New Mechanistic Insights on Carbon Nanotubes’ Nanotoxicity Using Isolated Submitochondrial Particles, Molecular Docking, and Nano-QSTR Approaches

Single-walled carbon nanotubes can induce mitochondrial F0F1-ATPase nanotoxicity through inhibition. To completely characterize the mechanistic effect triggering the toxicity, we have developed a new approach based on the combination of experimental and computational study, since the use of only one or few techniques may not fully describe the phenomena. To this end, the in vitro inhibition responses in submitochondrial particles (SMP) was combined with docking, elastic network models, fractal surface analysis, and Nano-QSTR models. In vitro studies suggest that inhibition responses in SMP of F0F1-ATPase enzyme were strongly dependent on the concentration assay (from 3 to 5 µg/mL) for both pristine and COOH single-walled carbon nanotubes types (SWCNT). Besides, both SWCNTs show an interaction inhibition pattern mimicking the oligomycin A (the specific mitochondria F0F1-ATPase inhibitor blocking the c-ring F0 subunit). Performed docking studies denote the best crystallography binding pose obtained for the docking complexes based on the free energy of binding (FEB) fit well with the in vitro evidence from the thermodynamics point of view, following an affinity order such as: FEB (oligomycin A/F0-ATPase complex) = −9.8 kcal/mol > FEB (SWCNT-COOH/F0-ATPase complex) = −6.8 kcal/mol ~ FEB (SWCNT-pristine complex) = −5.9 kcal/mol, with predominance of van der Waals hydrophobic nano-interactions with key F0-ATPase binding site residues (Phe 55 and Phe 64). Elastic network models and fractal surface analysis were performed to study conformational perturbations induced by SWCNT. Our results suggest that interaction may be triggering abnormal allosteric responses and signals propagation in the inter-residue network, which could affect the substrate recognition ligand geometrical specificity of the F0F1-ATPase enzyme in order (SWCNT-pristine > SWCNT-COOH). In addition, Nano-QSTR models have been developed to predict toxicity induced by both SWCNTs, using results of in vitro and docking studies. Results show that this method may be used for the fast prediction of the nanotoxicity induced by SWCNT, avoiding time- and money-consuming techniques. Overall, the obtained results may open new avenues toward to the better understanding and prediction of new nanotoxicity mechanisms, rational drug design-based nanotechnology, and potential biomedical application in precision nanomedicineThis research was funded by FCT/MCTES through national funds (Michael González-Durruthy, Riccardo Concu, and M. Natália D.S. Cordeiro), grant UID/QUI/50006/2020, as well as by Xunta de Galicia (Juan M. Ruso), grant ED41E2018/08S

Identifying emerging trends of protein hydrogels for biological scaffolding

The strategies of bottom-up design of inorganic structures from biological templates enable cheap, ecofriendly and efficient fabrication of nano-structured materials. Here, template assembly of silica nanostructures were achieved using different protein hydrogels. Ovalbumin and fibrinogen gels were prepared by heat treatment at different pHs and protein concentrations. These hydrogels have been morphologically (SEM) and mechanically (rheology) well characterized. Next, a silica precursor is added, the condensation reaction is initiated and finally the protein hydrogel template is removed by calcination. A variety of 3D nanostructures ranging from highly porosity structures to spherical particles have been identified and characterized. Furthermore, it was observed that the fractal dimension of silica structures follow the same pattern than their corresponding templates. Consequently, the bio-scaffolding method proposed here helps the bottom-up assembly of silica precursors in nanostructures with defined three dimensional dimensions and provides a versatile route for the design of new architectures under green conditions.Fil: Messina, Paula Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; ArgentinaFil: Hassan, Natalia. Universite Pierre Et Marie Curie; Francia. Universidad de Chile. Facultad de Ciencias Químicas y Farmaceuticas. Laboratorio de Nanobiotecnología; ChileFil: Soltero, Armando. Universidad de Guadalajara; MéxicoFil: Ruso, Juan M.. Universidad de Santiago de Compostela; Españ

