News Article | April 28, 2017
Researchers have made the first detailed map of the regions into which the brain of one of the most closely related organisms to the vertebrates is divided, and which could give us an idea of what our ancestor was like. A study recently published in PLOS Biology provides information that substantially changes the prevailing idea about the brain formation process in vertebrates and sheds some light on how it might have evolved. The findings show that the interpretation maintained previously regarding the principal regions formed at the beginning of vertebrate brain development is not correct. This research was led jointly by the researchers José Luis Ferran and Luis Puelles of the Department of Human Anatomy and Psychobiology of the UMU; Manuel Irimia of the Centre for Genomic Regulation (CRG), and Jordi García Fernández of the Genetics Department of the University of Barcelona. The brain of an invertebrate organism, amphioxus (a fish-like marine chordate), whose place in the evolutionary tree is very close to the origin of the vertebrates, was used for the research. Using the data obtained, researchers have made the first detailed map of the regions into which the brain of this species, which inhabits the seabed and has a very simple life, is divided. “We set out to understand what the brain of the cephalocordate amphioxus was like. It is a very simple invertebrate organism, albeit very close to us in evolutionary terms, therefore it gives us some insights as to what our ancestors might have been like. Hence, by comparing the territories of the modern vertebrate brain to that of amphioxus, we analysed what might have occurred to lead them to multiply and how such a complex structure was formed in the course of our evolution,” explained the lecturer of the Department of Human Anatomy and Psychobiology of the University of Murcia (UMU) José Luis Ferrán, one of the researchers. “In this study, we used genoarchitecture as our main experimental framework to determine the regionalization of the amphioxus neural tube and compare it to that of vertebrates. Within this framework, we generated a molecular map of gene expression patterns in amphioxus, whose homologs are known to be involved in establishment and regionalization of the vertebrate brains,” explains Beatriz Albuixech-Crespo (Dept Genética, Microbiología y Estadística UB e IBUB), first author of the article. A new model that dismantles many existing ideas This work shows that the brain of vertebrates must have formed initially from two regions (anterior and posterior), and not three (forebrain, midbrain and hindbrain), as proposed by the current prosomeric model. No cerebral cortex or exclusive region giving rise to the formation of the vertebrate midbrain has been detected in amphioxi. However, a common territory inside the forebrain has been found, which they termed DiMes (Di-Mesencephalic primordium), from which both the midbrain and other important structures of the classic forebrain would derive. The DiMes territory yielded three important regions of the vertebrate brain that are used to process sensory information. “The three classic vertebrate cerebral regions (thalamus, pretectum and midbrain) would have emerged evolutionarily through the action of molecular signalling centres that lead to the expansion and division of a DiMes-like portion,” said Manuel Irimia of the Centre for Genomic Regulation (CRG) of Barcelona, one of the leading investigators of the study. This explains that if the function of these signalling centres, called secondary organizers, is eliminated in vertebrates there remains a single territory similar to the one observed in amphioxi. The study of the formation of these three important parts of the brain, which vertebrates use to process visual, auditory or propioceptive information (on the position and movement of the parts of the body), is useful in understanding how the brain has adapted to the environment and is capable of processing information around it. The idea that these regions were formed independently and that each one of them has given rise to other regions has been proven to be wrong. “The brain has not evolved in isolation, but rather through the interaction of these primitive animals with the environment,” clarified the lecturer from the UMU. In summary, both brains, amphioxus and vertebrate, are divided into two main regions: anterior and posterior. In amphioxus, the anterior region splits into two domains, whereas in vertebrates it is divided into many more portions, including the three aforementioned regions which, jointly, would correspond to one of the parts of amphioxus. Knowing the true history of the formation of the brain and the composition of its structures could have a major long-term impact, since it could “help to explain why both the composition and the function of a region are altered. For example, it could lead us to a better understanding of brain-related diseases and why some regions are affected jointly and others are not,” concluded the CRG researcher. The brain’s structure is the outcome of an evolutionary process The human brain has undergone an evolutionary process that began some 500 million years ago in the marine animals that lived submerged in the sand and which led to its first central nervous system building plan. This system has been progressively modified and is shared by all modern vertebrates. The study of the genetic networks that have given an identity to the different brain regions plays a key role in our understanding of how they have evolved. For this reason, genoarchitecture is a powerful tool for describing the regions of the nervous system, cells and their structures, making it possible to determine which genes are active in each territory or region during development and to characterise the limits between them, as well as to define, with the utmost precision, how many different components originate from each region. It is therefore useful in helping us to recognise, in detail, how the human brain resembles that of another vertebrate.
