lignans and Edema

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes cartilage damage. Anti-inflammatories are widely used in the management of RA, but they can have side effects such as gastrointestinal and/or cardiovascular disorders. Studies published by our group showed that the synthesis of hybrid triazole analogs neolignan-celecoxib containing the substituent groups sulfonamide (L15) or carboxylic acid (L18) exhibited anti-inflammatory activity in an acute model of inflammation, inhibited expression of P-selectin related to platelet activation and did not induce gastric ulcer, minimizing the related side effects. In continuation, the present study evaluated the anti-inflammatory effects of these analogs in an experimental model of arthritis and on the functions of one of the important cells in this process, macrophages. Mechanical hyperalgesia, joint edema, leukocyte recruitment to the joint and damage to cartilage in experimental arthritis and cytotoxicity, spread of disease, phagocytic activity and nitric oxide (NO) and hydrogen peroxide production by macrophages were evaluated. Pre-treatment with L15 and L18 reduced mechanical hyperalgesia, joint edema and the influx of leukocytes into the joint cavity after different periods of the stimulus. The histological evaluation of the joint showed that L15 and L18 reduced cartilage damage and there was no formation of rheumatoid pannus. Furthermore, L15 and L18 were non-cytotoxic. The analogs inhibited the spreading, the production of NO and hydrogen peroxide. L15 decreased the phagocytosis. Therefore, L15 and L18 may be potential therapeutic prototypes to treat chronic inflammatory diseases such as RA.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Celecoxib; Edema; Hydrogen Peroxide; Hyperalgesia; Lignans; Zymosan

This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Carrageenan; Celecoxib; Dose-Response Relationship, Drug; Edema; Lignans; Male; Mice; Molecular Structure; Peritonitis; Platelet Activation; Platelet Aggregation Inhibitors; Rats; Structure-Activity Relationship; Triazoles; Ulcer

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

Mast cells (MCs) play critical roles in allergic reactions and modulating the activation of MCs could be an effective strategy to treat allergic diseases, which cause a rapidly increasing threat to the public health. Herein, we described that Magnolin, a major component from Flos magnoliae could inhibit IgE-dependent MCs activation. We found Magnolin inhibited IgE/Ag-induced calcium mobilization, degranulation, and cytokines release in LAD2 cells. Magnolin was also found to attenuate IgE/Ag-induced mice paw swelling in a dose-dependent manner. Further mechanistic studies suggested a possible anti-allergic and anti-inflammatory effects of Magnolin in IgE/Ag-induced anaphylactic reactions. Thereby, Magnolin could be a potential therapeutic agent for preventing mast cell-related immediate and delayed allergic diseases.

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Antigens; Calcium; Cell Line; Cell Survival; Cytokines; Edema; Histamine; Humans; Hypersensitivity; Immunoglobulin E; Lignans; Male; Mast Cells; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Peptide Hydrolases

