Spanish Cell Therapy Network (TerCel) : 15 years of successful collaborative translational research

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice-certified cell manufacturing facilities- and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients

Benznidazole

The conformation of the title compound [systematic name: N-benzyl-2-(2-nitro­imidazol-1-yl)acetamide], C12H12N4O3, can be described in terms of the relative orientation of three planar fragments, the imidazol group (A), benzyl group (B), and the acetamide fragment (C), with corresponding dihedral angles: A/C = 88.17 (4), B/C = 67.12 (5) and A/B = 21.11 (4)°. The crystal packing is enhanced by a network of strong inter­molecular N—H⋯O hydrogen bonds

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.</p> <p>Methods</p> <p>We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.</p> <p>Results</p> <p>We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.</p> <p>Conclusion</p> <p>The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.</p

Evaluation of host-guest complex formation between a benzimidazolic derivative and cyclodextrins by UV-VIS spectrophotometry and differential scanning calorimetry

Abstract Interactions between a benzimidazolic derivative, omeprazole (OME), beta-cyclodextrin (ßCD) and a chemically modified ßCD, methyl-beta-cyclodextrin (MßCD) were investigated in aqueous solution by UV-VIS spectroscopy and in solid state by differential scanning calorimetry (DSC). Phase solubility studies were used to evaluate the complexation in aqueous solution. The two solubility diagrams obtained were AL type, indicating the formation of a drug-cyclodextrin complex with 1:1 stoichiometry. The complex of OME with MßCD showed a higher stability constant (K S) than those with ßCD. Some evidences of inclusion complexation in solid state were obtained from DSC. Only in thermal curves of OME-ßCD lyophilized product and in OME-MßCD spray-dried and lyophilized systems the melting point of the drug disappeared completely suggesting the possible formation of an inclusion complex

Effect of cyclodextrins on the solubility and antimycotic activity of sertaconazole: Experimental and computational studies

This study investigated the effects of the complexation of sertaconazole nitrate with different cyclodextrin (CD) derivatives (α-CD, β-CD, γ-CD, hydroxypropyl-β-CD, and hydroxypropyl-γ-CD) on the aqueous solubility and antimycotic activity of the drug. Phase solubility studies indicated that the solubility of sertaconazole in enzyme-free simulated gastric- and enzyme-free simulated enteric fluids was significantly increased in the presence of cyclodextrins. The observed order of solubility increasing effect was: γ-CD > HPγ-CD > HPβ-CD > β-CD > α-CD. Solid-state sertaconazole–cyclodextrin complexes were prepared by freeze drying, and characterized by X-ray powder difractometry, differential scanning calorimetry (DSC), and infrared spectroscopy (FTIR). Freeze-dried complexes showed markedly higher solubility than both physical mixtures and sertaconazole alone. The antimycotic activities of sertaconazole–cyclodextrin complexes in solution were evaluated by inhibition zone assays with Candida albicans. The activity ranking agrees with the solubility ranking observed for these complexes, with the γ-CD–sertaconazole complex showing the strongest antimycotic activity. Finally, molecular modeling studies were carried out using the MM2 force field method, for complexes in vacuum and in water. This enable indentification of the preferred orientation of sertaconazole in the γ-CD cavity and of the main structural features responsible for the enhancement of its solubility and antimycotic activity. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2408–2415, 200

NL MIND-BEST : a web server for ligands and proteins discovery--theoretic-experimental study of proteins of Giardia lamblia and new compounds active against Plasmodium falciparum

There are many protein ligands and/or drugs described with very different affinity to a large number of target proteins or receptors. In this work, we selected Ligands or Drug-target pairs (DTPs/nDTPs) of drugs with high affinity/non-affinity for different targets. Quantitative Structure-Activity Relationships (QSAR) models become a very useful tool in this context to substantially reduce time and resources consuming experiments. Unfortunately most QSAR models predict activity against only one protein target and/or have not been implemented in the form of public web server freely accessible online to the scientific community. To solve this problem, we developed here a multi-target QSAR (mt-QSAR) classifier using the MARCH-INSIDE technique to calculate structural parameters of drug and target plus one Artificial Neuronal Network (ANN) to seek the model. The best ANN model found is a Multi-Layer Perceptron (MLP) with profile MLP 20:20-15-1:1. This MLP classifies correctly 611 out of 678 DTPs (sensitivity=90.12%) and 3083 out of 3408 nDTPs (specificity=90.46%), corresponding to training accuracy=90.41%. The validation of the model was carried out by means of external predicting series. The model classifies correctly 310 out of 338 DTPs (sensitivity=91.72%) and 1527 out of 1674 nDTP (specificity=91.22%) in validation series, corresponding to total accuracy=91.30% for validation series (predictability). This model favorably compares with other ANN models developed in this work and Machine Learning classifiers published before to address the same problem in different aspects. We implemented the present model at web portal Bio-AIMS in the form of an online server called: Non-Linear MARCH-INSIDE Nested Drug-Bank Exploration & Screening Tool (NL MIND-BEST), which is located at URL: http://miaja.tic.udc.es/Bio-AIMS/NL-MIND-BEST.php. This online tool is based on PHP/HTML/Python and MARCH-INSIDE routines. Finally we illustrated two practical uses of this server with two different experiments. In experiment 1, we report by first time Quantum QSAR study, synthesis, characterization, and experimental assay of antiplasmodial and cytotoxic activities of oxoisoaporphine alkaloids derivatives as well as NL MIND-BEST prediction of potential target proteins. In experiment 2, we report sampling, parasite culture, sample preparation, 2-DE, MALDI-TOF, and -TOF/TOF MS, MASCOT search, MM/MD 3D structure modeling, and NL MIND-BEST prediction for different peptides a new protein of the found in the proteome of the human parasite Giardia lamblia, which is promising for anti-parasite drug-targets discovery

Spanish cell therapy network (TerCel): 15 years of successful collaborative translational research

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice certified cell manufacturing facilities and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients

Spanish cell therapy network (TerCel): 15 years of successful collaborative translational research

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice certified cell manufacturing facilities and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients