Warifteine, an alkaloid of Cissampelos sympodialis, modulates allergic profile in a chronic allergic rhinitis model

ABSTRACT Cissampelos sympodialis Eichler, Menispermaceae, a Brazilian medicinal plant and its alkaloid warifteine present immunomodulatory activity on asthma experimental model by reducing antigen-specific IgE levels, eosinophil infiltration and lung hyperactivity. Allergic rhinitis is a chronic inflammatory disorder of the nasal tissue that affect the quality of life and it is a risk factor for asthma exacerbation. This study evaluated the effect of inhaled warifteine in an allergic ovalbumin rhinitis model. Inhaled warifteine (2 mg/ml) treatment of ovalbumin-sensitized BALB/c mice significant decreased total and differential number of cells on the nasal cavity and decreased ovalbumin-specific IgE serum levels. Hematoxylin & eosin staining of histological preparations of ovalbumin nasal tissues showed changes such as congestion and a massive cell infiltration in the perivascular and subepithelial regions characterizing the nasal inflammatory process. However, inhaled warifteine or dexamethasone treatment decreased cell infiltration into the perivascular regions and it was observed an intact nasal tissue. Periodic acidic staining of nasal epithelium of ovalbumin animals demonstrated high amount of mucus production by goblet cells and inhaled warifteine or dexamethasone treatment modulated the mucus production. In addition, toluidine blue staining of the nasal epithelium of ovalbumin animals demonstrated an increase of mast cells on the tissue and inhaled warifteine or dexamethasone treatment decreased in average of 1.4 times the number of these cells on the nasal epithelium. Taken these data together we postulate that warifteine, an immunomodulatory alkaloid, can be a medicinal molecule prototype to ameliorate the allergic rhinitis conditions.

Phenolic constituents from Wissadula periplocifolia (L.) C. Presl. and anti-inflammatory activity of 7,4'-di-O-methylisoscutellarein.

This study reports the first phenolics from Wissadula genus (Malvaceae) and the anti-inflammatory activity of 7,4'-di-O-methylisoscutellarein. Using chromatographic methods, five phenolic compounds were isolated from aerial parts of Wissadula periplocifolia (L.) C. Presl. The compounds were identified as 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, trans-cinnamic acid, tamgermanetin and 7,4'-di-O-methylisoscutellarein using spectroscopic methods. The flavone 7,4'-di-O-methylisoscutellarein showed anti-inflammatory activity by inhibiting neutrophils recruitment in a mice model of pleurisy and by decreasing significantly the production of cytokines IL-1ß and TNF-α.

Curine, an alkaloid isolated from Chondrodendron platyphyllum inhibits prostaglandin E2 in experimental models of inflammation and pain.

Curine is a bisbenzylisoquinoline alkaloid that is isolated from Chondrodendron platyphyllum, a plant that is used to treat malaria, inflammation, and pain. Recent reports have demonstrated the antiallergic effects of curine at nontoxic doses. However, its anti-inflammatory and analgesic properties remain to be elucidated. This study investigated the anti-inflammatory and analgesic effects of curine in mice. We analyzed the effects of an oral treatment with curine in the formation of paw edema, vascular permeability, abdominal contortion, licking behavior, and hyperalgesia using different inflammatory stimuli. Curine significantly inhibited the formation of paw edema by decreasing vascular permeability, inhibited the acetic acid-induced writhing response, inhibited the licking behavior during inflammation but not during the neurogenic phase of the formalin test, and inhibited carrageenan-induced hyperalgesia. Finally, curine inhibited prostaglandin E2 production in vitro without affecting cyclooxygenase-2 expression. The effects of curine treatment were similar to the effects of indomethacin, but were different from the effects of morphine treatment, suggesting that the analgesic effects of curine do not result from the direct inhibition of neuronal activation but instead depend on anti-inflammatory mechanisms that, at least in part, result from the inhibition of prostaglandin E2 production. In conclusion, curine presents anti-inflammatory and analgesic effects at nontoxic doses and has the potential for use in anti-inflammatory drug development.

