Ciencias Morfolóxicas

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Synthesising a Fixed-Length Equispaced Linear Array to Produce Dolph–Chebyshev Patterns with Deep Nulls, a Desired Side Lobe Level and Different Beamwidths
(MDPI, 2025-03-01) Otero Gómez, Ibai; López Martín, María Elena; Rodríguez González, Juan Antonio; Ares Pena, Francisco José; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Departamento de Física Aplicada
A method for the synthesis of equally spaced antenna arrays based on the extension of the Orchard–Elliott–Stern technique to radiation patterns with three roots on the negative real axis of the Shelkunoff unit circle is presented. One of these roots is placed on the unit circle and the other two are off the unit circle with coordinates r and (Formula presented.). For a desired side lobe level (SLL), the synthesis of patterns with these roots allows for a multiplicity of solutions with different amplitude ratios, obtained by varying the value of r, each of which presents radiation patterns with different beamwidths and directivity, but with two fewer side lobes than the patterns obtained without these restrictions in the roots. The technique has been thoroughly applied to Dolph–Chebyshev patterns of 10, 18 and 40 elements, with a (Formula presented.) spacing and an SLL that guarantees maximum directivity in both cases. This approach ensures the study of examples of all sizes, from small to large. The findings derived from this technique would be applicable in the domain of wireless communications, where the necessity arises for radiation patterns that exhibit low SLL and adaptive beamwidth.
Gene expression analysis in circulating tumour cells to determine resistance to CDK4/6 inhibitors plus endocrine therapy in HR + /HER2- metastatic breast cancer patients
(BioMed Central, 2025-12-01) González Conde, Miriam; García-Caballero Parada, Tomás; López López, Rafael; Costa Nogueira, Clotilde; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina
Background: Metastatic breast cancer (BC) is the main cause of cancer-related mortality in women worldwide. HR + /HER2- BC patients are treated with endocrine therapy (ET), but therapeutic resistance is common. The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with ET was approved for metastatic BC patients and extended the median progression-free survival to 24 months. This therapy is not always effective, and in every patient, resistance ultimately occurs, but the underlying resistance mechanisms remain unclear. To address this gap, we explored circulating tumour cells (CTCs) as biomarkers to assess treatment response and resistance in metastatic HR + /HER2- BC patients receiving CDK4/6i plus ET. Methods: In total, 53 HR + /HER2- metastatic BC patients who received a CDK4/6i plus ET as first-line treatment were analysed, including samples from internal and external validation cohorts. CTCs were isolated using the negative enrichment approach RosetteSep (STEMCELL Technologies) or positive immunomagnetic selection targeting EpCAM, EGFR, and HER2 (AdnaTest EMT-2/StemCell Select™, QIAGEN). RNA was extracted from CTCs and PBMCs for nCounter analysis (Pancancer pathways panel) in a discovery phase. Subsequent validation was performed by RT-qPCR. Results: CTC gene expression analysis revealed that non responder patients (those who experienced disease progression before 180 days) exhibited elevated PRKCB (p-value: 0.011), MAPK3 (p-value: 0.006) and STAT3 (p-value: 0.008) expression, while responders showed increased CDK6 (p-value: 0.011) and CCND1 (p-value: 0.035) expression at baseline. CTC transcriptional characterization revealed a gene expression signature (STAT3highPRKCBhighCDK6low) that accurately classified HR + /HER2- metastatic BC patients who responded to CDK4/6i plus ET, regardless of the CTC isolation method (AUC > 0.8). CTC characterization at progression also identified biomarkers linked to therapy resistance, including the epigenetic regulators EZH2 and HDAC6 and the cell cycle regulator CDC7, which could guide the selection of subsequent therapy lines. The expression of the CDK4 and STAT3 genes in CTCs was associated with progression-free survival and overall survival, respectively. Likewise, the presence of ≥ one CTC after one cycle of therapy predicts a worse prognosis. Conclusions: CTC gene expression provides information about treatment outcomes in HR + /HER2- metastatic BC patients receiving CDK4/6i plus ET and could guide personalized strategies and improve prognosis.
