Revista Fisiología Diciembre 2020 plantilla

•Editor•Juan Antonio Rosado Dionisio. Departamento de Fisiología. Universidad de Extremadura. 10.003 Cáceres

Teléfono: 927 25 71 39 • Fax: 927 25 71 10 • E-mail: [email protected]•Comité editorial•

Diego Álvarez (Universidad de La Laguna, [email protected]),Teresa Giráldez (Universidad de La Laguna, [email protected]), Celestino González (Universidad deOviedo, [email protected]), Ana Ilundain (Universidad de Sevilla, [email protected]), Juan Martínez-Pinna (Universidad de Alicante, [email protected]) y Carlos

Villalobos (CSIC, [email protected]).

Diseño,Maquetación e Impresión: Imprema Gráficas Jardín S.L. - 927 62 63 89 - [email protected]

FisiologíaISSN: 1889-397XBoletín informativo de la SECF • Volumen 23 - nº 2 • Diciembre 2020

• TITULARES •

La revista Fisiología está buscando manuscritos relacionados con cualquiera de los aspectos básicos de la Fisiología celular, de tejidos, órganosy sistemas, incluyendo Fisiología humana, animal y comparada, así como aquellos dedicados al estudio de los desequilibrios de los procesosfisiológicos que dan como resultado alteraciones de la salud.

Los autores deben enviar sus manuscritos al editor, Dr. Juan Antonio Rosado, vía correo electrónico a [email protected], incluyendo el texto delmanuscrito y las figuras siguiendo el formato que se especifica en las instrucciones a los autores. Los manuscritos, que podrán estar redactados enespañol o inglés, serán revisados por el Comité Editorial, quienes podrán solicitar la opinión de expertos. Una vez aceptados, los manuscritos sepublicarán en el primer volumen disponible.

La revista Fisiología acepta manuscritos en los siguientes formatos: artículos originales, artículos de revisión, cartas, así como reseñas ycomentarios sobre libros que versen sobre cualquiera de los aspectos relacionados con la Fisiología.

• CALL FOR PAPERS •

• EDITORIAL •TRPV2: AN ELUSIVEPLAYER IN CENTRALNERVOUS SYSTEMPATHOPHYSIOLOGY

GESTATIONAL DIABETESMELLITUS RISK ISMEDIATED BY CHANGESIN THE CIRCULATINGMICRORNA EXPRESSIONPROFILE: UPDATES ANDPERSPECTIVES.

LIBROS RECOMENDADOS

Jennifer Enrich-Bengoa andAlexPerálvarez-Marín.

PaolaPinto-Hernández,CristinaTomás-Zapico andEduardoIglesias-Gutiérrez.

FisiologíaVeterinaria

E stimados amigos:Antes de fin de año, como viene siendohabitual, tenemos el placer de haceros llegar unnuevo ejemplar de la revista FISIOLOGÍA, que

en esta ocasión incorpora dos interesantes yestimulantes artículos.

La primera de las revisiones, a cargo de JenniferEnrich-Bengoa y Alex Perálvarez-Marín, delDepartamento de Bioquímica y Biología Molecular de laUniversidad Autónoma de Barcelona, nos introduce enel papel del canal TRPV2 en la fisiología y lafisiopatología del sistema nervioso central. Además deuna descripción del papel del canal en la función delsistema nervioso, así como su posible relación conciertas patologías, los autores mencionan distintosinhibidores farmacológicos del canal TRPV2 con unpotencial prometedor en la fisiopatología dedeterminados desórdenes del sistema nervioso.

La segunda de las revisiones, redactada por PaolaPinto-Hernández, Cristina Tomás-Zapico y EduardoIglesias-Gutiérrez, del Departamento de BiologíaFuncional de la Universidad de Oviedo, analiza loshallazgos recientes sobre el papel de los miRNA comobiomarcadores de diabetes mellitus gestacional, susactuales limitaciones y sus prometedoras perspectivasde futuro basadas en su potencial valor diagnóstico ytraslacional.

Esperamos que estos artículos resulten de vuestroagrado y que el año venidero sea amable con todosvosotros.

Juan A. Rosado

• CARTA DE LA PRESIDENTA

• Presidenta: Meritxell López Gallardo ([email protected])• Presidente Electo: Vicente Martínez Perea ([email protected])• Presidente Saliente: Jorge García Seoane ([email protected])• Secretaria: Eva María Marco López ([email protected]))• Tesorero: Antonio González Mateosz ([email protected])• Vocales: Jesús Francisco Rodríguez Huertas ([email protected]) y María Inmaculada García Fernández ([email protected]).Direcciones de contacto en: http://www.secf.es/ · D.L.: SE-321-2000

SOCIEDAD ESPAÑOLA DE CIENCIAS FISIOLÓGICAS

Q ueridos amigos y queridos compañeros de la Sociedad Española de Ciencias Fisiológicas.Mi primera carta como Presidenta Ejecutiva solo puede comenzar con el deseo de que tanto vosotros comovuestras familias y amigos os encontréis bien. Agradezco que confiarais en mi para desarrollar esta labor,es un gran reto y, a la vez, un gran orgullo, y me gustaría contar con vuestra colaboración tanto en los

proyectos que ya tenemos en marcha como en los nuevos que se iniciarán. En estos meses hemos aplicado el principiode la homeostasia que gobierna la fisiología a nuestras vidas: hemos aprendido que podemos cambiar nuestra formade vivir y trabajar para adaptarnos al nuevo medio que nos rodea. Son muchos los proyectos e ilusiones que hanquedado en el camino, pero debemos seguir luchando y recuperar las fuerzas, el entusiasmo y la motivación para nodejarlos abandonados, y así lo hemos hecho en la Asamblea General celebrada el pasado 26 de octubre, en modalidadvirtual. En dicha Asamblea se decidió que el 40 Congreso de la SECF mantenga su celebración en Badajoz en el año2022, algo que merecía el Comité Organizador por el gran trabajo realizado desde su elección como sede en elCongreso de Cádiz en 2018. Se informó de la aceptación por unanimidad de los miembros de la FEPS de lacandidatura de Granada para celebrar su próximo congreso en septiembre de 2021, en modalidad presencial, siempreque la situación lo permita. Los profesores Dr. D. Vicente Notario y Dra. Dña. Ana Ilundaín, dos grandes fisiólogos ypremios “Juan Negrín” y “Antonio Gallego” respectivamente, nos dedicaron unas emotivas palabras como anticipo ala entrega presencial que se realizará en la sesión que la SECF celebrará en el próximo Congreso de la FEPS. Tambiénnos dedicaron unas palabras de agradecimiento las premiadas por la Sociedad a la “Mejor Tesis Doctoral” (Dña.Eliana Barriocanal Casado) y “Premio SECF de Divulgación Científica” (Dña. Belén Gago Calderón).

