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Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis

Sonia Cabrera-Villalba, María José Gomara, Juan D. Cañete, Julio Ramírez, Georgina Salvador, Virginia Ruiz-Esquide, Maria Victoria Hernández, José Inciarte-Mundo, Isabel Haro and Raimon Sanmartí

Arthritis Research & Therapy (2017)

Background
To analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA).
Methods
ACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA.
Results
CCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA;
Conclusion
The ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA.
 

Computational Insights into the CH3Cl+OH Chemical Reaction Dynamics at the Air–Water Interface

Marilia T. C. Martins-Costa, Josep M. Anglada, and Manuel F. Ruiz-López

ChemPhysChem., 18, 1 – 10, 2017

The reaction of methyl chloride with the hydroxyl radical OH is an important process in the troposphere. The kinetics of this reaction has been thoroughly studied in the gas phase, both experimentally and theoretically, but little is known about the effect of water on this reaction. In particular, investigating the reaction mechanism at the air–water interface is key in order to better understand the role of cloud water droplets and aerosols on the overall oxidation capacity of the troposphere. In this work, we have implemented a “rare event” approach combined to QM/MM (quantum mechanics and molecular mechanics) molecular dynamics simulations to investigate the dynamics of the H-abstraction reaction CH3Cl+OH→CH2Cl+H2O at the air–water interface. For comparison, high-level ab initio calculations for the reaction mechanism in the gas phase are also reported and accurate kinetic constants at different temperatures are provided.
 

Micellization and Antimicrobial Properties of Surface-Active Ionic Liquids Containing Cleavable Carbonate Linkages

Garcia M.T., Ribosa I., Perez L., Manresa A., Comelles F.

Langmuir 33, 26, 6511-6520, 2017

Imidazolium-based ionic liquids (ILs) containing cleavable carbonate linkages, 1-alkyloxycarbonyloxyethyl-3-methylimidazolium chlorides with alkyl chains of 10, 12, and 14 carbon atoms, were synthesized, and their self-assembly behavior and antimicrobial activity were investigated. Differential scanning calorimetry and polarized optical microscopy studies reveal that carbonate-functionalized ILs form stable thermotropic smectic liquid-crystalline phases over a wide range of temperature. The surface activity and aggregation behavior of these new ILs were investigated by tensiometry, conductometry, potentiometry, and spectrofluorimetry. The size of aggregates was examined by dynamic light scattering (DLS). Carbonate-functionalized ILs display a higher adsorption efficiency and a lower critical micelle concentration (cmc) than simple alkyl-chain-substituted ILs. The insertion of a carbonate ester moiety in the alkyl side chain favors adsorption at the air-water interface and micellization in the bulk solution when compared to nonfunctionalized ILs. DLS measurements show that small micellelike aggregates are spontaneously formed above the cmc. Furthermore, carbonate-functionalized ILs were examined for their antimicrobial activity against a panel of clinically relevant microorganisms. Biological activity was found to increase with hydrophobicity. The presence of a carbonate ester moiety significantly enhances the antimicrobial efficiency as compared to nonfunctionalized ILs, with the susceptibility of Staphylococcus sp. toward the action of these compounds being particularly remarkable. It has been demonstrated that the functionalization of the alkyl side chain of the imidazolium salts can not only modify the aggregation behavior but also lead to differences in both efficiency and the spectrum of antimicrobial activity of amphiphilic

 

i-motif structures in long cytosine-rich sequences found upstream of the promoter region of the SMARCA4 gene

Sanae Benabou, Anna Aviñó, S. Lyonnais, C. González, Ramon Eritja, Anna De Juan, Raimundo Gargallo