E74-like ETS transcription factor 3 expression and regulation in human intervertebral disc
(Wiley, 2025-03-01) González-Rodríguez, María; Ait Eldjoudi, Djedjiga; Cordero Barreal, Alfonso; Farrag, Mariam; Varela García, María; Ruiz Fernández, Clara; Torrijos Pulpón, Carlos; Lago, Francisca; García-Caballero, Lucía; Farrag, Yosouf; Conde Aranda, Javier; Pino Mínguez, Jesús; Gualillo, Oreste; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Departamento de Cirurxía e Especialidades Médico-Cirúrxicas
Background: Intervertebral disc degeneration (IVDD) is one of the main causes of chronic low back pain. The degenerative process is often initiated by an imbalance between catabolic and anabolic pathways. Despite the large socio-economic impact, the initiation and progress of disc degeneration are poorly understood. Although intervertebral disc (IVD) and articular joint are not identical, their degenerative roads are remarkably similar. We, and another authors, previously demonstrated that E-74-like factor 3 (ELF3), a transcription factor induced by inflammatory mediators in various cell types including chondrocytes, is a central contributing factor for cartilage degradation. Thus, we aim to explore, for the first time, the expression, modulation, and the role of ELF3 in human IVD cells. Methods: The presence of ELF3 in healthy and degenerated IVD tissues was initially determined by immunohistochemistry in annulus fibrosus (AF) and nucleus pulposus (NP). mRNA and protein expression were measured, respectively, by RT-qPCR and Western blot in AF and NP IVD cells harvested from healthy individuals and IVDD patients. Overexpression of ELF3 was performed by transfection of AF IVDD cells with pESE-1: ELF3 expression vector or pCI: empty vector. Results: Our results unveiled, for the first time, the expression of ELF3 in IVD tissues. ELF3 is notably upregulated in degenerated tissues compared to those from healthy patients. In addition, the stimulation of IVDD AF cells with various proinflammatory stimuli, showed marked increase in both mRNA and protein expression of ELF3. ELF3 overexpression in AF IVDD cells resulted in the upregulation of proinflammatory and catabolic genes such as PTGS2, NOS2, LCN2, IL-6, MMP13, and ADAMTS-5; whereas, ELF3 silencing resulted in the opposite results. Conclusions: Our results support a novel role for ELF3 as a pro-inflammatory and pro-catabolic transcriptional mediator, whose targeting in IVD tissues might be of potential therapeutic relevance in disc degeneration.
Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis
(Elsevier, 2018-02) Porteiro Couto, Begoña; Fernández Fondevila, Marcos; Buque García, Xabier; González Rellán, María Jesús; Fernández Paz, Uxía; Mora Corral, Alfonso; Beiroa Tarrío, Daniel; Senra, Ana; Gallego Gómez, Rosalía; Fernø, Johan; López Pérez, Miguel A.; Sabio, Guadalupe; García Diéguez, Carlos; Aspichueta Celaá, Patricia; Nogueiras Pozo, Rubén; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Departamento de Fisioloxía; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
Objective Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2). Results The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion These data provide new evidence for targeting p53 as a strategy to treat liver disease
Obestatin controls skeletal muscle fiber-type determination