En estos momentos en los que la comunicación ha cambiado a un entorno on-line se hace más importante quenunca el empleo y uso de nuestra página web (h�ps://www.secf.es) en la que encontrareis toda la informaciónactualizada sobre las actividades y marcha de la sociedad. Os animo a tomar parte activa en esta comunicaciónhaciéndonos llegar vídeos resumen de vuestra actividad investigadora y docente; a que participéis en nuestra revistacientífica, a cuyo Comité Editorial agradezco el enorme esfuerzo que realiza; y a que nos enviéis vuestras sugerenciasde mejora e innovación; os animo además a seguir a la SECF en redes sociales (Facebook, Twi�er e Instagram); endefinitiva, os animo a que os impliquéis con nosotros ya que os necesitamos para poder avanzar como Sociedad.

Agradezco a la anterior Junta Directiva la gran labor realizada y su desinteresado trabajo, especialmente a los que,tras seis años de intensa actividad, acaban su periodo en ella. Todos los miembros de la actual Junta os deseamos que,a pesar de la pandemia que vivimos, podáis disfrutar de unas muy felices fiestas llenas de salud y amor que, aunquesea en la distancia, siempre se puede transmitir. Que el próximo 2021 nos traiga el retorno a la ansiada normalidadque todos deseamos, pues hoy por hoy es nuestra felicidad. Muchas gracias a todos por formar parte de esta Sociedad.

Un abrazo

Meritxell López Gallardo

Presidenta Ejecutiva de la SECF

A. Remisión de originalesLa remisión de originales se hará exclusivamente por correo electrónico a la dirección del editor o de cualquiera de los

miembros del comité editorial. Se puede utilizar cualquier procesador de texto, programa y formato gráfico, aunque es preferibleremitir el manuscrito en formatos usuales. En todo caso deben indicarse en la carta de remisión los formatos empleados paratexto, tablas, gráficos y fotografías. La utilización de formatos poco usuales retrasará la publicación. En caso de emplear algúnsistema de compresión para fotografías o gráficos, debe comprobarse que la descompresión no deteriora la calidad de lasimágenes. La carta de remisión debe incluirse en el cuerpo del mensaje electrónico y el original y las figuras en forma de archivosanexos. El texto del artículo debe adjuntarse como un único archivo, incluyendo la página con el título, el texto principal,bibliografía, etc. Cada tabla o figura debe remitirse en un anexo independiente, nombrando cada anexo con el nombre del primerautor y el número de tabla o figura que contenga (ejemplo: Cunqueiro-Fig.1).

Direcciones comité editorial:Juan Antonio Rosado ([email protected]), Diego Álvarez (Universidad de La Laguna, [email protected]), Teresa Giráldez

(Universidad de La Laguna, [email protected]), Celestino González (Universidad de Oviedo, [email protected]), Ana Ilundain(Universidad de Sevilla, [email protected]), Juan Martínez-Pinna (Universidad de Alicante, [email protected]) y CarlosVillalobos (CSIC, [email protected]).B. Composición de los originales

1. Primera página.•Título•Autores•Filiación de los autores•Autor y dirección para correspondencia si procede (incluir números de teléfono y fax, y una dirección de correo

electrónico).2. Segunda página.

Sumario, si procede, en una extensión un superior a 200 palabras, en el mismo idioma que el resto del artículo.3. Cuerpo del texto.

Los artículos no deberán sobrepasar las 2.500 palabras e irán en folios numerados. Deberán estar escritos en un estiloclaro y con pretensión divulgativa, de forma que puedan ser entendidos por cualquier fisiólogo,independientemente de su área de especialización. El procedimiento más simple es tomar como ejemplo cualquierartículo publicado previamente en Fisiología. En caso de no disponer de ningún ejemplar, puede solicitarse a cualquierade los miembros del comité editorial o a la Secretaría ([email protected]) para ser incluido en la lista de distribución.Alternativamente, pueden consultarse los artículos de los números anteriores en http://www.seccff.orgLos artículos podrán contener resultados ya publicados, siendo entonces responsabilidad exclusiva de los autores

obtener los permisos correspondientes de las revistas o libros donde hayan sido publicados originalmente. Debido a lapretensión divulgativa, cada autor podrá organizar el texto en la forma que crea más oportuna, si bien se sugiere unadivisión en secciones que facilite su lectura.

4. Otros.a.Notas (si las hubiere) y agradecimientos.b.Bibliografía. Las referencias, muy seleccionadas, se insertarán en el cuerpo del texto entre paréntesis (ejemplo: Chacóny Mairena, 1999). La relación completa de referencias bibliográficas deberá incluirse al final del texto, por ordenalfabético y cronológico, de acuerdo a los formatos más habituales. Ejemplo: Gómez J, Belmonte J (1910) Decipheringbullfighting. J Taurom 57: 200-235.c.Pies de figuras. Deberán incluirse a continuación de la bibliografía y en páginas aparte.d. Figuras. Su número no deberá ser superior a 2-3 por artículo, y el tamaño máximo aceptado será el de una hoja impresa(DIN-A4). En el caso de figuras previamente publicadas, si fuere necesario, deberá acompañarse autorización para sureproducción en Fisiología.e.Tablas.

• INSTRUCCIONES A LOS AUTORES

FISIOLOGÍA.BoletíninformativodelaSECF

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Transient Receptor Potential (TRP) channels are important pharmacological targets in pathophysiology. AmongTRP channels, TRPV2, the closest homologue of TRPV1, is ubiquitously expressed in human tissues. TRPV2 playsdistinct roles in cardiac, neuromuscular function, immunity, and metabolism, being associated to pathologiessuch as muscular dystrophy, cancer and cardiomyopathies. In this revision regarding TRPV2, we aim to overviewthis cation channel in the context of human physiology, to put the future focus on the role of TRPV2 in centralnervous system pathophysiology.

1Unitat de Biofísica, Departament de Bioquímica i de Biologia Molecular, Universitat Autònoma de Barcelona, 08193Bellaterra, Spain²Institute of Neurosciences, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain*Autor para la correspondencia: J. Enrich-Bengoa and A. Perálvarez-Marín.Centre d’Estudis encBiofísica, Unitat de Biofísica, Departament de Bioquímica i de Biologia Molecular, Facultat deMedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Catalonia, Spain Fax: +34 93 581 1907 Tel:+34 93 581 1907

TRPV2: AN ELUSIVE PLAYER IN CENTRALNERVOUS SYSTEM PATHOPHYSIOLOGY.Jennifer Enrich-Bengoa1,2 andAlexPerálvarez-Marín1,2.

TRPsuperfamily

Transient receptor potential (TRP) channels are agroup of non-selective cation channels that act aspolymodal cellular sensors, being capable to act inresponse to a wide spectrum of chemical and physicalstimuli (Zheng, 2013). These channels were firstlydescribed in amutant strain of Drosophilamelanogaster(Cosens and Manning, 1969). Mammalian TRPsuperfamily is divided into six subfamilies based onfounding members; trpa (ankyrin), TRPC (canonical),TRPM (melastatin), TRPV (vanilloid), TRPML(mucolipin) and TRPP (polycystic). In humans there are27 TRP channels (Figure 1A), which are classifiedregarding to their sequence homology and not by theirfunctional role (Claphamet al., 2003; Perálvarez-Marín etal., 2013). TRP superfamily diversity came from thecommon ancestor of teleost fishes and terrestrialvertebrates that through repeated gene duplications andfollowed by sequence divergence constitute the currentTRP repertoire (Saito et al., 2011).

