16 results on '"Herrero-Foncubierta P"'
Search Results
2. Corrigendum: The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene
- Author
-
Blair Armistead, Christopher Whidbey, Lakshminarayan M. Iyer, Pilar Herrero-Foncubierta, Phoenicia Quach, Ali Haidour, L. Aravind, Juan Manuel Cuerva, Heather B. Jaspan, and Lakshmi Rajagopal
- Subjects
Group B Streptococcus ,bacterial toxin ,microbial evolution ,virulence factor ,Gram-positive bacteria ,Microbiology ,QR1-502 - Published
- 2020
- Full Text
- View/download PDF
3. The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene
- Author
-
Blair Armistead, Christopher Whidbey, Lakshminarayan M. Iyer, Pilar Herrero-Foncubierta, Phoenicia Quach, Ali Haidour, L. Aravind, Juan Manuel Cuerva, Heather B. Jaspan, and Lakshmi Rajagopal
- Subjects
Group B Streptococcus ,bacterial toxin ,microbial evolution ,virulence factor ,Gram-positive bacteria ,Microbiology ,QR1-502 - Abstract
Group B Streptococcus (GBS) is a β-hemolytic, Gram-positive bacterium that commonly colonizes the female lower genital tract and is associated with fetal injury, preterm birth, spontaneous abortion, and neonatal infections. A major factor promoting GBS virulence is the β-hemolysin/cytolysin, which is cytotoxic to several host cells. We recently showed that the ornithine rhamnolipid pigment, Granadaene, produced by the gene products of the cyl operon, is hemolytic. Here, we demonstrate that heterologous expression of the GBS cyl operon conferred hemolysis, pigmentation, and cytoxicity to Lactococcus lactis, a model non-hemolytic Gram-positive bacterium. Similarly, pigment purified from L. lactis is hemolytic, cytolytic, and identical in structure to Granadaene extracted from GBS, indicating the cyl operon is sufficient for Granadaene production in a heterologous host. Using a systematic survey of phyletic patterns and contextual associations of the cyl genes, we identify homologs of the cyl operon in physiologically diverse Gram-positive bacteria and propose undescribed functions of cyl gene products. Together, these findings bring greater understanding to the biosynthesis and evolutionary foundations of a key GBS virulence factor and suggest that such potentially toxic lipids may be encoded by other bacteria.
- Published
- 2020
- Full Text
- View/download PDF
4. Coupled Excited-State Dynamics in N-Substituted 2-Methoxy-9-Acridones
- Author
-
M. Carmen Gonzalez-Garcia, Pilar Herrero-Foncubierta, Silvia Castro, Sandra Resa, Jose M. Alvarez-Pez, Delia Miguel, Juan M. Cuerva, Emilio Garcia-Fernandez, and Angel Orte
- Subjects
excited-state dynamics ,fluorophores ,excited-state proton transfer ,excimers ,kinetics ,computational photophysics ,Chemistry ,QD1-999 - Abstract
Fluorophores of the acridone family have been widely employed in many applications, such as DNA sequencing, the detection of biomolecules, and the monitoring of enzymatic systems, as well as being the bases of intracellular sensors and even antitumoral agents. They have been widely used in fluorescence imaging due to their excellent photophysical properties, in terms of quantum yield and stability. However, frequently, the fluorescence emission data from acridones are not easily interpretable due to complex excited-state dynamics. The formation of π-stacking aggregates and excimers and excited-state proton transfer (ESPT) reactions usually result in emission features that are dependent on the experimental conditions. Therefore, an in-depth understanding of the dynamics involved in the excited-state transients of these dyes is mandatory for their appropriate application. Herein, we synthesized and fully characterized different 2-methoxy-9-acridone dyes. Their transient fluorescence emission spectra exhibited a complex dynamic behavior that can be linked to several excited-state reactions. We performed a thorough study of the excited-state dynamics of these dyes by means of time-resolved fluorimetry supported by computational calculations. All this allowed us to establish a multistate kinetic scheme, involving an ESPT reaction coupled to an excimer formation process. We have unraveled the rich dynamics behind this complex behavior, which provides a better understanding of the excited states of these dyes.
- Published
- 2019
- Full Text
- View/download PDF
5. Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery
- Author
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Consuelo Ripoll, Pilar Herrero-Foncubierta, Virginia Puente-Muñoz, M. Carmen Gonzalez-Garcia, Delia Miguel, Sandra Resa, Jose M. Paredes, Maria J. Ruedas-Rama, Emilio Garcia-Fernandez, Mar Roldan, Susana Rocha, Herlinde De Keersmaecker, Johan Hofkens, Miguel Martin, Juan M. Cuerva, and Angel Orte
- Subjects
antitumor agents ,fluorescence lifetime imaging ,medicinal chemistry ,metabolic drug ,mitochondrial carrier ,Pharmacy and materia medica ,RS1-441 - Abstract
Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.
