Biological analysis of viologen‐based mitochondrial probes for reactive oxigenated species

[Resumen]: Las especies reactivas de oxígeno (ROS: reactive oxygen species) son fundamentales en la señalización celular de múltiples procesos como la expresión génica o la apoptosis. Asimismo, se ha descrito una relación entre el aumento de ROS intracelular y diversas patologías como el cáncer o el Alzheimer. Debido a esto, el desarrollo de herramientas que permitan regular los niveles de ROS es necesario. El presente trabajo de fin de grado se centró en el estudio preliminar de la citotoxicidad y la producción de ROS de distintos compuestos derivados del viológeno. Dos de estos compuestos presentan una unidad de viológeno en su estructura: el Paraquat (P), un herbicida conocido por su citotoxicidad y capacidad de inducción de estrés oxidativo y PTPP, un compuesto análogo al Paraquat que presenta un transportador mitocondrial que aporta selectividad en su diana celular. Los otros dos compuestos estudiados presentan un enlace hidrazona entre los anillos de piridinio de la unidad del viológeno: H es un compuesto de estructura similar a P pero con este enlace en su estructura y HTPP, un análogo de H dirigido a la mitocondria. La capacidad de estos compuestos de disminuir la viabilidad celular y de aumentar el estrés oxidativo fue estudiado en varias líneas celulares (RAW264.7, HeLa, A549), siendo las 2 últimas de origen tumoral. Los resultados obtenidos parecen indicar que los compuestos con enlace hidrazona en su estructura (H, HTPP) presentan patrones de citotoxicidad y de producción de ROS distintos a los observados con los derivados del viológeno (P, PTPP). Además, se encontró una citotoxicidad selectiva para las células cancerígenas del compuesto H, si bien, es necesario realizar más estudios para determinar su potencial antitumoral y mecanismo de actuación.[Resumo]: As especies reactivas de osíxeno (ROS: reactive oxygen species) son fundamentais na sinalización celular de múltiples procesos como a expresión xénica ou a apoptose. Do mesmo xeito, describiuse unha relación entre o aumento de ROS intracelular e distintas patoloxías coma o cancro ou o Alzheimer. Debido a isto, é necesario o desenvolvemento de ferramentas que permitan regular os niveis de ROS. Este traballo de fin de grado centrouse no estudo preliminar da citotoxicidade e a produción de ROS de distintos compostos derivados do violóxeno. Dous destes compostos presentan unha unidade de violóxeno na súa estrutura: O Paraquat (P), un herbicida coñecido pola súa citotoxicidade e a capacidade de inducir estrés oxidativo e PTPP, un composto análogo ao Paraquat que presenta un transportador mitocondrial, que aporta selectividade na diana celular. Os outros dous compostos estudados presentan un enlace hidrazona entre os aneis de piridinio do violóxeno : H é un composto cunha estrutura similar a P pero con este enlace na súa estrutura e, HTPP, é un análogo de H dirixido á mitocondria. A capacidade destes compostos de diminuír a viabilidade celular e aumentar o estrés oxidativo estudouse en varias liñas celulares (RAW264.7, HeLa, A549), sendo as últimas dúas de orixe tumoral. Os resultados obtidos parecen indicar que os compostos con enlace hidrazona na súa estrutura (H, HTPP) presentan patróns de citotoxicidade e de produción de ROS distintos aos observados nos derivados do violóxeno (P, PTPP). Ademais, encontrouse unha citotoxicidade selectiva para as células canceríxenas do composto H, aínda que é necesario realizar máis estudos para determinar o seu potencial antitumoral e o seu mecanismo de acción.[Abstract]: Reactive oxygen species (ROS) are essential in cell signalling of multiple processes such as gene expression or apoptosis. Likewise, a relationship between the increase in intracellular ROS and various pathologies such as cancer or Alzheimer's has been described. Due to this, the development of tools to regulate ROS levels is necessary. This TFG is focused on the preliminary study of cytotoxicity and ROS production of different compounds derived from viologen. Two of these compounds contains a viologen moiety: Paraquat (P), an herbicide known for its cytotoxicity and capacity to induce oxidative stress, and PTPP, an analog of Paraquat bearing a mitochondrial carrier that provides selectivity in its cellular target. The other two compounds studied have a hydrazone bond between the pyridinium rings of the viologen: H, that is a compound with a similar structure to P but with this bond in its structure, and HTPP, an analog of H targeted to the mitochondria. The ability of these compounds to decrease cell viability and increase oxidative stress was studied in several cell lines (RAW264.7, HeLa, A549), being the last 2 ones from tumor origin. The results obtained seem to indicate that the compounds with hydrazone bond in their structure (H, HTPP) presented patterns of cytotoxicity and ROS production different from those observed with the viologen derivatives (P, PTPP). In addition, a selective cytotoxicity for cancer cells of compound H was found, although more studies are needed to determine its antitumor potential and mechanism of action.Traballo fin de grao (UDC.CIE). Bioloxía. Curso 2020/202

