Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the ␤ common receptor. In the present work, we have delimited tissueprotective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58 -82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia-reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.cognition ͉ cytoprotection ͉ excitotoxicity ͉ ischemia-reperfusion injury ͉ wound healing

Rosmarinic acid is a polyphenolic compound and main constituent of Rosmarinus officinalis and has been shown to possess antioxidant and anti-inflammatory properties. We aimed to evaluate the anti-inflammatory properties of rosmarinic acid and of an extract of R. officinalis in local inflammation (carrageenin-induced paw oedema model in the rat), and further evaluate the protective effect of rosmarinic acid in rat models of systemic inflammation: liver ischaemia-reperfusion (I/R) and thermal injury models. In the local inflammation model, rosmarinic acid was administered at 10, 25 and 50 mg/kg (p.o.), and the extract was administered at 10 and 25 mg/kg (equivalent doses to rosmarinic acid groups) to male Wistar rats. Administration of rosmarinic acid and extract at the dose of 25 mg/kg reduced paw oedema at 6 hr by over 60%, exhibiting a dose-response effect, suggesting that rosmarinic was the main contributor to the anti-inflammatory effect. In the liver I/R model, rosmarinic acid was administered at 25 mg/kg (i.v.) 30 min. prior to the induction of ischaemia and led to the significant reduction in the serum concentration of transaminases (AST and ALT) and LDH. In the thermal injury model, rosmarinic acid was administered at 25 mg/ kg (i.v.) 5 min. prior to the induction of injury and significantly reduced multi-organ dysfunction markers (liver, kidney, lung) by modulating NF-jB and metalloproteinase-9. For the first time, the anti-inflammatory potential of rosmarinic acid has been identified, as it causes a substantial reduction in inflammation, and we speculate that it might be useful in the pharmacological modulation of injuries associated to inflammation.Rosmarinus officinalis L., popularly named rosemary, has been used in folk medicine with several pharmacological effects being associated to its consumption, including its antiinflammatory effects [1,2], and rosmarinic acid (RA) is one of its main phenolic compounds [3].Two studies have evaluated the kinetics of rosmarinic acid when administered orally to rats [4,5]. These studies showed that rosmarinic acid was readily absorbed in the gastrointestinal tract (according to Konishi and Kobayashi [6], it crosses intestinal epithelium by passive diffusion) and reaches the peak plasma concentration at 0.5 hr post-administration. Metabolites formed are a result of glucuronidation, sulphation and methylation of rosmarinic acid and are then eliminated in the urine. The effect of R. officinalis and rosmarinic acid on metabolizing enzymes was also studied in Wistar rats [7]. This study demonstrated that the extract of R. officinalis was able to induce the enzymes CYP1A1, CYP2B1/2, CYP2E1, glutathione S-transferase and UDP-glucuronosyl transferase, but this effect was not observed when rosmarinic acid was administered alone. The authors have attributed this effect to the presence of flavones and monoterpenes.It has been widely recognized for many years that certain types of inflammatory tissue injury are mediated by reactive oxygen metabolites and that in ad...

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience.

Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general.

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PPAR-β/δ protects against multiple organ injury and dysfunction, and inflammation caused by endotoxic shock and improves survival in polymicrobial sepsis by a mechanism that may involve activation of Akt and inhibition of GSK-3β and NF-κB.

The antihyperglycaemic effect of eight standard flavonoids, previously identified in the ethanol extract of the claimed antidiabetic plant Genista tenera, was evaluated on streptozotocin (STZ)‐induced diabetic Wistar rats. The aglycones apigenin, chrysoeriol and genistein, the monoglucosides apigenin 7‐O‐glucoside, luteolin 7‐O‐glucoside and genistein 7‐O‐glucoside and the diglycosides rutin and luteolin 7,3′‐di‐O‐glucoside were administered i.p. for 7 days (4 mg/kg b.w./day). The protective effect of these compounds over liver and kidneys of STZ–diabetic models was also evaluated by the determination of seric AST, ALT and urea levels. After 7 days of treatment, apigenin, chrysoeriol and genistein significantly lowered the blood glucose levels of diabetic animals; this effect was more pronounced (P < 0.01) in the oral glucose tolerance test. Glucose tolerance was also significantly improved in the rutin (P < 0.01) and in the genistein 7–O–glucoside (P < 0.05) treated groups. In addition, almost all the tested compounds effectively protected the liver and kidneys against STZ‐induced damage in rats. Copyright © 2010 John Wiley & Sons, Ltd.

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