Physalin pool from Physalis angulata L. leaves and physalin D inhibit P2X7 receptor function in vitro and acute lung injury in vivo.

P2X7 receptor promotes inflammatory response and neuropathic pain. New drugs capable of impairing inflammation and pain-reducing adverse effects extracted from plant extracts have been studied. Physalis angulate L. possesses traditional uses and exhibits antiparasitic, anti-inflammatory, antimicrobial, antinociceptive, antimalarial, antileishmanial, immunosuppressive, antiasthmatic. diuretic, and antitumor activities. The most representative phytochemical constituents identified with medicinal importance are the physalins and withanolides. However, the mechanism of anti-inflammatory action is scarce. Although some physalins and withanolides subtypes have anti-inflammatory activity, only four physalins subtypes (B, D, F, and G) have further studies. Therefore, we evaluated the crude ethanolic extract enriched with physalins B, D, F, and G from P. angulata leaves, a pool containing the physalins B, D, F, G, and the physalins individually, as P2X7 receptor antagonists. For this purpose, we evaluated ATP-induced dye uptake, macroscopic currents, and interleukin 1-ß (IL-1ß) in vitro. The crude extract and pool dose-dependently inhibited P2X7 receptor function. Thus, physalin B, D, F, and G individually evaluated for 5'-triphosphate (ATP)-induced dye uptake assay, whole-cell patch-clamp, and cytokine release showed distinct antagonist levels. Physalin D displayed higher potency and efficacy than physalin B, F, and G for all these parameters. In vivo mice model as ATP-induced paw edema was potently inhibited for physalin D, in contrast to physalin B, F, and G. ATP and lipopolysaccharide (LPS)-induced pleurisy in mice were reversed for physalin D treatment. Molecular modeling and computational simulation predicted the intermolecular interactions between the P2X7 receptor and physalin derivatives. In silico results indicated physalin D and F as a potent allosteric P2X7 receptor antagonist. These data confirm physalin D as a promisor source for developing a new P2X7 receptor antagonist with anti-inflammatory action.

8-Hydroxy-2-(1H-1,2,3-triazol-1-yl)-1,4-naphtoquinone derivatives inhibited P2X7 Receptor-Induced dye uptake into murine Macrophages.

Extracellular adenosine 5'-triphosphate (ATP) triggers the P2X7 receptor (P2X7R) ionic channel to stimulate the release of the interleukin-IL-1ß cytokine into macrophages. The current study explored the reaction of six structurally diverse triazole derivatives on P2X7-mediated dye uptake into murine peritoneal macrophages. P2X7R activity determined by ATP-evoked fluorescent dye uptake. Triazole derivatives toxicity measured using dextran rhodamine exclusion based colorimetric assay. A740004 and BBG, both P2X7R antagonist, inhibited ATP-induced dye uptake. In contrast, the derivatives 5a, 5b, 5e, and 5f did not diminish P2X7R activity in concentrations until 100 µM. 5c and 5d analogs caused a potent inhibitory activity on P2X7-induced dye uptake. Dextran Rhodamine exclusion measurements after 24 h of continuous treatment with triazole derivatives indicated a moderated toxicity for all molecules. In conclusion, this study showed that a series of new hybrid 1,2,3-triazolic naphthoquinones reduces P2X7R-induced dye uptake into murine macrophages. In silico analysis indicates a good pharmacokinetic profile and molecular docking results of these analogs indicate the potential to bind into an allosteric site located into the P2X7R pore and juxtaposed with the ATP binding pocket. In this manner, the compounds 5c and 5d may be used as a scaffold for new P2X7R inhibitors with reduced toxicity, and good anti-inflammatory activity.

1,4-Naphthoquinones potently inhibiting P2X7 receptor activity.

P2X7 receptor (P2X7R) is an ATP-gated ion-channel with potential therapeutic applications. In this study, we prepared and searched a series of 1,4-naphthoquinones derivatives to evaluate their antagonistic effect on both human and murine P2X7 receptors. We explored the structure-activity relationship and binding mode of the most active compounds using a molecular modeling approach. Biological analysis of this series (eight analogues and two compounds) revealed significant in vitro inhibition against both human and murine P2X7R. Further characterization revealed that AN-03 and AN-04 had greater potency than BBG and A740003 in inhibiting dye uptake, IL-1ß release, and carrageenan-induced paw edema in vivo. Moreover, we used electrophysiology and molecular docking analysis for characterizing AN-03 and AN-04 action mechanism. These results suggest 1,4-napthoquinones, mainly AN-04, as potential leads to design new P2X7R blockers and anti-inflammatory drugs.

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases.

AIM: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N'-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). METHODS: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPARTAN' 08 program, in silico ADMET screening and the Lipinski " rule of five " using Osiris Property Explorer and molinspiration on-line programs. RESULTS: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c - IC(50)=61 microM and 68 microM respectively) almost 5-fold more potent than aspirin (IC(50)=300 microM). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. CONCLUSION: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.

