and the most important cause of acquired adult disability. Many evidences suggest that inflammation accounts for the progression of cerebral ischemic injury. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignin isolated from certain plants, has shown anti-inflammatory activity against diabetes and Alzheimer's disease. In this study, we tested whether arctigenin can protect middle cerebral artery occluded (MCAO) rats. Male Sprague-Dawley rats were pretreated with arctigenin or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Rats were evaluated at 24 h after MCAO for neurological deficit scoring. Furthermore, the mechanism of the anti-inflammatory effect of arctigenin was investigated with a focus on inflammatory cells, proinflammatory cytokines, and transcriptional factors. Arctigenin significantly reduced cerebral infarction and improved neurological outcome. Arctigenin suppressed the activation of microglia and decreased the expression of interleukin (IL)- 1β and tumor necrosis factor (TNF)-α. These results revealed that arctigenin has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Arctium; Furans; Infarction, Middle Cerebral Artery; Inflammation; Interleukin-1beta; Lignans; Macrophages; Male; Microglia; Neuroprotective Agents; Phytotherapy; Rats; Rats, Sprague-Dawley; Seeds; Tumor Necrosis Factor-alpha

While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti-fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation-induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy.

Topics: Animals; Antioxidants; Butylene Glycols; Dietary Carbohydrates; Eating; Female; Flax; Glucosides; Inflammation; Lignans; Lung; Mice; Mice, Inbred C57BL; Phenols; Radiation Pneumonitis; Radiation-Protective Agents; Survival Analysis; Thorax; Weight Loss

In a search for secondary plant compounds that bind to the glucocorticoid receptor (GR), the cyclobutane lignan endiandrin A was discovered from the rainforest tree Endiandra anthropophagorum Domin. Our present study aims to characterize the effect of endiandrin A on GR-dependent induction of colonic sodium transport. The effect of endiandrin A was analyzed in GR-expressing colonic HT-29/B6 cells (HT-29/B6-GR). GR transactivation and subcellular localization were investigated by reporter gene assay and immunofluorescence. Epithelial sodium channel (ENaC) was analyzed by qRT-PCR and by measuring amiloride-sensitive short-circuit current (I(sc)) in Ussing chambers. Endiandrin A (End A) has been identified as GR receptor binder. However, it did not cause significant GR transactivation as pGRE-luciferase activity was only 7% of that of the maximum effect of dexamethasone. Interestingly, endiandrin A had a significant impact on dexamethasone-dependent sodium absorption in cells co-exposed to tumor necrosis factor (TNF)-α. This was in part due to up-regulation of β- and γ-ENaC subunit expression. Endiandrin A potentiated GR-mediated transcription by increasing GR protein expression and phosphorylation. It inhibited c-Jun N-terminal kinase (JNK) activation induced by dexamethasone and/or TNF-α and increased levels of GR localized to the nucleus. Additionally, endiandrin A increased the serum- and glucocorticoid-induced kinase (sgk)-1 via activation of p38. Finally, the regulation of ENaC function by endiandrin A was confirmed in rat native colon. In conclusion, endiandrin A potentiates glucocorticoid-driven activation of colonic epithelial sodium channels via JNK inhibition and p38 activation due to transcriptional up-regulation of β- and γ-ENaC-subunits along with induction of sgk-1.

Topics: Animals; Colon; Cyclobutanes; Dexamethasone; Enzyme Activation; Epithelial Sodium Channels; Glucocorticoids; HT29 Cells; Humans; Immediate-Early Proteins; Inflammation; Intestinal Absorption; Lauraceae; Lignans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Receptors, Glucocorticoid; Sodium; Transcriptional Activation

Respiratory burst mediates crucial bactericidal mechanism in neutrophils. However, undesirable respiratory burst leads to pathological inflammation and tissue damage. This study investigates the effect and the underlying mechanism of 5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2), a lignan extracted from the fruit of Melicope Semecarprifolia, on fMLP-induced respiratory burst in human neutrophils and suggests a possible therapeutic approach to ameliorate disease associated with neutrophil hyperactivation. MSF-2 inhibited fMLP-induced neutrophil superoxide anion production, cathepsin G release and migration in human neutrophils isolated from healthy volunteers, reflecting inhibition of phosphatidylinositol 3-kinase (PI3K) activation. Specifically, PI3K/AKT activation results in migration, degranulation and superoxide anion production in neutrophils. MSF-2 suppresses PI3K activation and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production, and consequently inhibits downstream activation of PDK1 and AKT. Further, PI3K also stimulates respiratory burst via PLC-dependent elevation of intracellular calcium. MSF-2 reduces fMLP-mediated PLCγ2 activation and intracellular calcium accumulation notably through extracellular calcium influx in a PI3K and PLC-dependent manner. However, MSF-2 is not a competitive or allosteric antagonist of fMLP. Additionally, in an in vivo study, MSF-2 prevents fMLP-induced neutrophil infiltration and inflammation in mice. In conclusion, MSF-2 opposes fMLP-mediated neutrophil activation and inflammation by inhibiting PI3K activation and subsequent activation of AKT and PLCγ2.

Topics: Adult; Animals; Calcium; Cathepsin G; Cell Movement; Cyclic AMP; Flavones; Fluorescein-5-isothiocyanate; Humans; Inflammation; Intracellular Space; Lignans; Mice; Models, Biological; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Activation; Neutrophils; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phospholipase C gamma; Phosphorylation; Receptors, Formyl Peptide; Respiratory Burst; Signal Transduction; Superoxides; Young Adult

Zanthoxylum armatum DC. is a traditional Chinese medicine that is prescribed to alleviate pain and treat inflammatory disorders. This species is distributed mainly in the southeast and southwest regions of China. In the present study, we found that ethyl acetate fraction of ethanolic extract of Z. armatum could significantly decrease acetic acid-induced writhing numbers, and suppress formalin induced licking times in the first phase at the highest dose and in the second phase at all tested doses. This observation revealed that Z. armatum extract possessed powerful antinociceptive activity. The mechanisms of the antinociceptive effect might be mainly involved in the periphery inflammatory analgesic. In addition, the ethyl acetate fraction also inhibited xylene-induced ear swelling in a dose-dependent manner in mice. Eight lignans [eudesmin, horsfieldin, fargesin, kobusin, sesamin, asarinin, planispine A, and pinoresinol-di-3,3-dimethylallyl] were identified as major components of the ethyl acetate fraction. Considering related studies reporting the anti-inflammatory activity for the identified lignans, lignan might be responsible for its anti-inflammatory activity. Our results confirm that the traditional use of Z. armatum in the treatment of inflammation and pain is warranted.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Behavior, Animal; Dose-Response Relationship, Drug; Ear; Edema; Formaldehyde; Inflammation; Lignans; Mice; Pain; Phytotherapy; Plant Extracts; Plant Roots; Plant Stems; Zanthoxylum