(Springer nature, 2017-05-18) Santos Zas, Icía; Cid Díaz, Tania; González Sánchez, Jessica; Gurriarán Rodríguez, Uxía; Seoane Mosteiro, Carlos; Porteiro Couto, Begoña; Nogueiras Pozo, Rubén; Casabiell Pintos, Jesús Antonio; Relova Quinteiro, José Luis; Gallego Gómez, Rosalía; Mouly, Vincent; Pazos Randulfe, Yolanda; Pérez Camiña, Jesús; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Obestatin/GPR39 signaling stimulates skeletal muscle growth and repair by inducing both G-protein-dependent and -independent mechanisms linking the activated GPR39 receptor with distinct sets of accessory and effector proteins. In this work, we describe a new level of activity where obestatin signaling plays a role in the formation, contractile properties and metabolic profile of skeletal muscle through determination of oxidative fiber type. Our data indicate that obestatin regulates Mef2 activity and PGC-1α expression. Both mechanisms result in a shift in muscle metabolism and function. The increase in Mef2 and PGC-1α signaling activates oxidative capacity, whereas Akt/mTOR signaling positively regulates myofiber growth. Taken together, these data indicate that the obestatin signaling acts on muscle fiber-type program in skeletal muscle
Laser-induced transient skin disruption to enhance cutaneous drug delivery
(Elsevier, 2020-09-03) Río Sancho, Sergio del; Pan Delgado, Diego; Fuente, Germán F. de la; García-Caballero Parada, Tomás; Taboada Suárez, Antonio; Csaba, Noemi Stefania; Bao Varela, María del Carmen; Alonso Fernández, María José; Universidade de Santiago de Compostela. Departamento de Física Aplicada; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Departamento de Farmacia e Tecnoloxía Farmacéutica
The use of pressure waves (PW) to disrupt the stratum corneum (SC) temporarily is an effective strategy to increase the deposition of drug molecules into the skin. However, given the rather modest outcomes when compared with ablation-assisted drug delivery, its potential has been underestimated. Accordingly, the aim of this study was to examine the impact of Resonant Amplitude Waves (RAWs) on increasing cutaneous delivery. RAW phenomena are triggered by focusing a high-peak-power pulsed laser onto an appropriate transducer structure, under space- and time-controlled resolution. In order to determine the optimal conditions for the generation and use of RAWs, a screening of laser parameters setting and an analysis of different geometries of the impact pattern over diverse materials used as transducers was performed, analyzing the footprint of the RAW waves in an agarose gel. The results obtained were then checked and fine-tuned using human skin samples instead of agarose. Furthermore, ex vivo experiments were carried out to characterize the effect of the RAWs in the cutaneous delivery of diclofenac (DIC) and lidocaine (LID) administered in the form of gels. The application of RAWs resulted in an increased delivery of DIC and LID to the skin, whose intensity was dependent on the composition of the formulation. In fact, the maximum observed for DIC and LID in short-time experiments (39.1 ± 11.1 and 153 ± 16 µg/cm2 , respectively) was comparable to those observed using ablation-assisted drug delivery under the same conditions. In conclusion, the combination of RAWs with specific formulation strategies is a feasible alternative for the cutaneous delivery of drug candidates when short onset of action is required.
Haemodynamic-dependent arrest of circulating tumour cells at large blood vessel bifurcations as new model for metastasis
(Nature, 2021-12-01) Casas Arozamena, Carlos; Otero Cacho, Alberto; Carnero Groba, Bastián; Almenglo Buzón, Cristina; Aymerich López, María de la Inmaculada; Alonso Alconada, Lorena; Ferreirós, Alba; Abalo Piñeiro, Alicia; Bao Varela, María del Carmen; Flores Arias, María Teresa; Álvarez Castro, Ezequiel; Pérez Muñuzuri, Alberto; Abal Posada, Miguel; Universidade de Santiago de Compostela. Departamento de Física Aplicada; Universidade de Santiago de Compostela. Facultade de Física; Universidade de Santiago de Compostela. Facultade de Óptica e Optometría; Universidade de Santiago de Compostela. Centro Interdisciplinar de Investigación en Tecnoloxías Ambientais (CRETUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Homing of circulating tumour cells (CTC) at distant sites represents a critical event in