Cirugía de salvación del miembro en el tratamiento de osteosarcoma de Peroné con supervivencia a los diecisiete años / Salvation surgery treatment in osteosarcoma of the fibula with seventeen years survival

El osteosarcoma es el tumor óseo primario más frecuente habiendo dos picos de incidencia, uno en torno a los 15 años (adolescentes) y otro en ancianos. Caso clínico: Paciente de 14 años con clínica de dolor en región proximal de perné. Se diagnosticó mediante estudios radiológicos y biopsia osteosarcoma localizado con infiltración de cortical y periostio y extensión hacia epífisis de peroné. Tras quimioterapia preoperatorio se realizó exéresis tumoral con márgenes de 5cm. Siguiendo criterios de Enneking (cirurgia de salvación del miembro). Completamos varios ciclos de quimioterapia postoperatoria. La paciente está libre de enfermedad a los diecisiete años. Discusión: Años atrás en el tratamiento del osteosarcoma localizado se procedía a la amputación radical por norma. Actualmente debido al avance de las técnicas quirurgicas y diagnósticas (capaces de detectar precozmente la diseminación local y a distancia del tumor) es posible efectuar otras modalidades terapéuticas que preservan el miembro hasta en terapéuticas que preservan el miembro hasta en el 90% de los pacientes. Gracias al uso de la quimioterapia la tasa de supervivencia hoy dia se aproxima al 70% en aquellos casos diagnosticados previamente a la aparición de metástasis. Actualmente en quellos casos en los cuales la enfermedad esté localizada, el tamaño tumoral sea reducido y haya una buena respuesta a la quimioterapia preoperatoria es más aconsejable optar por una cirugía de salvación del miembro haciendo una prudente resección a distancia de los márgenes de la tumoración y acompañándola de ciclos de quimioterapia combinada.

Osteosarcoma is the most frequent primary bony tumor with two picks of incidence, one around the 15 years (adolescents) and another in old people. CLINICAL CASE: Patient of 14 years with pain clinic in proximal fibula. It was diagnosed by radiological studies and biopsy of located osteosarcoma with infiltration of cortical and periostium and extension toward fibula epiphysis. After preoperatory chemotherapy she was carried out tumoral resection with margins of 5 cm. following approaches of Enneking (surgery of salvation of the member). Several cycles of chemotherapy were completed after surgery. The patient, after seventeen years, is free of illness. DISCUSSION: Traditionally in the treatment of the located osteosarcoma you proceeded to the radical amputation for norm. At the moment due to the advances of the surgical and diagnostic techniques (able to detect precociously the local and distant dissemination of the tumor) it is possible to make other therapeutic modalities that preserve the member until in 90% of the patients. Thanks to the use of the chemotherapy the rate of survival nowadays approaches to 70% in those cases diagnosed previously to the metastasis appearance. At the moment in those cases in which the illness is located, the tumoral size is reduced and have a good answer to the preoperatroy chemotherapy, it is more advisable to opt for a surgery of salvation of the limb making a wise resection at distance of the margins of the tumor and accompanying it of cycles of combined chemotherapy.

Results in displaced radial neck fractures in children. Metaizeau technique versus arthrotomy.

The aim of the present article is to ascertain the differences between two surgical treatments commonly used in displaced radial neck fractures in children. We report the retrospective results of 20 displaced radial neck fractures with > 30 degrees of tilt (Judet grades 3-4) in children aged between 7 and 14 years treated with closed intramedullary pinning according to the Metaizeau technique (6 cases) or with arthrotomy and pinning (14 cases). Sex distribution was 14 girls and 6 boy. The average follow-up was 43 months. We found no relationship between delay in the surgical treatment and functional results. On the other hand, a relationship between residual final tilt and poorer functional results appears. The Metaizeau technique produced better results and fewer complications than arthrotomy and pinning, and, in our opinion, is the treatment of choice in this type of fracture.

Severe malformations in males from families with osteopathia striata with cranial sclerosis.

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by longitudinal striations of the long bones and sclerosis of the craniofacial bones. Affected patients show macrocephaly, ocular hypertelorism, frontal bossing, broad nasal bridge and abnormalities of the palate. Anomalies such as hearing loss, congenital heart defect, vertebral anomalies and mental impairment have also been reported. Pedigree analysis has suggested an autosomal dominant inheritance, but a recent report of a family with significantly more affected males than females suggested the possibility of X-linked inheritance. Here we describe a new family with OS-CS (the twelfth in the literature) with four affected individuals (two males and two females) spanning three generations. The affected male in the third generation was stillborn with multiple congenital anomalies, whereas the other three affected individuals had mild features. This family may represent another example of X-linked OS-CS where the mutated gene(s) is more severe in males.