- Published
- 2021
- Full Text
- View/download PDF
6. Building Accurate Intracellular Polarity Maps through Multiparametric Microscopy
- Author
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M. Carmen Gonzalez-Garcia, Pilar Herrero-Foncubierta, Emilio Garcia-Fernandez, and Angel Orte
- Subjects
biosensing ,cellular microenvironment ,fluorescence imaging ,fluorescence lifetime imaging microscopy (FLIM) ,lifetime ,acridones ,Biology (General) ,QH301-705.5 - Abstract
The precise knowledge of intracellular polarity, a physiological parameter that involves complex and intertwined intracellular mechanisms, may be relevant in the study of important diseases like cancer or Alzheimer’s. In this technical note, we illustrate our recently developed, accurate method for obtaining intracellular polarity maps employing potent fluorescence microscopy techniques. Our method is based on the selection of appropriate luminescent probes, in which several emission properties vary with microenvironment polarity, specifically spectral shifts and luminescence lifetime. A multilinear calibration is performed, correlating polarity vs. spectral shift vs. luminescence lifetime, to generate a powerful and error-free 3D space for reliable interpolation of microscopy data. Multidimensional luminescence microscopy is then used to obtain simultaneously spectral shift and luminescence lifetime images, which are then interpolated in the 3D calibration space, resulting in accurate, quantitative polarity maps.
- Published
- 2020
- Full Text
- View/download PDF
7. A Red-Emitting, Multidimensional Sensor for the Simultaneous Cellular Imaging of Biothiols and Phosphate Ions
- Author
-
Pilar Herrero-Foncubierta, Jose M. Paredes, Maria D. Giron, Rafael Salto, Juan M. Cuerva, Delia Miguel, and Angel Orte
- Subjects
dual probes ,fluorescent sensors ,fluorescence lifetime imaging ,FLIM ,cellular stress ,photoreceptor cells ,Chemical technology ,TP1-1185 - Abstract
The development of new fluorescent probes for cellular imaging is currently a very active field because of the large potential in understanding cell physiology, especially targeting anomalous behaviours due to disease. In particular, red-emitting dyes are keenly sought, as the light in this spectral region presents lower interferences and a deeper depth of penetration in tissues. In this work, we have synthesized a red-emitting, dual probe for the multiplexed intracellular detection of biothiols and phosphate ions. We have prepared a fluorogenic construct involving a silicon-substituted fluorescein for red emission. The fluorogenic reaction is selectively started by the presence of biothiols. In addition, the released fluorescent moiety undergoes an excited-state proton transfer reaction promoted by the presence of phosphate ions, which modulates its fluorescence lifetime, τ, with the total phosphate concentration. Therefore, in a multidimensional approach, the intracellular levels of biothiols and phosphate can be detected simultaneously using a single fluorophore and with spectral clearing of cell autofluorescence interferences. We have applied this concept to different cell lines, including photoreceptor cells, whose levels of biothiols are importantly altered by light irradiation and other oxidants.
- Published
- 2018
- Full Text
- View/download PDF
8. Dynamic Excimer (DYNEX) Imaging of Lipid Droplets.
- Author
-
Gonzalez-Garcia, M. Carmen, Salto-Giron, Carmen, Herrero-Foncubierta, Pilar, Peña-Ruiz, Tomás, Giron-Gonzalez, Maria Dolores, Salto-Gonzalez, Rafael, Perez-Lara, Angel, Navarro, Amparo, Garcia-Fernandez, Emilio, and Orte, Angel
- Published
- 2021
- Full Text
- View/download PDF
9. Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery.
- Author
-
Ripoll C, Herrero-Foncubierta P, Puente-Muñoz V, Gonzalez-Garcia MC, Miguel D, Resa S, Paredes JM, Ruedas-Rama MJ, Garcia-Fernandez E, Roldan M, Rocha S, De Keersmaecker H, Hofkens J, Martin M, Cuerva JM, and Orte A
- Abstract
Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.
- Published
- 2021
- Full Text
- View/download PDF
10. Building Accurate Intracellular Polarity Maps through Multiparametric Microscopy.
- Author
-
Gonzalez-Garcia MC, Herrero-Foncubierta P, Garcia-Fernandez E, and Orte A
- Abstract
The precise knowledge of intracellular polarity, a physiological parameter that involves complex and intertwined intracellular mechanisms, may be relevant in the study of important diseases like cancer or Alzheimer's. In this technical note, we illustrate our recently developed, accurate method for obtaining intracellular polarity maps employing potent fluorescence microscopy techniques. Our method is based on the selection of appropriate luminescent probes, in which several emission properties vary with microenvironment polarity, specifically spectral shifts and luminescence lifetime. A multilinear calibration is performed, correlating polarity vs. spectral shift vs. luminescence lifetime, to generate a powerful and error-free 3D space for reliable interpolation of microscopy data. Multidimensional luminescence microscopy is then used to obtain simultaneously spectral shift and luminescence lifetime images, which are then interpolated in the 3D calibration space, resulting in accurate, quantitative polarity maps.
- Published
- 2020
- Full Text
- View/download PDF
11. Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection.
- Author
-
Armistead B, Herrero-Foncubierta P, Coleman M, Quach P, Whidbey C, Justicia J, Tapia R, Casares R, Millán A, Haidour A, Granger JR, Vornhagen J, Santana-Ufret V, Merillat S, Adams Waldorf K, Cuerva JM, and Rajagopal L
- Subjects
- Adult, Animals, B-Lymphocytes, Bacterial Toxins chemistry, Bacterial Vaccines, CD4-Positive T-Lymphocytes, Disease Models, Animal, Female, Humans, Infant, Newborn, Lipids immunology, Lipids toxicity, Male, Mice, Mice, Inbred C57BL, Polyenes immunology, Pregnancy, Streptococcal Infections immunology, Streptococcal Infections microbiology, Streptococcal Infections prevention & control, Streptococcus agalactiae, Vaccination, Hemolysis, Lipids chemistry, Polyenes chemistry, Premature Birth microbiology, Streptococcal Infections metabolism
- Abstract
Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene's toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.
- Published
- 2020
- Full Text
- View/download PDF
12. Corrigendum: The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene.
- Author
-
Armistead B, Whidbey C, Iyer LM, Herrero-Foncubierta P, Quach P, Haidour A, Aravind L, Cuerva JM, Jaspan HB, and Rajagopal L
- Abstract
[This corrects the article DOI: 10.3389/fmicb.2019.03123.]., (Copyright © 2020 Armistead, Whidbey, Iyer, Herrero-Foncubierta, Quach, Haidour, Aravind, Cuerva, Jaspan and Rajagopal.)
- Published
- 2020
- Full Text
- View/download PDF
13. The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene.
- Author
-
Armistead B, Whidbey C, Iyer LM, Herrero-Foncubierta P, Quach P, Haidour A, Aravind L, Cuerva JM, Jaspan HB, and Rajagopal L
- Abstract
Group B Streptococcus (GBS) is a β-hemolytic, Gram-positive bacterium that commonly colonizes the female lower genital tract and is associated with fetal injury, preterm birth, spontaneous abortion, and neonatal infections. A major factor promoting GBS virulence is the β-hemolysin/cytolysin, which is cytotoxic to several host cells. We recently showed that the ornithine rhamnolipid pigment, Granadaene, produced by the gene products of the cyl operon, is hemolytic. Here, we demonstrate that heterologous expression of the GBS cyl operon conferred hemolysis, pigmentation, and cytoxicity to Lactococcus lactis , a model non-hemolytic Gram-positive bacterium. Similarly, pigment purified from L. lactis is hemolytic, cytolytic, and identical in structure to Granadaene extracted from GBS, indicating the cyl operon is sufficient for Granadaene production in a heterologous host. Using a systematic survey of phyletic patterns and contextual associations of the cyl genes, we identify homologs of the cyl operon in physiologically diverse Gram-positive bacteria and propose undescribed functions of cyl gene products. Together, these findings bring greater understanding to the biosynthesis and evolutionary foundations of a key GBS virulence factor and suggest that such potentially toxic lipids may be encoded by other bacteria., (Copyright © 2020 Armistead, Whidbey, Iyer, Herrero-Foncubierta, Quach, Haidour, Aravind, Cuerva, Jaspan and Rajagopal.)
- Published
- 2020
- Full Text
- View/download PDF
14. Coupled Excited-State Dynamics in N-Substituted 2-Methoxy-9-Acridones.
- Author
-
Gonzalez-Garcia MC, Herrero-Foncubierta P, Castro S, Resa S, Alvarez-Pez JM, Miguel D, Cuerva JM, Garcia-Fernandez E, and Orte A
- Abstract
Fluorophores of the acridone family have been widely employed in many applications, such as DNA sequencing, the detection of biomolecules, and the monitoring of enzymatic systems, as well as being the bases of intracellular sensors and even antitumoral agents. They have been widely used in fluorescence imaging due to their excellent photophysical properties, in terms of quantum yield and stability. However, frequently, the fluorescence emission data from acridones are not easily interpretable due to complex excited-state dynamics. The formation of π-stacking aggregates and excimers and excited-state proton transfer (ESPT) reactions usually result in emission features that are dependent on the experimental conditions. Therefore, an in-depth understanding of the dynamics involved in the excited-state transients of these dyes is mandatory for their appropriate application. Herein, we synthesized and fully characterized different 2-methoxy-9-acridone dyes. Their transient fluorescence emission spectra exhibited a complex dynamic behavior that can be linked to several excited-state reactions. We performed a thorough study of the excited-state dynamics of these dyes by means of time-resolved fluorimetry supported by computational calculations. All this allowed us to establish a multistate kinetic scheme, involving an ESPT reaction coupled to an excimer formation process. We have unraveled the rich dynamics behind this complex behavior, which provides a better understanding of the excited states of these dyes.
