Alberto Federman Neto

Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation

Heme oxygenase (HO) activity is known to down‐regulate inflammatory events. Here, we address the role of HO and its metabolites, carbon monoxide (CO) and biliverdin (BVD), in leukocyte rolling, adhesion and neutrophil migration during inflammatory processes.

Hydrogen sulfide improves neutrophil migration and survival in sepsis via K+ATP channel activation.

RATIONALE Recovering the neutrophil migration to the infectious focus improves survival in severe sepsis. Recently, we demonstrated that the cystathionine gamma-lyase (CSE)/hydrogen sulfide (H(2)S) pathway increased neutrophil recruitment to inflammatory focus during sterile inflammation. OBJECTIVES To evaluate if H(2)S administration increases neutrophil migration to infectious focus and survival of mice. METHODS Sepsis was induced by cecal ligation and puncture (CLP). MEASUREMENTS AND MAIN RESULTS The pretreatments of mice with H(2)S donors (NaHS or Lawessons reagent) improved leukocyte rolling/adhesion in the mesenteric microcirculation as well as neutrophil migration. Consequently, bacteremia levels were reduced, hypotension and lung lesions were prevented, and the survival rate increased from approximately 13% to approximately 80%. Even when treatment was delayed (6 h after CLP), a highly significant reduction in mortality compared with untreated mice was observed. Moreover, H(2)S pretreatment prevented the down-regulation of CXCR2 and l-selectin and the up-regulation of CD11b and G protein-coupled receptor kinase 2 in neutrophils during sepsis. H(2)S also prevented the reduction of intercellular adhesion molecule-1 expression in the endothelium of the mesenteric microcirculation in severe sepsis. Confirming the critical role of H(2)S on sepsis outcome, pretreatment with dl-propargylglycine (a CSE inhibitor) inhibited neutrophil migration to the infectious focus, enhanced lung lesions, and induced high mortality in mice subjected to nonsevere sepsis (from 0 to approximately 80%). The beneficial effects of H(2)S were blocked by glibenclamide (a ATP-dependent K(+) channel blocker). CONCLUSIONS These results showed that H(2)S restores neutrophil migration to the infectious focus and improves survival outcome in severe sepsis by an ATP-dependent K(+) channel-dependent mechanism.

Hydrogen sulfide augments neutrophil migration through enhancement of adhesion molecule expression and prevention of CXCR2 internalization: role of ATP-sensitive potassium channels.

In this study, we have addressed the role of H2S in modulating neutrophil migration in either innate (LPS-challenged naive mice) or adaptive (methylated BSA (mBSA)-challenged immunized mice) immune responses. Treatment of mice with H2S synthesis inhibitors, dl-propargylglycine (PAG) or β-cyanoalanine, reduced neutrophil migration induced by LPS or methylated BSA (mBSA) into the peritoneal cavity and by mBSA into the femur/tibial joint of immunized mice. This effect was associated with decreased leukocyte rolling, adhesion, and P-selectin and ICAM-1 expression on endothelium. Predictably, treatment of animals with the H2S donors, NaHS or Lawesson’s reagent, enhanced these parameters. Moreover, the NaHS enhancement of neutrophil migration was not observed in ICAM-1-deficient mice. Neither PAG nor NaHS treatment changed LPS-induced CD18 expression on neutrophils, nor did the LPS- and mBSA-induced release of neutrophil chemoattractant mediators TNF-α, keratinocyte-derived chemokine, and LTB4. Furthermore, in vitro MIP-2-induced neutrophil chemotaxis was inhibited by PAG and enhanced by NaHS treatments. Accordingly, MIP-2-induced CXCR2 internalization was enhanced by PAG and inhibited by NaHS treatments. Moreover, NaHS prevented MIP-2-induced CXCR2 desensitization. The PAG and NaHS effects correlated, respectively, with the enhancement and inhibition of MIP-2-induced G protein-coupled receptor kinase 2 expression. The effects of NaHS on neutrophil migration both in vivo and in vitro, together with CXCR2 internalization and G protein-coupled receptor kinase 2 expression were prevented by the ATP-sensitive potassium (KATP+) channel blocker, glybenclamide. Conversely, diazoxide, a KATP+ channel opener, increased neutrophil migration in vivo. Together, our data suggest that during the inflammatory response, H2S augments neutrophil adhesion and locomotion, by a mechanism dependent on KATP+ channels.