Curine inhibits mast cell-dependent responses in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Curine is a bisbenzylisoquinoline alkaloid and the major constituent isolated from Chondrodendron platyphyllum, a plant that is used to treat inflammatory diseases in Brazilian folk medicine. This study investigates the effectiveness of curine on mast cell-dependent responses in mice. MATERIALS AND METHODS: To induce mast cell-dependent responses, Swiss mice were subcutaneously sensitized with ovalbumin (OVA-12 µg/mouse) and Al(OH)3 in a 0.9% NaCl solution. Fifteen days later, the animals were challenged with OVA through different pathways. Alternatively, the animals were injected with compound 48/80 or histamine, and several parameters, including anaphylaxis, itching, edema and inflammatory mediator production, were analyzed. Promethazine, cromoglycate, and verapamil were used as control drugs, and all of the treatments were performed 1h before the challenges. RESULTS: Curine pre-treatment significantly inhibited the scratching behavior and the paw edema induced by either compound 48/80 or OVA, and this protective effect was comparable in magnitude with those associated with treatment with either cromoglycate or verapamil. In contrast, curine was a weak inhibitor of histamine-induced paw edema, which was completely inhibited by promethazine. Curine and verapamil significantly inhibited pleural protein extravasations and prostaglandin D2 (PGD2) and cysteinyl leukotrienes (CysLTs) production following allergen-induced pleurisy. Furthermore, like verapamil, curine inhibited the anaphylactic shock caused by either compound 48/80 or an allergen. In in vitro settings, these treatments also inhibited degranulation as well as PGD2 and CysLT production through IgE-dependent activation of the mast cell lineage RBL-2H3. CONCLUSION: Curine significantly inhibited immediate allergic reactions through mechanisms more related to mast cell stabilization and activation inhibition than interference with the pro-inflammatory effects of mast cell products. These findings are in line with the hypothesis that the alkaloid curine may be beneficial for the treatment of allergic disorders.

Metabonomics reveals drastic changes in anti-inflammatory/pro-resolving polyunsaturated fatty acids-derived lipid mediators in leprosy disease.

Despite considerable efforts over the last decades, our understanding of leprosy pathogenesis remains limited. The complex interplay between pathogens and hosts has profound effects on host metabolism. To explore the metabolic perturbations associated with leprosy, we analyzed the serum metabolome of leprosy patients. Samples collected from lepromatous and tuberculoid patients before and immediately after the conclusion of multidrug therapy (MDT) were subjected to high-throughput metabolic profiling. Our results show marked metabolic alterations during leprosy that subside at the conclusion of MDT. Pathways showing the highest modulation were related to polyunsaturated fatty acid (PUFA) metabolism, with emphasis on anti-inflammatory, pro-resolving omega-3 fatty acids. These results were confirmed by eicosanoid measurements through enzyme-linked immunoassays. Corroborating the repertoire of metabolites altered in sera, metabonomic analysis of skin specimens revealed alterations in the levels of lipids derived from lipase activity, including PUFAs, suggesting a high lipid turnover in highly-infected lesions. Our data suggest that omega-6 and omega-3, PUFA-derived, pro-resolving lipid mediators contribute to reduced tissue damage irrespectively of pathogen burden during leprosy disease. Our results demonstrate the utility of a comprehensive metabonomic approach for identifying potential contributors to disease pathology that may facilitate the development of more targeted treatments for leprosy and other inflammatory diseases.

Effectiveness of Cissampelos sympodialis and its isolated alkaloid warifteine in airway hyperreactivity and lung remodeling in a mouse model of asthma.

BACKGROUND: Cissampelos sympodialis Eichl. (Menispermaceae) is a plant found in Northeastern and Southeast of Brazil and hot water infusion of C. sympodialis root bark is largely used in the indigenous and folk medicine to treat several inflammatory disorders, including asthma. Asthma is a chronic inflammatory allergic disease characterized by airway hyperreactivity (AHR), eosinophil tissue infiltration and lung remodeling. The aim of this study was to evaluate the therapeutic effect of C. sympodialis and its isolated alkaloid warifteine on allergen triggered airway hyperreactivity (AHR) and lung remodeling in murine model of asthma. METHODOLOGY/PRINCIPAL FINDINGS: The oral pre-treatment with C. sympodialis or warifteine inhibited allergen-induced AHR to inhaled methacholine and IL-13 levels in the bronchoalveolar lavage (BAL). In order to investigate the therapeutic potential of C. sympodialis and warifteine, animals were treated 1h after the last ovalbumin (OVA) challenge in sensitized animals. Similarly to the pre-treatment, post-treatment with warifteine was effective to inhibit significantly AHR to inhaled methacholine and to reduce IL-13 levels in the BAL. In addition, oral pre- or post-treatments with C. sympodialis or warifteine reduced OVA-induced eosinophil tissue infiltration, mucus production and subepithelial fibrosis to values similar to nonallergic controls. CONCLUSIONS: Our data show the anti-allergic and immunoregulatory properties of C. sympodialis, acting mostly through the active compound warifteine, to inhibit the airway hyperreactivity and lung remodeling through a mechanism at least partially dependent of IL-13 and eosinophil inhibition. Therefore placing warifteine as an interesting therapeutic candidate in allergic inflammation and corroborating the folk medicine use of C. sympodialis as anti-allergic plant.

Leptin and mTOR: partners in metabolism and inflammation.