At the structural level all members of TRPsuperfamily consist of two cytosolic domains N- and C-terminal and a six-segment (S1-S6) transmembranedomain (TMD), with a pore-forming loop between S5andS6. (Figure1B).ThediversityofN-andC-terdomainsand corresponding structural and functional propertiesdefines the diversity of TRP subfamilies. The basicsubunit is defined by the S1-S6 transmembrane domain,where the S5-S6 segments define the pore where cations(mostly mono- and divalent) flow upon the sensing ofdiverse stimuli inwhat is called somatosensation (Figure1C).

TRPVsubfamily

The first reportedmember of the TRPV subfamilywas OSM-9 (osmotic avoidance abnormal familymember 9) from Caenorhabditis elegans (Colbert et al.,1997). OSM-9 is involved in olfactation,mechanosensation and olfactory adaptation (Perálvarez-Marín et al., 2013). InC. elegans there is a total of 5TRPVschannels; OSM-9 and other four osm-9/capsaicinreceptor related genes (OCR-1-4) (Xiao and Xu, 2011). Inmammals, there are sixmembers (TRPV1-6) in theTRPVsubfamily that are widely distributed in practically allbody tissues and cell types. The six members of thisfamily are divided into two groups a�ending to theirsequence homology and cation selectivity; TRPV1-4 andTRPV5-6 groups, with a global sequence identity of 20%and 75%, respectively, being TRPV1-4 non-selective andTRPV5-6 selective for Ca2+, respectively. TRPV1 andTRPV2 show sequence identity of 50% (Gunthorpe et al.,2002). TRPV1-4 group ismainly formed by non-selectivelowpermeable calcium channels and can be activated byawide spectrum of physical and chemical stimuli, beingconsidered thermosensitive as are activated by heat. Thisgroup has been described for being involved in a widespectrumoffunctionssuchasnociception, thermoceptionand osmolality. The other group formed byTRPV5-6 arecalcium-selective channels important for general Ca2+homeostasisandarenotactivatedbyheat (Montell, 2005).

TRPV2physiologyandpathophysiology

TRPV2 is the most unknown member of themammalian TRPV subfamily and was firstly named asVRL-1 based on the homology to themost characterizedmember of this subfamily, TRPV1 (Perálvarez-Marín etal., 2013). As previously said, TRPV1-4 channels are


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Figure 1. TRP superfamily repertoire. (A) Human TRP subfamilies phylogeny. (B) TRP structural features,showing the six-transmembrane segments, and the cytosolic N- and C- termini. In dark blue, the segments S5-S6,clustered in the center of the channel and forming the ion pore. In orange the transmembrane segments S1-S4,surrounding the ion channel gate. (C) Physiological overview of the TRP-related cation transport process in thesomatosensation physiological process.

temperature dependent and each one have a differentthreshold of temperature activation and all of them areactivated by different stimuli (Tominaga, 2007). In thecase of TRPV2 is activated by noxious heat (>52 °C) andcan also be modulated by some chemical compounds(Caterina et al., 1999; Perálvarez-Marín et al., 2013).TRPV2 activation is temperature dependent but the roleof TRPV2 in temperature sensing remains controversial.Recently, it has been shown that TRPV2 is endogenouslyactivated by oxidative stress. Oxidation of specificmethionines in TRPV2 drive cation influx, becoming thefirst report of endogenous activation of this elusivechannel (Fricke et al., 2019).

Studies in a TRPV2 knockout mice show similarthermal responses towild-typemice (Park et al., 2011). ItisknownthatTRPV2isactivatedatnoxioustemperaturesbut the knowledge in pharmacology is still limited, andsomeof these compoundsarenot specific forTRPV2andare also specie-dependent. It has been demonstrated thatcannabis sativa derivatives are potent agonists of TRPV2,

although they are not specific for TRPV2 leading to thedifficulties to assess the effect of these compounds toTRPV2 physiology (Perálvarez-Marín et al., 2013; DePetrocellis et al., 2011; Qin et al., 2008). Among cannabissativa derivatives, (−)trans-delta-9-tetrahydrocannabinol,cannabidiol and delta-9-tetrahydrocannabivarin are thestronger activators of TRPV2. Cannabinoic acids are theleastactivatorsofTRPV2(DePetrocellisetal.,2011;Vrienset al., 2009). Other compound that has shown effects onTRPV2modulation is 2-Aminoethoxydiphenyl borate (2-APB). This compound was the first TRPV2 agonistidentified, however is not specific for TRPV2 and thesensitivity is variable among species, being humanTRPV2 insensitive (Hu et al., 2004; Juvin et al., 2007;Neeper et al., 2007). A related compound,diphenylboronic anhydride (DPBA) is able to activatemouseTRPV2butnothuman(Chungetal., 2005; Juvinetal., 2007). Some TRPV2 blockers have been identifiedalthough they are not specific for TRPV2; SKF96365,diuretic amiloride, RutheniumRed, trivalent cations andcitral (Juvin et al., 2007; Perálvarez-Marín et al., 2013;


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Figure 2. (A)TRPV2 crosstalk in CNS. TRPV2 is expressed in microglia, astrocytes, and neurons in CNS,becoming an environmental sensor for several physicochemical stimuli in the brain. (B) TRPV2 agonists andantagonists with potential impact in CNS physiology and pharmacology. TRPV2 structure derived form PDB code6U88. Abbreviations for TRPV2 agonists: 2-Aminoethyl diphenylborinate (2-APB); Lysophosphatidylcholine (LPC).Abbreviations for TRPV2 antagonists for TRPV2: 4,4′-[3-[2-[1-Ethyl-4(1H)-quinolinylidene]ethylidene]-1-propene-1,3-diyl]bis(1-ethylquinolinium) diiodide (Lumin (NK-4)); N-(Furan-2-ylmethyl)-3-((4-(N7-methyl-N′-propylamino)-6-(trifluoromethyl)-pyrimidin-2-yl)thio)-propanamide (SET2); arachidonoyl ethanolamide (AEA);linoleoyl ethanolamide (LEA).

Vriens et al., 2009). More specific TRPV2modulators areprobenecid and tranilast, as activator and inhibitor,respectively. These compounds are not TRPV2 specificbut both of them show higher affinity for TRPV2(Perálvarez-Marín et al., 2013).

