Aminophosphine ligands as a privileged platform for development of antitumoral ruthenium(ii) arene complexes.

The rapid and modular synthesis of the aminophosphine core has been exploited as a tool for rapid development of antitumoral metallodrug candidates. Starting with a series of structurally diverse aminophosphines, all obtained in a single step from commercial amines, a family of Ru(ii)-cymene complexes have been generated and tested in vitro for anti-tumoral activity in a series of cell lines, including the platinum-resistant A2780R. Through this approach, Ru(ii)-aminophosphine complexes have been identified with the IC50 value range as low as 10-0.8 µM. Several biological assays were carried out to gain insight into the mechanism of action. Cell death by apoptosis and pH-independent action has been demonstrated. In addition, a selective cytotoxicity profile for tumoral cells over non-tumoral cells has been identified. Importantly, for the key candidates no loss of activity was observed when applied to the Pt-resistant A2780R, which highlights the potential utility of the bis-phospinoamine scaffold as an easily-tunable auxiliary ligand core in both drug discovery and subsequently a logical design of new anticancer metal-containing drugs. The complexes are characterised by NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction.

Neutral high-generation phosphorus dendrimers inhibit macrophage-mediated inflammatory response in vitro and in vivo.

Inflammation is part of the physiological response of the organism to infectious diseases caused by organisms such as bacteria, viruses, fungi, or parasites. Innate immunity, mediated by mononuclear phagocytes, including monocytes and macrophages, is a first line of defense against infectious diseases and plays a key role triggering the delayed adaptive response that ensures an efficient defense against pathogens. Monocytes and macrophages stimulation by pathogen antigens results in activation of different signaling pathways leading to the release of proinflammatory cytokines. However, inflammation can also participate in the pathogenesis of several diseases, the autoimmune diseases that represent a relevant burden for human health. Dendrimers are branched, multivalent nanoparticles with a well-defined structure that have a high potential for biomedical applications. To explore new approaches to fight against the negative aspects of inflammation, we have used neutral high-generation phosphorus dendrimers bearing 48 (G3) or 96 (G4) bisphosphonate groups on their surface. These dendrimers show no toxicity and have good solubility and chemical stability in aqueous solutions. Here, we present data indicating that neutral phosphorus dendrimers show impressive antiinflammatory activities both in vitro and in vivo. In vitro, these dendrimers reduced the secretion of proinflammatory cytokines from mice and human monocyte-derived macrophages. In addition, these molecules present efficient antiinflammatory activity in vivo in a mouse model of subchronic inflammation. Taken together, these data suggest that neutral G3-G4 phosphorus dendrimers have strong potential applications in the therapy of inflammation and, likely, of autoimmune diseases.

La pertinencia de la formación del químico farmacéutico biólogo. Un elemento de responsabilidad social universitaria / The relevance of the formation of a pharmaceutical chemist biologist. An element of social renponsability of universities

Este estudio de tipo exploratorio, transversal y de campo es solo una fase del proyecto de seguimiento de egresados de la licenciatura en Química Farmacéutico Biológica (QFB) de la Facultad de Estudios Superiores “Zaragoza”. Este proyecto permite retroalimentar el plan curricular, además de establecer el lugar que han ocupado los egresados de esta institución en el mercado laboral, además de detectar las principales áreas de oportunidad en campos profesionales no explorados por los egresados. Así como la determinación de los conocimientos, habilidades, actitudes y valores obtenidos durante su formación y que le han sido indispensables en su desarrollo profesional(AU)

This study was exploratory, transversal and field is just one phase of the project following graduates of the FES Zaragoza. This project will provide feedback to the curriculum of the race Pharmaceutical Biological Chemistry (QFB), to establish where they have occupied the graduates of this institution in the labor market, in addition to identifying the main areas of opportunity in professional fields unexplored by the graduates. And the determination of the knowledge, skills, attitudes and values obtained during training and to have been indispensable in their professional development(AU)