Analysis of the molecular association of rifampicin with hydroxypropyl-²-cyclodextrin

Foram preparados complexos de inclusao de rifampicina (RP) com hidroxipropil-²-ciclodextrina (HP²CD). A solubilidade da RP em agua aumentou linearmente com a concentracao de ciclodextrina na faixa de concentracao utilizada no diagrama de solubilidade. Os resultados foram analisados quantitativamente atraves do modelo de Higuchi e Connors. Os valores da constante de estabilidade (K) para o complexo RP/HP²CD em pH 6,9 foram 18 e 120-125 M-1 para as forcas ionicas 0,01 e 0,18 M, respectivamente. A analise dos dados de deslocamento quimico de 1H e 15N-NMR para a RP livre e do complexo de inclusao RP/HP²CD revelou que somente os picos da cadeia lateral relacionada com o anel piperazina modificaram substancialmente, provavelmente devido a interacao desta regiao da molecula da RP com a cavidade hidrofobica da HP²CD. Com base no estudo de modelagem molecular foi proposta a estrutura otimizada para o complexo de inclusao RP/HP²CD. A estrutura proposta esta de acordo com os resultados dos espectros de 1H e 13C-NMR e 15N-NMR .

Preparation and characterization of chitosan-treated alginate microparticles incorporating all-trans retinoic acid

Chitosan treated alginate microparticles were prepared with the purpose of incorporating all-trans retinoic acid (ATRA) using an inexpensive, simple and fast method, enhancing dermal localization and sustaining the release of ATRA into the skin. Microparticles characterization, drug–polymer interaction, release profile and in vitro skin retention were investigated. Microparticles presented spherical shape and drug loading capacity of 47%. The drug content of these microparticles was affected by ATRA concentration and by the solvent used and it was more weakly affected by chitosan concentration. The release of ATRA was also affected by chitosan concentration. Microparticles prepared with 0.4% chitosan (w/w) resulted in drug release with a more sustained profile. The results of in vitro retention studies showed that chitosan treated alginate microparticles decreased the drug retention in the stratum corneum (SC), where occur the skin irritation, but maintained the ATRA concentration in the deeper skin layers, where occur the pathologies treated with ATRA. Then, the microparticles developed in this work can be a good candidate to improve the topical therapy with retinoid.

Improvements in the Preparation of Cyclopentadienyl Thallium and Methylcyclopentadienylthallium and in Their Use in Organometallic Chemistry

Abstract Improved preparation methods of cyclopentadienylthallium and methyl-cyclopentadienylthallium, giving quantitative yields and incorporating ultrasound techniques, are described. Their use as starting materials for a wide range of organometallic syntheses is discussed and demonstrated. Referee I: H. Schumann Referee II: W. Frank

Mercury(II) Trichloroacetate. Part II. Formation and Use as a Versatile Reagent in Ferrocene Chemistry

Abstract The preparation of a methanolic solution of mercury(II) trichloroacetate is described. This reagent is used in an improved decamercuration of ferrocene. Decamercurated ferrocene is converted to decahaloferrocenes and used as the starting material in a new method for the synthesis of decadeuteroferrocene. Referee I: T. J. Haas Referee II: P. F. Brandt

Nanoparticles of Molybdenum Chlorophyllin Photosensitizer and Magnetic Citrate‐Coated Cobalt Ferrite Complex Available to Hyperthermia and Photodynamic Therapy Clinical Trials

This study report on the synthesis and characterization of molybdenum chlorophyllin (Mo‐Chl) compounds associated in a complex with magnetic nanoparticles (citrate‐coated cobalt ferrite), the latter prepared as a biocompatible magnetic fluid (MF). The complex material was developed for application as a synergic drug for cancer treatment using Photodynamic Therapy (PDT) and Hyperthermia (HPT). Chlorophyllin was obtained from alkaline extraction of Ilex paraguariensis following molybdenum insertion from hydrolysis with molybdate sodium. Fluorescence quantum yield (Φf) of Mo‐Chl/dimethyl‐sulphoxide (DMSO) was lower than 0.1, with a lifetime of 5.0 ns, as obtained from time‐correlated single‐photon counting technique. The oxygen quantum yield of Mo‐Chl was carried out using laser flash‐photolysis studies in homogeneous medium saturated with O2(g) (ΦΔ = 0.50). Cellular viability was also evaluated via the classical MTT assay using gingival fibroblasts cells as a biological model. Studies performed with the com...

Síntese de sulfadiazina e sulfadiazina de prata em escala semi-micro: prática experimental em síntese de fármacos

The total synthesis of sulfadiazine and silver sulfadiazine from readily available starting materials was adapted to semi-micro laboratory scale and is proposed as an experiment in drug synthesis for undergraduate courses.

Um método simples para preparação de metalocenos sensíveis ao ar

A simple laboratory technique is described for the synthesis of cyclopentadienylthallium and methylcyclopentadienylthallium and their use in the preparation of air sensitive metallocenes in solution. It does not use manifold, drybox or any other special glassware and was applied to the synthesis of cobaltocene, nickelocene and their methyl substituted analogs.