TRPV2 is ubiquitously expressed through thebody (Doñate-Macián et al., 2019a), thus TRPV2impairment could lead todifferent pathologies, althoughknock-out mice present a mild phenotype(Park et al.,2011). In recentyears,TRPV2isgainingmucha�ention inskeletal andcardiacmuscle (Ague�azet al., 2017; Jones etal., 2017;Lorinet al., 2015;Robbinset al., 2013; Sabourinetal., 2009;Watanabe et al., 2009). It has been observed thatTRPV2 isnecessary fora correctmaintenanceof structureand cardiac function (Katanosaka et al., 2014; Rubinsteinet al., 2014). In some muscular pathologies such asDuchenne muscular dystrophy (DMD), it has beenobserved the contribution of TRPV2 in a defective Ca2+influx in dystrophic myocites contributing to thispathophysiological phenotype (Lorin et al., 2015). TPRV2is also being studied as a possible therapy target forcardiomyopathies in DMD patients (Iwata andMatsumura, 2019). TRPV2 has also been localized insmooth muscle and endothelial cells of arteries in both;rabbit (Park et al., 2003) andhuman (Fantozzi et al., 2003),and in smooth muscle cells of veins in rats (Peng et al.,2010).Theseevidencessuggest thepossibleroleofTRPV2in the circulatory system. TRPV2 is also expressed inpancreatic β-cells and studies performed by Kojima Lab(Hisanaga et al., 2009) suggest theTRPV2 involvement in

insulin action. TRPV2 expression is also relevant in theimmune system (Caterina et al., 1999; Link et al., 2010;Santoni et al., 2013). This channel is found in immuneorgans such as spleen, and also in different types of cellsregulating the immune system (Kojima and Nagasawa,2014; Perálvarez-Marín et al., 2013; Santoni et al., 2013).TheroleofTRPV2incancerhasalsobeenafocusofstudyduring the last years. TRPV2 up and down-regulationhave been associated with oncogenic and tumorsuppressor roles during carcinogenesis (Liberati et al.,2014). TRPV2 overexpression has been found in severalcancer types and cell lines (Caprodossi et al., 2008;Doñate-Macián et al., 2018a; Santoni et al., 2020). Recentstudies suggest that increasing TRPV2 expression bycannabidiol induces the apoptosis of human glioma celllines by increasing the chemosensitivity of humanGlioblastoma multiforme (GBM) cells to the cytotoxiceffects of the chemotherapeutic agents. This observationslead to the conclusion that TRPV2 functions as anegativeregulator of glioma cell survival and proliferation(Nabissi et al., 2010, 2013), but more importantly , se�lesthe question about thephysiological role of TRPV2 in thenervoussystem.It isalreadyknownthatTRPV2iswidelyexpressed in both central and peripheral nervous system(CNS and PNS, respectively) in charge of fine-tuning ofcation-mediated signaling. TRP channels assomatosensory receptors have been widely studied inperipheral nervous system (PNS), especially in dorsalroot and trigeminal ganglia (Ahluwalia et al., 2002;Caterina et al., 1999; IchikawaandSugimoto, 2000).


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TRPV2 in the centralnervous system

TRPV2 in central nervous system (CNS) isexpressed in several cell types (Figure 2A) becoming aninteresting regulatory target. TRPV2 is specifically foundin medium-to-large neurons that have myelinated fibers(Caterina et al., 1999) and also needed for the axon andneurite outgrowthofmotor and sensoryneurons (Cohenetal., 2015; Shibasaki et al., 2010).TRPV2 isalsoexpressedin other glial cells such as astroglia (Shibasaki et al., 2013)and microglia (Maksoud et al., 2019). In microglia,TRPV2 and phagocytosis are upregulated by oxidativestress and nitric oxide. This channel has also beendetected in important brain regions, such as the cerebralcortex (Liapi and Wood, 2005) and the forebrain andhindbrain regions in rats (Nedungadi et al., 2012), thehypothalamo-neurohypophysial system in macaques(Wainwrightetal., 2004)andthemature forebrain inmice(Cahoy et al., 2008). TRPV2 is the highest expressingTRPV in the neurons ofmouse forebrain regions (Cahoyet al., 2008). TRPV2 localization correlates with brainstructures related to osmoregulation andsomatosensation, suggesting the role of this channel inosmosensory mechanisms and maintenance of osmoticbalance (Perálvarez-Marín et al., 2013).

It is already known that TRPV2 plays a role in theCNSphysiology (Cohenet al., 2015; Shibasaki et al., 2010)and also recent published results in our laboratory(Doñate-Macián et al., 2018a) revealed that TRPV2 isinteracting with key myelin proteins and with otherproteins involved in neoplasms and diseases of thenervous system (Santoni and Amantini, 2019). Theseresults from our laboratory (Doñate-Macián et al., 2018a)add new perspectives in the role of TRPV2 in CNSdevelopment an in (re)myelination. Results obtainedfrom our lab (Doñate-Macián et al., 2018a) show TRPV2and TRPV4 interactors involved in trafficking. Theseresults points out, with other published papers (Doñate-Macian et al., 2015; Doñate-Macián and Perálvarez-Marín, 2014; Doñate-Macián et al., 2018b, 2019a, 2019b)from our laboratory, about the proteins involved in theregulated and constitutive trafficking of these twomechanosensory cation channels.

In our laboratory it has beenperformedan in silicoand proteomics approach to discover the TRPV2interactors by using GBM patient cohort, to be�erunderstand the role of this channel based on protein-protein interactions.Someof thefoundinteractorsarekeymyelinproteins in theCNS, suchas proteolipidprotein1(PLP1),Opalin, andneurotrimin (NTM) (Doñate-Maciánet al., 2018a). Other proteins involved in CNS diseasesand neoplasm have also been identified in this article asimportant TRPV2 interactors such as ABR, FGF1,KCNJ10, PEBP1,PLP1, andSDC3proteins.

Recent studies by Hainz et al. (Hainz et al., 2016,

2017a, 2017b) showed how probenecid, one of the mostspecific TRPV2 agonists, is capable to prevent and arrestthe progression of clinical symptoms in an experimentalautoimmune encephalomyelitis (EAE) in mice (Hainz etal., 2016, 2017a), and reduce demyelination in thecurprizone model of demyelination/remyelination(Hainz et al., 2017b). Hainz et al. focus on the inhibitoryeffects of probenecid in theATP ion channel pannexin-1(Panx1) that is responsible of oligodendrocytes death.However, our working hypothesis is that probenecid inEAEmay exert a dual pathway by inhibiting Panx1 andactivating TRPV2, simultaneously. Effects on Panx1 andTRPV2seemsanother importantpointof interest tostudyand also suggest the importance of TRPV2 inmyelination.Amice EAE studyusing tranilast (a specificblocker forTRPV2)amelioratesmiceparalysis improvingMS outcome in this experimental model (Pla�en et al.,2005).At thepharmacological level, TRPV2has remainedelusive, but new and specific TRPV2 agonists andantagonists are being identified (Figure 2B), withpromising potential for the study of TRPV2pathophysiology.With all these evidences,wehave beena�racted to the idea to develop a research line regardingthe TRPV2-mediated cellular crosstalk of CNS cell types(Figure2A) inmyelinationduringCNSdevelopmentandin pathological conditions, such as multiple sclerosis,Pelizaeus-Merzbacher disease, and otherleukodystrophies.