metastasis dissemination. In addition to physical entrapment, probably responsible of the majority of the homing events, the vascular system provides with geometrical factors that govern the flow biomechanics and impact on the fate of the CTC. Here we mathematically explored the distribution of velocities and the corresponding streamlines at the bifurcations of large blood vessel and characterized an area of low-velocity at the carina of bifurcation that favours the residence of CTC. In addition to this fluid physics effect, the adhesive capabilities of the CTC provide with a biological competitive advantage resulting in a marginal but systematic arrest as evidenced by dynamic in vitro recirculation in Y-microchannels and by perfusion in in vivo mice models. Our results also demonstrate that viscosity, as a main determinant of the Reynolds number that define flow biomechanics, may be modulated to limit or impair CTC accumulation at the bifurcation of blood vessels, in agreement with the apparent positive effect observed in the clinical setting by anticoagulants in advanced oncology disease
The sensory penis: A comprehensive immunohistological and ontogenetic exploration of human penile innervation
(Wiley, 2025-09-19) Cepeda Emiliani, Alfonso; Otero Alén, María; Suárez Quintanilla, Juan; Gándara Cortés, Marina; García-Caballero Parada, Tomás; Gallego Gómez, Rosalía; García-Caballero, Lucía; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Background: Penile sexual sensation relies on intricate neural structures that remainincompletely characterized. Immunohistological insights into their development andorganization can enhance understanding of penile neuroanatomy and function, whileoptimizing surgical outcomes. Objectives: To elucidate the ontogeny, organization, and immunohistological featuresof human penile innervation in fetal and adult specimens, primarily focusing on thefrenular delta, sensory corpuscles, and related structures to address gaps in anatomicalknowledge and inform surgical practices. Materials and methods: Formalin-fixed, paraffin-embedded tissues from 30 fetal (8–24 weeks) and 14 adult cadaveric penile specimens were analyzed. Routine histologicalstains and immunohistochemical markers targeting neural structures were applied.Serial sections were examined for histology, neuroanatomical mapping, sensorycorpuscle characterization, and neural density assessments. Results: Fetal penile neurodevelopment exhibited two phases: the pre-corpuscularstage (8–16 weeks), marked by axonal hyperinnervation and exuberant ventral intraep-ithelial nerve fibers, and the corpuscular stage (17–24 weeks), characterized byPacinian corpuscle emergence and targeted neural pruning. Adult specimens showedregion-specific neural distributions, with heightened densities in the frenular delta.Intracorporeally, sensory corpuscles exhibited a bimodal intraspongiosal distribution,with Pacinians in the bulb and glans. Molecular profiles of sensory corpuscles, includingnovel immunoreactivities, were comprehensively documented. The preputial dartosand vasculature displayed dense autonomic innervation. A superficial glans tunicaalbuginea was identified, with implications for neural organization. Discussion: These findings reveal previously unrecognized transitions during fetalpenile neural development and into adulthood, providing a foundation for the neurode-velopmental biology of the human penis and documenting the frenular delta’s uniqueinnervation. The characterization of penile neural components and the glans tunica albuginea addresses longstanding anatomical and sexological questions. Our resultsinform current debates on penile circumcision and neurotomy. Conclusion: This study provides a comprehensive ontogenetic framework of penileinnervation, emphasizing the frenular delta as a specialized center of sexual sensation.