Inhibition of interleukin-6 (IL-6) has been postulated to be an effective therapy in the pathogenesis of several inflammatory diseases. The current study was performed to examine potential effects of manassantin A and B isolated from Saururus chinensis on the IL-6-induced response to human hepatoma cells. We found that manassantin A and B inhibit signal transducer and activator of transcription 3 (Stat3) activity stimulated by IL-6. We also found that both compounds decreased IL-6-induced Stat3 phosphorylation and nuclear translocation. Both compounds blocked suppressor of cytokine signaling 3 (SOCS-3)-mRNA expression induced by IL-6. In addition, we found that Stat3 inhibitory effects of these compounds could be related to protein tyrosine phosphatase. These findings suggest that manassantin A and B could be useful remedies for treatment of inflammatory diseases by inhibiting IL-6 action.

Topics: Active Transport, Cell Nucleus; Carcinoma, Hepatocellular; Furans; Humans; Inflammation; Interleukin-6; Lignans; Phosphorylation; Protein Tyrosine Phosphatases; Saururaceae; Signal Transduction; STAT3 Transcription Factor; Tumor Cells, Cultured

Sepsis has a high mortality rate despite the recent advances in intensive care medicine and antibiotics. Honokiol, a low molecular weight natural product, is known to possess anti-inflammatory activity. Here, we investigate whether honokiol can ameliorate acute lung injury and lethal response in murine models of sepsis.. Mice were intraperitoneally given vehicle or honokiol 30 min after the induction of sepsis by cecal ligation and puncture (CLP) and endotoxemia by administration of E. coli lipopolysaccharide (LPS).. The productions of serum tumor necrosis factor-α (TNF-α), nitric oxide (NO), and high mobility group box 1 (HMGB 1) were increased in mice during sepsis, which could be reversed by honokiol. Honokiol could also effectively reduce the increased blood lipid peroxidation and nitrotyrosine in septic mice. Honokiol significantly reversed the inductions of inducible NO synthase and nuclear factor-κB (NF-κB) activation in the lungs of mice during sepsis. Honokiol also effectively rescued the lung edema, lung pathological changes, and lethality in septic mice.. These findings suggest that honokiol is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the potential use of honokiol as a therapeutic agent for the conditions associated with septic shock.

Topics: Acute Lung Injury; Animals; Anti-Infective Agents; Biphenyl Compounds; Endotoxemia; Inflammation; Lignans; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Sepsis

Gomisin N is a bioactive compound and a prominent anti-allergic agent found in the fruits of tree Schizandra chinensis. However, its effects on the bone marrow-derived mast cell (BMMC)-mediated allergy and inflammation mechanism remain unknown. In this study, the biological effects of gomisin were evaluated while focusing on its effects on the allergic mediator in PMA + A23187-stimulated BMMCs. The anti-allergic effect of gomisin has shown that inhibited PMA + A23187-induced interleukin-6 (IL-6) production. An investigation was also conducted to determine its effects on the production of several allergic mediators including prostaglandin D(2) (PGD(2)), leukotriene C(4) (LTC(4)), β-hexosaminidase (β-Hex), and cyclooxygenase-2 (COX-2) protein. The results revealed that gomisin inhibited the PMA + A23187-induced production of IL-6, PGD(2), LTC(4), β-Hex, and COX-2 protein. Taken together, these findings indicate that gomisin N has the potential for use in the treatment of allergy.

Topics: Animals; Anti-Allergic Agents; Bone Marrow Cells; Calcimycin; Calcium Ionophores; Carcinogens; Cells, Cultured; Cyclooctanes; Gene Expression Regulation; Hypersensitivity; Inflammation; Inflammation Mediators; Interleukin-6; Lignans; Male; Mast Cells; Mice; Mice, Inbred BALB C; Polycyclic Compounds; Tetradecanoylphorbol Acetate

The lipopolysaccharide (LPS) of Porphyromonas gingivalis is thought to induce periodontitis. In this study, we isolated Schisandrin from the dried fruits of Schisandra chinensis and examined the anti-inflammatory effect of Schisandrin in macrophages stimulated with LPS from P. gingivalis. First, Schisandrin inhibited LPS-induced pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. And Schisandrin suppressed the nuclear translocation and activity of NF-κB and phosphorylation of IκBα in LPS-stimulated RAW 264.7 cells. Next, the presence of a selective inhibitor of HO-1 (SnPP) and a siRNA specific for HO-1 inhibited Schisandrin-mediated anti-inflammatory activity. Furthermore, Schisandrin induced HO-1 expression of RAW 264.7 cells through Nrf-2, PI3K/Akt, and ERK activation. Therefore, these results suggest that the anti-inflammatory effects of Schisandrin on P. gingivalis LPS-stimulated RAW 264.7 cells may be due to a reduction of NF-κB activity and induction of the expression of HO-1, leading to TNF-α, IL-1β, and IL-6 down-regulation.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cell Nucleus; Cyclooctanes; Enzyme Activation; Gene Expression Regulation; Heme Oxygenase-1; Inflammation; Inflammation Mediators; Lignans; Lipopolysaccharides; Macrophages; Mice; NF-E2-Related Factor 2; NF-kappa B; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Porphyromonas gingivalis; Protein Transport; Proto-Oncogene Proteins c-akt; Signal Transduction; Up-Regulation