Viologen-based mitochondrial probes for reactive oxygenated species

[Resumen]: Las especies reactivas de oxígeno (ROS) son fundamentales en la señalización celular de múltiples procesos, como por ejemplo la expresión génica o la apoptosis. Asimismo, se ha reportado una relación entre el aumento de ROS intracelular y diversas patologías, como el cáncer o el Alzheimer. Debido a esto, el desarrollo de herramientas que permitan monitorizar y regular los niveles de ROS mitocondrial se ha convertido en un objetivo importante y necesario en el campo de la biomedicina. El presente trabajo de fin de grado se centra en la síntesis y caracterización de intermedios en la preparación de nuevas sondas mitocondriales. En particular, se presenta la síntesis de una nueva especie que presenta la N,N’- 4,4’-bipiridina como unidad productora de ROS, un grupo alquiltrifenilfosfonio como transportador mitocondrial y el fluoróforo TAMRA como unidad transductora. Además, se presenta la síntesis de un modelo simplificado de esta sonda, carente de la unidad fluorogénica, con el que se realiza un estudio cualitativo de su asociación con receptores macrocíclicos de la familia de los cucurbiturilos.[Resumo]:As especies reactivas de osíxeno (ROS) son fundamentais na sinalización celular de múltiples procesos, como por exemplo da expresión xénica ou da apoptose. Ademais, tense reportado unha relación entre o aumento da ROS intracelular e diversas patoloxías como o cancro ou o Alzheimer. Debido a isto, o desenvolvemento de ferramentas que permitan monitorizar e regular os niveis das ROS mitocondriáis converteuse nun obxectivo importante e necesario no campo da biomedicina. O presente traballo de fin de grao céntrase na síntese e caracterización de intermedios na preparación de novas sondas mitocondriáis. En particular, preséntase a síntese dunha nova especie que presenta a N,N’- 4,4’-bipiridina como unidade produtora de ROS, un grupo alquiltrifenilfosfonio como transportador mitocondrial e o fluoróforo TAMRA como unidade transdutora. Ademais, preséntase a síntese dun modelo simplificado desta sonda, carente da unidade fluoroxénica, có que se realiza un estudo cualitativo da sua asociación con receptores macrocíclicos da familia dos cucurbiturilos.[Abstract]: The reactive oxygen species (ROS) are essential in cell signalling of multiple processes, such as gene expression or apoptosis. In addition, a relationship between the increase in intracellular ROS and various pathologies, such as cancer or Alzheimer’s, has been reported. Due to this, the development of tools to monitor and regulate mitochondrial ROS levels has become an important and necessary objective in the field of biomedicine. This TFG focuses on the synthesis and characterization of intermediates in the preparation of new mitochondrial probes. In particular, the synthesis of a new species is presented. This probe includes N,N’-4,4’-bipyridine as a ROS-producing unit, an alkyl triphenyl phosphonium group as a mitochondrial targeting, and the TAMRA fluorophore as a transducer unit. Furthermore, the synthesis of a simplified model of this probe, lacking the fluorogenic unit, is presented, with which a qualitative study of its association with macrocyclic receptors of the cucurbituril family is carried out.Traballo fin de grao (UDC.CIE). Química. Curso 2020/202

