Publications by authors named "María Esteban-Lopez"

11 Publications

  • Page 1 of 1

Multiple Drug-Induced Stress Responses Inhibit Formation of Escherichia coli Biofilms.

Appl Environ Microbiol 2020 10 15;86(21). Epub 2020 Oct 15.

Max Planck Institute for Terrestrial Microbiology, Marburg, Germany

In most ecosystems, bacteria exist primarily as structured surface-associated biofilms that can be highly tolerant to antibiotics and thus represent an important health issue. Here, we explored drug repurposing as a strategy to identify new antibiofilm compounds, screening over 1,000 compounds from the Prestwick Chemical Library of approved drugs for specific activities that prevent biofilm formation by Most growth-inhibiting compounds, which include known antibacterial but also antiviral and other drugs, also reduced biofilm formation. However, we also identified several drugs that were biofilm inhibitory at doses where only a weak effect or no effect on planktonic growth could be observed. The activities of the most specific antibiofilm compounds were further characterized using gene expression analysis, proteomics, and microscopy. We observed that most of these drugs acted by repressing genes responsible for the production of curli, a major component of the biofilm matrix. This repression apparently occurred through the induction of several different stress responses, including DNA and cell wall damage, and homeostasis of divalent cations, demonstrating that biofilm formation can be inhibited through a variety of molecular mechanisms. One tested drug, tyloxapol, did not affect curli expression or cell growth but instead inhibited biofilm formation by suppressing bacterial attachment to the surface. The prevention of bacterial biofilm formation is one of the major current challenges in microbiology. Here, by systematically screening a large number of approved drugs for their ability to suppress biofilm formation by , we identified a number of prospective antibiofilm compounds. We further demonstrated different mechanisms of action for individual compounds, from induction of replicative stress to disbalance of cation homeostasis to inhibition of bacterial attachment to the surface. Our work demonstrates the potential of drug repurposing for the prevention of bacterial biofilm formation and suggests that also for other bacteria, the activity spectrum of antibiofilm compounds is likely to be broad.
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http://dx.doi.org/10.1128/AEM.01113-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580552PMC
October 2020

Diverse functions of insulin-like 3 peptide.

J Endocrinol 2020 10;247(1):R1-R12

Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Miami, Florida, USA.

Insulin-like 3 peptide (INSL3) is a member of the insulin-like peptide superfamily and is the only known physiological ligand of relaxin family peptide receptor 2 (RXFP2), a G protein-coupled receptor (GPCR). In mammals, INSL3 is primarily produced both in testicular Leydig cells and in ovarian theca cells, but circulating levels of the hormone are much higher in males than in females. The INSL3/RXFP2 system has an essential role in the development of the gubernaculum for the initial transabdominal descent of the testis and in maintaining proper reproductive health in men. Although its function in female physiology has been less well-characterized, it was reported that INSL3 deletion affects antral follicle development during the follicular phase of the menstrual cycle and uterus function. Since the discovery of its role in the reproductive system, the study of INSL3/RXFP2 has expanded to others organs, such as skeletal muscle, bone, kidney, thyroid, brain, and eye. This review aims to summarize the various advances in understanding the physiological function of this ligand-receptor pair since its first discovery and elucidate its future therapeutic potential in the management of various diseases.
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http://dx.doi.org/10.1530/JOE-20-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453995PMC
October 2020

The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy.

Aging Dis 2020 Jul 23;11(4):895-915. Epub 2020 Jul 23.

1Departments of Immunology and Nano-medicine.

With advances in medical technology, the number of people over the age of 60 is on the rise, and thus, increasing the prevalence of age-related pathologies within the aging population. Neurodegenerative disorders, cancers, metabolic and inflammatory diseases are some of the most prevalent age-related pathologies affecting the growing population. It is imperative that a new treatment to combat these pathologies be developed. Although, still in its infancy, the CRISPR-Cas9 system has become a potent gene-editing tool capable of correcting gene-mediated age-related pathology, and therefore ameliorating or eliminating disease symptoms. Deleting target genes using the CRISPR-Cas9 system or correcting for gene mutations may ameliorate many different neurodegenerative disorders detected in the aging population. Cancer cells targeted by the CRISPR-Cas9 system may result in an increased sensitivity to chemotherapeutics, lower proliferation, and higher cancer cell death. Finally, reducing gene targeting inflammatory molecules production through microRNA knockout holds promise as a therapeutic strategy for both arthritis and inflammation. Here we present a review based on how the expanding world of genome editing can be applied to disorders and diseases affecting the aging population.
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http://dx.doi.org/10.14336/AD.2019.0927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390517PMC
July 2020

Flagellum-Mediated Mechanosensing and RflP Control Motility State of Pathogenic Escherichia coli.

mBio 2020 03 24;11(2). Epub 2020 Mar 24.