Delivery of monoclonal antibodies to the brain: the impact of nanocarrier structure
(Springer Nature, 2025) Piñeiro Alonso, Laura; Rubio Prego, Inés; López Estévez, Ana María; Garrido Gil, Pablo; Valenzuela Limiñana, Rita; Labandeira García, José Luis; Aguiar Fernández, Pablo; Rodríguez Pérez, Ana Isabel; Alonso Fernández, María José; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica; Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Monoclonal antibodies (mAbs) are promising therapeutic agents for neurological disorders due to their high specificity. However, their clinical application is significantly hindered by their poor transport across the blood-brain barrier (BBB) and their limited diffusion within the brain parenchyma. While significant efforts have been oriented to tackle the first barrier, the challenge of efficient brain diffusion remains largely underexplored. To address this, we have developed and evaluated two structurally distinct nanosystems for mAb delivery to the brain: PEGylated polyglutamic acid nanocapsules (PGA-PEG NCs) and PGAC14-based nanoassemblies (PGAC14 NAs). Both formulations encapsulated efficiently the model mAb bevacizumab (BVZ) while they exhibited different physicochemical properties. Namely, PGA-PEG NCs displayed a size of 80 nm and a neutral zeta potential, whereas PGAC14 NAs featured an ultra-small size of 40 nm and a negative surface charge. After assessing their diffusion capacity using immunofluorescence, we concluded that PGAC14 NAs exhibited the highest brain diffusion together with a favorable neuroinflammatory profile. This was likely driven by their small size and negative charge, along with a selective ability to interact with and deliver BVZ intracellularly to neuronal cells upon intraparenchymal administration. These findings provide key insights into optimizing nanocarrier design for improved mAb delivery to the brain
Plasma and neurostructural biomarkers in the clinical-biological characterization of early stages of the Alzheimer's disease continuum: findings from the Compostela Aging Study
(Elsevier, 2025) Zurrón Ocio, Montserrat; Pereiro Rozas, Arturo X.; Rodríguez Pérez, Ana Isabel; Galdo Álvarez, Santiago; Ansede, Juan José; Lojo Seoane, Cristina; Lindín Novo, Mónica; Facal Mayo, David; Rivas-Fernández, Miguel Ángel; Campos Magdaleno, María; Carracedo Álvarez, Ángel; Labandeira García, José Luis; Díaz Fernández, Fernando; Universidade de Santiago de Compostela. Departamento de Psicoloxía Evolutiva e da Educación; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Instituto de Psicoloxía (IPsiUS); Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Psicoloxía Clínica e Psicobioloxía
Recent technical advances in peripheral blood analysis have enabled precise quantification of Alzheimer´s Disease (AD) biomarkers in the early stages of the AD continuum, in an economical, non-invasive and safe manner. The main objective of this study was to contribute to the clinical-biological characterization of the initial stages of cognitive impairment by measurement of blood and neurostructural AD biomarkers in groups of participants classified according to their cognitive clinical phenotype. Plasma concentrations of p-tau217, p-tau181, total tau, neurofilament light chain and amyloid-β 42/40 ratio biomarkers were measured along with APOE gene variants, hippocampal volume and cortical thickness of the AD signature regions. The cohort of 329 participants included Cognitively Unimpaired (CU), Subjective Cognitive Decline (SCD), single-domain amnestic Mild Cognitive Impairment (sd-aMCI), multidomain aMCI (md-aMCI), and single-domain non-amnestic MCI (sd-naMCI) groups. P tau217 concentrations were significantly higher in the md-aMCI and sd-aMCI groups than in the CU, SCD and sd-naMCI groups. P-tau181 concentrations were significantly higher in md-aMCI group than in CU, SCD and sd-naMCI groups. Hippocampal volume and AD signature cortical thickness were significantly lower in the md-aMCI group than in the CU, SCD and sd-naMCI groups. No across group differences were found in the distribution of carriers/non-carriers of APOE-ε4. Mediation analysis revealed that hippocampal volume and AD signature cortical thickness mediated the relationship between p-tau217 and p-tau181 levels and cognitive performance. Sd-aMCI and md-aMCI represent two distinct and sequential clinical-biological stages of the AD continuum. Conversely, sd-naMCI does not appear to be associated with AD pathology. Finally, the SCD group does not seem to display a higher risk of progression along the AD continuum than the CU group.
Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms
(Elsevier, 2025) Lage Pita, Lucía; Rodríguez Pérez, Ana Isabel; Labandeira García, José Luis; Domínguez Meijide, Antonio; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.
