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Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate (Punica granatum L.) and in wood and bark of some tree species. Structurally, EA is a dilactone of hexahydroxydiphenic acid (HHDP), a dimeric gallic acid derivative, produced mainly by hydrolysis of ellagitannins, a widely distributed group of secondary metabolites. EA is attracting attention due to its antioxidant, anti-inflammatory, antimutagenic, and antiproliferative properties. EA displayed pharmacological effects in various in vitro and in vivo model systems. Furthermore, EA has also been well documented for its antiallergic, antiatherosclerotic, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties. This review reports on the health-promoting effects of EA, along with possible mechanisms of its action in maintaining the health status, by summarizing the literature related to the therapeutic potential of this polyphenolic in the treatment of several human diseases.

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Background: Omalizumab is a recombinant anti-immunoglobulin E (IgE) antibody used in the treatment of patients with chronic spontaneous urticaria (CSU). Objective: This multicentric study assessed the safety and efficacy of omalizumab in patients (n=322) with CSU refractory to second-generation antihistamines, also investigating predictors of poor treatment outcome and time lag to response to anti-IgE therapy by serum auto-reactivity. Methods: This retrospective observational study comprised a 4-week pretreatment period, a 24-week treatment period with omalizumab (300 mg/month), and a 16-week follow-up period. Primary efficacy endpoints were mean and median change in 7-day urticaria activity score (UAS7), weekly itch severity score (ISS), and hive score from baseline to 4-, 12-, and 24-week values. Secondary endpoints included the proportion of patients (defined “responders”) with well-controlled urticaria (UAS7 ≤ 6) and complete treatment response (UAS7=0). Safety in terms of side effects was also assessed. Results: Omalizumab significantly and consistently reduced the mean UAS7, ISS, and hive score from baseline to weeks 4, 12, and 24, with a clear decreasing trend over time. At the end of the treatment period (week 24), 84.2% of patients had a UAS7 score of 6 or less and 66.7% had a UAS7 of 0. Higher pretreatment IgE levels were less likely to be associated with poor treatment response (ie, UAS7 > 6). Patients with a positive autologus serum skin test (ASST) were significantly more likely to be “slow responders” to omalizumab treatment (ie, response beyond 8 days since omalizumab administration) than ASST-negative patients (P

Background Omalizumab therapy is effective and safe in patients with chronic spontaneous urticaria (CSU) resistant to nonsedating histamine 1 (H 1 ) antihistamines (nsAHs). Objective To evaluate the efficacy and safety of omalizumab in elderly (aged ≥65 years) patients with nonsedating H 1 -antihistamine–refractory CSU in a real-life setting. Methods Patients with nonsedating H 1 -antihistamine–refractory CSU (n = 322) treated with omalizumab administered every 4 weeks in doses of 300 mg for 24 weeks were divided into 2 groups according to age at omalizumab treatment onset: 15 to 64 years and 65 years or older. Treatment response was assessed using a 7-day urticaria activity score (UAS7). Adverse effects of omalizumab therapy were recorded. Results Among patients, 32 (9.9%) were 65 years or older. At baseline, CSU characteristics were generally similar among the groups, although the presence of angioedema was statistically significantly lower in patients younger than 65 years. Any differences in weekly itch severity score, hive score, and UAS7 between the 2 age groups were not significant at weeks 4, 12, and 24, with the exception of the hive score at 24 weeks and the UAS7 at week 24. No significant between-group differences were seen in the proportion of patients with a UAS7 of 6 or lower and with a UAS7 score of 0 at weeks 4, 12, 24, and 40. The proportion of patients with at least one adverse event reported as suspected to be caused by study drug was 10% in the younger group vs 6.3% in the older group ( P = .53). Conclusion Our study found that omalizumab is a well-tolerated and effective therapy for elderly patients with nonsedating H 1 -antihistamine–refractory CSU.