Max Planck Institute for Terrestrial Microbiology, Marburg, Germany

Bacterial flagellar motility plays an important role in many processes that occur at surfaces or in hydrogels, including adhesion, biofilm formation, and bacterium-host interactions. Consequently, expression of flagellar genes, as well as genes involved in biofilm formation and virulence, can be regulated by the surface contact. In a few bacterial species, flagella themselves are known to serve as mechanosensors, where an increased load on flagella experienced during surface contact or swimming in viscous media controls gene expression. In this study, we show that gene regulation by motility-dependent mechanosensing is common among pathogenic strains. This regulatory mechanism requires flagellar rotation, and it enables pathogenic to repress flagellar genes at low loads in liquid culture, while activating motility in porous medium (soft agar) or upon surface contact. It also controls several other cellular functions, including metabolism and signaling. The mechanosensing response in pathogenic depends on the negative regulator of motility, RflP (YdiV), which inhibits basal expression of flagellar genes in liquid. While no conditional inhibition of flagellar gene expression in liquid and therefore no upregulation in porous medium was observed in the wild-type commensal or laboratory strains of , mechanosensitive regulation could be recovered by overexpression of RflP in the laboratory strain. We hypothesize that this conditional activation of flagellar genes in pathogenic reflects adaptation to the dual role played by flagella and motility during infection. Flagella and motility are widespread virulence factors among pathogenic bacteria. Motility enhances the initial host colonization, but the flagellum is a major antigen targeted by the host immune system. Here, we demonstrate that pathogenic strains employ a mechanosensory function of the flagellar motor to activate flagellar expression under high loads, while repressing it in liquid culture. We hypothesize that this mechanism allows pathogenic to regulate its motility dependent on the stage of infection, activating flagellar expression upon initial contact with the host epithelium, when motility is beneficial, but reducing it within the host to delay the immune response.
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http://dx.doi.org/10.1128/mBio.02269-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157525PMC
March 2020

Chemotaxis and cyclic-di-GMP signalling control surface attachment of Escherichia coli.

Mol Microbiol 2020 04 16;113(4):728-739. Epub 2019 Dec 16.

Max Planck Institute for Terrestrial Microbiology & LOEWE Center for Synthetic Microbiology (SYNMIKRO), Marburg, Germany.

Attachment to surfaces is an important early step during bacterial infection and during formation of submerged biofilms. Although flagella-mediated motility is known to be important for attachment of Escherichia coli and other bacteria, implications of motility regulation by cellular signalling remain to be understood. Here, we show that motility largely promotes attachment of E. coli, including that mediated by type 1 fimbriae, by allowing cells to reach, get hydrodynamically trapped at and explore the surface. Inactivation or inhibition of the chemotaxis signalling pathway improves attachment by suppressing cell reorientations and thereby increasing surface residence times. The attachment is further enhanced by deletion of genes encoding the cyclic diguanosine monophosphate (c-di-GMP)-dependent flagellar brake YcgR or the diguanylate cyclase DgcE. Such increased attachment in absence of c-di-GMP signalling is in contrast to its commonly accepted function as a positive regulator of the sessile state. It is apparently due to the increased swimming speed of E. coli in absence of YcgR-mediated motor control, which strengthens adhesion mediated by the type 1 fimbriae. Thus, both signalling networks that regulate motility of E. coli also control its engagement with both biotic and abiotic surfaces, which has likely implications for infection and biofilm formation.
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http://dx.doi.org/10.1111/mmi.14438DOI Listing
April 2020

Blood-brain barrier dysfunction underlying Alzheimer's disease is induced by an SSAO/VAP-1-dependent cerebrovascular activation with enhanced Aβ deposition.

Biochim Biophys Acta Mol Basis Dis 2019 09 30;1865(9):2189-2202. Epub 2019 Apr 30.

Biochemistry and Molecular Biology Department, Institute of Neurosciences (INc), Universitat Autònoma de Barcelona (UAB), Bellaterra, Barcelona, Spain. Electronic address:

Dysfunctions of the vascular system directly contribute to the onset and progression of Alzheimer's disease (AD). The blood-brain barrier (BBB) shows signs of malfunction at early stages of the disease. When Abeta peptide (Aβ) is deposited on brain vessels, it induces vascular degeneration by producing reactive oxygen species and promoting inflammation. These molecular processes are also related to an excessive SSAO/VAP-1 (semicarbazide-sensitive amine oxidase) enzymatic activity, observed in plasma and in cerebrovascular tissue of AD patients. We studied the contribution of vascular SSAO/VAP-1 to the BBB dysfunction in AD using in vitro BBB models. Our results show that SSAO/VAP-1 expression is associated to endothelial activation by altering the release of pro-inflammatory and pro-angiogenic angioneurins, most highly IL-6, IL-8 and VEGF. It is also related to a BBB structure alteration, with a decrease in tight-junction proteins such as zona occludens or claudin-5. Moreover, the BBB function reveals increased permeability and leukocyte adhesion in cells expressing SSAO/VAP-1, as well as an enhancement of the vascular Aβ deposition induced by mechanisms both dependent and independent of the enzymatic activity of SSAO/VAP-1. These results reveal an interesting role of vascular SSAO/VAP-1 in BBB dysfunction related to AD progression, opening a new window in the search of alternative therapeutic targets for fighting AD.
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http://dx.doi.org/10.1016/j.bbadis.2019.04.016DOI Listing
September 2019

Targeting the relaxin/insulin-like family peptide receptor 1 and 2 with small molecule compounds.