Redox cell signalling triggered by black carbon and/or radiofrequency electromagnetic fields: Influence on cell death
(Elsevier, 2024-09-05) López Martín, María Elena; Sueiro-Benavides, Rosana; Leiro Vidal, José Manuel; Rodríguez González, Juan Antonio; Ares Pena, Francisco José; Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas; Universidade de Santiago de Compostela. Departamento de Física Aplicada
The capacity of environmental pollutants to generate oxidative stress is known to affect the development and progression of chronic diseases. This scientific review identifies previously published experimental studies using preclinical models of exposure to environmental stress agents, such as black carbon and/or RF-EMF, which produce cellular oxidative damage and can lead to different types of cell death. We summarize in vivo and in vitro studies, which are grouped according to the mechanisms and pathways of redox activation triggered by exposure to BC and/or EMF and leading to apoptosis, necrosis, necroptosis, pyroptosis, autophagy, ferroptosis and cuproptosis. The possible mechanisms are considered in relation to the organ, cell type and cellular-subcellular interaction with the oxidative toxicity caused by BC and/or EMF at the molecular level. The actions of these environmental pollutants, which affect everyday life, are considered separately and together in experimental preclinical models. However, for overall interpretation of the data, toxicological studies must first be conducted in humans, to enable possible risks to human health to be established in relation to the progression of chronic diseases. Further actions should take pollution levels into account, focusing on the most vulnerable populations and future generations.
Increased Risk of Mortality Associated With Pancreatic Exocrine Insufficiency in Patients With Chronic Pancreatitis
(Lippincott, Williams & Wilkins, 2018-09) Iglesia-García, Daniel de la; Vallejo-Senra, Nicolau; Iglesias-García, Julio; López López, Andrea; Nieto, Laura; Domínguez Muñoz, Juan Enrique
Background: Pancreatic exocrine insufficiency (PEI) is a common serious complication in chronic pancreatitis (CP); however, little is known about its effect on mortality in these patients. In this study, we assessed the mortality risk of PEI in patients with CP. Study: A prospective, longitudinal cohort study conducted in patients with CP under long-term follow-up. CP and PEI were diagnosed using pancreatic imaging and the 13C-labeled mixed triglyceride breath test, respectively. Multivariate analysis was performed to evaluate the impact of PEI and other clinical features on mortality risk. Results: Patients (N=430) were analyzed (79.1% male; mean age, 47.8 y) during a mean follow-up of 8.6±4.6 years. PEI prevalence was 29.3% and mortality was 10.9%. Most frequent causes of death were cancer (40.4%), infection (21.3%), and acute cardiovascular event (14.9%). Multivariate analyses showed associations between increased mortality and presence of PEI [hazard ratio (HR), 2.59; 95% confidence interval (CI), 1.42-4.71; P<0.003], liver cirrhosis (HR, 3.87; 95% CI, 1.95-7.69; P<0.001), age at diagnosis (HR, 1.05; 95% CI, 1.03-1.09; P<0.001), toxic etiology of CP (HR, 3.11; 95% CI, 1.11-8.70; P<0.05) and respiratory comorbidity (HR, 2.19; 95% CI, 1.12-4.31; P<0.03). Nutritional markers were significantly lower in patients with PEI versus those without PEI (P<0.001) and in those who died versus survivors (P<0.001). Conclusions: PEI was a significant independent risk factor for mortality in patients with CP. These results support further research into the optimal treatment of PEI to reduce mortality in this population.
Pancreatic exocrine insufﬁciency and cardiovascular risk in patients with chronic pancreatitis: A prospective, longitudinalcohort study
(Wiley, 2018-08-29) Iglesia, Daniel de la; Vallejo-Senra, Nicolau; López López, Andrea; Iglesias-García, Julio; Lariño-Noia, Jose; Nieto-García, Laura; Domínguez Muñoz, Juan Enrique
Background and aim: Previous studies have suggested that chronic pancreatitis (CP) is associated with increased risk of cardiovascular (CV) disease independently of other major risk factors. We evaluated the risk of CV events in a well-phenotyped cohort of patients with CP and its association with pancreatic exocrine insufficiency (PEI) among other CV risk factors. Methods: This was a prospective, longitudinal cohort study of patients with CP, followed up at the Pancreas Unit of the University Hospital of Santiago de Compostela, Spain. Results: Four hundred thirty patients were included (mean 47.8 ± 14.4 years of age, 79.1% male). Mean follow-up was 8.6 ± 4.6 years. CP etiology was toxic (alcohol and/or smoking) in 290 patients (67.4%). PEI and pancreatogenic diabetes mellitus (DM) were present in 29.3% and 29.5% of the patients, respectively. A total of 45 CV events was recorded (10.5%); 21 patients had a major CV event (stroke or myocardial infarction) and 27 developed clinically relevant peripheral arterial disease. A higher incidence of CV events was recorded in patients with PEI than in those without (incidence rate ratio 3.67, 95% confidence interval [CI] 1.92-7.24; P < 0.001). In the multivariate analysis, PEI without DM (OR 4.96; 95% CI 1.68 to 14.65), coexistence of PEI and DM (OR 6.54; 95% CI 2.71 to 15.77), arterial hypertension (OR 3.40; 95% CI 1.50 to 7.72), and smoking (OR 2.91, 95% CI 1.07 to 7.97) were independently associated with increased CV risk. Conclusions: Together with known major CV risk factors like smoking and hypertension, PEI is significantly associated with the risk of CV events in patients with CP.