The seeds of Vitex negundo, with rich lignans metabolites, have been widely used as a traditional Chinese medicine and Ayurvedic herbal medicine for the treatment of rheumatism and joint inflammation. The total lignans of Vitex negundo seeds (TOV) were suggested to play an important role in the treatment of arthritis.. The aim of the study was designed to investigate the anti-arthritic effects of TOV on collagen-induced arthritis (CIA) in rats as well as its possible mechanisms.. TOV was prepared by combined macroporous resin and polyamide column chromatography, and constituents of TOV were analyzed by HPLC. CIA model in rats was established by immunization with chicken type II collagen and then the rats were intragastrically administrated with TOV for 30 days. Rat arthritis was evaluated by measurements of hind paw edema, arthritis index score, weight growth and indices of thymus and spleen, and by histological examination. Levels of serum MMP-2, MMP-3, MMP-9, IL-1β, IL-6, IL-8, IL-10, IL-17A and TNF-α were also examined. In addition, the expression of COX-2, iNOS and IκB, p-IκB in synovial tissues was evaluated by western blotting. The analgesic and anti-inflammatory effects of TOV were also evaluated in acetic acid-induced writhing and xylene-induced ear edema in mice, respectively. In addition, acute toxicity test was employed to preliminarily assess the safety of TOV.. TOV significantly inhibited the paw edema and decreased the arthritis index, with no influence on the body weight and the indices of thymus and spleen of CIA rats. Meanwhile, TOV dose-dependently reduced the infiltration of inflammatory cells, synovial hyperplasia and attenuated cartilage damage. Additionally, the serum levels of IL-1β, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9 were markedly decreased, while the level of serum IL-10 was increased in TOV-treated rats. The significant reduction of the expression of COX-2, iNOS and p-IκB and the notable increase of IκB in synovial tissues were also observed in TOV-treated animals. TOV also significantly inhibited acetic acid-induced writhing and decreased xylene-induced ear edema in mice. Finally, the maximal tolerable dose (MTD) of TOV was determined to be 16.0 g/kg.. These results suggest that TOV has significant anti-arthritic effects on collagen-induced arthritis in rats, which may be attributed to the inhibition of the levels of IL-1β, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9, and the increase of IL-10 in serum as well as down-regulation of the protein expression of COX-2 and iNOS in synovial tissues via suppressing the phosphorylation and degradation of IκB. Due to its high efficacy and safety, TOV can be regarded as a promising drug candidate for rheumatoid arthritis treatment.

Topics: Animals; Arthritis, Experimental; Chickens; Collagen Type II; Cyclooxygenase 2; Cytokines; Edema; Female; Lignans; Male; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Medicine, Chinese Traditional; Mice; Mice, Inbred ICR; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Seeds; Synovial Membrane; Vitex

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

Topics: Alcohols; Analgesics; Animals; Anti-Inflammatory Agents; Dextrans; Edema; Female; Formaldehyde; Glycosides; Lignans; Male; Naphthalenes; Phyllanthus; Plant Extracts; Plant Leaves; Rats, Wistar; Water

We examined the anti-inflammatory effects of (+)-syringaresinol (SGRS), a lignan isolated from Rubia philippinensis, in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells using enzyme-based immuno assay, Western blotting, and RT-PCR analyses. Additionally, in vivo effects of SGRS in the acute inflammatory state were examined by using the carrageenan-induced hind paw edema assay in experimental mice. As a result, treatment with SGRS (25, 50, and 100 μM) inhibited protein expression of lipopolysaccharide-stimulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) as well as production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) induced by LPS. Moreover, SGRS also reduced LPS-induced mRNA expression levels of iNOS and COX-2, including NO, PGE2, TNF-α, IL-1β, and IL-6 cytokines in a dose-dependent fashion. Furthermore, carrageenan-induced paw edema assay validated the in vivo anti-edema effect of SGRS. Interestingly, SGRS (30 mg/kg) suppressed carrageenan-induced elevation of iNOS, COX-2, TNF-α, IL-1β, and IL-6 mRNA levels as well as COX-2 and NF-κB protein levels, suggesting SGRS may possess anti-inflammatory activities.

Topics: Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Edema; Extracellular Signal-Regulated MAP Kinases; Furans; Inflammation Mediators; Lignans; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Mice, Inbred ICR; NF-kappa B; RAW 264.7 Cells

Nortrachelogenin is a pharmacologically active lignan found in knot extracts of

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cells, Cultured; Disease Models, Animal; Edema; Furans; Lignans; Macrophages; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type II; Pinus sylvestris; Proteasome Inhibitors

(-)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (-)-hinokinin (HK) and (-)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween® 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 - cyclooxygenase-2) interaction in comparison with CUB and HK.