Sound absorption and diffusion by 2D arrays of Helmholtz resonators

[EN] We report a theoretical and experimental study of an array of Helmholtz resonators optimized to achieve both efficient sound absorption and diffusion. The analysis starts with a simplified 1D model where the plane wave approximation is used to design an array of resonators showing perfect absorption for a targeted range of frequencies. The absorption is optimized by tuning the geometry of the resonators, i.e., by tuning the viscothermal losses of each element. Experiments with the 1D array were performed in an impedance tube. The designed system is extended to 2D by periodically replicating the 1D array. The 2D system has been numerically modeled and experimentally tested in an anechoic chamber. It preserves the absorption properties of the 1D system and introduces efficient diffusion at higher frequencies due to the joint effect of resonances and multiple scattering inside the discrete 2D structure. The combined effect of sound absorption at low frequencies and sound diffusion at higher frequencies, may play a relevant role in the design of noise reduction systems for different applications.This research was funded by the European Space Agency under the Networking/Partnering Initiative (NPI) contract number 441-2015. In memoriam to Julián Santiago-Prowald, Senior Advisor for the Structures, Mechanisms and Materials Division of ESA, a great man that always gave us his tireless support. AC acknowledges financial support from Generalitat Valenciana through the grant APOSTD/2018/229. VRG acknowledges the financial support from RFI Le Mans Acoustique (Région Pays de la Loire) in the framework of the project HYPERMETA funded under the program Étoiles Montantes of the Région Pays de la Loire. Authors acknowledge the support of the European Space Agency under contract 441-2015 Co- Sponsored PhD ¿Acoustic Reduction Methods for the Launch Pad¿ and project TRP ESA AO/1-9479/18/NL/LvH ¿Launch Sound Level Reduction¿. This article is based upon work from COST Action DENORMS CA15125, supported by COST (European Cooperation in Science and Technology).Herrero-Durá, I.; Cebrecos, A.; Picó Vila, R.; Romero-García, V.; García-Raffi, LM.; Sánchez Morcillo, VJ. (2020). Sound absorption and diffusion by 2D arrays of Helmholtz resonators. Applied Sciences. 10(5):1-15. https://doi.org/10.3390/app10051690S115105Sigalas, M. M., & Economou, E. N. (1992). Elastic and acoustic wave band structure. Journal of Sound and Vibration, 158(2), 377-382. doi:10.1016/0022-460x(92)90059-7Matlack, K. H., Bauhofer, A., Krödel, S., Palermo, A., & Daraio, C. (2016). Composite 3D-printed metastructures for low-frequency and broadband vibration absorption. 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Science, 289(5485), 1734-1736. doi:10.1126/science.289.5485.1734Fang, N., Xi, D., Xu, J., Ambati, M., Srituravanich, W., Sun, C., & Zhang, X. (2006). Ultrasonic metamaterials with negative modulus. Nature Materials, 5(6), 452-456. doi:10.1038/nmat1644Sugimoto, N., & Horioka, T. (1995). Dispersion characteristics of sound waves in a tunnel with an array of Helmholtz resonators. The Journal of the Acoustical Society of America, 97(3), 1446-1459. doi:10.1121/1.412085Theocharis, G., Richoux, O., García, V. R., Merkel, A., & Tournat, V. (2014). Limits of slow sound propagation and transparency in lossy, locally resonant periodic structures. New Journal of Physics, 16(9), 093017. doi:10.1088/1367-2630/16/9/093017Jiménez, N., Cox, T. J., Romero-García, V., & Groby, J.-P. (2017). Metadiffusers: Deep-subwavelength sound diffusers. Scientific Reports, 7(1). doi:10.1038/s41598-017-05710-5Ballestero, E., Jiménez, N., Groby, J.-P., Dance, S., Aygun, H., & Romero-García, V. (2019). Experimental validation of deep-subwavelength diffusion by acoustic metadiffusers. Applied Physics Letters, 115(8), 081901. doi:10.1063/1.5114877Romero-García, V., Sánchez-Pérez, J. V., & Garcia-Raffi, L. M. (2011). Tunable wideband bandstop acoustic filter based on two-dimensional multiphysical phenomena periodic systems. Journal of Applied Physics, 110(1), 014904. doi:10.1063/1.3599886Lagarrigue, C., Groby, J. P., & Tournat, V. (2013). Sustainable sonic crystal made of resonating bamboo rods. The Journal of the Acoustical Society of America, 133(1), 247-254. doi:10.1121/1.4769783Krynkin, A., Umnova, O., Yung Boon Chong, A., Taherzadeh, S., & Attenborough, K. (2010). Predictions and measurements of sound transmission through a periodic array of elastic shells in air. The Journal of the Acoustical Society of America, 128(6), 3496-3506. doi:10.1121/1.3506342Koussa, F., Defrance, J., Jean, P., & Blanc-Benon, P. (2013). Acoustical Efficiency of a Sonic Crystal Assisted Noise Barrier. 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Angular bandgaps in sonic crystals: evanescent waves and spatial complex dispersion relation