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Gestational diabetes mellitus (GDM) is defined as thepresence of high blood glucose levels with onset orfirst recognition during second or third trimester ofgestation. It may affect one out of five pregnancies,leading to perinatal morbidity, adverse neonataloutcomes, and high risk of chronic metabolic andcardiovascular injuries in both mother and offspring.Currently, GDM diagnosis is based on measuringblood glucose levels at 24-28 gestational weeks,presenting a small window of opportunity toimplement interventions to improve the outcomes. Inrecent years, molecular biomarkers, such asmicroRNAs (miRNAs), short and stable RNAsequences that repress protein synthesis throughinterference with messenger RNA translation,received considerable interest as diagnosis screeningtools for GDM. Some miRNAs were shown to bedysregulated in plasma and placenta from GDMwomen before changes in blood glucose becomedetectable However, the information available is stillscarce, contradictory, and incomplete, not strongenough to consider them valid biomarkers of GDM.Therefore, the purpose of this review is to provide anoverview of the current knowledge of miRNAs asGDM biomarkers and provide somerecommendations for future research avenues.

Keywords: gestational diabetes mellitus, microRNAs,biomarkers,

La diabetes mellitus gestacional (DMG) se definecomo la presencia de concentraciones altas de glucosaen sangre que se detectan por primera vez durante elsegundo o tercer trimestre de la gestación. Puedeafectar a uno de cada cinco embarazos, causandomorbilidad perinatal, resultados adversos neonatalesy un alto riesgo de desarrollar enfermedadesmetabólicas y cardiovasculares crónicas tanto en lamadre como en el feto. Actualmente, el diagnóstico deDMG se basa en determinar las concentraciones deglucosa en sangre a las 24-28 semanas de gestación, loque presenta una pequeña ventana de oportunidadespara implementar intervenciones que mejoren elpronóstico. En los últimos años, algunosbiomarcadores moleculares, como los microRNA(miRNA), secuencias de ARN cortas y estables quereprimen la síntesis de proteínas a través de lainterferencia con la traducción de RNA mensajero,han recibido un interés considerable comoherramientas de detección para el diagnóstico de laDMG. En este sentido, se demostró que algunosmiRNA estaban desregulados en el plasma y en laplacenta de mujeres con DMG antes de que loscambios en la glucemia fueran detectables. Sinembargo, la información disponible es aún escasa,contradictoria e incompleta como para considerarlosbiomarcadores válidos de DMG. Por tanto, elpropósito de esta revisión es proporcionar una visióngeneral del conocimiento actual de los miRNA comobiomarcadores de esta enfermedad y proporcionaralgunas recomendaciones para futuras vías deinvestigación.

¹Department of Functional Biology (Physiology), University of Oviedo, Asturias, Spain²Health Research Institute of the Principality of Asturias (ISPA), Asturias, Spain*Autor para la correspondencia: Eduardo Iglesias Gutiérrez. Dpto. de Biología Funcional, Universidad de Oviedo.Avda. Julián Clavería, s/n. 33006 Oviedo. Asturias. E-mail: [email protected]

GESTATIONAL DIABETES MELLITUSRISK IS MEDIATED BY CHANGES IN THECIRCULATING MICRORNA EXPRESSIONPROFILE: UPDATES AND PERSPECTIVESPaola Pinto-Hernández¹, Cristina Tomás-Zapico¹�² and Eduardo Iglesias-Gutiérrez*¹�²

Introduction

Gestational diabetes mellitus (GDM) is definedas any degree of carbohydrate intolerance, with onsetor first recognition during the second or third trimes-ter of gestation (Bascones-Martinez et al., 2014). It isconsidered the most frequent metabolic problemduring pregnancy, representing about 90% of riskypregnancies (Sanchez-Muniz et al., 2013). The globalepidemic of obesity anddiabetes has resulted in an in-

crease in the prevalence of diabetes mellitus in wo-men of childbearing age and it is estimated that, cu-rrently, 5% to 20% of pregnancies are affected byGDM worldwide. These large ranges are due to di-fferences in population demographics, diagnostic cri-teria, screening methods, and maternal lifestyle (Pfei-ffer et al., 2020). Despite there is no consensusregarding the test to use, diagnosis is usually madeusing a sequential model of universal screening witha 50-g one-hour glucose challenge test (GCT), follo-


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wed by a diagnostic 100-g three-hour oral glucose to-lerance test (OGTT) forwomenwith a positive screen-ing test (Ferrara, 2007). However, OGTT test iscumbersome to conduct, requires fasting andmultiple blood draws, and its associationwith nauseaand vomiting leads to decreased patient compliance(Dias et al., 2018). Additionally, screening for GDM isusually performed at 24-28 weeks of gestation, ac-cording to the recommendations of international as-sociations and commi�ee (Liu et al., 2016), which lea-ves a small window of opportunity to implement li-festyle interventions to improve pregnancy outcomes.

Diabetes in pregnancy

During healthy pregnancy, several metabolicand physiological changes take place. Among them,insulin resistance increases due to the secretion of aseries of antagonist placental hormones (cortisol, pro-lactin, progesterone, and lactogen), ultimately cau-sing blood glucose to rise (Zhao et al., 2011).Furthermore, in thosewomenwho sufferGDM, insu-lin production is insufficient to counteract this increa-sing resistance, due to an increased apoptotic rate inβ-pancreatic cells which leads to an abnormal insulinproduction and secretion (Ibarra et al., 2018). Giventhat, blood glucose easily goes through placenta byfacilitated diffusion, reaching the fetus andproducing

fetal hyperglycemia (He et al., 2017). This expositionof fetal tissues to the diabetic maternal environmentcan translate into an increased risk for developmentof macrosomia, prenatal morbidity, prematurity, andcardiomyopathy, aswell as an increased risk of obesi-ty and insulin resistance in adulthood (Osmond et al.,2000, Clausen et al., 2008) as a result of developmentalprogramming (Casas-Agustench et al., 2015).Womenwho develop GDM increase their risk of adversehealth outcomes, such as considerably elevated riskfor type 2 diabetes mellitus (T2D) in the years follo-wing pregnancy (Clausen et al., 2008).

The role of miRNAs in GDM

Thepathophysiology ofGDMis not completelyunderstood, but epigenetic changes induced by thisaltered intra-uterine milieu are implicated (Casas-Agustench et al., 2015).Among the epigenetic proces-ses potentially involved, there is now increasing evi-dence that non-coding RNAs, like microRNAs (miR-NAs), play a role in the development of metabolic di-seases, such as GDM (Guay and Regazzi, 2013).

MiRNAs are small non-coding RNAs (approxi-mately 20 nucleotides in length) that regulate gene ex-pression and diverse cellular functions by directingdegradation or inhibiting the translation of mRNA

HDL

Exosomes

Lipoproteins

Protein complex

Argonaute-2

Maternal Blood

miR-16-5pmiR-17-5pmiR-20a-5pmiR-222-3pmiR-29a

147

G G

G G

Insulin signaling pathway

GINS G G G

IRS1

PP

P

GLUT4GDMwoman

Figure 1. Circulating miRNAs described in maternal blood from GDM women. miRNAs upregulated duringthe second trimester of pregnancy are shown in green. miRNAs downregulated at the second and third trimesters ofpregnancy are shown in red. miRNAs in blue have been described to present a changing expression pa�erndepending on the trimester of pregnancy. All these miRNAs target genes encoding proteins which ultimately blockinsulin signaling pathway, causing insulin resistance. INS: Insulin; IRS1: Insulin Receptor Substrate 1; GLUT4:Glucose transporter type 4.