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Catalytic Domain; Computer Simulation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyproheptadine; Dextrans; Dinoprostone; Dioxoles; Edema; Furans; Indomethacin; Ligands; Lignans; Male; Mice; Molecular Docking Simulation; Polysorbates; Rats, Wistar; Rutaceae

Recent studies suggested that TLR4 signaling pathways played an important role in the development of LPS-induced acute lung injury (ALI). Sesamin, a sesame lignan exacted from sesame seeds, has been shown to exhibit significant anti-inflammatory activity. The purpose of this study was to investigate the anti-inflammatory effects of sesamin on LPS-induced ALI in mice. Mice ALI model was induced by intratracheal instillation of LPS. Sesamin was given 1 h after LPS challenge. Our results showed that sesamin inhibited LPS-induced lung pathological change, edema, and myeloperoxidase (MPO) activity. Sesamin suppressed LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1β production. Furthermore, sesamin inhibited LPS-induced TLR4 expression and NF-κB activation. In conclusion, the results of this study indicated that sesamin protected against LPS-induced ALI by inhibition of TLR4 signaling pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Dioxoles; Edema; Enzyme Activation; Interleukin-1beta; Interleukin-6; Lignans; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Signal Transduction; 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

Dioxins and dioxin-like compounds (DLCs) enter the body mainly through diet and cause various toxicological effects through activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. Some plant extracts and phytochemicals are reported to suppress this transformation. However, most of these reports have been from in vitro experiments and few reports have been from in vivo experiments. In addition, there has been no report of foodstuffs that effectively prevent AhR-associated morphological abnormalities such as deformities caused by dioxins and DLCs in vivo. In this study, we show that secoisolariciresinol (SECO), a natural lignan-type polyphenolic phytochemical found mainly in flaxseed, has a rescuing effect, actually suppressing morphological abnormalities (pericardial edema) in zebrafish embryos exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB congener. Importantly, the rescuing effect of SECO was still evident when it was applied 16 h after the beginning of exposure to PCB126. This study suggests that SECO may be useful as a natural suppressive agent for morphological abnormalities caused by dioxins and DLCs.

Topics: Abnormalities, Drug-Induced; Animals; Butylene Glycols; Dioxins; Edema; Embryo, Nonmammalian; Lignans; Pericardial Effusion; Phytoestrogens; Zebrafish

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

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

Anemarrhena asphodeloides is widely used in traditional Chinese medicine, and is known to possess antidiabetic and anti-inflammatory properties. Because inducible nitric oxide synthase (iNOS) plays an important role in inflammation, we investigated the inhibitory effects of two known phenolic compounds, nyasol (1) and broussonin A (2), from A. asphodeloides, on iNOS and its plausible mechanism of action. Compounds 1 and 2 exhibited inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Compounds 1 and 2 also suppressed the expressions of iNOS protein and mRNA. Moreover, compounds 1 and 2 suppressed the expression of inflammatory cytokines such as interleukin-1β (IL-1β) and interferon-β (IFN-β). They also inhibited the transcriptional activity of NF-κB and degradation of IκB-α, as well as the activation of Akt and ERK in LPS-stimulated RAW 264.7 cells. In in vivo animal model, compounds 1 and 2 significantly inhibited TPA-induced mouse ear edema. These results suggest that 1 and 2 suppress LPS-stimulated iNOS expression at the transcriptional level through modulating NF-κB and down-regulation of the Akt and ERK signaling pathways. Taken together, these findings indicate that the suppressive effects of 1 and 2 on iNOS expression might provide one possible mechanism for their anti-inflammatory activities.

Topics: Anemarrhena; Animals; Anti-Inflammatory Agents; Cell Line; Down-Regulation; Edema; I-kappa B Proteins; Lignans; Lipopolysaccharides; Macrophages; Mice; NF-KappaB Inhibitor alpha; Nitric Oxide; Nitric Oxide Synthase Type II; Phenols; Transcriptional Activation

Magnolol, a tradition Chinese herb, displays an array of activities including antifungal, antibacterial, and antioxidant effects. To investigate the protective effect of magnolol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intratracheal instillation of magnolol (5 μg/kg) 30 min before LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. Expression of cyclooxygenase (COX)-2 in lung tissues was determined by Western blot analysis. Magnolol pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by magnolol pretreatment. The expression of COX-2 was significantly suppressed by magnolol pretreatment. Magnolol potently protected against LPS-induced ALI and the protective effects of magnolol may attribute partly to the suppression of COX-2 expression.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Disease Models, Animal; Edema; Interleukin-1beta; Lignans; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Peroxidase; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