Phononic crystals are artificial materials made of a periodic distribution of solid scatterers embedded into a solid host medium with different physical properties. An interesting case of phononic crystals, known as sonic crystals (SCs), appears when the solid scatterers are periodically embedded in a fluid medium. In SCs only longitudinal modes are allowed to propagate and both the theoretical and the experimental studies of the properties of the system are simplified without loss of generality. The most celebrated property of these systems is perhaps the existence of spectral band gaps. However, the periodicity of the system can also affect to the spatial dispersion, making possible the control of the diffraction inside these structures. In this work we study the main features of the spatial dispersion in SCs from a novel point of view taking into account the evanescent properties of the system, i.e., studying the complex spatial dispersion relations. The evanescent behavior of the propagation of waves in the angular band gaps are theoretically and experimentally observed in this work. Both the numerical predictions and the experimental results show the presence of angular band gaps in good agreement with the complex spatial dispersion relation. The results shown in this work are independent of the spatial scale of the structure, and in principle the fundamental role of the evanescent waves could be also expected in micro- or nanoscale phononic crystals.This work was supported by MCI Secretaria de Estado de Investigacion (Spanish government) and the FEDER funds, under Grant Nos. MAT2009-09438, FIS2011-29734-C02-02, and from Generalitat Valencia through Project No. GV/2011/055. V.R.G. is grateful for the support of "Programa de Contratos Post-Doctorales con Movilidad UPV (CEI-01-11)." We acknowledge the Centro de Tecnologias Fisicas: Acustica, Materiales y Astrofisica and the Sonic Crystal Technologies Research Group of the Universitat Politecnica de Valencia for the use of the anechoic chamber and the 3DReAMS respectively.Romero García, V.; Picó Vila, R.; Cebrecos Ruiz, A.; Staliünas, K.; Sánchez Morcillo, VJ. (2013). Angular bandgaps in sonic crystals: evanescent waves and spatial complex dispersion relation. Journal of Vibration and Acoustics. 135(4):410121-410126. https://doi.org/10.1115/1.4023832S4101214101261354Yablonovitch, E. (1987). Inhibited Spontaneous Emission in Solid-State Physics and Electronics. Physical Review Letters, 58(20), 2059-2062. doi:10.1103/physrevlett.58.2059John, S. (1987). Strong localization of photons in certain disordered dielectric superlattices. Physical Review Letters, 58(23), 2486-2489. doi:10.1103/physrevlett.58.2486Ruffa, A. A. (1992). Acoustic wave propagation through periodic bubbly liquids. 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Spectral gaps for electromagnetic and scalar waves: Possible explanation for certain differences. Physical Review B, 50(5), 3393-3396. doi:10.1103/physrevb.50.3393Martínez-Sala, R., Sancho, J., Sánchez, J. V., Gómez, V., Llinares, J., & Meseguer, F. (1995). Sound attenuation by sculpture. Nature, 378(6554), 241-241. doi:10.1038/378241a0Sánchez-Pérez, J. V., Caballero, D., Mártinez-Sala, R., Rubio, C., Sánchez-Dehesa, J., Meseguer, F., … Gálvez, F. (1998). Sound Attenuation by a Two-Dimensional Array of Rigid Cylinders. Physical Review Letters, 80(24), 5325-5328. doi:10.1103/physrevlett.80.5325Kushwaha, M. S. (1997). Stop-bands for periodic metallic rods: Sculptures that can filter the noise. Applied Physics Letters, 70(24), 3218-3220. doi:10.1063/1.119130Robertson, W. M., & Rudy, J. F. (1998). Measurement of acoustic stop bands in two-dimensional periodic scattering arrays. 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Vermellogens and the Development of CB[8]-Based Supramolecular Switches Using pH-Responsive and Non-Toxic Viologen Analogues