Honokiol (HNK) is a phenolic compound isolated from the bark of houpu (Magnolia officinalis), a plant widely used in traditional Chinese and Japanese medicine. While substantial evidence indicates that HNK possesses anti-inflammatory activity, its effect on dendritic cells (DCs) during the inflammatory reaction remains unclear. The present study investigates how HNK affects lipopolysaccharide (LPS)-stimulated human monocyte-derived DCs. Our experimental results show that HNK inhibits the inflammatory response of LPS-induced DCs by (1) suppressing the expression of CD11c, CD40, CD80, CD83, CD86, and MHC-II on LPS-activated DCs, (2) reducing the production of TNF-α, IL-1β, IL-6, and IL-12p70 but increasing the production of IL-10 and TGF-β1 by LPS-activated DCs, (3) inhibiting the LPS-induced DC-elicited allogeneic T-cell proliferation, and (4) shifting the LPS-induced DC-driven Th1 response toward a Th2 response. Further, our results show that HNK inhibits the phosphorylation levels of ERK1/2, p38, JNK1/2, IKKα, and IκBα in LPS-activated DCs. Collectively, the findings show that the anti-inflammatory actions of HNK on LPS-induced DCs are associated with the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways.

Topics: Biphenyl Compounds; Cell Differentiation; Cell Line; Cell Proliferation; Cell Survival; Cytokines; Dendritic Cells; Endocytosis; Enzyme Activation; Humans; Inflammation; Lignans; Lipopolysaccharides; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Monocytes; NF-kappa B; Phenotype; Th1 Cells; Th2 Cells

In this study, manassantin A (Man A), an herbal medicine isolated from Saururus chinensis (S. chinensis), markedly inhibited 5-lipoxygenase (5-LO)-dependent leukotriene C(4) (LTC(4)) generation in bone marrow-derived mast cells (BMMCs) in a concentration-dependent manner. To investigate the molecular mechanisms underlying the inhibition of LTC(4) generation by Man A, we assessed the effects of Man A on phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) and mitogen-activated protein kinases (MAPKs). Inhibition of LTC(4) generation by Man A was accompanied by a decrease in cPLA(2) phosphorylation, which occurred via the MAPKs including extracellular signal-regulated protein kinase-1/2 (ERK1/2) as well as p38 and c-Jun N-terminal kinase (JNK) pathways. Taken together, the present study suggests the Man A represents a potential therapeutic approach for the treatment of airway allergic-inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Bone Marrow; Dose-Response Relationship, Drug; Enzyme Activation; Inflammation; Leukotriene C4; Lignans; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Phospholipases A2; Phosphorylation; Phytotherapy; Plant Extracts; Saururaceae

Periodontitis, a chronic inflammatory periodontal disease that develops from gingivitis, is caused by periodontal pathogenic bacteria such as Porphyromonas gingivalis. Recent studies have focused on the antioxidant, anti-human immunodeficiency virus, anticarcinogenic, and anti-inflammatory properties of gomisins. However, the anti-inflammatory activities of gomisin plants through heme oxygenase-1 (HO-1) signals remain poorly defined. We found that gomisins' anti-inflammatory activity occurs via the induction of HO-1 expression. Gomisins G and J inhibit the production of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 and also block nuclear factor-κB activation in Raw264.7 cells stimulated with P. gingivalis lipopolysaccharide. Furthermore, pro-inflammatory cytokine production is inhibited through the induction of HO-1 expression. HO-1 expression is induced by all gomisins, but their anti-inflammatory activity via HO-1 signaling is observed with gomisins G and J, and not A. We found that gomisins G and J extracted from Schisandria chinensis can inhibit the P. gingivalis lipopolysaccharide induced-inflammatory responses in Raw264.7 cells.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cyclooctanes; Dioxoles; Fruit; Heme Oxygenase-1; Inflammation; Interleukin-1beta; Interleukin-6; Lignans; Lipopolysaccharides; Membrane Proteins; Mice; NF-kappa B; Plant Extracts; Polycyclic Compounds; Porphyromonas gingivalis; Schisandra; Signal Transduction; Tumor Necrosis Factor-alpha

It has been suggested that lignan intake may decrease the risk for cardiovascular disease (CVD) by modifying traditional risk factors as well as aortic stiffness. However, the role of dietary lignans on the vascular system is largely unknown. The objective was to investigate whether dietary intake of plant lignans in a free-living population was associated with markers of vascular inflammation and function.. We performed a cross-sectional study in 242 (151 males) men and post-menopausal women. Anthropometric characteristics and lignan intake were evaluated. Soluble intercellular adhesion molecule-1 (sICAM-1), insulin, high-sensitive C-reactive protein, glucose, total cholesterol, HDL-cholesterol and triacylglycerols were measured in fasting blood samples. Brachial flow-mediated dilation (FMD) measurements were available for 101 subjects (56 males). Median (interquartile range) daily intake of matairesinol (MAT), secoisolariciresinol (SECO), pinoresinol (PINO), lariciresinol (LARI), and total lignans was 20.9 microg (17.4), 335.3 microg (289.1), 96.7 microg (91.1), 175.7 microg (135.8), and 665.5 microg (413.7), respectively, as assessed by 3-day weighed food record. Plasma concentrations of sICAM-1 (whole sample) significantly decreased (mean (95%CI) = 358 microg/L (320-401), 276 microg/L (252-303), 298 microg/L (271-326), and 269 microg/L (239-303), P per trend 0.013) and FMD values (FMD sub-group) significantly increased (4.1% (2.2-6.0), 5.7% (4.3-7.2), 6.4% (4.9-7.8), and 8.1% (6.3-10.0), P per trend 0.016) across quartiles of energy-adjusted MAT intake, even after adjustment for relevant clinical and dietary variables. Intake of SECO was also inversely related to plasma sICAM-1 (P per trend 0.018), but not to FMD values. No relationship between intake of PINO, LARI or total lignans and either sICAM-1 or FMD values was observed.. Higher MAT intakes in the context of a typical Northern Italian diet are associated to lower vascular inflammation and endothelial dysfunction, which could have some implications in CVD prevention.