News Article | May 4, 2017
Researchers at the Hospital del Mar Medical Research Institute (IMIM) and the University of Barcelona have uncovered a mutation that makes bone vulnerable to bisphosphonates, drugs used to combat osteoporosis. Instead of strengthening bone and preventing fractures, these medicines induce a critical problem that makes the femur more prone to breaks. This discovery, enormously significant clinically, was published today in the New England Journal of Medicine, the most important biomedical journal in terms of potential impact. Osteoporosis causes fractures that affect up to 40% of people over the age of 50. Bisphosphonates are efficient and cheap, making them the first line of treatment for this condition. Nevertheless, they have been associated with atypical fracturing of the femur. "Despite the rarity of this complication and the fact that many more fractures are prevented than induced, fear of this complication has led to the prescription of these drugs being criticised, especially for long-term treatment", explains study leader Dr. Adolf Díez, emeritus head of internal medicine at Hospital del Mar and a researcher in the musculoskeletal research group at the IMIM. The consequence of this is that the majority of people at high risk of fracture due to osteoporosis (for example, those who have already suffered fractures) do not receive treatment. The infrequency of this problem made us suspicious that a genetic predisposition makes some people more likely to present atypical fracturing. "The opportunity offered by three cases of atypical fracture in three sisters treated with bisphosphonates over several years, gave us the possibility of looking into a genetic basis that, otherwise, would have been almost impossible to detect", says Dr. Xavier Nogués, head of internal medicine at Hospital del Mar and coordinator of IMIM's musculoskeletal research group. An exhaustive study of their genome, using the whole exome sequencing technique, enabled us to find a mutation common to the three sisters that could explain why they presented this unusual fracturing. The mutation damages a protein (GGPPS) that is part of a metabolic chain essential for bone health, known as the mevalonate pathway. It is believed that this mutation makes bone vulnerable to the drug, and instead of strengthening it and preventing fractures, it makes it more prone to fractures. Given this finding, broader studies are needed to be able to transfer genetic analysis techniques to patient care, allowing clinicians to detect people prone to this atypical fracture and who, therefore, should not receive biophosphonates. This would be the first step in confidently prescribing a treatment received by millions of people around the world. It is also the reason the discovery was chosen as the highest impact study at the world's most important conference on bone diseases, the annual meeting of the American Society for Bone and Mineral Research, and its publication in the New England Journal of Medicine. The work was developed thanks to collaboration between doctors and researchers from the Hospital del Mar Medical Research Institute and the internal medicine service at the same hospital, pertaining to the Centres for Biomedical Network Research on Healthy Ageing (CIBERFES), and experts from the Human Molecular Genetics group at the University of Barcelona, belonging to the Institute of Biomedicine at that university (IBUB), and the Centres for Biomedical Network Research on Rare Diseases (CIBERER) led by Dr. Daniel Grinberg and Dr. Susana Balcells. The study also involved the collaboration of the University of Oxford and Reina Sofia Hospital in Cordoba. "GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates" The New England Journal of Medicine
Santos R.C.,University of Coimbra |
Salvador J.A.R.,University of Coimbra |
Marin S.,IBUB |
Cascante M.,IBUB |
And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010
Chemical transformation studies were conducted on betulin and betulinic acid, common plant-derived lupane-type triterpenes. The concise synthesis, via a stepwise approach, of betulin and betulinic acid carbamate and N-acylheterocyclic containing derivatives is described. All new compounds, as well as betulinic acid were tested in vitro for their cytotoxic activity. Most of the compounds have shown a better cytotoxic profile than betulinic acid, including the synthesized betulin derivatives. Compounds 25 and 32 were the most promising derivatives, being up to 12-fold more potent than betulinic acid against human PC-3 cell lines (IC50 values of 1.1 and 1.8 μM, respectively). © 2010 Elsevier Ltd. All rights reserved.
Barragan F.,IBUB |
Barragan F.,University of Barcelona |
Lopez-Senin P.,IBUB |
Salassa L.,University of Warwick |
And 5 more authors.
Journal of the American Chemical Society | Year: 2011
A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as "tumor-targeting devices" since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium-peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV-vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η 6-p-cym)Ru(bpm)(H 2O)] 2+, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, 5′dCATGGCT and 5′dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide-oligonucleotide hybrid, Phac-His-Gly-Met-linker-p 5′dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids. © 2011 American Chemical Society.
Barragan F.,IBUB |
Barragan F.,University of Barcelona |
Carrion-Salip D.,University of Girona |
Gomez-Pinto I.,CSIC - Institute of Physical Chemistry "Rocasolano" |
And 8 more authors.
Bioconjugate Chemistry | Year: 2012
Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η6-bip)Os(4-CO2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η6-p-cym)RuCl(dap)]+ (p-cym = p-cymene) (5), and [(η6-p-cym)RuCl(imidazole-CO 2H)(PPh3)]+ (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC50 = 63 ± 2 μ in MCF-7 cells and IC50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society.
News Article | December 2, 2016
Since it is based on a different principle, this method complements conventional tools and allows going forward in the path of rational drug design. ICREA researcher Xavier Barril, from the Faculty of Pharmacy and Food Sciences and The Institute of Biomedicine of the University of Barcelona (IBUB), has led this project, which has the participation of professor Francesc Xavier Luque and PhD student Sergio Ruiz Carmona, members of the same Faculty. The improvement on efficiency and effectiveness in the discovery of drugs is a key target in pharmaceutical research. In this process, the target are molecules that can be added to a target protein and modify its behavior according to clinical needs. "All current methods to predict if a molecule will join the wished protein are based on affinity, that is, in the complex's thermodynamic stability. What we are proving is that molecules have to create complexes that are structurally stable, and that it is possible to distinguish between active and inactive by looking at what specific interactions are hard to break", says Professor Xavier Barril. This approach has been applied in software that identifies molecules with more possibilities to join the targeted protein. "The method allows selecting molecules that can be starting points to create new drugs", says Barril. "Moreover, -he continues- the process is complementary with existing methods and allows multiplying five times the efficiency of the current processes with lower computational prices. We are actually using it successfully in several projects in the field of cancer and infectious diseases, among others". A new vision for the protein-ligand drugs This work introduces a new way of thinking regarding the ligand-protein interaction. "We don't look at the balancing situation, where two molecules make the best possible interactions, but we also think how the complex will break, which the breaking points are and how we can improve the drug to make it more resistant to separation. Now we have to focus on this phenomenon to understand it better and see if by creating more complex models we can still improve our predictions", says the researcher. The team of the University of Barcelona is already using this method, which is open to all the scientific community. Explore further: New therapeutic target for diseases caused by lack of oxygen More information: Sergio Ruiz-Carmona et al. Dynamic undocking and the quasi-bound state as tools for drug discovery, Nature Chemistry (2016). DOI: 10.1038/nchem.2660