Biochimie, 140, 20-33, 2017
Cytosine-rich oligonucleotides are capable of forming complex structures known as i-motif with increasingly studied biological properties. The study of sequences prone to form i-motifs located near the promoter region of genes may be difficult because these sequences not only contain repeats of cytosine tracts of disparate length but also these may be separated by loops of varied nature and length. In this work, the formation of intramolecular i-motif structures by a long sequence located upstream of the promoter region of the SMARCA4 gene has been demonstrated. Nuclear Magnetic Resonance, Circular Dichroism, Gel Electrophoresis, Size-Exclusion Chromatography, and multivariate analysis have been used. Not only the wild sequence (5‘-TC3T2GCTATC3TGTC2TGC2TCGC3T2G2TCATGA2C4-3’) has been studied but also several other truncated and mutated sequences. Despite the apparent complex sequence, the results showed that the wild sequence may form a relatively stable and homogeneous unimolecular i-motif structure, both in terms of pH or temperature. The model ligand TMPyP4 destabilizes the structure, whereas the presence of 20% (w/v) PEG200 stabilized it slightly. This finding opens the door to the study of the interaction of these kind of i-motif structures with stabilizing ligands or proteins.

 

Unraveling the Multistimuli Responses of a Complex Dynamic System of Pseudopeptidic Macrocycles

Valdivielso, A. M., Puig-Castellví, F., Atcher, J., Solà, J., Tauler, R. and Alfonso, I.

Chem. Eur. J. 2017

The understanding of increasingly complex chemical networks is a major challenge in Systems Chemistry. In this work, the effect of different stimuli on a dynamic combinatorial library of pseudopeptidic macrocycles has been analyzed using chemometrics. The approach is especially useful when several stimuli with overlapping effects are applied simultaneously

 

Influence of polymer concentration on the properties of nano-emulsions and nanoparticles obtained by a low-energy method

Maria Homs, Gabriela Calderó, Marta Monge, Daniel Morales and Conxita Solans

Colloids and Surfaces A: Physicochemical and Engineering Aspects, 536, 5, 204-212, 2018

This study concerns the effect of polymer content on the properties of nano-emulsions formulated by the PIC low-energy method and on the nanoparticles prepared from nano-emulsions by solvent evaporation. The region of nano-emulsion formation, droplet size and stability as a function of polymer content were investigated. Nano-emulsions were formed in a wide range of oil-to-surfactant weight ratios (Ros) and water contents higher than 45%. For nanoparticles, droplet size, stability, encapsulation efficiency, pH, drug release and cytotoxicity effect were evaluated as a function of polymer content. Nano-emulsion droplet size (Rh = 8–75 nm) and nanoparticle size (Rh = 8–55 nm) increase with the polymer content. No desestabilization process such as creaming or sedimentation was observed by light transmittance/backscattering neither in nano-emulsions nor in nanoparticle dispersions. The morphology and size of nano-emulsions and nanoparticles were comfirmed by Cryo-TEM and TEM techniques, respectively. The pH of nanoparticle dispersions was in the range of 5–6.5 during the studied experimental time (7days), an indication of no polymer degradation. Moreover, Dexamethasone (DXM) encapsulated in the polymeric nanoparticles (0.18 wt% DXM in the oil phase of the template nano-emulsion) did not modify the nanoparticle size. No effect of polymer concentration was found in the encapsulation efficiency (close to 90%) of DXM. In vitro drug release studies indicated Fick’s diffusion as the main drug release mechanism from the nanoparticle to the receptor solution. DXM loaded and non-loaded nanoparticles showed cell viability higher than 70%. This study reports a promising system to be used as template for polymeric nanoparticle preparation suitable for biomedical applications.

 

Insights on the Interaction between Transthyretin and Aß in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal

Ana Gimeno, Luis M. Santos, Mobina Alemi, Josep Rivas, Daniel Blasi, Ellen Y. Cotrina, Jordi Llop, Gregorio Valencia, Isabel Cardoso, Jordi Quintana, Gemma Arsequell, and Jesús Jiménez-Barbero

J. Med. Chem. 60 (13), 5749–5758, 2017

Several strategies against Alzheimer disease (AD) are directed to target Aß-peptides. The ability of transthyretin (TTR) to bind Aß-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR–Aß interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Aß(12–28) peptide (3), the essential recognition element of Aß, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related to the role of the TTR stabilizer iododiflunisal (IDIF, 5) on the TTR–Aß complex have been also examined. The NMR results, assisted by molecular modeling protocols, have provided a structural model for the TTR–Aß interaction, as well as for the ternary complex formed in the presence of IDIF. This basic structural information could be relevant for providing light on the mechanisms involved in the ameliorating effects of AD symptoms observed in AD/TTR± animal models after IDIF treatment and eventually for designing new molecules toward AD therapeutic drugs.
 