Fracturas del pilón tibial. Resultados funcionales a largo plazo / Fractures of the tibial pilon. Long-term functional results

Objetivo. Estudio epidemiológico y funcional a largo plazo de las fracturas de pilón tibial ingresadas en nuestro servicio a lo largo de cinco años cuyo objetivo es determinar cuál fue la evolución a largo plazo de las mismas, analizar la posible influencia de la calidad de la reducción obtenida y del estado de las partes blandas en los resultados clínicos, y evaluar la relación existente entre el tipo de fractura, los signos degenerativos radiográficos y los resultados obtenidos.Material y método. Se revisan 91 fracturas de pilón tibial en 87 pacientes (4 bilaterales), de las que 29 fueron mujeres (31,9%) y 62 varones (68,1%). Se realiza un estudio retrospectivo de todas las historias clínicas, citando posteriormente a los pacientes para la encuesta de funcionalidad según la escala de Duquennoy para el tobillo, la valoración objetiva de parámetros y la actualización de las radiografías.Resultados. Los factores más afectados por la fractura, en la escala de valoración de Duquennoy, fueron la capacidad de carrera/salto con una media de 1,6/5 y la deambulación sobre terrenos irregulares (2,6/5); los que menos se vieron influidos por la lesión fueron la necesidad de utilizar bastones (4,3/5) y el perímetro de marcha (8,4/10). Destaca un elevado número de complicaciones iniciales para reducir (27,1%) y/o fijar (12,8%) la fractura; complicaciones precoces comoproblemas en las partes blandas perifractuarias, y destacando entre las tardías la gran incidencia de la rigidez articular (51,4%) y las consolidaciones viciosas (24,3%).Conclusiones. Las fracturas de pilón tibial habitualmente se asocian a una alta tasa de complicaciones que hace muy difícil la predicción de los resultados a largo plazo. Existe una relación directa entre la existencia de signos radiográficosde artrosis y los malos resultados obtenidos con el paso del tiempo. Una excelente reducción articular no asegura unos excelentes resultados a largo plazo, pero sí una mayor probabilidad de que éstos estén presentes (AU)

Purpose. This is a functional and epidemiological long-term study of tibial pilon fractures treated in our hospital over a five-year period. Our aim was to determine the long-term evolution of these fractures, to assess the potential effect of the quality of the reduction obtained and of the condition ofthe soft tissues on the final outcome and to evaluate the relationship between fracture type, radiographical degenerative signs and the results obtained.Materials and methods. Ninety-one tibial pilon fractureswere reviewed in 87 patients (4 bilateral ones), 29 of which were women (31.9%) and 62 men (68.1%). A retrospective study was carried out of all clinical records, further to which patients were called in to be evaluated with respect to the Duquennoy ankle scale and to have their parameters objectively assessed and their radiographs updated.Results. On the Duquennoy scale, the factors most significantly affected by the fracture were the ability to run and to jump, with a mean value of 1.6/5 points and walking on uneven ground (2.6/5). The factors least affected by the injury were the need of a walking-stick (4.3/5) and the gait perimeter (8.4/10). There was a high incidence of initial complications to reduce (27.1%) and/or fixate (12.8%) the fracture. There were also a few early complications such as soft tissue-related problems in the area around the fractureand some late complications such as a high incidence ofjoint stiffness (51.4%) and malunions (24.3%).Conclusions. Tibial pilon fractures are often associated to a high complications rate that makes it very difficult to anticipate long-term results. There is a direct relationship between the presence of radiographic signs of arthritis and poor long-term results. An excellent joint reduction does not guaranteethe attainment of excellent long-term results; but it does lead to a higher probability of success (AU)

Acetaminophen potentiates staurosporine-induced death in a human neuroblastoma cell line.