[Abstract] We present herein the “vermellogens”, a new class of pH-responsive viologen analogues, which replace the direct linking between para-substituted pyridinium moieties within those by a hydrazone functional group. A series of such compounds have been efficiently synthesized in aqueous media by hydrazone exchange reactions, displaying a marked pH-responsivity. Furthermore, the parent N,N′-dimethylated “vermellogen”: the “red thread”, an analogue of the herbicide paraquat and used herein as a representative model of the series, showed anion-recognition abilities, non-reversible electrochemical behavior, and non-toxicity of the modified bis-pyridinium core. The host–guest chemistry for the “red thread” with the CB[7,8] macrocyclic receptors has been extensively studied experimentally and by dispersion corrected density functional theory methods, showing a parallel behavior to that previously described for the herbicide but, crucially, swapping the well-known redox reactive capabilities of the viologen-based inclusion complexes by acid–base supramolecular responsiveness.This work is supported by Grants PID2019-105272GB-I00 and CTQ2017-89166-R funded by MCIN/AEI/10.13039/501100011033 and the Consellería de Educación, Universidade e Formación Profesional, Xunta de Galicia (ED431C 2018/39 and 508/2020). A.B.-G., I.N., and R.S. thank, respectively, Xunta de Galicia (ED481B-2021-099), the MECD (FPU program), and Erasmus+ program for financial support. We are very grateful for helpful discussions with Professors Hao Li (Zhejiang University), Patrice Woisel (Université de Lille) and José Luis Barriada (Universidade da Coruña). We also acknowledge the use of RIAIDT-USC analytical facilities, and CESGA (Xunta de Galicia) for computational time.Xunta de Galicia; ED431C 2018/39Xunta de Galicia; ED431C 508/2020Xunta de Galicia; ED481B-2021-09

Lichenoid areas may arise in early stages of proliferative verrucous leukoplakia: a long-term study of 34 patients

Background: Proliferative verrucous leukoplakia is considered an uncommon oral potentially malignant disorder with a high malignant transformation rate. The objective of this paper was to define its cancer incidence and related risk factors.: Method: A retrospective audit of 34 patients diagnosed with proliferative verrucous leukoplakia from a university-based unit, during the period from 1995 to 2019 was performed. The mean number of visits was 23 ± 18.6. The follow-up was divided into four-time intervals to evaluate the clinical presentation, number of lesions, dysplasia grade, and malignant transformation rate. Results: The majority of patients were females 29 (85.3%), with verrucous component (77.8%), with a gingival presentation (31.8%), and with a preceding lichenoid area (44.1%). Eleven patients (32.4%) were affected by oral cancer during the follow-up, developing a total of 15 carcinomas. The mean age of malignant transformation was 67.2 ± 12.9 years, particularly 8 ± 8.5 from the onset of the lesions. Warty forms presented a higher mean estimate for malignant transformation (15.2 years, 95% confidence interval 4.4–26 years) than nodular forms (1.9 years, 95% confidence interval 1.9–1.9) (p = 0.019). Patients with an initial proliferative verrucous leukoplakia diagnosis suffered a higher risk of malignancy, particularly 15.55 times (95% confidence interval 1.69–143.17; p = 0.015) than those who did present a preceding area with lichenoid morphology. Conclusion: Proliferative verrucous leukoplakia presented a high malignant transformation rate and sometimes displayed preceding oral lichenoid areas in early stages. Further studies are needed to understand the impact of these lichenoid areas in proliferative verrucous leukoplakia progressionS

Heart of Darkness: Heart Rate Variability on Patients with Risk of Suicide

Heart Rate Variability (HRV) is an emerging research field in the study of diverse pathologies, as long as it allows considering another measurement for detecting possible aggravations. The aim of this work is to study the applicability of the analysis of HRV in order to establish if a person is at risk of suffering from suicidal ideation. This work includes the development and testing of a heart rate acquisition and automatic analysis system, with friendly software for clinicians, customized to the necessities of an emergency unit. Furthermore, it includes the analysis of the obtained data with the purpose of assessing possible correlations between HRV parameters and personality impulsive traits. 20 patients and 10 normal cases were selected to develop this pilot study. Results show significant statistical difference (p<0.05) among patients and normal cases for pNN50, IRRR, MADRR, total HRV power, Approximate Entropy and Fractal Dimension