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

The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Austria; Benzofurans; Cyclooxygenase 1; Edema; Intramolecular Oxidoreductases; Krameriaceae; Lignans; Male; Mice; NF-kappa B; Plant Roots; Prostaglandin-E Synthases

A chemical and biological validation of the traditional use of Hyoscyamus niger seeds as anti-inflammatory drug has been established. The methanolic extract of seeds of H. niger (MHN) was evaluated for its analgesic, anti-inflammatory and antipyretic activities in experimental animal models at different doses. MHN produced significant increase in hot plate reaction time, while decreasing writhing response in a dose-dependent manner indicating its analgesic activity. It was also effective in both acute and chronic inflammation evaluated through carrageenin-induced paw oedema and cotton pellet granuloma methods. In addition to its analgesic and anti-inflammatory activity, it also exhibited antipyretic activity in yeast-induced pyrexia model. Furthermore, the bioactive MHN under chemical investigation showed the presence of coumarinolignans as major chemical constituent and yielded a new coumarinolignan, cleomiscosin A methyl ether (1) along with four known coumarinolignans, cleomiscosin A (2), cleomiscosin B (3), cleomiscosin A-9'-acetate (4) and cleomiscosin B-9'-acetate (5). The structure elucidation of 1 was done by spectroscopic data interpretation and comparative HPLC analysis. Cleomiscosin A, but not its isomer cleomiscosin B, reduced dry and wet weight of cotton pellet granuloma in mice. This suggests that cleomiscosin A is an important constituent of MHN responsible for anti-inflammatory activity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Behavior, Animal; Carrageenan; Cotton Fiber; Coumarins; Disease Models, Animal; Edema; Fever; Granuloma; Hyoscyamus; Lignans; Mice; Molecular Structure; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Seeds; Yeasts

The bioactive constituents isolated from the bark of Magnolia officinalis such as magnolol, honokiol and obovatol have anti-inflammatory properties through the inactivation of NF-kappaB which is an important factor in the regulation of inflammatory reaction. We recently isolated neolignan compound, 4-O-methylhonokiol, from M. officinalis. In the present study, we investigated whether or not 4-O-methylhonokiol inhibits inflammatory reaction through the inhibition of NF-B activity [corrected]. The results showed that 4-O-methylhonokiol (2.5-10 microM) inhibited LPS (1 microg/ml)-induced NO generation in macrophage Raw 264.7 cells in a concentration-dependent manner with IC(50) value 9.8 microM. The inhibition of NO generation by 4-O-methylhonokiol was consistent with the inhibitory effect on the expression as well as transcriptional activity of inducible nitric oxide synthase (iNOS). In addition, 4-O-methylhonokiol inhibited the LPS-induced transcriptional and DNA binding activities of NF-kappaB as well as p50 and p65 translocation into the nucleus. Topical application of 4-O-methylhonokiol (0.1-1 mg/ear) inhibited 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory ear edema formation, NF-kappaB activity, and iNOS and COX-2 expression. The present results provided evidence that 4-O-methylhonokiol has anti-inflammatory properties through inhibition of the NF-kappaB pathway, and suggested that 4-O-methylhonokiol can be used as an anti-inflammatory agent.

Topics: Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Cell Line, Tumor; Cyclooxygenase 2; Ear Diseases; Edema; Lignans; Lipopolysaccharides; Magnolia; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Tetradecanoylphorbol Acetate; Transcription, Genetic

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

To search the anti-inflammatory fraction of Albizia julibrissin.. Inflammatory model of Kunming mice ear edema induced by croton oil and determination combined with the LC-MS-MS-guided fractionation and isolation were used.. The n-butanol fraction (AJ-B) obtained from the ethanolic extract of the Cortex albiziae was the major active fraction. The lignan glycosides fraction (AJ-B-1), which was further isolated from AJ-B, showed significant anti-inflammatory activity and exhibited dose-dependent relationship in the dose of 5 to 20 mg x kg(-1).. The method of bioassay-guided fractionation and isolation combined with the LC-MS-MS determination may be of benefit to the logical studies on the bioactive fractions or constituents of traditional Chinese materia medica.