G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a target for the treatment of cardiac hypertrophy, and the mechanism of action of reported compounds is unknown. To identify novel scaffolds that selectively inhibit GRK5, a differential scanning fluorometry screen was used to probe a library of 4480 compounds. The best hit was amlexanox, an FDA-approved anti-inflammatory, anti-allergic immunomodulator. The crystal structure of amlexanox in complex with GRK1 demonstrates that its tricyclic aromatic ring system forms ATP-like interactions with the hinge of the kinase domain, which is likely similar to how this drug binds to IκB kinase ε (IKKε), another kinase known to be inhibited by this compound. Amlexanox was also able to inhibit myocyte enhancer factor 2 transcriptional activity in neonatal rat ventricular myocytes in a manner consistent with GRK5 inhibition. The GRK1 amlexanox structure thus serves as a springboard for the rational design of inhibitors with improved potency and selectivity for GRK5 and IKKε.

Ocular allergies comprise a spectrum of conditions that are underreported and underdiagnosed, and are frequently associated with rhinoconjunctivitis. Although allergic conjunctivitis is often not a sight-threatening condition, it could have a significant impact on a person's quality of life, morbidity and productivity. A variety of agents are available for the treatment of allergic conjunctivitis, including antihistamines, mast-cell stabilizers, dual action agents, glucocorticoids, calcineurin inhibitors and immunotherapy.The goal of this review is to investigate new therapeutic strategies for the treatment of ocular allergy. Within, the authors analyze the pharmacological management of allergic conjunctivitis and highlight Phase II clinical trial studies.Recent findings about the pathophysiology of allergic conjunctivitis have enabled us to gain a better understanding of the molecular and cellular mechanisms of ocular disease. This, in turn, has led to the identification of novel targets, which, in turn, has led to the development of new therapeutic agents that are currently under evaluation in the first phases of clinical development. The most interesting agents, under development, are the new topical glucocorticoids, leukotriene receptor antagonists, resolvins, interleukin-1 receptor antagonists and integrin antagonists. The authors now await promising results, which can confirm the therapeutic value of these novel emerging drugs for treating allergic conjunctivitis.

Objective— To determine whether the inhibitory action of the antiallergic cromone “mast cell stabilizing” drugs on polymorphonuclear leukocyte (PMN) trafficking is mediated through an annexin-A1 (Anx-A1) dependent mechanism. Methods and Results— Intravital microscopy was used to monitor the actions of cromones in the inflamed microcirculation. Reperfusion injury provoked a dramatic increase in adherent and emigrated leukocytes in the mesenteric vascular bed, associated with augmented tissue levels of myeloperoxidase. Nedocromil, 2 to 20 mg/kg, significantly ( P −/− mice. Short pretreatment of human PMNs with nedocromil, 10 nmol/L, inhibited cell adhesion ( P Conclusion— We propose a novel mechanism to explain the antiinflammatory actions of cromones on PMN trafficking, an effect that has long puzzled investigators.

1.We investigated the role of Annexin (ANX)-A1 and its receptor, ALX/FPR2, in the regulation of mast cell degranulation produced by compound 48/80. 2.Both human cord-blood derived mast cells (CBDMCs) and murine bone marrow derived mast cells (BMDMCs) release phosphorylated ANX-A1 during treatment with glucocorticoids or the mast cell 'stabilising' drugs ketotifen and nedocromil. 3.Compound 48/80 also stimulated ANX-A1 phosphorylation and release and this was also potentiated by nedocromil. Anti-ANX-A1 neutralising monoclonal antibodies (Mabs) enhanced the release of pro-inflammatory mediators in response to compound 48/80. 4.Nedocromil and ketotifen potently inhibited the release of histamine, PGD2, tryptase and β-hexosaminidase from mast cells challenged with compound 48/80. Anti-ANX-A1 neutralising Mabs prevented the inhibitory effect of these drugs. 5.BMDMCs derived from Anx-A1−/− mice were insensitive to the inhibitory effects of nedocromil or ketotifen but cells retained their sensitivity to the inhibitory action of hu-r-ANX-A1. 6.The fpr2/3 antagonist WRW4 blocked the action of nedocromil on PGD2, but not histamine, release. BMDMCs derived from fpr2/3−/− mice were insensitive to the inhibitory effects of nedocromil on PGD2, but not histamine release. 7.Compound 48/80 stimulated both p38 and JNK phosphorylation in CBDMCs and this was inhibited by nedocromil. Inhibition of p38 phosphorylation was ANX-A1 dependent. 8.We conclude that ANX-A1 is an important regulator of mast cell reactivity to compound 48/80 exerting a negative feedback effect through a mechanism that depends at least partly on the FPR receptor.