p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1
(Nature Research, 2018) Quiñones Téllez, María del Mar; Al-Massadi, Omar; Folgueira, Cintia; Gallego Gómez, Rosalía; Torres-Leal, Leonardo; Hernández-Bautista, Rene; Beiroa, Daniel; Sánchez-Rebordelo, Estrella; Senra, Ana; Hernández Malagón, José Ángel; Valerio, Patricia; Fernández Fondevila, Marcos; Diéguez González, Carlos; López Pérez, Miguel A.; Nogueiras Pozo, Rubén; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.
Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia
(Springer, 2024-10-22) Quijano Ocampo, Aloia; Rodríguez Pérez, Ana Isabel; Costa Besada, María Alicia; López López, Andrea; Guerra Seijas, María Josefa Natividad; Labandeira García, José Luis; Valenzuela Limiñana, Rita; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Renin-angiotensin system (RAS) dysfunctions have been associated to life-spam, and aging-related diseases, including neurodegenerative diseases, such as Parkinson's disease, and the neuroinflammatory associated processes. Mitochondrial dysfunctions play a major role in aging-related diseases, including dopaminergic neurodegeneration and neuroinflammation. However, the mechanisms of RAS/mitochondria interactions remain to be clarified. In the present work, we studied the role of major RAS components in the mitochondrial dynamics in dopaminergic neurons and microglia using in vitro and in vivo models. In dopaminergic neurons, we observed that activation of the RAS pro-oxidative/pro-inflammatory axis (Angiotensin II/Angiotensin type-1 receptor, AT1/NADPH oxidase complex) produces a dysregulation of mitochondrial dynamics towards mitochondrial fission, via Drp1 phosphorylation at Ser616 and translocation to mitochondria. However, activation of the RAS antioxidative/anti-inflammatory axis, using Angiotensin 1-7, counteracts this effect. RAS components also modulated the microglial inflammatory response through mitochondrial dynamic changes. After interferon-γ-induced activation of human microglial cells, we observed increased mitochondrial fission and superoxide production that was inhibited by Angiotensin 1-7 treatment. Angiotensin 1-7 also inhibited mitochondrial metabolic changes induced by pro-inflammatory microglial activation. The role of RAS in mitochondrial dynamic changes was confirmed in vivo using the LPS-induced inflammation model in wild-type, AT1-KO, and AT2-KO mice. The effect of Angiotensin 1-7 is mediated by IL-10, specifically by decreasing the post-transcriptional phosphorylated Drp1 form, and translocation of STAT3 to mitochondria. Angiotensin 1-7, acting on mitochondrial Angiotensin 1-7 receptors (Mas/Mas related receptors), increased the phosphorylated form of STAT3 at Ser727, which is mediated by mitochondrial PKA activation. In conclusion, the present findings show the role of RAS components in modulation of mitochondrial dynamics and mitochondrial function, revealing the associated signaling pathways. The results lead to better understanding of the effects of RAS dysfunction in aging-related diseases, and particularly dopaminergic degeneration and neuroinflammation in Parkinson's disease.