Topics: Aged; Biomarkers; Butylene Glycols; Cardiovascular Diseases; Cross-Sectional Studies; Diet; Diet Records; Diet, Mediterranean; Endothelium, Vascular; Female; Furans; Hemodynamics; Humans; Inflammation; Italy; Lignans; Male; Middle Aged; Phytoestrogens; Surveys and Questionnaires; Vascular Diseases

UVB irradiation (290-320 nm) is the most damaging component of the UV spectrum and causes both direct and indirect damage to the basal cell layer of the epidermis; this results in the activation of a number of signaling pathways involved in pathophysiological processes in the skin, such as photoaging and inflammation. In photoaging UVB irradiation promotes degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) and, in inflammation, UVB irradiation promotes the expression of inducible cyclooxygenase (COX-2), leading to overproduction of inflammatory mediators.. We first investigated the protective effects of macelignan from Myristica fragrans Houtt. on immortalized human keratinocytes (HaCaT) against UVB damage. We then explored the inhibitory effects of macelignan on UVB-induced MMP-9 and COX-2 and investigated the molecular mechanism underlying those effects.. HaCaT cells were treated with macelignan for the indicated times followed by irradiation with UVB. Secretion of MMP-9 was measured by gelatin zymography. Expression of COX-2, mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), c-Fos, c-Jun, and CREB were assayed by western analysis.. Macelignan at a concentration of 0.1-1 microM increased the viability of HaCaT cells following UVB irradiation and inhibited MMP-9 secretion and COX-2 expression in a concentration-dependent manner. An inhibitory effect was also seen in the signal transduction network, where macelignan treatment reduced the activation of UVB-induced MAPKs, PI3K/Akt, and their downstream transcription factors.. These results suggest that macelignan protects skin keratinocytes from UVB-induced damage and inhibits MMP-9 and COX-2 expression by attenuating the activation of MAPKs and PI3K/Akt.

Topics: Cell Line, Transformed; Cell Survival; Cyclic AMP Response Element-Binding Protein; Cyclooxygenase 2; Enzyme Activation; Humans; Inflammation; Keratinocytes; Lignans; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinases; Myristica; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Signal Transduction; Ultraviolet Rays

The reaction of human leukocytes to chemoattractants is an important component of the host immune response and also plays a crucial role in the development of inflammation. Sesamin has been shown to inhibit lipid peroxidation and regulate cytokine production. In this study, we examined the effect of sesamin on inflammatory responses elicited by the bacterial chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF) in vitro and in vivo and explored the mechanisms involved. fMLF is recognized by a human G protein-coupled receptor formyl peptide receptor (FPR) on phagocytic leukocytes. Sesamin at concentrations between 12.5 and 50 micromol/L inhibited fMLF-induced chemotaxis of human monocyte cell line THP-1 differentiated with dibutyryl cyclic AMP (P < 0.01). Similarly, sesamin inhibited FPR-transfected rat basophilic leukemia cell [epitope-tagged human FPR (ETFR) cell] migration toward fMLF (P < 0.01). In fMLF-induced inflammation in a murine air-pouch model, intraperitoneal administration of sesamin (12 mgkg(-1)d(-1) for 2 d) suppressed leukocyte infiltration into the air pouch induced by fMLF [(62.89 +/- 7.93) x 10(4) vs. (19.67 +/- 4.43) x 10(4) cells/air pouch; n = 9; P < 0.001]. Ca(2+) mobilization and mitogen-activated protein kinase extracellular signal-regulated kinase (ERK1/2) activation are involved in fMLF-induced leukocyte migration. Pretreatment of ETFR cells with sesamin inhibited fMLF-induced ERK1/2 phosphorylation in a dose-dependent manner but did not affect fMLF-induced Ca(2+) flux. Electrophoretic mobility shift assay showed that pretreatment of THP-1 cells with sesamin dose dependently inhibited fMLF-induced nuclear factor-kappaB (NF-kappaB) activation. These results suggest that sesamin inhibits leukocyte activation by fMLF through ERK1/2- and NF-kappaB-related signaling pathways and thus is a potential compound for the management of inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Bacteria; Basophils; Bucladesine; Calcium; Cell Line; Cell Line, Tumor; Chemotaxis, Leukocyte; Dioxoles; Dose-Response Relationship, Drug; Humans; Inflammation; Leukemia; Leukemic Infiltration; Lignans; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Models, Animal; Monocytes; N-Formylmethionine Leucyl-Phenylalanine; NF-kappa B; Phosphorylation; Phytotherapy; Plant Extracts; Rats; Receptors, Formyl Peptide; Sesamum; Signal Transduction

Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (-)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE)(-/-) gene-knockout mouse.. Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta (P<0.05 versus ApoE(-/-) control mice). Quercetin significantly reduced aortic F(2)-isoprostane, vascular superoxide, vascular leukotriene B(4), and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion (P<0.05 versus control ApoE(-/-) mice). Theaflavin showed similar, although less extensive, significant effects. Although (-)-epicatechin significantly reduced F(2)-isoprostane, superoxide, and endothelin-1 production (P<0.05 versus control ApoE(-/-) mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (-)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE(-/-) controls.. Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE(-/-) gene-knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Biflavonoids; Biomarkers; Catechin; Chlorogenic Acid; Cholesterol; Diet; Dioxoles; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; F2-Isoprostanes; Fatty Acids; Flavonoids; Heme Oxygenase-1; Inflammation; Leukotriene B4; Lignans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Oxidative Stress; P-Selectin; Phenols; Polyphenols; Quercetin; Superoxides

We previously reported that arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan isolated from Forsythia koreana, exhibits anti-inflammatory, antioxidant, and analgesic effects in animal models. In addition, arctigenin inhibited eosinophil peroxidase and activated myeloperoxidase in inflamed tissues. In this study, we tested the effects of arctigenin on type I-IV allergic inflammation and pro-inflammatory enzymes in vitro and in vivo. Arctigenin significantly inhibited the heterologous passive cutaneous anaphylaxis induced by ovalbumin in mice at 15 mg/kg, p.o., and compound 48/80-induced histamine release from rat peritoneal mast cells at 10 microM. Arctigenin (15 mg/kg, p.o.) significantly inhibited reversed cutaneous anaphylaxis. Further, arctigenin (15 mg/kg, p.o.) significantly inhibited the Arthus reaction to sheep's red blood cells, decreasing the hemolysis titer, the hemagglutination titer, and the plaque-forming cell number for SRBCs. In addition, arctigenin significantly inhibited delayed type hypersensitivity at 15 mg/kg, p.o. and the formation of rosette-forming cells at 45 mg/kg, p.o. Contact dermatitis induced by picrylchloride and dinitrofluorobenzene was significantly (p < 0.05) inhibited by surface treatment with arctigenin (0.3 mg/ear). Furthermore, arctigenin dose-dependently inhibited pro-inflammatory enzymes, such as cyclooxygenase-1 and 2, 5-lipoxygenase, phospholipase A2, and phosphodiesterase. Our results show that arctigenin significantly inhibited B- and T-cell mediated allergic inflammation as well as pro-inflammatory enzymes.

Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; B-Lymphocytes; Enzyme Inhibitors; Furans; Guinea Pigs; Hemagglutination; Histamine Antagonists; Histamine Release; Hypersensitivity; Inflammation; Lignans; Lung; Male; Mast Cells; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Skin; T-Lymphocytes

Plant-derived compounds with potent anti-inflammatory activity have attracted a great deal of attention as a source for novel anti-arthritic agents with minimal side effects. We attempted to determine the anti-arthritic effects of orally administered honokiol isolated from Magnolia species. The oral administration of honokiol inhibited the progression and severity of type II collagen (CII)-induced arthritis (CIA) by reducing clinical arthritis scores and paw swelling. The histological analysis demonstrated preserved joint space; and the immunohistochemical data showed that the levels of interleukin (IL)-17, matrix metalloproteinase (MMP)-3, MMP-9, MMP-13, and receptor activator for nuclear factor-κB ligand, as well as nitrotyrosine formation, were substantially suppressed in the honokiol-treated CIA mice. The elevated serum levels of tumor necrosis factor-α and IL-1β in the CIA mice were also restored to control levels via honokiol treatment. In the CIA mice, honokiol inhibited CII- or lipopolysaccharide-stimulated cytokine secretion in spleen cells, as well as CII-stimulated spleen cell proliferation. Furthermore, honokiol treatment reduced CIA-induced oxidative damage in the liver and kidney tissues of CIA mice. Collectively, the oral administration of honokiol inhibited CIA development by reducing the production of pro-inflammatory cytokines, MMP expressions, and oxidative stress. Thus, honokiol is an attractive candidate for an anti-arthritic agent.

Topics: Animals; Arthritis, Experimental; Biphenyl Compounds; Cattle; Cytokines; Disease Progression; Inflammation; Inflammation Mediators; Lignans; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred DBA; Oxidation-Reduction; Oxidative Stress

Honokiol, a bioactive component isolated from the Chinese herb Magnolia officinalis, is known for its potent antioxidative and anti-inflammatory effects. To study whether honokiol can protect skeletal muscle from sports injuries, we set up an eccentric exercise bout protocol for rats consisting of downhill running on a treadmill and examined the effect of oral administration of honokiol at 1 h before eccentric exercise at a dose of 5 mg/kg on day 1 (HK5 x 1) or 1 mg/kg/day for 5 consecutive days (HK1 x 5). Eccentric exercise was implemented for 3-5 consecutive days, and induced remarkable tissue damage. This damage was associated with an increase in serum creatine levels, increase in protein nitrotyrosylation, poly-ADP-ribose-polymerase (PARP) upregulation, lipid peroxidation, and leukocyte infiltration. The degree of muscle damage also paralleled dramatic gene expression for cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and inflammation-associated cytokines (interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1), possibly through activation of nuclear factor kappa-B (NF-kappaB), a crucial proinflammatory transcription factor. Both honokiol treatments (HK5 x 1 and HK1 x 5) significantly ameliorated eccentric exercise-induced muscle damage as revealed by suppression of cell fragmentation, protein nitrotyrosylation and PARP upregulation, as well as reductions in lipid peroxidation and leukocyte infiltration, possibly through downregulating gene expression for COX-2, iNOS, and the proinflammatory cytokines by modulation of NF-kappaB activation. In conclusion, the present study demonstrates for the first time that honokiol exhibits protective effects against eccentric exercise-induced skeletal muscle damage in rats, probably by modulating inflammation-mediated damage to muscle cells.

Topics: Animals; Biphenyl Compounds; Chemokine CCL2; Creatinine; Cyclooxygenase 2; Dose-Response Relationship, Drug; Gene Expression; Inflammation; Interleukin-1beta; Interleukin-6; Lignans; Lipid Peroxidation; Male; Muscle, Skeletal; Oxidative Stress; Physical Conditioning, Animal; Poly(ADP-ribose) Polymerases; Proteins; Rats; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E2 (PGE2) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE2-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.

Topics: Analgesics; Animals; Anti-Infective Agents; Biphenyl Compounds; Dinoprostone; Excitatory Amino Acid Agents; Glycine; Immunohistochemistry; Inflammation; Lignans; Male; Mice; N-Methylaspartate; Phenylacetates; Proto-Oncogene Proteins c-fos; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

To assess the anti-inflammatory activity of constituents from the rhizomes of Anemarrhena asphodeloides, (-)-nyasol {cis-hinokiresinol, 4,4-[1Z,3R]-3-ethenyl-1-propene-1,3-diyl]bisphenol} was isolated and its anti-inflammatory activity was examined in lipopolysaccharide (LPS)-treated RAW 264.7 cells and A23187-treated RBL-1 cells. In vivo activity was measured using carrageenan-induced paw edema assay. At > 1 microM, (-)-nyasol significantly inhibited cyclooxygenase-2 (COX-2)-mediated PGE2 production and inducible nitric oxide synthase (iNOS)-mediated NO production in LPS-treated RAW 264.7 cells, a mouse macrophage-like cell line, but did not affect the expression levels of COX-2 and iNOS. (-)-Nyasol also inhibited 5-lipoxygenase (5-LOX)-mediated leukotriene production in A23187-treated RBL-1 cells. Furthermore, (-)-nyasol potently inhibited carrageenan-induced paw edema in mice (28.6-77.1% inhibition at 24-120 mg/kg). Therefore, (-)-nyasol is a potential new lead compound and may contribute to the anti-inflammatory action of A. asphodeloides, possibly by inhibiting COX-2, iNOS and 5-LOX.