Topics: Albizzia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Assay; Butanols; Chromatography, High Pressure Liquid; Croton Oil; Drugs, Chinese Herbal; Edema; Glycosides; Lignans; Male; Mice; Phytotherapy; Plant Bark; Plants, Medicinal; Tandem Mass Spectrometry

The anti-inflammatory and analgesic effects of three dibenzylbutyrolactone lignans, (-)-hinokinin (2), (-)-6,6'-dinitrohinokinin (3), and (-)-6,6'-diaminohinokinin (4), obtained by partial synthesis from (-)-cubebin (1), were investigated using different animal models. It was observed that compounds (1) and (2) inhibited the edema formation in the rat paw edema assay at the same level and that all responses were dose dependent. Also, at the dose of 30 mg/kg, compounds 1, 2, 3, and 4 inhibited the edema formation by 53%, 63%, 54%, and 82%, respectively, at the third hour of the experiment. In the acetic acid-induced writhing test in mice, compounds 2 and 4 produced inhibition levels of 97% and 92%, respectively, while 3 displayed lower effect (75%), which was still higher than 1. The assayed compounds neither displayed activity in the cell migration test nor in the hot plate test.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Edema; Lactones; Lignans; Pain Threshold; Rats

This study assessed the anti-inflammatory effect of the extracts and purified lignans obtained from Phyllanthus amarus. Given orally, the hexane extract (HE), the lignan-rich fraction (LRF), or the lignans phyltetralin, nirtetralin, niranthin, but not hypophyllanthin or phyllanthin, inhibited carrageenan (Cg)-induced paw oedema and neutrophil influx. The HE, the LRF or nirtetralin also inhibited the increase of IL1-beta tissue levels induced by Cg. Furthermore, bradykinin (BK)-, platelet activating factor (PAF)- and endothelin-1 (ET-1)-induced paw oedema were significantly inhibited by the HE or LRF while histamine- and substance P-induced paw oedema were unaffected. Finally, nirtetralin or phyltetralin caused inhibition of paw oedema induced by PAF or ET-1. These results show that the HE, the LRF and the lignans niranthin, phyltetralin and nirtetralin exhibited marked anti-inflammatory properties and suggest that these lignans seem to be the main active principles responsible for the anti-inflammatory properties reported for the HE of P. amarus.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Dose-Response Relationship, Drug; Edema; Lignans; Male; Mice; Phyllanthus; Phytotherapy; Plant Extracts

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

Four taxoids (taxusin, baccatin VI, baccatin III and 1beta-hydroxybaccatin I) and five lignans (lariciresinol, taxiresinol, 3'-demethylisolariciresinol-9'-hydroxyisopropylether, isolariciresinol and 3-demethylisolariciresinol) were isolated from the heartwood of Taxus baccata L. (Taxaceae) growing in Turkey through chromatographic techniques. In vivo anti-inflammatory and antinociceptive activity of these compounds were investigated. All the compounds were shown to possess significant antinociceptive activity against p-benzoquinone-induced abdominal contractions, while only lignan derivatives significantly inhibited carrageenan-induced hind paw edema in mice.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Benzoquinones; Carrageenan; Colic; Edema; Lignans; Male; Mice; Phytotherapy; Plant Extracts; Plant Stems; Taxoids; Taxus; Toxicity Tests, Acute