Trends in Nanoparticles for Leishmania Treatment: A Bibliometric and Network Analysis

Leishmaniasis is a neglected tropical illness with a wide variety of clinical signs ranging from visceral to cutaneous symptoms, resulting in millions of new cases and thousands of fatalities reported annually. This article provides a bibliometric analysis of the main authors’ contributions, institutions, and nations in terms of productivity, citations, and bibliographic linkages to the appli- cation of nanoparticles (NPs) for the treatment of leishmania. The study is based on a sample of 524 Scopus documents from 1991 to 2022. Utilising the Bibliometrix R-Tool version 4.0 and VOSviewer software, version 1.6.17 the analysis was developed. We identified crucial subjects associated with the application of NPs in the field of antileishmanial development (NPs and drug formulation for leishmaniasis treatment, animal models, and experiments). We selected research topics that were out of date and oversaturated. Simultaneously, we proposed developing subjects based on multiple analyses of the corpus of published scientific literature (title, abstract, and keywords). Finally, the technique used contributed to the development of a broader and more specific “big picture” of nanomedicine research in antileishmanial studies for future projects

Surface characterization of human serum albumin and sodium perfluorooctanoate mixed solutions by pendant drop tensiometry and circular dichroism

The interfacial behavior of mixed human serum albumin (HSA)/sodium perfluorooctanoate (C8FONa) solutions is examined by using two experimental techniques, pendant drop tensiometry and circular dichroism spectroscopy. Through the analysis of the surface tension of the mixed solutions, surface competitive adsorption at the air-water interface between C8FONa and HSA is detected. The dynamic adsorption curves exhibit the distinct regimes in their time-dependent surface tension. The nature of these regimes is further analyzed in terms of the variation of the molecules surface areas. As a consequence, a compact and dense structure was formed where protein molecules were interconnected and overlapped. Thus, a reduction of the area occupied per molecule from 100 to 0.2 nm2 is interpreted as a gel-like structure at the surface. The presence of the surfactant seems to favor the formation of this interfacial structure. Finally, measurements of circular dichroism suggests a compaction of the protein due to the association with the surfactant given by an increase of α-helix structure in the complexes as compared to that of pure protein.Fil: Messina, Paula Verónica. Universidad de Santiago de Compostela; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Prieto, Gerardo. Universidad de Santiago de Compostela; EspañaFil: Dodero, Veronica Isabel. Universidad de Santiago de Compostela; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Cabrerizo-Vilchez, M.A.. Universidad de Granada. Facultad de Ciencias; EspañaFil: Maldonado Valderrama, J.. Universidad de Granada. Facultad de Ciencias; EspañaFil: Ruso, Juan M.. Universidad de Santiago de Compostela; EspañaFil: Sarmiento, Félix. Universidad de Santiago de Compostela; Españ

MIANN models in medicinal, physical and organic chemistry

[Abstract] Reducing costs in terms of time, animal sacrifice, and material resources with computational methods has become a promising goal in Medicinal, Biological, Physical and Organic Chemistry. There are many computational techniques that can be used in this sense. In any case, almost all these methods focus on few fundamental aspects including: type (1) methods to quantify the molecular structure, type (2) methods to link the structure with the biological activity, and others. In particular, MARCH-INSIDE (MI), acronym for Markov Chain Invariants for Networks Simulation and Design, is a well-known method for QSAR analysis useful in step (1). In addition, the bio-inspired Artificial-Intelligence (AI) algorithms called Artificial Neural Networks (ANNs) are among the most powerful type (2) methods. We can combine MI with ANNs in order to seek QSAR models, a strategy which is called herein MIANN (MI & ANN models). One of the first applications of the MIANN strategy was in the development of new QSAR models for drug discovery. MIANN strategy has been expanded to the QSAR study of proteins, protein-drug interactions, and protein-protein interaction networks. In this paper, we review for the first time many interesting aspects of the MIANN strategy including theoretical basis, implementation in web servers, and examples of applications in Medicinal and Biological chemistry. We also report new applications of the MIANN strategy in Medicinal chemistry and the first examples in Physical and Organic Chemistry, as well. In so doing, we developed new MIANN models for several self-assembly physicochemical properties of surfactants and large reaction networks in organic synthesis. In some of the new examples we also present experimental results which were not published up to date.Ministerio de Ciencia e Innovación; CTQ2009-07733Universidad del Pais Vasco; UFI11/22Universidad del Pais Vasco; GIU 094

Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study

In this work, one of the most prevalent polypharmacology drug–drug interaction events that occurs between two widely used beta-blocker drugs—i.e., acebutolol and propranolol—with the most abundant blood plasma fibrinogen protein was evaluated. Towards that end, molecular docking and Density Functional Theory (DFT) calculations were used as complementary tools. A fibrinogen crystallographic validation for the three best ranked binding-sites shows 100% of conformationally favored residues with total absence of restricted flexibility. From those three sites, results on both the binding-site druggability and ligand transport analysis-based free energy trajectories pointed out the most preferred biophysical environment site for drug–drug interactions. Furthermore, the total affinity for the stabilization of the drug–drug complexes was mostly influenced by steric energy contributions, based mainly on multiple hydrophobic contacts with critical residues (THR22: P and SER50: Q) in such best-ranked site. Additionally, the DFT calculations revealed that the beta-blocker drug–drug complexes have a spontaneous thermodynamic stabilization following the same affinity order obtained in the docking simulations, without covalent-bond formation between both interacting beta-blockers in the best-ranked site. Lastly, experimental ultrasound density and velocity measurements were performed and allowed us to validate and corroborate the computational obtained resultsThis research was funded by FCT/MCTES through national funds (Michael González-Durruthy, Riccardo Concu, and M. Natália D.S. Cordeiro), grant UID/QUI/50006/2020, as well as by Xunta de Galicia (Juan M. Ruso), grant ED41E2018/08S

Estrategia marina demarcación marina levantino-balear parte IV. Descriptores del buen estado ambiental. Descriptor 1: biodiversidad evaluación inicial y buen estado ambiental

El descriptor 1 de la Ley 41/2010 de protección del medio marino, trasposición a la ley española de la Directiva Marco sobre la Estrategia Marina (DMEM: 2008/56/CE) dice textualmente "Se mantiene la biodiversidad. La calidad y la frecuencia de los hábitats y la distribución y abundancia de las especies están en consonancia con las condiciones fisiográficas, geográficas y climáticas". Según el Convenio sobre la Diversidad Biológica (UNCED, 1992), ésta se define como: "La variabilidad de organismos vivos de cualquier fuente, incluidos, entre otras cosas, los ecosistemas terrestres y marinos y otros ecosistemas acuáticos y los complejos ecológicos de los que forman parte; comprende la diversidad dentro de cada especie, entre especies y de los ecosistemas"

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

© The Author(s) 2019.A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Models for self-assembly of nanoscale systems with biomedical applications

Background: Understanding the physicochemical basis and the different models of nanosystems is nowadays fundamental in a great number of scientific areas and industrial processes. Results: Here, we focus on nanosystems created by self-assembly, molecular or inorganic. The organization of single units at these scales is a challenging matter in light of the inherently small dimensions involved, the sensitivity of the system to small perturbations, and the problem of scaling up such a process for widespread use and implementation. Conclusion: This review examines the different self-assembly routes used to create nanostructures in both the equilibrium and non-equilibrium/dynamic systems and discusses their limits and applications. The connection to biomedicine and pharmaceutical design has been emphasized.Fil: Messina, Paula Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Rial, Ramón. Universidad de Santiago de Compostela. Facultad de Física; EspañaFil: Ruso, Juan M.. Universidad de Santiago de Compostela. Facultad de Física; Españ