Background and Purpose Although the ‘cromones’ (di-sodium cromoglycate and sodium nedocromil) are used to treat allergy and asthma, their ‘mast cell stabilising’ mechanism of pharmacological action has never been convincingly explained. Here, we investigate the hypothesis that these drugs act by stimulating the release of the anti-inflammatory protein Annexin-A1 (Anx-A1) from mast cells. Experimental approach We used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice. Key results CDMCs activated by IgE-FcRe1 crosslinking, released histamine and prostaglandin (PG) D2, which were inhibited (30–65%) by 5 min pre-treatment with cromoglycate (10 nM) or nedocromil (10 nM), as well as dexamethasone (2 nM) and human recombinant Anx-A1 (1–10 nM). In CDMCs cromones potentiated (2–5 fold) protein kinase C (PKC) phosphorylation and Anx-A1 phosphorylation and secretion (3–5 fold). Incubation of CDMCs with a neutralising anti-Anx-A1 monoclonal antibody reversed the cromone inhibitory effect. Nedocromil (10 nM) also inhibited (40–60%) the release of mediators from murine bone marrow derived-mast cells from wild type mice activated by compound 48/80 and IgE-FcRe1 cross-linking, but were inactive in such cells when these were prepared from Anx-A1 null mice or when the neutralising anti-Anx-A1 antibody was present. Conclusions and Implications We conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy. These findings also highlight a new pathway for reducing mediator release from these cells.

Immunotherapy is a recognized treatment for allergic respiratory diseases.

OBJECTIVE: To test in vitro and in vivo the hypothesis that sodium nedocromil could modulate the expression of surface molecules on airway epithelial cells. METHODS: Human bronchial epithelial cells, obtained from surgically resected bronchi, were cultured and stimulated with recombinant IFN-gamma in the presence of sodium nedocromil. The intensity of the expression of surface molecules HLA-DR and ICAM-1 molecules on bronchial epithelial cells in vitro, was quantified by specific antibody staining and flow-cytometry analysis. Furthermore, we studied the effect of the drug on airway inflammation in vivo and on allergic rhinitis patients sensitized to house dust mites. Nasal epithelial cells were collected by brushing, at baseline and 2 to 3 weeks after treatment with sodium nedocromil. The expression of HLA-DR and ICAM-1 molecules was measured by flow-cytometry, and the proportions of neutrophils and eosinophils "contaminating" the epithelial cells evaluated by light microscopy examination of nasal brushings. RESULTS: The enhanced HLA-DR and ICAM-1 expression, induced by IFN-gamma, was effectively downregulated, in a dose-dependent manner, by sodium nedocromil. At all the concentrations tested (10(-9) to 10(-4) M), the inhibitory activity of the drug was stronger on HLA-DR than on ICAM-1 expression (P.05) on nasal epithelial cells, and higher proportions of nasal eosinophils (P.05), and induced a mild, but not statistically significant, decrease of nasal eosinophilia (P>.05). CONCLUSION: These data demonstrate that the antiinflammatory activity of sodium nedocromil may include modulation of surface molecule expression on airway epithelial cells.