BACKGROUND AND PURPOSE: Neuroblastoma is the most common solid tumour in infants characterized by a high resistance to apoptosis. Recently, the cyclo-oxygenase pathway has been considered a potential target in the treatment of different kinds of tumours. The aim of the present work was to investigate a possible relationship between cyclo-oxygenase pathway and stauroporine-induced apoptosis in the neuroblastoma cell line SH-SY5Y. EXPERIMENTAL APPROACH: Cellular viability was measured by release of LDH. DNA fragmentation was visualized by electrophoresis on agarose gel containing ethidium bromide. Cyclo-oxygenase activity was measured in microsomal fractions obtained from cells by quantification of its final product PGE2 by RIA. Caspase-3 activity was measured fluorimetrically and Western blot analysis was performed to assess cytochrome c expression. KEY RESULTS: We have found that staurosporine (500 nM) induced cellular death in a time-dependent manner in SH-SY5Y human neuroblastoma cells. Cyclo-oxygenase enzymatic activity was present in SH-SY5Y human neuroblastoma cells under basal conditions and pharmacological experiments using COX inhibitors indicate that cyclo-oxygenase-1 and cyclo-oxygenase-3 are the active isoforms in these cells. Co-incubation of SH-SY5Y cells with staurosporine (500 nM) and acetaminophen for 24 h potentiated staurosporine-mediated cellular death in a concentration-dependent manner. This process is mediated by an increase in cytochrome c release and caspase 3 activation and is prevented by N-acetylcysteine or the superoxide dismutase mimetic, MnTBAP. CONCLUSIONS AND IMPLICATIONS: Acetaminophen potentiates staurosporine-mediated neuroblastoma cell death. The mechanism of action of acetaminophen seems to be related to production of reactive oxygen species and decreased intracellular glutathione levels.

Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production and the expression of nitric oxide synthase.

In a previous study, we reported a new bioactive sesquiterpenoid, named dysidotronic acid, to be a potent, selective human synovial phospholipase A(2) inhibitor. Dysidotronic acid is a novel, non-complex manoalide analogue lacking the pyranofuranone ring. We now investigate the effect of this compound on cytokine, nitric oxide and prostanoid generation on the mouse macrophage cell line RAW 264.7, where it showed a dose-dependent inhibition with inhibitory concentration 50% values in the micromolar range. This effect was also confirmed in the mouse air pouch injected with zymosan. Dysidotronic acid inhibited the production of tumor necrosis factor alpha and interleukin-1 beta as well as the production of nitric oxide, prostaglandin E(2) and leukotriene B(4). Decreased nitric oxide generation was the consequence of inhibition of the expression of nitric oxide synthase, whereas PGE(2) and LTB(4) reduction was due to inhibition of arachidonic acid bioavailability through a direct inhibitory effect of dysodotronic acid on secretory phospholipase A(2).

Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis.

OBJECTIVE: Weekly low-dose methotrexate (MTX) remains the mainstay of second-line therapy for rheumatoid arthritis (RA). We have previously reported that adenosine, acting at specific receptors on inflammatory cells, mediates the antiinflammatory effects of MTX in both in vitro and in vivo models of acute inflammation, but the mechanism by which MTX suppresses the chronic inflammation of arthritis remains controversial. The present study was undertaken to further investigate the means by which adenosine mediates the antiinflammatory effects of MTX. METHODS: The effects of 2 nonselective adenosine receptor antagonists, theophylline and caffeine, were examined, using the rat adjuvant arthritis model of RA. These agents were given alone and in conjunction with MTX, and arthritis severity was assessed clinically, radiologically, and histologically. Since rodent adenosine A3 receptors are not blocked by theophylline, selective A1, A2A, and A2B receptor antagonists were tested as well. RESULTS: Control animals developed severe arthritis, which was markedly attenuated by weekly treatment with MTX (0.75 mg/kg/week). Neither theophylline alone nor caffeine alone (each at 10 mg/kg/day) significantly affected the severity of the arthritis, but both agents markedly reversed the effect of MTX as measured by a severity index, hindpaw swelling, and hindpaw ankylosis. Radiographic and histologic analyses confirmed these observations. Neither A1, A2A, nor A2B receptor antagonists affected the capacity of MTX to ameliorate inflammation in adjuvant arthritis. CONCLUSION: These results provide strong evidence that adenosine mediates the antiinflammatory effects of MTX in this model of RA. Moreover, the findings suggest that abstinence from caffeine, a ubiquitous food additive and medication, may enhance the therapeutic effects of MTX in RA.

Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase expression in the time-course of murine inflammation.

Many in vitro studies have used cell cultures to focus on the relationships between cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) isoforms. We have investigated the time-course of regulation and the role of COX-2 and iNOS in a model of experimental inflammation in mice, the air pouch injected with zymosan. This study demonstrates that there is an early acute phase (4 h) mediated mainly by eicosanoids, with high levels of prostaglandin E2 (PGE2) produced by cyclo-oxygenase-1. In addition, in the later phase (from 12 h) there is a participation of nitric oxide (NO) and PGE2 accompanied by co-induction of both iNOS and COX-2. These enzymes were detected in migrating leukocytes as well as in macrophages lining the air pouch. Administration of NS398 or indomethacin inhibited PGE2 levels and COX activity, but also nitrite levels and iNOS activity, which was accompanied by a reduction in iNOS expression. Aminoguanidine inhibited nitrite levels and iNOS activity in addition to exerting inhibitory effects on the COX pathway. Treatment of animals with dexamethasone reduced nitrite and PGE2 concentrations in air pouch exudates, as well as iNOS and COX-2 expression in migrating cells. Our results indicate that PGE2 and NO may play in vivo mutual modulatory roles in the inflammatory response caused by zymosan injection into the mouse air pouch, a suitable model to study drugs acting on those pathways.

Cavernolide: a new inhibitor of human sPLA2 sharing unusual chemical features.

The inhibitory effect of cavernolide, a novel C2, terpene lactone isolated from the sponge Fasciospongia cavernosa, on PLA2 and other enzyme activities involved in the inflammatory process was studied. Cavernolide inhibited human synovial sPLA2 in a concentration-dependent manner with an IC50 value of 8.8 microM. Besides, this compound decreased in the nanomolar range the myeloperoxidase degranulation process using different stimuli. Cavernolide also inhibited TNFalpha, NO and PGE2 production in intact cell experiments. NO and PGE2 reduction was the consequence of the inhibition on iNOS and COX-2 expression because it did not affect inducible nitric oxide synthase and cyclooxygenase-2 activities in intact cells.

Suppression of leukotriene B4 and tumour necrosis factor alpha release in acute inflammatory responses by novel prenylated hydroquinone derivatives.

A series of prenyl hydroquinone derivatives synthesized as structural analogs of marine products were tested for their effects on inflammatory responses in vitro and in vivo. 2-Prenyl-1,4-hydroquinone (H1), 2-diprenyl-1,4-hydroquinone (H2), 2-triprenyl-1,4-hydroquinone (H3) and 2-tetraprenyl-1,4-hydroquinone (H4) scavenged reactive oxygen species and inhibited 5-lipoxygenase (5-LO) activity in human neutrophils. The inhibition of 5-LO activity was demonstrated in vivo in the mouse air pouch injected with zymosan and arachidonic acid-induced ear inflammation. The four compounds suppressed the production of tumour necrosis factor alpha (TNFalpha) in J774 cells stimulated with lipopolysaccharide (LPS) and also in vivo in the mouse air pouch injected with zymosan. In addition, all prenyl-hydroquinones inhibited the release of nitrite and PGE2 in LPS-stimulated J774 cells, without direct effects on cyclo-oxygenase-1 (COX-1), cyclo-oxygenase-2 (COX-2) or inducible nitric oxide synthase (iNOS) activities in several cell-free systems. The reduction in the length of the lateral chain in prenyl-hydroquinones (1-4 isoprene units) with respect to their marine analogs (7-8 isoprene units) has improved the anti-inflammatory activity of this class of compounds. Marine natural products may be a model to design new anti-inflammatory agents.