Leptin is both a hormone/cytokine that plays a major role in the regulation of feeding and energy expenditure. Beyond its central role in the hypothalamus, leptin modulates peripheral tissues' responses to growth and storage based on nutrient availability, and it regulates the innate and adaptive immune responses. mTOR (mammalian Target of Rapamycin) is a core component of intracellular signaling for cellular growth, mRNA translation, and metabolism. Here, we review recent findings on the cross talk between mTOR and leptin signaling. Important roles for mTOR on leptin signaling have been established both in hypothalamic centers to control food intake and in peripheral cells to regulate lipid metabolism and inflammation. Leptin directly activates resident macrophages to form ADRP-enriched lipid droplets and enhances eicosanoid production via a mechanism that is dependent on activation of the PI3K/mTOR pathway. Leptin-induced mTOR activation may have implications for obesity-related pathophysiological conditions such as diabetes, cardiovascular disease and cancer.

Analgesic and anti-inflammatory activity of the aqueous extract of Rheedia longifolia Planch & Triana.

Rheedia longifolia Planch et Triana belongs to the Clusiaceae family. This plant is widely distributed in Brazil, but its chemical and pharmacological properties have not yet been studied. We report here that leaves aqueous extract of R. longifolia (LAE) shows analgesic and anti-inflammatory effects. Oral or intraperitoneal administration of this extract dose-dependently inhibited the abdominal constrictions induced by acetic acid in mice. The analgesic effect and the duration of action were similar to those observed with sodium diclofenac, a classical non-steroidal analgesic. In addition to the effect seen in the abdominal constriction model, LAE was also able to inhibit the hyperalgesia induced by lipopolysaccharide from gram-negative bacteria (LPS) in rats. We also found that R. longifolia LAE inhibited an inflammatory reaction induced by LPS in the pleural cavity of mice. Acute toxicity was evaluated in mice treated with the extract for seven days with 50 mg/kg/day. Neither death, nor alterations in weight, blood leukocyte counts or hematocrit were noted. Our results suggest that aqueous extract from R. longifolia leaves has analgesic and anti-inflammatory activity with minimal toxicity and are therefore endowed with a potential for pharmacological control of pain and inflammation.

Analgesic and anti-inflammatory activity of the aqueous extract of Rheedia longifolia Planch & Triana

Rheedia longifolia Planch et Triana belongs to the Clusiaceae family. This plant is widely distributed in Brazil, but its chemical and pharmacological properties have not yet been studied. We report here that leaves aqueous extract of R. longifolia (LAE) shows analgesic and anti-inflammatory effects. Oral or intraperitoneal administration of this extract dose-dependently inhibited the abdominal constrictions induced by acetic acid in mice. The analgesic effect and the duration of action were similar to those observed with sodium diclofenac, a classical non-steroidal analgesic. In addition to the effect seen in the abdominal constriction model, LAE was also able to inhibit the hyperalgesia induced by lipopolysaccharide from gram-negative bacteria (LPS) in rats. We also found that R. longifolia LAE inhibited an inflammatory reaction induced by LPS in the pleural cavity of mice. Acute toxicity was evaluated in mice treated with the extract for seven days with 50 mg/kg/day. Neither death, nor alterations in weight, blood leukocyte counts or hematocrit were noted. Our results suggest that aqueous extract from R. longifolia leaves has analgesic and anti-inflammatory activity with minimal toxicity and are therefore endowed with a potential for pharmacological control of pain and inflammation.

Anti-allergic properties of Cissampelos sympodialis and its isolated alkaloid warifteine.

Development of new agents capable of regulating eosinophilic inflammation can uncover novel therapeutic approaches for the treatment of allergic diseases, such as asthma. Here, we evaluated the anti-allergic properties of an extract of the Brazilian Menispermaceae Cissampelos sympodialis, focusing on its effects on allergic eosinophilia. By studying two models of allergic inflammation, an asthma model and the allergic pleurisy in actively sensitized Balb/c mice, we observed that the oral pre-treatment with C. sympodialis reduced pleural eosinophil influx triggered by allergen challenge in a dose-dependent manner. The mechanism involved in C. sympodialis inhibitory effect appeared to be independent of a direct effect on eosinophil locomotory machinery, but depend on a blockage of eotaxin production, a key eosinophil chemoattractant with important roles in allergic reactions. C. sympodialis was also able to affect eosinophil activation, as attested by its ability of inhibiting formation of new cytoplasmic lipid bodies and the secretion of cysteinyl leukotrienes. The alkaloid warifteine isolated from the C. sympodialis extract represents an active component responsible for the anti-eosinophilic effects of the extract, since warifteine was able to reproduce C. sympodialis inhibitory effects on allergic eosinophilia and cysteinyl leukotrienes production. Of interest, C. sympodialis and warifteine post-treatments also effectively inhibited eosinophilic reaction observed after allergic challenge. Therefore, C. sympodialis/warifteine may be a promising anti-allergic therapy, inasmuch as it presents potent anti-eosinophil and anti-leukotrienes activities.

