[8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10.

Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.

Galactomannan of Delonix regia seeds modulates cytokine expression and oxidative stress eliciting anti-inflammatory and healing effects in mice cutaneous wound.

The galactomannans property of forming viscous solutions, along with the traditional use of Delonix regia as anti-inflammatory, antinociceptive and wound healing, justify the investigation of the healing mechanism of Delonix regia galactomannan (GM-DR) in a model of excisional cutaneous wound. GM-DR (% 0.01-1) was topically applied to the wounds of female Swiss mice during 14 days. The wound healing effect of GM-DR was evaluated by the following parameters: wound closure and clinical signs (hyperemia, edema and exudate by macroscopy, nociception by analgesimetry), oxidative stress markers (malondialdehyde - MDA, reduced glutathione - GSH) by ELISA, histopathological (HE and Picrosirius red), and histomorphometric (collagenesis, blood vessels, polymorphonuclear, mononuclear, fusiform cells) and immunohistochemistry (inflammatory and growth factor mediators) by tissue microarrayer. GM-DR reduced wound area (7-14th day) and hypernociception (6 h - 5th day), leukocyte infiltration (2 -7th days), expression and levels of IL-1ß (2th day), IL-6 (2th day), MDA (44% - 2th day), and increased fusiform cells, granulation tissue, collagen deposition, GSH (25 - 50%, 2-5th day), expression of the transforming growth factor beta (TGF-ß) (7-10th day) and smooth muscle alpha actin (α-SMA) (7-14th day). In conclusion, GM-DR accelerates the mice healing process acting both in the inflammatory and proliferative phases.

Contribution of the carbohydrate-binding ability of Vatairea guianensis lectin to induce edematogenic activity.

Vatairea guianensis lectin (VGL), Dalbergiae tribe, is a N-acetyl-galactosamine (GalNAc)/Galactose (Gal) lectin previously purified and characterized. In this work, we report its structural features, obtained from bioinformatics tools, and its inflammatory effect, obtained from a rat paw edema model. The VGL model was obtained by homology with the lectin of Vatairea macrocarpa (VML) as template, and we used it to demonstrate the common characteristics of legume lectins, such as the jellyroll motif and presence of a metal-binding site in the vicinity of the carbohydrate-recognition domain (CRD). Protein-ligand docking revealed favorable interactions with N-acetyl-d-galactosamine, d-galactose and related sugars as well as several biologically relevant N- and O-glycans. In vivo testing of paw edema revealed that VGL induces edematogenic effect involving prostaglandins, interleukins and VGL CRD. Taken together, these data corroborate with previous reports showing that VGL interacts with N- and/or O-glycans of molecular targets, particularly in those presenting galactosides in their structure, contributing to the lectin inflammatory effect.

Modulator effect of a polysaccharide-rich extract from Caesalpinia ferrea stem barks in rat cutaneous wound healing: Role of TNF-α, IL-1ß, NO, TGF-ß.

ETHNOPHARMACOLOGICAL RELEVANCE: In folk medicine stem barks of Caesalpinia ferrea (Caesalpinioideae) are used to treat enterocolitis, rheumatism and wounds and in experimental procedures, its aqueous extracts demonstrated antiulcer, anti-inflammatory, analgesic, and healing effects. AIM OF THE STUDY: The healing mechanism of the polyssacharide-rich extract of C. ferrea stem barks (TPL-Cf) was investigated in a model of excisional cutaneous wound in Wistar rats. MATERIALS AND METHODS: Excisional wounds received topical treatment with TPL-Cf (0.025-0.1%) during 21 days. Hypernociception, macroscopical, histological and immunohistochemical parameters were evaluated and analyzed by ANOVA, Bonferroni and Kruskal-Wallis tests, followed by Dunn and Chi-Square tests. RESULTS: TPL-Cf (0.1%) reduced wound area and hypernociception, and increased wound contraction. TPL-Cf reduced leukocyte infiltration and vascular permeability, and stimulated fibroblasia, angiogenesis, well formed granulation tissue, collagen deposition and epithelial layer formation. TPL-Cf reduced TNF-α expression and the levels of PGE2 (73%-day 5), IL-1 (42%-day 2), MDA (38%-day 5), total protein (53%-day 2; 73%-day 5) and MPO activity (53%-day 2), but increased the expression of i-NOS (days 5 and 7), TGF-ß (day 5) and the levels of NO (3.6 fold-day 5). CONCLUSION: The polysaccharide-rich extract of C. ferra stem barks accelerates wound healing by the control of the inflammatory phase and attenuates hypernociception via modulation of inflammatory mediators (TNF-α, IL-1ß, NO, TGF-ß).

Agglutinin isolated from the red marine alga Hypnea cervicornis J. Agardh reduces inflammatory hypernociception: involvement of nitric oxide.