Topics: Anemarrhena; Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Eicosanoids; Inflammation; Lignans; Lipopolysaccharides; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; Nitric Oxide; Nitric Oxide Synthase Type II; Phenols; Rats; Rhizome

Schisandrin is the main active ingredient isolated from the fruit of Schisandra chinensis Baill. Recent studies have demonstrated that schisandrin exhibits anti-oxidative effects in vivo. In the present study, the effect of schisandrin on plasma nitrite concentration in lipopolysaccharide (LPS)-treated mice was evaluated. It also significantly inhibited carrageenan-induced paw edema and acetic acid-induced vascular permeability in mice. Furthermore, schisandrin had a protective effect on lipopolysaccharide (LPS)-induced sepsis. In vitro, our results are the first that show that the anti-inflammatory properties of schisandrin result from the inhibition of nitric oxide (NO) production, prostaglandin E(2) (PGE(2)) release, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, which in turn results from the inhibition of nuclear factor-kappaB (NF-kappaB), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activities in a RAW 264.7 macrophage cell line.

Topics: Animals; Anti-Inflammatory Agents; Capillary Permeability; Cell Line; Cyclooctanes; Cyclooxygenase 2; Dinoprostone; Fruit; Gene Expression Regulation; Inflammation; Lignans; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred ICR; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Polycyclic Compounds; Schisandra; Sepsis

Previous studies have shown that macelignan has anti-inflammatory and neuroprotective effects. Subsequently, in the current study, we demonstrate that oral administrations of macelignan reduce the hippocampal microglial activation induced by chronic infusions of lipopolysaccharide (LPS) into the fourth ventricle of Fisher-344 rat brains. A Morris water maze was used to evaluate the status of the hippocampal-dependent spatial learning in control rats with an artificial cerebrospinal fluid infusion, rats with chronic LPS infusions, and rats with chronic LPS infusions and oral administrations of macelignan. The rats with chronic LPS infusions showed spatial memory impairments relative to the control rats in the performance of the memory task. Daily administration of macelignan reduced the spatial memory impairments induced by the chronic LPS infusions. The results indicate that macelignan may possess therapeutic potential for the prevention of Alzheimer's disease.

Topics: Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Histocompatibility Antigens Class II; Inflammation; Learning Disabilities; Lignans; Lipopolysaccharides; Male; Maze Learning; Microglia; Rats; Rats, Inbred F344; Reaction Time; Space Perception

The fruits of Forsythia koreana have long been used in Chinese medicine to treat inflammatory disorders. However, the pharmacological data is not sufficient to clearly establish a scientific rationale for the anti-inflammatory medicinal use of this plant material, and the search for its active principles has been limited so far.. Phylligenin (lignan) was isolated from the fruits of Forsythia koreana and its anti-inflammatory activity was examined.. Phylligenin (1-100 microM) and the methanol extract of Forsythia koreana fruits inhibited cyclooxygenase-2 (COX-2)-mediated prostaglandin E(2) and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) synthesis from lipopolysaccharide-treated RAW 264.7 cells. In the mechanism study, phylligenin inhibited iNOS expression and nuclear factor-kappaB (NF-kappaB) activation but had no effect on COX-2 expression. Moreover, phylligenin significantly inhibited mouse carrageenan-induced paw edema by intraperitoneal administration (22.1-34.7% inhibition at 12.5-100 mg/kg). These pharmacological properties indicate that phylligenin possesses significant anti-inflammatory activity in vitro and in vivo, and may provide the scientific rationale for anti-inflammatory use of the fruits of Forsythia koreana.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Forsythia; Fruit; Inflammation; Lignans; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Plant Extracts

Honokiol (HNK), a phenolic compound isolated and purified from magnolia, has been found to have a number of pharmacologic benefits, including anti-angiogenic and anti-inflammatory properties. HNK has long been used in traditional Asian medicine without toxic side effects. We and others have extensively studied signaling to B cells by CD40 and its Epstein Barr viral mimic, latent membrane protein 1 (LMP1), which has been implicated in exacerbation of chronic autoimmune disease. We asked whether HNK could inhibit CD40 and LMP1 inflammatory signaling mechanisms. In vivo, HNK stabilized the severity of symptomatic collagen-induced arthritis in both CD40-LMP1 transgenic mice and their congenic C57BL/6 counterparts. Ex vivo studies, including collagen-specific serum Ab and Ag recall responses, as well as CD40 or LMP1-mediated activation of splenic B cells, supported the anti-inflammatory effects of HNK. In mouse B cell lines expressing the human CD40-LMP1 chimeric receptor, CD40- and LMP1-mediated NF-kappaB and AP-1 activation were abrogated in a dose-dependent manner, with a concomitant decrease in TNF-alpha and IL-6. These promising findings suggest that the nontoxic anti-inflammatory properties of HNK could be valuable for blocking the autoimmune response.

Topics: Animals; Anti-Allergic Agents; Arthritis, Experimental; B-Lymphocytes; Biphenyl Compounds; CD40 Antigens; Cell Line; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Lignans; Magnolia; Mice; Mice, Transgenic; NF-kappa B; Phytotherapy; Plant Preparations; TNF Receptor-Associated Factor 2; Transcription Factor AP-1

We have evaluated the anti-inflammatory and analgesic properties of the leaves (LCE) and stem bark (BCE) crude extracts of Zanthoxylum riedelianum (Rutaceae). Different fractions of the stem bark extract (hexane, BCEH; dichloromethane, BCED; ethyl acetate, BCEE; and lyophilized aqueous residual, BCEW) were also investigated. We studied the effects of the extracts and fractions using the rat paw oedema test induced by carrageenan, dextran, histamine or nystatin; the mouse abdominal constriction test; the mouse hot-plate test (only for LCE and BCE); and the mouse formalin test. Both extracts and all BCE fractions displayed anti-inflammatory activity in the carrageenan-induced oedema model, but not for dextran, histamine or nystatin. Considering the analgesic models, both extracts showed antinociceptive activity, but BCE was more active than LCE in models of central pain. All BCE fractions showed significant inhibition in the abdominal constriction test and in both phases of the formalin test. When BCED was submitted to phytochemical procedures it led to the isolation of six lignans (sesamin, methylpluviatolide, dimethylmatairesinol, piperitol-4(')-O-(gamma),(gamma)-dimethylallyl ether, kaerophyllin and hinokinin), and a triterpene (lupeol). Inhibition of cyclooxygenase and its metabolites may have been involved in the mechanism of action of this plant, considering previous studies reporting the anti-inflammatory and analgesic activity for the identified lignans, as well as anti-inflammatory activity for lupeol.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Lignans; Male; Mice; Pain; Pain Measurement; Pentacyclic Triterpenes; Plant Bark; Plant Extracts; Plant Leaves; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Triterpenes; Zanthoxylum