Anti-allergic properties of the bromeliaceae Nidularium procerum: inhibition of eosinophil activation and influx.

New therapeutic approaches for the treatment of allergic diseases can be aided by the development of agents capable of regulating eosinophilic leukocytes. Here, we evaluated the anti-allergic properties of a crude extract of the Brazilian bromeliaceae Nidularium procerum, focusing on its effects on allergic eosinophilia. By studying allergic pleurisy in actively sensitized C57Bl/6 mice, we observed that pretreatment with N. procerum (2 mg/kg; i.p.) reduced pleural eosinophil influx triggered by allergen challenge. N. procerum was also able to reduce lipid body numbers found within infiltrating eosinophils, indicating that N. procerum in vivo is able to affect both migration and activation of eosinophils. Consistently, pretreatment with N. procerum blocked pleural eosinophil influx triggered by PAF or eotaxin, key mediators of the development of allergic pleural eosinophilia. The effect of N. procerum was not restricted to eosinophils, since N. procerum also inhibited pleural neutrophil and mononuclear cell influx. Of note, N. procerum failed to alter the acute allergic reaction, characterized by mast cell degranulation, oedema, and cysteinyl leukotriene release. N. procerum also had direct effects on murine eosinophils, since it inhibited both PAF- and eotaxin-induced eosinophil chemotaxis on an in vitro chemotactic assay. Therefore, N. procerum may be a promising anti-allergic therapy, inasmuch as it presents potent anti-eosinophil activity.

Mechanisms of increased survival after lipopolysaccharide-induced endotoxic shock in mice consuming olive oil-enriched diet.

We examined the impact of dietary fatty acid intake on lipopolysaccharide (LPS)-induced endotoxic shock. C57Bl/6J mice were fed for 6 weeks with a commercial laboratory chow (CC) or with test chows containing 7% (w/w) canola oil (CO), sesame oil (SeO), soybean oil (SO), or virgin olive oil (OO). The increase in body weight and energy consumption were similar for all diets tested. In the sixth week, mice were injected intraperitoneally with 400 microg of bacterial LPS to induce endotoxic shock. LPS induced a massive neutrophil infiltration into the peritoneal cavity and an increase in lipid body (LB) formation in leukocytes recovered from the peritoneal fluid of mice fed with CC, CO, SeO, or SO. In addition, there were increases in prostaglandin E(2) (PGE(2)), leukotriene B4 (LTB(4)), and cytokines IL-6, IL-10, and MCP-1 in peritoneal lavage, as well as in plasma TNF-alpha. In contrast, mice fed with OO exhibited reduced neutrophil accumulation and LB formation, and also had lower levels of PGE(2), LTB(4), MCP-1, and TNF-alpha. All mice fed with CC, CO, SeO, or SO died within 48 to 72 h after LPS injection. Interestingly, mice fed with the OO diet were resistant to endotoxic shock, with 60% survival at 168 h. These data indicate that intake of OO may have a beneficial role, reducing the magnitude of the inflammatory process triggered by endotoxic shock through modulation of LB formation and of the production of inflammatory mediators.

Antibiotic treatment in a murine model of sepsis: impact on cytokines and endotoxin release.

Experimental and clinical studies in sepsis indicate that antibiotic therapy may induce the release of endotoxin (LPS) from the outer membrane of gram-negative bacteria and therefore may affect the physiologic response and survival. The aim of this study was to evaluate if antibiotics commonly used to treat secondary peritonitis are capable of changing survival rates, proinflammatory and anti-inflammatory cytokine concentrations, and the release of endotoxin in a murine model of sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in Swiss mice using an 18-gauge needle. The animals received injections of saline solution or imipenem or a combination of ciprofloxacin plus clindamycin every 8 h for 3 days. Antibiotic treatment induced an increase in survival rate and decreased plasma and peritoneal fluid levels of TNF-alpha and IL-6 at 6 and 24 h after CLP as compared with saline-treated animals. Antibiotic-treated animals also showed an early (6 h) decrease and a late (24 h) increase in IL-10 concentration in the peritoneal fluid. LPS concentrations were elevated in all groups, but imipenem-treated animals showed higher levels (2.2 EU/mL) than ciprofloxacin plus clindamycin (1.3 EU/mL) and saline-treated (1.5 EU/mL) groups. We conclude that antibiotic-induced endotoxin release is not a major determinant in the inflammatory response and prognosis in murine models of sepsis.