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transcripts (Tafrihi and Hasheminasab, 2019). Bydoing so, it has been demonstrated that certain miR-NAs regulate genes involved in metabolic processessuch as glucose homeostasis, insulin signalling, pan-creatic β-cell function, lipid metabolism, and inflam-mation (Ebert and Sharp, 2012, Guay and Regazzi,2013), all of them related to the development of diabe-tic disease. It has also been demonstrated that miR-NAs are not only located intracellularly, but they canalso be released from the cells and exist stably ascirculating miRNAs (c-miRNAs) in blood and inother easily accessible biological fluids, such as urine,saliva, amniotic fluid, andbreastmilk. It has been sho-wn that c-miRNAs can be actively or passively relea-sed from tissues and regulate the gene expression ofdistant cells, acting as a true intercellular commu-nication mechanism in an autocrine, paracrine or en-docrine mode (Li et al., 2015). These extracellularmiRNAs can be transported in vesicles (exosomes ormicrovesicles) or by binding to proteins, includingargonaute proteins and lipoproteins (Boon andVickers, 2013, Wang et al., 2018).

Interestingly, Li et al. in 2015 demonstrated thatsmall non-coding RNAs can be transplacentaltransmi�ed from themother to the fetus, contributingto the maternal-fetal crosstalk and to the epigeneticlegacy. Furthermore, in 2013, genome-wide analysisdemonstrated that more than 600 miRNAs are ex-pressed in the placenta and many of them are dys-regulated during GDM (Dias et al., 2018). These miR-NAs hold potential as biomarkers of placentaldysfunction andGDM, since they can be released intomaternal circulation (Chim et al., 2008).

Circulating miRNAs as biomarkers of GDM

Prompt identification ofGDMrisk, before diag-nosis, is a critical need, as an early appropriate treat-ment can reduce both mild and severe GDM-relatedcomplications. Therefore, there is a need for a goodbiomarker for the early identification of GDM risk. Tothis end, c-miRNAs present themselves as promisingcandidates, since it has been demonstrated thatchanges in the levels of specific c-miRNAs occurduring GDM, before changes in blood glucose beco-me detectable (24-28 weeks) (Pfeiffer et al., 2020). Ingeneral, miRNAs show optimal characteristics andnumerous advantages to be considered optimal bio-markers: 1) they are very stable against ribonucleaseactivity, freezing/thawing cycles and other drasticconditions; 2) samples can, therefore, be stored forlong periods of time without observing a noticeableRNA degradation (Guay and Regazzi, 2013); 3) asthey are found in several easily accessible biologicalfluids, they can be detected by highly sensitive andspecific techniques, such as real-time polymerasechain reaction (qPCR); and 4) most of them are

convoluted evolutionarily, which facilitates the ex-trapolation of the results of in vivo animals studies tohumans (Zhao et al., 2013). However, the informationavailable on the usefulness and feasibility of c-miR-NAs as biomarkers of GDM is scarce and, to some ex-tent, contradictory and incomplete.

Most authors have analyzed c-miRNA profilesin maternal blood samples, mainly plasma or serum,since it is an easily accessible and non-invasive fluid(Ibarra et al., 2018, Gillet et al., 2019). In other studies,maternal samples were obtained after delivery, suchas placental tissues (Ding et al., 2018, Ibarra et al.,2018, Li et al., 2018, Nair et al., 2018, Wang et al., 2019,Wang et al., 2019), omental adipose tissue (Ibarra etal., 2018) and human umbilical vein endothelial cells(HUVECs) (Ibarra et al., 2018, Peng et al., 2018). Mo-reover, two studies have assessedmiRNA expressionin the offspring: one in skeletal muscle of adult offsp-ring of women who had developed GDM (Ibarra etal., 2018) and the other in feto-placental endothelialcells (fpEC) (Stru� et al., 2018).

The first study considering serum c-miRNAs ascandidate biomarkers for predictingGDM in the rela-tively early pregnancy (16-19 gestational weeks) con-sisted on a systematic screening by using the TaqmanLow Density Array (TLDA) chips (Zhao et al., 2011).The expression of miR-132, miR-29a-3p, and miR-222were significantly decreased in the GDM group(Zhao et al., 2011). Since then, a considerable amountof information has been published describing the as-sociation of GDMwith the expression of certain miR-NAs. For instance, a more recent study observed thatthe expression ofmiR-222was also lower in the serumof GDM women at 13-31 gestational weeks (Pheifferet al., 2018). Additionally, it has also been described adifferential profile of c-miRNAs at 16-19 gestationalweeks in GDM vs. healthy women, although thechanges observed involved a different set of miRNAs(Zhu et al., 2015). These authors reported in their pilotstudy the upregulation of miR-16-5p, miR-17-5p,miR-19a-3p, miR-19b-3p and miR-20a-5p in plasmasamples of GDMwomen. These resultswere tested ina larger group of patients and at different gestationalweeks (Cao et al., 2017). The same results were obtai-ned, but only for miR-16-5p, miR-17-5p andmiR-20a-5p, which were significantly upregulated in GDMwomen at 16-20 weeks, 20-24 weeks and 24-28 weeksof pregnancy (Cao et al., 2017). Two studies analyzedthe expression ofmiR-222-3p andmiR-29a-3p (Zhu etal., 2015, Wander et al., 2017). However, they did notsee differences between GDM case and controlgroups, although miR-29a-3p was associated withGDM risk in the analysis restricted to male offspring,but not women offspring in one of the studies(Wander et al., 2017). In another work, miR-29a was


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identified as one of the specific miRNAs in the deve-lopment of GDM (Collares et al., 2013).

The scenario is even more complex, heteroge-neous and hardly comparable for the rest of the stu-dies (Sebastiani et al., 2017,Houshmand-Oeregaard etal., 2018, Stru� et al., 2018, Hocaoglu et al., 2019,Martinez-Ibarra et al., 2019). Many other miRNAshave been reported to exhibit an altered expressionduring GDM, although they have only been descri-bed in one study each. Furthermore, miRNA expres-sion may be affected by population characteristics,including gestational age, biological sample analysed,measurement platform, type and number ofmiRNAsanalysed, and normalization strategies, resulting inthe heterogeneous results observed in the differentstudies.