The antinociceptive actions of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were evaluated using tail-flick, hot-plate and formalin tests in mice. The effects of honokiol and magnolol on the formalin-induced c-Fos expression in the spinal cord dorsal horn as well as motor coordination and cognitive function were examined. Data showed that honokiol and magnolol did not produce analgesia in tail-flick, hot-plate paw-shaking and neurogenic phase of the overt nociception induced by intraplantar injection of formalin. However, honokiol and magnolol reduced the inflammatory phase of formalin-induced licking response. Consistently, honokiol and magnolol significantly decreased formalin-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol and magnolol did not elicit motor incoordination and memory dysfunction at doses higher than the analgesic dose. These results demonstrate that honokiol and magnolol effectively alleviate the formalin-induced inflammatory pain without motor and cognitive side effects, suggesting their therapeutic potential in the treatment of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Central Nervous System Depressants; Disease Models, Animal; Drug Evaluation, Preclinical; Fixatives; Formaldehyde; Inflammation; Lignans; Lumbosacral Region; Magnolia; Memory; Mice; Pain; Posterior Horn Cells; Proto-Oncogene Proteins c-fos

Flaxseed (FS) is a nutritional supplement with high concentrations of (n-3) fatty acids and lignans that have anti-inflammatory and antioxidant properties. The use of FS in the prevention or treatment of acute lung disease is unknown. In this study, we evaluated diets with high FS content in experimental murine models of acute lung injury and inflammation. The kinetics of lignan accumulation in blood, following 10% FS supplementation, was determined using liquid chromatography tandem mass spectrometry. Mice were fed isocaloric control and 10% FS-supplemented diets for at least 3 wk and challenged by hyperoxia (80% oxygen), intratracheal instillation of lipopolysaccharide, or acid aspiration. Bronchoalveolar lavage was evaluated for white blood cells, neutrophils, and proteins after a 24 h postintratracheal challenge of hydrochloric acid or lipopolysaccharide, or after 6 d of hyperoxia. Lung lipid peroxidation was assessed by tissue malondialdehyde concentrations. The plasma concentrations of the FS lignans, enterodiol and enterolactone, were stable after mice had eaten the diets for 2 wk. Following hyperoxia and acid aspiration, bronchoalveolar lavage neutrophils decreased in FS-supplemented mice (P = 0.012 and P = 0.027, respectively), whereas overall alveolar white blood cell influx tended to be lower (P = 0.11). In contrast, neither lung injury nor inflammation was ameliorated by FS following lipopolysaccharide instillation. Lung malondialdehyde levels were lower in hyperoxic mice than in unchallenged mice (P = 0.0001), and decreased with FS treatment following acid aspiration (P = 0.011). Dietary FS decreased lung inflammation and lipid peroxidation, suggesting a protective role against pro-oxidant-induced tissue damage in vivo.

Topics: Animals; Diet; Disease Models, Animal; Female; Flax; Inflammation; Lignans; Mice; Mice, Inbred C57BL; Oxidative Stress; Phytotherapy; Respiratory Distress Syndrome; Seeds

Previous studies have shown that the extracts obtained from Phyllanthus amarus, and some of the lignans isolated from it, exhibit pronounced antiinflammatory properties. In the present study, we have assessed whether the antiinflammatory actions of these lignans can be mediated by interaction with platelet activating factor (PAF) receptor or interference with the action of this lipid. The local administration of nirtetralin, phyltetralin or niranthin (30 nmol/paw), similar to WEB2170 (a PAF receptor antagonist, 30 nmol/paw), significantly inhibited PAF-induced paw oedema formation in mice. The extracts of P. amarus (100 microg/ml) and niranthin (30 microM), but not nirtetralin or phyltetralin (30 microM), decreased the specific binding of [(3)H]-PAF in mouse cerebral cortex membranes. Furthermore, both niranthin and WEB2170 displaced, in a concentration-dependent manner, the [(3)H]-PAF binding sites. The mean IC(50) values from these effects were 6.5 microM and 0.3 microM, respectively. Additionally, both niranthin and WEB2170 (30 nmol/paw) inhibited the increase of myeloperoxidase activity induced by PAF injection in the mouse paw. When assessed the mouse model of pleurisy induced by PAF, pretreatment with niranthin (100 micromol/kg, p.o.) or WEB2170 (1.7 micromol/kg, i.p.) significantly inhibited PAF-induced protein extravasations. Moreover, in the rat model of PAF-induced allodynia, both niranthin (30 nmol/paw) and WEB2170 (30 nmol/paw) treatment significantly inhibited PAF-induced allodynia. In addition, niranthin had a rapid onset and long-lasting antiallodynic action when compared with WEB2170. Collectively, the present findings suggest that niranthin exhibits antiinflammatory and antiallodynic actions which are probably mediated through its direct antagonistic action on the PAF receptor binding sites.

Topics: Analgesics; Animals; Anisoles; Anti-Inflammatory Agents; Azepines; Binding, Competitive; Carrageenan; Cerebral Cortex; Dioxoles; Inflammation; Lignans; Male; Mice; Pain Measurement; Pain Threshold; Peroxidase; Phyllanthus; Plant Extracts; Platelet Activating Factor; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Pleurisy; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Tetrahydronaphthalenes; Time Factors; Triazoles

