Immune-Mediated Drug Induced Liver Injury: A Multidisciplinary Approach

This thesis presents an approach to expose relationships between immune mediated drug induced liver injury (IMDILI) and the three-dimensional structural features of toxic drug molecules and their metabolites. The series of analyses test the hypothesis that drugs which produce similar patterns of toxicity interact with targets within common toxicological pathways and that activation of the underlying mechanisms depends on structural similarity among toxic molecules. Spontaneous adverse drug reaction (ADR) reports were used to identify cases of IMDILI. Network map tools were used to compare the known and predicted protein interactions with each of the probe drugs to explore the interactions that are common between the drugs. The IMDILI probe set was then used to develop a pharmacophore model which became the starting point for identifying potential toxicity targets for IMDILI. Pharmacophore screening results demonstrated similarities between the probe IMDILI set of drugs and Toll-Like Receptor 7 (TLR7) agonists, suggesting TLR7 as a potential toxicity target. This thesis highlights the potential for multidisciplinary approaches in the study of complex diseases. Such approaches are particularly helpful for rare diseases where little knowledge is available, and may provide key insights into mechanisms of toxicity that cannot be gleaned from a single disciplinary study

Immune-Mediated Drug Induced Liver Injury: A Multidisciplinary Approach

This thesis presents an approach to expose relationships between immune mediated drug induced liver injury (IMDILI) and the three-dimensional structural features of toxic drug molecules and their metabolites. The series of analyses test the hypothesis that drugs which produce similar patterns of toxicity interact with targets within common toxicological pathways and that activation of the underlying mechanisms depends on structural similarity among toxic molecules. Spontaneous adverse drug reaction (ADR) reports were used to identify cases of IMDILI. Network map tools were used to compare the known and predicted protein interactions with each of the probe drugs to explore the interactions that are common between the drugs. The IMDILI probe set was then used to develop a pharmacophore model which became the starting point for identifying potential toxicity targets for IMDILI. Pharmacophore screening results demonstrated similarities between the probe IMDILI set of drugs and Toll-Like Receptor 7 (TLR7) agonists, suggesting TLR7 as a potential toxicity target. This thesis highlights the potential for multidisciplinary approaches in the study of complex diseases. Such approaches are particularly helpful for rare diseases where little knowledge is available, and may provide key insights into mechanisms of toxicity that cannot be gleaned from a single disciplinary study

Genetic characterization of Rhodococcus rhodochrous ATCC BAA-870 with emphasis on nitrile hydrolysing enzymes

Includes abstract.Includes bibliographical references.Rhodococcus rhodochrous ATCC BAA-870 (BAA-870) had previously been isolated on selective media for enrichment of nitrile hydrolysing bacteria. The organism was found to have a wide substrate range, with activity against aliphatics, aromatics, and aryl aliphatics, and enantioselectivity towards beta substituted nitriles and beta amino nitriles, compounds that have potential applications in the pharmaceutical industry. This makes R. rhodochrous ATCC BAA-870 potentially a versatile biocatalyst for the synthesis of a broad range of compounds with amide and carboxylic acid groups that can be derived from structurally related nitrile precursors. The selectivity of biocatalysts allows for high product yields and better atom economy than nonselective chemical methods of performing this reaction, such as acid or base hydrolysis. In order to apply BAA-870 as a nitrile biocatalyst and to mine the organism for biotechnological uses, the genome was sequenced using Solexa technology and an Illumina Genome Analyzer. The Solexa sequencing output data was analysed using the Solexa Data Analysis Pipeline and a total of 5,643,967 reads, 36-bp in length, were obtained providing 4,273,289 unique sequences. The genome sequence data was assembled using the software Edena, Velvet, and Staden. The best assembly data set was then annotated automatically using dCAS and BASys. Further matepaired sequencing, contracted to the company BaseClear® BV in Leiden, the Netherlands, was performed in order to improve the completeness of the data. The scaffolded Illumina and mate-paired sequences were further assembled and annotated using BASys. BAA-870 has a GC content of 65% and contains 6997 predicted protein-coding sequences (CDS). Of this, 54% encodes previously identified proteins of unknown function. The completed 5.83 Mb genome (with a sequencing coverage of 135 X) was submitted to the NCBI Genome data bank with accession number PRJNA78009. The genome sequence of R. rhodochrous ATCC BAA-870 is the seventh rhodococcal genome to be submitted to the NCBI and the first R. rhodochrous subtype to be sequenced. An analysis of the genome for nitril