An ACE2/Mas-related receptor MrgE axis in dopaminergic neuron mitochondria
(Elsevier, 2021-07-22) Valenzuela Limiñana, Rita; Rodríguez Pérez, Ana Isabel; Costa Besada, María Alicia; Rivas Santisteban, Rafael; Garrido Gil, Pablo; López López, Andrea; Navarro, Gemma; Lanciego Pérez, José Luis; Franco Fernández, Rafael; Labandeira García, José Luis; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
ACE2 plays a pivotal role in the balance between the pro-oxidative pro-inflammatory and the anti-oxidative anti-inflammatory arms of the renin-angiotensin system. Furthermore, ACE2 is the entry receptor for SARS-CoV-2. Clarification of ACE2-related mechanisms is crucial for the understanding of COVID-19 and other oxidative stress and inflammation-related processes. In rat and monkey brain, we discovered that the intracellular ACE2 and its products Ang 1-7 and alamandine are highly concentrated in the mitochondria and bind to a new mitochondrial Mas-related receptor MrgE (MrgE) to produce nitric oxide. We found MrgE expressed in neurons and glia of rodents and primates in the substantia nigra and different brain regions. In the mitochondria, ACE2 and MrgE expressions decreased and NOX4 increased with aging. This new ACE2/MrgE/NO axis may play a major role in mitochondrial regulation of oxidative stress in neurons, and possibly other cells. Therefore, dysregulation of the mitochondrial ACE2/MrgE/NO axis may play a major role in neurodegenerative processes of dopaminergic neurons, where mitochondrial dysfunction and oxidative stress play a crucial role. Since ACE2 binds SARS-CoV-2 spike protein, the mitochondrial ACE2/MrgE/NO axis may also play a role in SARS-CoV-2 cellular effects.
Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
(MDPI, 2023-07-19) López López, Andrea; Valenzuela Limiñana, Rita; Rodríguez Pérez, Ana Isabel; Guerra Seijas, María Josefa Natividad; Labandeira García, José Luis; Muñoz Patiño, Ana María; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson's disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms.
Physical Exercise Improves Aging-Related Changes in Angiotensin, IGF-1 SIRT1, SIRT3, and VEGF in the Substantia Nigra
(Oxford University Press, 2018-04-04) Labandeira García, José Luis; Díaz Ruiz, María del Carmen; Costa Besada, María Alicia; López López, Andrea; Corrêa, Clynton L.; Muñoz Patiño, Ana María; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Dysregulation of tissue renin-angiotensin system (RAS) is involved in oxidative and inflammatory processes observed in major aging-related diseases, including neurodegenerative diseases such as Parkinson's disease (PD). Physical exercise has beneficial effects against aging-related changes, dopaminergic neuron vulnerability, and PD progression. The present study indicates that sedentary aged rats have an increase in activity of the nigral angiotensin (Ang) II/Ang type 1 receptor (AT1) axis (ie, the pro-oxidative pro-inflammatory arm), and a decrease in the activity of the RAS protective arm (ie, Ang II/AT2 and Ang 1-7/Mas receptor axis) in comparison with young rats. In addition, sedentary aged rats showed a decrease in levels of nigral IGF-1, SIRT1, SIRT3, and VEGF. Treadmill running induced a significant increase in levels of IGF-1, SIRT1, SIRT3, and VEGF, as well as an increase in expression of the protective Ang 1-7/Mas axis and inhibition of the Ang II/AT1 axis. The exercise-induced increase in IGF-1 and sirtuins may mediate the effects of exercise on the nigral RAS. However, exercise may induce the increase in VEGF and modulation of RAS activity by different pathways. Exercise, via RAS, contributes to inhibition of the pro-oxidative and proinflammatory state that increase dopaminergic neuron vulnerability and risk of PD with aging.
Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson's Disease and Adverse Effects of L-DOPA
(Frontiers, 2020-06-04) Muñoz Patiño, Ana María; López López, Andrea; Labandeira Guerra, Carmen; Labandeira García, José Luis; Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS); Universidade de Santiago de Compostela. Departamento de Ciencias Morfolóxicas
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a "false" transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD.

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