Despite the heterogeneity of the results (Figure1), some conclusions can be drawn about which c-miRNAs could be the most promising biomarkers ofGDM, when obtained from maternal blood. On theone hand, we could consider miR-16-5p, miR-17-5pand miR-20a-5p, which are upregulated in plasma ofGDMwomen at 16–20weeks, 20–24weeks and 24–28weeks of pregnancy, that is, before serum glucose ab-normality (24-28 weeks) is tested and GDM diag-nosed. ThesemiRNAs aremainly associatedwith fivepathways: MAPK signaling, insulin signaling, type 2diabetes mellitus, TGF-β signaling, and mTOR sig-naling (Zhu et al., 2015). For example, miR-16 targetsgenes encoding the insulin receptor substrate (IRS)proteins 1 and 2, thus, the upregulation of miR-16-5pin GDMwomen will block insulin signaling, causinginsulin resistance (Kantharidis et al., 2011). For theirpart, miR-17-5p and miR-20a-5p are associated withangiogenesis and upregulation of these miRNAs mi-ght lead to an abnormal pregnancy, because theytarget several genes important for this process such asHIF1A, MMP2, VEGFA, TIMP2, and IL-8. HIF1A is atranscription factor highly sensitive to oxygen tensioncritical for placental development and function throu-gh regulating the expression of many hypoxia-res-ponsive genes, including VEGFA (Wang et al., 2012).The downregulation of miR-222-3p has been descri-bed in GDMwomen at 13-31 gestational weeks. Thisis a placental miRNA associated with proliferation ofendometrial stromal cells and it is a potential regu-lator of estrogen receptor a (ERa) expression in estro-gen-induced insulin resistance in GDM (Pheiffer etal., 2018). Finally, miR-29a presents an expressionpa�ern that changes depending on the trimester ofpregnancy. Thus, downregulation of miR-29a couldincrease Insig1 expression level, an endoplasmic re-ticulummembrane protein that regulates glucose ho-meostasis and subsequently increased the level ofPCK2, a key enzyme in gluconeogenesis in hepatic ce-lls, causing hyperglycemia (Zhao et al., 2011).

Future perspectives

Although evidence accumulates that changesin the plasma miRNA profile occur during GDM, atthis moment neither a single c-miRNA nor a specificc-miRNA profile provide a reliable biomarker ofGDM. The results obtained in the different studies arequite heterogeneous and hardly comparable, mostlikely due to huge differences in the methodologicaland experimental approaches. There are also severallimitations, such as the lack of a solid and globally ac-cepted procedure for data processing or a commondiagnostic criterion to defineGDM. The existence of asolid and common strategy for miRNA data analysisshould be a priority that would tremendously impro-ve the impact of the results in terms of translationaland diagnostic value.

Furthermore, there is still a lack of a paramountperspective on the regulatory role of c-miRNAs th-roughout healthy and diabetic gestations, as well astheir value as biomarkers. As far as we know, nolongitudinal study has analysed the changes in the c-miRNA profile throughout the three trimesters ofpregnancy in healthy women and in those who deve-lop any kind of obstetrical syndrome during preg-nancy, including GDM. This information would alsohelp in a be�er understanding of the transgeneratio-nal metabolic risk inheritance, optimizing the designand implementation of lifestyle interventions aimedto reduce metabolic risk.

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1. Introducción a la Fisiología. Concepto. Evolución.HomeostasisAlbinoGarcía Sacristán (Univ. ComplutenseMadrid)2. Comunicación celular. Ciclo vitalGinésM. Salido Ruiz (Univ. Extremadura)

PARTE I: FISIOLOGÍADELNERVIOYMÚSCULOCoordinador:AlbinoGarcía Sacristán3. Fisiología del nervioSara Benedito Castellote (Univ. ComplutenseMadrid)4. Contracción delmúsculo esqueléticoLuis Rivera de losArcos (Univ. ComplutenseMadrid)5. Contracción de losmúsculos cardíaco y lisoLuis Rivera de losArcos (Univ. ComplutenseMadrid)6. Transmisión sináptica. Unión neuromuscularAlbinoGarcía Sacristán (Univ. ComplutenseMadrid)

PARTE II: SISTEMANERVIOSOCoordinador:AlbinoGarcía Sacristán7. Receptores sensoriales. Vías sensitivasJuanAntonioMadrid Pérez (Univ.Murcia)8. Sensibilidad somatovisceralJuanAntonioMadrid Pérez (Univ.Murcia)9. Fotorrecepción, el ojo y la visión

Ana B. RodríguezMoratinos (Univ. Extremadura)10. Fisiología de la audiciónJoséAntonio Pariente Llanos (Univ. Extremadura)11. QuimiorrecepciónJuanAntonio RosadoDionisio (Univ. Extremadura)12. Funciones motoras de la médula espinal y deltronco del encéfaloSergioAgüera Carmona (Univ. Córdoba)13. Ganglios basales y cerebeloSergioAgüera Carmona (Univ. Córdoba)14. Control cortical de las funciones superioresSergioAgüera Carmona (Univ. Córdoba)15. Sistema nervioso autónomoAlbinoGarcía Sacristán (Univ. ComplutenseMadrid)16. Sueño y vigilia. Conducta animalSalvador Ruiz López (Univ.Murcia)

PARTE III:MEDIO INTERNOCoordinador: Javier González Gallego17. Fluidos corporalesJuan Pablo Barrio Lera (Univ. León)18. Eritrocitos, glóbulos rojos o hematíesPaz Recio Visedo (Univ. ComplutenseMadrid)19. Leucocitos o glóbulos blancos

Sobre el libro:La dimensión y amplitud de contenidos que compendia la obra, así como la calidad y prestigio de los autores quehan intervenido en ella, hacen de este manual un texto indispensable para profesionales de la veterinaria. Unambicioso proyecto que se extiende a lo largo de casi 1300 páginas, divididas en 11 bloques temáticos y 82capítulos, y en el que han intervenido profesores y catedráticos de casi todas las facultades de Veterinaria públicasde España, así como otras 6 universidades de ámbito internacional.En los 20 años transcurridos desde que el catedrático de FisiologíaAlbino García Sacristán coordinara por primeravez la primera edición de este libro, se han logrado nuevas respuestas a los procesos fisiológicos de los seres vivos.Los mecanismos fisiológicos pueden explicarse, cada vez más, en términos moleculares y biofísicos, en lugar desimplemente como una serie de fenómenos biológicos independientes, lo que motiva la revisión constante de cadaproceso funcional. Por ello, los 82 temas que componen la obra se han ampliado y actualizado de acuerdo a estaevolución. Además, se han incluido cientos de ilustraciones a color que ayudan al estudiante a comprender losconceptos explicados en el texto de un modo esquemático, atractivo y didáctico, orientado exclusivamente almundo animal.Los autores:58 autores de 9 universidades españolas y 6 internacionales, seleccionados por su especialidad en cada materia,han sido los encargados de desarrollar este completo manual, que ha contado con la edición general de AlbinoGarcía Sacristán, quien ya estuviera al frente de otro conocido manual que durante años ha sido referencia en elsector.