Hypnea cervicornis agglutinin (HCA), a lectin isolated from the red marine alga has been previously shown to have an antinociceptive effect. In the present study in rats, mechanisms of action of HCA were addressed regarding mechanical hypernociception induced by carrageenan, ovalbumin (as antigen), and also by prostaglandin E(2) in rats. The lectin administered intravenously inhibited carrageenan- and antigen-induced hypernociception at 1, 3, 5 and 7h. This inhibitory effect was completely prevented when lectin was combined with mucin, demonstrating the role of carbohydrate-binding sites. The inhibition of inflammatory hypernociception by HCA was associated with the prevention of neutrophil recruitment to the plantar tissue of rats but was not associated with the inhibition of the release of pro-hypernociceptive cytokines (TNF-alpha, IL-1 beta and CINC-1). HCA also blocked mechanical hypernociception induced by PGE(2), which was prevented by the administration of nitric oxide synthase inhibitors. These results were corroborated by the increased circulating levels of NO metabolites following HCA treatment. These findings suggest that the anti-hypernociceptive effects of HCA are not associated with the inhibition of pro-inflammatory cytokine production. However, these effects seem to involve the inhibition of neutrophil migration and also the increase in NO production.

Pharmacological analysis of the neutrophil migration induced by D. rostrata lectin: involvement of cytokines and nitric oxide.

In the present study, we investigated the involvement of resident cell and inflammatory mediators in the neutrophil migration induced by chemotactic activity of a glucose/mannose-specific lectin isolated from Dioclea rostrata seeds (DrosL). Rats were injected i.p. with DrosL (125-1000 microg/cavity), and at 2-96 h thereafter the leukocyte counts in peritoneal fluid were determined. DrosL-induced a dose-dependent neutrophil migration accumulation, which reached maximal response at 24 h after injection and declines thereafter. The carbohydrate ligand nearly abolished the neutrophil influx. Pre-treatment of peritoneal cavities with thioglycolate which increases peritoneal macrophage numbers, enhanced neutrophil migration induced by DrosL by 303%. However, the reduction of peritoneal mast cell numbers by treatment of the cavities with compound 48/80 did not modify DrosL-induced neutrophil migration. The injection into peritoneal cavities of supernatants from macrophage cultures stimulated with DrosL (125, 250 and 500 microg/ml) induced neutrophil migration. In addition, DrosL treatment induced cytokines (TNF-alpha, IL-1beta and CINC-1) and NO release into the peritoneal cavity of rats. Finally, neutrophil chemotaxis assay in vitro showed that the lectin (15 and 31 microg/ml) induced neutrophil chemotaxis by even 180%. In conclusion, neutrophil migration induced by D. rostrata lectin occurs by way of the release of NO and cytokines such as IL-1beta, TNF-alpha and CINC-1.

Antinociceptive and anti-inflammatory effects of a mucin-binding agglutinin isolated from the red marine alga Hypnea cervicornis.

The agglutinin from the red marine alga Hypnea cervicornis (HCA) was tested in models of nociception and inflammation. The role of carbohydrate-binding sites and the systemic toxicity were assessed. HCA (10(-1), 1, and 10 mg/kg) administered i.v. to mice inhibited writhes induced by acetic acid and, at 10 mg/kg, inhibited the second phase of the formalin test, but did not alter the response latency in the hot-plate test. HCA (1 mg/kg) administered i.v. to rats reduced carrageenan-induced paw edema at 1, 2, and 3 h after challenge, but not edema induced by dextran. The neutrophil migration induced by both N-formyl-methionyl-leucyl-phenylalanine (fMLP) and carrageenan was inhibited by HCA at 10(-1), 1, and 10 mg/kg. The combination of HCA (1 mg/kg) and its ligand mucin reversed the lectin inhibitory effect on carrageenan-induced neutrophil migration and acetic acid-induced writhes. The i.v. treatment of rats with HCA (1 mg/kg) for 7 days did not affect body mass; liver, kidney or heart wet weight; blood leukocyte counts; urea, creatinine or serum transaminase activity; or macroscopy of the organs examined. In short, H. cervicornis agglutinin showed important antinociceptive and anti-inflammatory activity via interaction with the lectin carbohydrate-binding site.

Modulation of acute inflammation by a chitin-binding lectin from Araucaria angustifolia seeds via mast cells.

The effects of a lectin (AaL) from seeds of Araucaria angustifolia were investigated in the model of rat paw edema. In vivo anti-and pro-inflammatory activities, role of sugar residues, inflammatory mediators and systemic toxicity were assessed. Intravenous injection of AaL (0.1-1 mg/kg) dose-dependently inhibited the dextran-induced increase in edema and vascular permeability, which were prevented by association of the lectin with its binding sugar N-acetyl-glucosamine (Glyc-Nac). AaL also significantly inhibited edema induced by serotonin (18%) and compound 48/80 (33%), but not edema induced by histamine. In contrast, when applied by the s.c. route, AaL evoked a paw edema that peaked 1 h later and was partially prevented by association with Glyc-Nac (59%) or by prior i.v. administration of the lectin itself (38.8%). This AaL edematogenic activity was significantly inhibited by pentoxifylline (44.4%) or dexamethasone (51%) and also by depletion of rat paw mast cells (45.6%), but not by L-N-nitro-arginine methyl ester or indomethacin, excluding involvement of nitric oxide and prostaglandins. Treatment of animals with a single anti-inflammatory dose of AaL (1 mg/kg, i.v.) for 7 days did not affect rat corporal mass, liver, kidney, spleen or stomach wet weight, blood leukocyte count, and urea, creatinine or serum transaminase activity. Systemic toxicity was apparent only at much higher doses (LD50=88.3 mg/kg) than those required for the anti-inflammatory effect. Summarizing, AaL exerts anti-and pro-edematogenic actions via interaction with its specific lectin domain. These actions may share a common pathway involving either activation or inhibition of inflammatory mediators from resident mast cells.