Comparative Study of Surface Chemical Composition and Oxide Layer Modification upon Oxygen Plasma Cleaning and Piranha Etching on a Novel Low Elastic Modulus Ti25Nb21Hf Alloy

Virginia Paredes, Emiliano Salvagni, Enrique Rodríguez-Castellón and José María Manero

Metall and Mat Trans A,  2017

Metals are widely employed for many biological artificial replacements, and it is known that the quality and the physical/chemical properties of the surface are crucial for the success of the implant. Therefore, control over surface implant materials and their elastic moduli may be crucial to avoid undesired effects. In this study, surface modification upon cleaning and activation of a low elastic modulus Ti alloy (Ti25Hf21Nb) was investigated. Two different methods, oxygen plasma (OP) cleaning and piranha (PI) solution, were studied and compared. Both surface treatments were effective for organic contaminant removal and to increase the Ti-oxide layer thickness rather than other metal-oxides present at the surface, which is beneficial for biocompatibility of the material. Furthermore, both techniques drastically increased hydrophilicity and introduced oxidation and hydroxylation (OH)-functional groups at the surface that may be beneficial for further chemical modifications. However, these treatments did not alter the surface roughness and bulk material properties. The surfaces were fully characterized in terms of surface roughness, wettability, oxide layer composition, and hydroxyl surface density through analytical techniques (interferometry, X-ray photoelectron spectroscopy (XPS), contact angle, and zinc complexation). These findings provide essential information when planning surface modifications for cleanliness, oxide layer thickness, and surface hydroxyl density, as control over these factors is essential for many applications, especially in biomaterials.

 

Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase[S]

Francesca Cingolani, Fabio Simbari, Jose Luis Abad, Mireia Casasampere, Gemma Fabrias, Anthony H. Futerman† and Josefina Casas

The Journal of Lipid Research, 58, 1500-1513, 2017

Sphingolipids (SLs) have been extensively investigated in biomedical research due to their role as bioactive molecules in cells. Here, we describe the effect of a SL analog, jaspine B (JB), a cyclic anhydrophytosphingosine found in marine sponges, on the gastric cancer cell line, HGC-27. JB induced alterations in the sphingolipidome, mainly the accumulation of dihydrosphingosine, sphingosine, and their phosphorylated forms due to inhibition of ceramide synthases. Moreover, JB provoked atypical cell death in HGC-27 cells, characterized by the formation of cytoplasmic vacuoles in a time and dose-dependent manner. Vacuoles appeared to originate from macropinocytosis and triggered cytoplasmic disruption. The pan-caspase inhibitor, z-VAD, did not alter either cytotoxicity or vacuole formation, suggesting that JB activates a caspase-independent cell death mechanism. The autophagy inhibitor, wortmannin, did not decrease JB-stimulated LC3-II accumulation. In addition, cell vacuolation induced by JB was characterized by single-membrane vacuoles, which are different from double-membrane autophagosomes. These findings suggest that JB-induced cell vacuolation is not related to autophagy and it is also independent of its action on SL metabolism.
 

Bioanalytical methods for cytostatic therapeutic drug monitoring and occupational exposure assessment

Marta Broto, Roger Galve, M.-Pilar Marco

TrAC Trends in Analytical Chemistry, 93, 152–170, 2017

Chemotherapy is the use of chemical substances to treat cancer. However, traditional chemotherapeutic agents do not show sufficient specificity for the cancer cells, which means that also healthy cells are strongly affected by these treatments. In parallel, manufacturers and health-care workers are continuously exposed to these cytostatic drugs through the usual procedures. Thus, there is a need to control the real internal dose received by this sector. Bioanalytical techniques may show great potential as tools for establishing a more personalized treatment procedure since therapeutic drug monitoring (TDM) could support clinicians on making and establishing decisions adapted to each patient. Similarly, these bioanalytical procedures may be implemented on those occupational sectors in which risk for exposure to these hazardous drugs exists. In this review, we present the overall situation in that respect and provide information of the bioanalytical techniques reported up to date for the most important cytostatic families.
 


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