FISIOLOGÍA VETERINARIAAlbino García Sacristán (editor).200 x 280 mm1296 páginasISBN: 978-84-7360-571-7h�ps://www.tebarflores.com/inicio/285-fisiologia-veterinaria-9788473606448.html

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MarAlmar Galiana (Univ. León)20. Linfocitos e inmunidadPilar Sánchez Collado (Univ. León)21. HemostasiaSonia Sánchez Campos (Univ. León)

PARTE IV: SISTEMA CARDIOVASCULARCoordinador: Francisco CastejónMontijano22. Consideraciones generales sobre la circulaciónMaría Dolores Rubio Luque (Univ. Córdoba)23. Electrofisiología del corazón. ElelectrocardiogramaRafael Santisteban Valenzuela (Univ. Córdoba)24. El ciclo cardíacoEstrellaAgüera Buendía (Univ. Córdoba)25. Regulación de la actividad cardíacaPablo I. Trigo (Univ. Nac. de la Plata, Argentina)26. Fisiología de los vasos sanguíneosRafael Santisteban Valenzuela (Univ. Córdoba)27. Presión sanguínea Pulso arterial, venoso y capilarBegoñaMª Escribano Durán (Univ. Córdoba)28. Regulación de la circulación vascularDolores Prieto Ocejo (Univ. ComplutenseMadrid)29. Circulación por áreas especialesBegoñaMª Escribano Durán (Univ. Córdoba)

PARTE V: SISTEMA RESPIRATORIOCoordinadora: Mª DivinaMurillo López de Silanes30. Ventilación pulmonarMª DivinaMurillo López de Silanes (Univ. Zaragoza)31. Intercambio de gases a través de la membranarespiratoriaMarcel Jiménez Farrerons (Univ. Autónoma deBarcelona)32. Transporte de gases a través de la sangreNyurky Matheus Cortez (Univ. Lisandro Alvarado,Venezuela)33. Regulación de la respiraciónMª DivinaMurillo López de Silanes (Univ. Zaragoza)34. Fisiología de la respiración en las avesAna IsabelAlcalde Herrero (†) (Univ. Zaragoza)

PARTE VI: SISTEMA EXCRETORCoordinador: Javier González Gallego35. Función renalMaría Jesús Tuñón González (Univ. León)36. Función tubularAna Isabel Álvarez de Felipe (Univ. León)37. Mecanismos de concentración y dilución de laorinaGracia Merino Peláez (Univ. León)38. Equilibrio ácido-baseJosé Luis Mauriz Gutiérrez (Univ. León)39. Fisiología de las vías urinariasMedardo V. Hernández Rodríguez (UCM)

PARTE VII: SISTEMA DIGESTIVOCoordinador: GinésM. Salido Ruiz

40. NutriciónMª Rosario Pascual y Pascual (Univ. Extremadura)41. IngestaAntonio GonzálezMateos (Univ. Extremadura)42. Transporte de los alimentos en el tracto digestivoMiguel Ángel Plaza Carrión (Univ. Zaragoza)43. Secreción salivalAntonio GonzálezMateos (Univ. Extremadura)44. Secreción gástricaCristina CamelloAlmaraz (Univ. Extremadura)45. Secreción pancreática exocrinaPedro J. CamelloAlmaraz (Univ. Extremadura)46. Secreción intestinalJuanAntonio Rosado Dionisio (Univ. Extremadura)47. Hígado y secreción biliarJavier González Gallego (Univ. León)48. Fisiología digestiva de los rumiantesMª PilarArruebo Loshuertos (Univ. Zaragoza)49. Fisiología digestiva de las avesPedro Cosme Redondo Liberal (Univ. Extremadura)50. Procesos de absorción intestinalMaría Jesús Rodríguez-Yoldi (Univ. Zaragoza)

PARTE VIII: SISTEMA ENDOCRINOCoordinador: Luis Felipe de la Cruz Palomino51. Concepto y definición de endocrinología.Biosíntesis y transporte de hormonasLuis Felipe de la Cruz Palomino (Univ. Santiago)52. Mecanismos de acción hormonalJesús Casabiell Pintos (Univ. Santiago)53. Hipotálamo. NeurohipófisisGraça Ferreira-Dias (Univ. Téc. Lisboa. Portugal)54. AdenohipófisisMiguel López Pérez (Univ. Santiago)55. La glándula pinealMercedes Rodríguez Vieytes (Univ. Santiago)56. TiroidesLuis Felipe de la Cruz Palomino (Univ. Santiago)57. Hormonas reguladoras del calcio y fósforoMercedes Rodríguez Vieytes (Univ. Santiago)58. Hormonas gastrointestinalesJoséAntonio Tapia García (Univ. Extremadura)59. Secreciones endocrinas del páncreasFernando Cordido Carballido (Univ. A Coruña)60. Corteza adrenalAura Antunes Colaço (Univ. Trás-os-Montes e AltoDouro. Portugal)61. Médula adrenalPaz Recio Visedo (Univ. ComplutenseMadrid)62. Riñón. Timo. ProstaglandinasPaulaA. Martins de Oliveira (Univ. Trás-os-Montes eAlto Douro. Portugal)63. Fisiología del crecimientoCarlos Diéguez (Univ. Santiago)PARTE IX: SISTEMA REPRODUCTORCoordinador: Luis Felipe de la Cruz Palomino64. Aparato genital masculinoEstrellaAgüera Buendia (Univ. Córdoba)


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65. Bases fisiológicas de la reproducción en la hembraAngelina Chiappe Barbará (Univ. BuenosAires)66. Fisiología de la gestaciónLuis Felipe de la Cruz Palomino (Univ. Santiago)67. Fisiología del partoAlbino García Sacristán (Univ. ComplutenseMadrid)68. Fisiología de la lactaciónDolores Prieto Ocejo (Univ. ComplutenseMadrid)69. Reproducción en equinosRafael Vivo Rodríguez (Univ. Córdoba)70. Reproducción en bóvidosAlejandroCórdova Izquierdo (U.Autón.Metropolita-na. México)71. Reproducción en ovejas y cabrasCarmenMatás Parra (Univ. Murcia)72. Reproducción en porcinosSalvador Ruiz López (Univ. Murcia)73. Reproducción en perros y gatosMedardo V. Hernández Rodríguez (UCM)74. Reproducción en animales de laboratorioPedro Lorenzo González (UCM)75. Reproducción aviar. Fisiología de la puestaMaríaArias Álvarez (UCM)

PARTE X: TERMORREGULACIÓNCoordinadora: Mª DivinaMurillo López de Silanes76. Metabolismo energético y generación de calorJosé Emilio Mesonero Gutiérrez (Univ. Zaragoza)

77. Regulación de la temperatura corporal.Adaptación y acomodaciónJosé Emilio Mesonero Gutiérrez (Univ. Zaragoza)

PARTE XI: FISIOLOGÍA DEL EJERCICIOCoordinador: Francisco CastejónMontijano78. Bases energéticas del ejercicio en el caballoFrancisco CastejónMontijano (Univ. Córdoba)79. Respuestas hematológicas, cardiovasculares yrespiratorias al ejercicioPablo I. Trigo (Univ. Nac. de la Plata. Argentina)80. Adaptaciones musculares al ejercicio y alentrenamiento. Biomecánica de la locomociónAnaMuñoz Juzado (Univ. Córdoba)81. Reg. neuroendocrina del ejercicio y elentrenamientoAnaMuñoz Juzado (Univ. Córdoba)82. Evaluación de la tolerancia al ejercicio y estado deforma físicaFrancisco CastejónMontijano (Univ. Córdoba)

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