20 compounds were isolated from the leaves of Magnolia denudata including 16 lignans, which belong to 6 structural types. Except for (7R, 8S, 1'S)-delta8' -1', 4'- dihydro-5'-methoxy-3,4-methylenedioxy-4'-oxo-7.0.2', 8.1'-neolignan (6), magliflonenone (9), 2, 5'-diene-2', 8'-epoxy-5'-methoxy-8-methyl-4'-oxo-3,4- methylenedioxy-spiro (5, 5)-undecane (10), veraguensin (16) and beta-sitosterol (20), the other 15 compounds were obtained from this species for the first time. The absolute configurations of 3 compounds (1, 4, 10) were determined by CD spectroscopy for the first time. The anti-inflammatory activities of compounds 1, 2 and 16 were assessed and 2 was shown to have significant inhibition effect on mice hind-paw edema induced by carrageenan.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; China; Edema; Gas Chromatography-Mass Spectrometry; Lignans; Magnoliaceae; Mice; Nuclear Magnetic Resonance, Biomolecular; Optical Rotation; Plant Extracts; Plant Leaves; Spectrophotometry, Infrared

Investigations on croconazole, a novel imidazole compound, suggested antiphlogistic properties in vitro. Hence, its anti-inflammatory capacity was tested in vivo using the arachidonic acid-induced mouse ear swelling test, which is a suitable model for screening inhibitors of the lipoxygenase and/or the cyclooxygenase. Topical application of croconazole (1%/0.01%) to the mouse ear induced a maximal inhibition of edema (inhibition: 39%/33%; p = 0.01) which was as strong as the reference nordihydroguaiaretic acid (inhibition: 38.9%; p = 0.01). These results justify further investigations on croconazole to study potential inhibitory effects on proinflammatory arachidonic acid metabolites.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antifungal Agents; Arachidonic Acid; Ear, External; Edema; Female; Guaiacol; Imidazoles; Lignans; Lipoxygenase Inhibitors; Mice; Mice, Inbred Strains

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

Magnolol, isolated from Magnolia officinalis, inhibited mouse hind-paw edema induced by carrageenan, compound 48/80, polymyxin B and reversed passive Arthus reaction. Acetic acid-induced writhing response was depressed by magnolol, indomethacin and ibuprofen. The lethality of endotoxin challenge was reduced by pretreatment with magnolol, indomethacin and BW755C, a dual cyclo-oxygenase/lipoxygenase inhibitor. The recovered myeloperoxidase activity in edematous paw was significantly decreased in mice pretreated with magnolol and BW755C. Suppression of edema was demonstrated not only in normal mice but also in adrenalectomized animals. Magnolol was less potent on reducing PGD2 formation in rat mast cell than that of indomethacin. Unlike dexamethasone, magnolol did not increase liver glycogen level. The results suggest that the anti-inflammatory effect of magnolol was neither mediated by glucocorticoid activity nor through releasing steroid hormones from adrenal gland. The action of magnolol is proposed to be dependent on reducing the level of eicosanoid mediators.

Topics: Adrenalectomy; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Dexamethasone; Edema; Female; Indomethacin; Lignans; Liver; Mice; Mice, Inbred ICR; Peroxidase; Polymyxin B; Prostaglandin D2; Rats; Rats, Wistar

Platelet activating factor (PAF), a potent lipid-like vasoactive agent, induced rat foot edema when it was injected subplantarly. The edema reached its maximum 1 h after PAF challenge. Indomethacin did not inhibit the peak edematous response whereas both PAF antagonists, kadsurenone and L-652,731, inhibit the PAF-induced rat foot edema (PFE). Both PAF antagonists also partially block the first phase of the carrageenin-induced rat foot edema (CFE). Using the inhibition of [3H]PAF receptor binding to prepared rabbit platelet membranes, release of PAF or PAF-like materials in carrageenin-injected rat hindpaw was observed. These results suggest that the released PAF or PAF-like materials together with the released histamine and kinin evoke the first phase hindpaw edema in the rats. Indomethacin or PAF antagonist, administered alone, does not block the first phase or the second phase of CFE, respectively. However, PAF antagonist potentiated the inhibitory effects of indomethacin suggesting that the released PAF may also be involved in the biosynthesis of prostaglandins to initiate the second phase of rat CFE.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Benzopyrans; Carrageenan; Edema; Lignans; Male; Platelet Activating Factor; Rats; Rats, Inbred Strains; Time Factors