Compuestos multidiana derivados de chalconas para el tratamiento y diagnóstico de enfermedades neurodegenerativas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 01-07-2022Neurological disorders are a great burden for health systems worldwide. These diseases are characterized by a disfunction in neurons and the type of neuron affected and the way it is affected will depend on the disorder. Among these disorders, Alzheimer´s disease, Parkinson´s disease and epilepsy stand out as they affect a great number of patients and there is an increasing tendency in their incidence and prevalence. The ethology of these diseases is complex, as there are numerous factors involved in their establishment and progression. In the cases of Alzheimer´s and Parkinson’s disease, these factors involve protein misfolding, an increase in oxidative stress, different types of neuronal dysfunction (cholinergic neurons in Alzheimer´s disease and dopaminergic neurons in Parkinson´s disease) and a deregulated immune response. In the case of epilepsy, the cause underlies in an unbalance between excitatory and inhibitory neurotransmission, with predomination of the former...Los trastornos neurológicos suponen una gran carga para los sistemas sanitarios mundiales. Estas enfermedades se caracterizan por una disfunción de las neuronas y el modo de afectación de éstas depende de la enfermedad en cuestión. Entre ellas, destacan la enfermedad del Alzheimer, la enfermedad de Parkinson y la epilepsia ya que afectan a un gran número de personas en el mundo y hay una tendencia creciente en cuanto a su incidencia y prevalencia. La etiología de estas enfermedades suele ser compleja al haber múltiples factores involucrados en su establecimiento y progresión. En el caso de la enfermedad de Alzheimer y de Parkinson se produce un mal plegamiento proteico, un aumento del estrés oxidativo, una disfunción de distintos tipos de neuronas (colinérgicas en caso del Alzheimer y dopaminérgicas en caso del Parkinson) y una respuesta inmune exacerbada. En el caso de la epilepsia, la causa suele ser un desbalance en el equilibrio excitatorio-inhibitorio del cerebro, a favor de la excitación...Fac. de FarmaciaTRUEunpu

Women in Bioorganic Chemistry

Issues relating to the gender schism and its effect on the career advancement of women in the Academy, especially in the field of STEM disciplines, deserve our attention and the efforts of all the scientific community to mitigate the gender gap. In order to embrace gender equality, recognize the career progression of women, and to celebrate the achievements of women in the field of bioorganic chemistry, we present contributions both from highly renowned female scientists and young female researchers who are in the early stages of their careers. This Special Issue includes fifteen manuscripts, including eleven high-quality research articles and four comprehensive review articles in the area of bioorganic chemistry, published from mid-2020 to early 2022. The scope of this Special Issue covers a wide range of topics at the organic chemistry–biology interface, including the synthesis and derivatization of natural compounds and their analogues, and the investigation of their biological activities in the human health field (for instance as antitumorals, antioxidants and antimicrobial agents), as well as their possible application in the crop protection field as agrochemicals. An example of nanoparticle-based biomaterial is also included. The techniques employed, besides organic synthesis, are in silico studies (docking procedures and molecular modeling), FT-IR spectroscopy, laser diffraction, PET, fluorescence, STD-NMR studies, enzymatic evaluation, experiments on cell lines and in vivo studies on mice

Multitarget and network-driven medicinal chemistry strategies for the treatment of neuroinflammatory diseases

Neuroinflammatory based-diseases are a very challenging area for medicinal chemists. Several efforts have been made during the years; however, an effective treatment for these diseases, such as Alzheimer’s disease (AD) and multiple sclerosis (MS), does not exist yet. Neuroinflammatory -based diseases are multifactorial in nature with still unclear pathogenic mechanisms and scarce information on how neuroinflammation is interconnected with other concomitant events, such as neurodegeneration. Polypharmacology is one of the milestones for the development of therapies able to combat multifactorial diseases. Particularly, the development of multitarget compounds through different strategies (linking, fusing, merging) has permitted to expand the potential arsenal to treat multifactorial diseases. Based on these considerations, this thesis was focused on the development of multitarget molecules for combating neuroinflammatory diseases through different and innovative polyphamacological approaches in four projects. Projects 1 & 2 focused on the development of fatty acids (FAs)/drug conjugates for the treatment of MS and AD, respectively. Particularly, we applied a conjugation strategy among omega-3 FAs and valproic acid (project 1) or P2Y6-agonists (project 2), in order to obtain innovative multitarget molecules with potentially increased property in terms of efficacy and pharmacokinetics, and less cytotoxicity. Projects 3 & 4 focused on the design and synthesis of multitarget molecules derived from food byproduct (cashew nut-shell liquid) for the treatment of AD. Particularly, we developed different series of molecules as potentially globally accessible drugs, by applying a hybridization strategy. Notably, we developed a small library of dual sustainable HDAC/ferroptosis inhibitors (project 3), and a library of cholinergic inhibitors with potential anti-inflammatory profile (project 4) as multitarget hybrids for the treatment of AD

Development of Novel Reaction-based Fluorescent Probes

Fluorescent probes have been proved to be very valuable tools in chemical and biological applications, and extensive exploration has been made. Recently, reaction-based fluorescent probes became a new design trend and displayed great potential with remarkable implementation to the conventional design method. However, this field is still underdeveloped, and a lot of problems remain to be solved. As part of our groups research interest, my Ph. D. study centered on the development of new reaction-based fluorescent probes. Firstly, our previous research on Hg2+ was continued. In this work, we developed a novel ratiometric fluorescent probe for Hg2+ with impressive sensitivity, selectivity and imaging property; also, a new fluorescent probe with excellent detection limit was explored. Secondly, the first FRET-based ratiometric fluorescent probe for nerve agent was designed and synthesized, and it exhibited great potential for practical application. Furthermore, a new design strategy for H2S probe development was discovered, and the new probe displayed excellent sensitivity and specificity. Finally, probes for Fe2+ were intensively investigated due to their biological significance and urgent demand, and the real time and off-on fluorescence detection of Fe2+ was achieved for the first time