This study investigated the anti-allodynic and anti-oedematogenic effects of the hexanic extract, lignan-rich fraction and purified lignans from a plant used in the traditional medicine, Phyllanthus amarus, in the inflammatory and neuropathic models of nociception. The hexanic extract inhibited the allodynia and the oedema induced by the intraplantar injection of complete Freund's adjuvant (CFA). The inhibition observed was 76 +/- 7% (ipsilateral paw), 64 +/- 7% (contralateral paw), and 41 +/- 2% (oedema). Otherwise, the lignan-rich fraction or the pure lignans did not affect CFA-induced allodynia. Administered chronically, the lignan fraction reduced CFA-induced paw oedema (39 +/- 9%). When evaluated in the model of neuropathic pain caused by partial ligation of sciatic nerve, the hexanic extract inhibited the mechanical allodynia (77 +/- 7%), with a similar efficacy to the gabapentin (71 +/- 10%). The anti-allodynic effects of hexanic extract of P. amarus seem not to be associated with the impairment of motor co-ordination or with the development of tolerance. Finally, the treatment with hexanic extract inhibited the increase of myeloperoxidase activity, either following intraplantar injection of CFA or after sciatic nerve injury. It is concluded that, apart from its anti-inflammatory actions, which are probably linked to the presence of lignans, another as yet unidentified active principle(s) present in the hexanic extract of P. amarus produces pronounced anti-allodynia in two models of inflammatory and neuropathic pain. Considering that few drugs are currently available for the treatment of chronic pain, especially of the neuropathic type, the present results may have clinical relevance and open new possibilities for the development of new anti-allodynic drugs.

Topics: Acetates; Amines; Analgesics; Animals; Anti-Inflammatory Agents; Cyclohexanecarboxylic Acids; Edema; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Freund's Adjuvant; Gabapentin; gamma-Aminobutyric Acid; Hexanes; Inflammation; Ligation; Lignans; Male; Mice; Motor Activity; Neutrophil Infiltration; Pain; Peripheral Nervous System Diseases; Peroxidase; Phyllanthus; Physical Stimulation; Plant Extracts; Psychomotor Performance; Sciatica; Solvents

In the present study, we demonstrated the inhibitory effect of magnolol on the plasma leakage in passive cutaneous anaphylactic (PCA) reaction, neurogenic inflammation, dorsal skin and ear edema in mice. Hind-paw skin plasma extravasation caused by antidromic stimulation of the saphenous nerve was reduced in mice pretreated with magnolol, diphenydramine or methysergide, but not with indomethacin. Ear edema formation in the PCA reaction was reduced by magnolol in dose-dependent manner. In addition, histamine-, serotonin-, compound 48/80-, bradykinin- and substance P-induced ear edema in mice was also suppressed by magnolol. A dose- and time-dependency of the inhibitory effect of magnolol was demonstrated in histamine- and compound 48/80-induced dorsal skin edema. The maximal inhibitory effect produced by a single dose of magnolol (10 mg/kg) persisted for 1 h, and significant suppression lasted for at least 3 h. In compound 48/80-pretreated mice, the histamine content of the ear was greatly reduced. Bradykinin- and substance P-induced ear edema in compound 48/80-pretreated mice was less severe than that seen in normal mice, but was still significantly reduced by magnolol pretreatment. Moreover, the inhibitory effect of magnolol was more marked than that of diphenhydramine combined with methysergide. These results suggest that the inhibitory effect of magnolol on local edema formation probably occurs through a nonselective inhibition on vascular tissue to prevent the permeability change caused by various mediators.

Topics: Adrenalectomy; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Capillary Permeability; Edema; Electric Stimulation; Exudates and Transudates; Histamine; Inflammation; Lignans; Mast Cells; Mice; Mice, Inbred ICR; Neurons, Afferent; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Regional Blood Flow; Serotonin Antagonists; Skin; Skin Absorption

Gomisin A, isolated from the fruits of Schisandra chinensis, is one of the dibenzocyclooctadiene lignans. Application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1 microgram/ear), a tumor-promoting agent, to the ears of mice induces inflammation. Among seven dibenzocyclooctadiene lignans assayed, gomisin A, gomisin J, and wuweizisu C inhibited the inflammatory activity induced by TPA in mice. The ED50 of these compounds for TPA-induced inflammation was 1.4-4.4 mumol. Gomisin A, with an ED50 of 1.4 mumol, showed the strongest inhibitory effect. Furthermore, at 5 mumol/mouse, it markedly suppressed the promotion effect of TPA (2.5 micrograms/mouse) on skin tumor formation in mice following initiation with 7,12-dimethylbenz[a]anthracene (50 micrograms/mouse). It is assumed that the inhibition of tumor promotion by gomisin A is due to its anti-inflammatory activity.

Topics: Animals; Anticarcinogenic Agents; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Female; Inflammation; Lignans; Mice; Mice, Inbred ICR; Polycyclic Compounds; Skin Neoplasms; Tetradecanoylphorbol Acetate

During inflammation polymorphonuclear cells (PMNs) are exposed to agonistic stimuli including activated complement, kallikrein, arachidonic acid metabolites, monokines, and platelet-activating factor (PAF). We report that PAF not only directly activates PMNs but in miniscule quantities (10(-12) mol/L) "primes" them as well, that is, permits PMNs to respond to subsequent stimuli that would be otherwise ineffectual. PAF priming of responses including superoxide generation, elastase release, and aggregation is time dependent and is maximal within five minutes. PAF need not be present during the subsequent exhibition of PMN agonists, but priming is inhibited by cold and is also inhibited by the PAF receptor antagonists BN 52021, L-652, and kadsurenone. An intact PAF molecule is required because lyso-PAF and methoxy-PAF do not prime PMN responses. PAF priming is associated with both enhanced expression of the adhesive glycoprotein identified by OKM-1 antibody and an enhanced rise in intracellular calcium levels in response to the subsequent addition of agonists such as FMLP. PMNs primed with PAF and stimulated with either F-Met-Leu-Phe or phorbol esters are more effective in lysing and detaching cultured human endothelial cells--damage that can also be inhibited by the PAF antagonists. Because PAF is synthesized and exhibited on surfaces of endothelial cells perturbed by coagulation, we suggest that this lipid may potentiate otherwise trivial activators of marginated PMNs so that they become damaging to the PAF-synthesizing endothelium itself. If so, our studies suggest a possible therapeutic role for PAF inhibitors in excessive inflammatory states.

Topics: Benzofurans; Cell Aggregation; Cell Survival; Diterpenes; Endothelium, Vascular; Fetal Hemoglobin; Furans; Ginkgolides; Hemoglobins, Abnormal; Humans; Inflammation; Lactones; Lignans; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pancreatic Elastase; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Superoxides