Management options for low-dose methotrexate-induced oral ulcers : a systematic review

Oral ulcers caused by methotrexate (MTX) at low doses are a known side effect of this drug. Although increasingly more patients are medicated with MTX, these painful ulcers, without traumatic origin and resistant to any type of treatment, are not usually identified by health professionals as a side effect of the medication. In the absence of a consensus protocol for the effective treatment of oral lesions produced by MTX, the objective of this article was to review and analyse the information from articles related to oral ulcers produced by low-dose MTX and to record the clinical management performed and the MTX dose given to the patient. Data sources - Medline, Web of Science, and Cochrane Library. Participants - Patients treated with low-dose MTX (less than 25 mg/week). Interventions - Management of oral lesions caused by MTX. Study eligibility criterion, study appraisal and synthesis method: An initial search was carried out in the aforementioned databases with the terms ?methotrexate AND oral OR ulcer?. The search was carried out using both medical subject heading (MeSH) terms and a free search between January 2003 and January 2018. Of the results obtained, two independent researchers analysed abstracts that met the search criteria, that is, those that mentioned oral ulcers produced by MTX at low doses. Next, both researchers read the complete article and determined whether it met the following inclusion criteria: written in English, specified the dose of MTX prescribed for the patient and specified the protocol of action for the ulcers. A third investigator acted as a mediator in cases of dispute. Agreement was calculated using Cohen?s kappa coefficient, with a k value of 0.82. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide for systematic reviews was used. The initial search resulted in a total of 66 articles, of which 30 were selected to assess their inclusion in this study. Finally, 16 met the inclusion criteria. Using the Pierson and Newcastle-Ottawa scales and Bradford Hill criteria modified for studies of case series and ?in relation to a case?, 2 were rated as high quality, 2 were rated as low quality and 12 were rated as medium quality. The limitations of this study are based on the fact that all of the articles available to carry out the systematic review were ?in relation to a case or series of cases?, with the heterogeneity of data that this implies. Evidence on the management of oral ulcers in the oral cavity produced by MTX at low doses is scarce due to the heterogeneity of data and the measures adopted in the selected studies. Therefore, it seems that this management is relegated to the perception of the clinician rather than to a specific protocol of action. Studies with a longer follow-up duration and larger sample size are needed to guide different health professionals on the management of these lesions

Acoustic Bessel-like beam formation by an axisymmetric grating

We report Bessel-like beam formation of acoustic waves by means of an axisymmetric grating of rigid tori. The results show that the generated beam pattern is similar to that of Bessel beams, characterized by elongated non-diffracting focal spots. A multiple foci structure is observed, due to the finite size of the lens. The dependence of the focal distance on the frequency is also discussed, on the basis of an extended grating theory. Experimental validation of acoustic Bessel-like beam formation is also reported for sound waves. The results can be generalized to wave beams of different nature, as optical or matter waves.The work was supported by the Spanish Ministry of Science and Innovation and the European Union FEDER through projects FIS2011-29731-C02-01 and -02, also MAT2009-09438, MTM2012-36740-C02-02 and UPV-PAID 2012/253. VR-G acknowledges financial support from the "Pays de la Loire" through the post-doctoral programme.Jimenez, N.; Romero García, V.; Picó Vila, R.; Cebrecos Ruiz, A.; Sánchez Morcillo, VJ.; García-Raffi, LM.; Sánchez Pérez, JV.... (2014). Acoustic Bessel-like beam formation by an axisymmetric grating. EPL. 106(2):240051-240055. doi:10.1209/0295-5075/106/24005240051240055106

Analysis of the unpredictable migration of impacted mandibular third molars : a pilot study

Eruption of an impacted mandibular third molar (3MM) is often unpredictable. The objective of this study was to establish the radiographic parameters of migration in patients whose 3MMs evolved unpredictably. This was a retrospective observational stud