Mol Cell Endocrinol 2019 05 24;487:40-44. Epub 2018 Dec 24.

Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA. Electronic address:

The peptide hormone relaxin has beneficial roles in several organs through its action on its cognate G protein-coupled receptor, RXFP1. Relaxin administration is limited to intravenous, subcutaneous, intramuscular, or spinal injection. Another drawback of peptide-based therapy is the short half-life, which requires continuous delivery of the drug to achieve efficient concentration in target organs. The discovery of a non-peptide small molecule agonist of RXFP1, ML290, provides an alternative to the natural ligand. This review summarizes the development of ML290 and its potential future therapeutic applications in various diseases, including liver fibrosis and cardiovascular diseases. We also discuss the development of small molecule agonists targeting the insulin-like 3 receptor, RXFP2, and propose the potential use of these small molecules in the context of bone and muscle remodeling.
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http://dx.doi.org/10.1016/j.mce.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451876PMC
May 2019

Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis.

J Neurosci Res 2018 12 11;96(12):1831-1846. Epub 2018 Sep 11.

Departments of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D deficiency, Epstein-Barr viral and Herpesvirus (HHV-6) infections are strongly implicated in the activation of T cells and MS-pathogenesis. Despite precise knowledge of how these factors could be operating alone or in combination to facilitate and aggravate the disease progression, it is clear that prolonged induction of inflammatory molecules and recruitment of other immune cells by the activated T cells results in demyelination and axonal damage. It is imperative to understand the risk factors associated with MS progression and how these factors contribute to disease pathology. Understanding of the underlying mechanisms of what factors triggers activation of T cells to attack myelin antigen are important to strategize therapeutics and therapies against MS. Current review provides a detailed literature to understand the role of both pathogenic and non-pathogenic factors on the impact of MS.
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http://dx.doi.org/10.1002/jnr.24322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167107PMC
December 2018

Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.

J Allergy Clin Immunol 2010 Jun;125(6):1269-1278.e2

Centro de Estudios de Mastocitosis de Castilla La Mancha, Hospital Virgen del Valle, Toledo, Spain.

Background: Systemic mast cell activation disorders (MCADs) are characterized by severe and systemic mast cell (MC) mediators-related symptoms frequently associated with increased serum baseline tryptase (sBt).

Objective: To analyze the clinical, biological, and molecular characteristics of adult patients presenting with systemic MC activation symptoms/anaphylaxis in the absence of skin mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies.

Methods: Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into indolent systemic mastocytosis without skin lesions (ISMs(-); n = 48) and other c-MCADs (n = 3)-both with CD25(++) BM MCs and either positive mast/stem cell growth factor receptor gene (KIT) mutation or clonal human androgen receptor assay (HUMARA) tests-and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics.

Results: Most clonal patients (48/51; 94%) met the World Health Organization criteria for systemic mastocytosis and were classified as ISMs(-), whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs(-) and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex (P = .01), presyncopal and/or syncopal episodes (P = .009) in the absence of urticaria and angioedema (P = .003), and sBt >25 microg/L (P = .006) as independent predictive factors.

Conclusions: Patients with c-MCAD and ISMs(-) display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs(-) diagnosed at early phases of the disease.
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http://dx.doi.org/10.1016/j.jaci.2010.02.019DOI Listing
June 2010

Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis.

J Allergy Clin Immunol 2008 Feb 4;121(2):519-26. Epub 2008 Jan 4.

Allergy Unit, Hospital de Fuenlabrada, Madrid, Spain.

Background: Anaphylaxis after Hymenoptera sting has been described in patients with mastocytosis. Venom immunotherapy (VIT) is a safe and effective way to treat patients with Hymenoptera anaphylaxis, but few studies have addressed its usefulness in patients with systemic mastocytosis.

Objective: To study the effectiveness and safety of VIT in patients with systemic mastocytosis having anaphylaxis after Hymenoptera sting.

Methods: A total of 21 mastocytosis patients-4 women (19%) and 17 men (81%) with a median age of 50 years (range, 29-74 years)-with Hymenoptera sting anaphylaxis who were treated with VIT and followed for a median of 52 months (range, 2-250 months) were studied.

Results: In 18 of 21 patients-16 of them lacking skin involvement-anaphylaxis was the presenting symptom. Six patients (29%) experienced adverse reactions during VIT, 3 during initiation and 3 during maintenance. Twelve patients (57%) were resting while undergoing VIT; 9 (75%) presented local reactions and 3 (25%) systemic reactions, 1 of which required intubation. The Hymenoptera specific IgE decreased from 4.15 kU/L (range, 0.44-100 kU/L) before immunotherapy to 1.2 kU/L (range, 0.34-69.4 kU/L) after 4 years (P < .003).

Conclusion: Venom immunotherapy is effective to treat IgE-mediated Hymenoptera anaphylaxis in patients with mastocytosis. Its use is recommended despite a relatively high risk of adverse reactions during the build-up phase because it provides protection from anaphylaxis in around 3/4 of the patients.
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http://dx.doi.org/10.1016/j.jaci.2007.11.010DOI Listing
February 2008