- Published
- 2019
- Full Text
- View/download PDF
15. A Red-Emitting, Multidimensional Sensor for the Simultaneous Cellular Imaging of Biothiols and Phosphate Ions.
- Author
-
Herrero-Foncubierta P, Paredes JM, Giron MD, Salto R, Cuerva JM, Miguel D, and Orte A
- Subjects
- Fluorescein, Fluorescent Dyes, Protons, Spectrometry, Fluorescence, Phosphates analysis
- Abstract
The development of new fluorescent probes for cellular imaging is currently a very active field because of the large potential in understanding cell physiology, especially targeting anomalous behaviours due to disease. In particular, red-emitting dyes are keenly sought, as the light in this spectral region presents lower interferences and a deeper depth of penetration in tissues. In this work, we have synthesized a red-emitting, dual probe for the multiplexed intracellular detection of biothiols and phosphate ions. We have prepared a fluorogenic construct involving a silicon-substituted fluorescein for red emission. The fluorogenic reaction is selectively started by the presence of biothiols. In addition, the released fluorescent moiety undergoes an excited-state proton transfer reaction promoted by the presence of phosphate ions, which modulates its fluorescence lifetime, τ , with the total phosphate concentration. Therefore, in a multidimensional approach, the intracellular levels of biothiols and phosphate can be detected simultaneously using a single fluorophore and with spectral clearing of cell autofluorescence interferences. We have applied this concept to different cell lines, including photoreceptor cells, whose levels of biothiols are importantly altered by light irradiation and other oxidants., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
- Full Text
- View/download PDF
16. ELAC (3,12-di-O-acetyl-8-O-tigloilingol), a plant-derived lathyrane diterpene, induces subventricular zone neural progenitor cell proliferation through PKCβ activation.
- Author
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Murillo-Carretero M, Geribaldi-Doldán N, Flores-Giubi E, García-Bernal F, Navarro-Quiroz EA, Carrasco M, Macías-Sánchez AJ, Herrero-Foncubierta P, Delgado-Ariza A, Verástegui C, Domínguez-Riscart J, Daoubi M, Hernández-Galán R, and Castro C
- Subjects
- Animals, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Diterpenes chemistry, Diterpenes isolation & purification, Dose-Response Relationship, Drug, Mice, Molecular Conformation, Structure-Activity Relationship, Diterpenes pharmacology, Neural Stem Cells drug effects, Protein Kinase C beta metabolism
- Abstract
Background and Purpose: Pharmacological strategies aimed to facilitate neuronal renewal in the adult brain, by promoting endogenous neurogenesis, constitute promising therapeutic options for pathological or traumatic brain lesions. We have previously shown that non-tumour-promoting PKC-activating compounds (12-deoxyphorbols) promote adult neural progenitor cell (NPC) proliferation in vitro and in vivo, enhancing the endogenous neurogenic response of the brain to a traumatic injury. Here, we show for the first time that a diterpene with a lathyrane skeleton can also activate PKC and promote NPC proliferation., Experimental Approach: We isolated four lathyranes from the latex of Euphorbia plants and tested their effect on postnatal NPC proliferation, using neurosphere cultures. The bioactive lathyrane ELAC (3,12-di-O-acetyl-8-O-tigloilingol) was also injected into the ventricles of adult mice to analyse its effect on adult NPC proliferation in vivo., Key Results: The lathyrane ELAC activated PKC and significantly increased postnatal NPC proliferation in vitro, particularly in synergy with FGF2. In addition ELAC stimulated proliferation of NPC, specifically affecting undifferentiated transit amplifying cells. The proliferative effect of ELAC was reversed by either the classical/novel PKC inhibitor Gö6850 or the classical PKC inhibitor Gö6976, suggesting that NPC proliferation is promoted in response to activation of classical PKCs, particularly PKCß. ELAC slightly increased the proportion of NPC expressing Sox2. The effects of ELAC disappeared upon acetylation of its C7-hydroxyl group., Conclusions and Implications: We propose lathyranes like ELAC as new drug candidates to modulate adult neurogenesis through PKC activation. Functional and structural comparisons between ELAC and phorboids are included., (© 2017 The British Pharmacological Society.)
- Published
- 2017
- Full Text
- View/download PDF
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