Browsing by Author "Fernández, Ricardo"
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Publication Genetic and epigenetic landscape of early-onset oral squamous cell carcinoma: Insights of genomic underserved and underrepresented populations(2024) Adorno, Daniela; Morales, Sebastián; Gischkow, Guilherme; Margarit, Sonia; Fernández, RicardoOral squamous cell carcinoma (OSCC) has a poor prognosis and the treatment employed generates significant physical deformity in patients. In recent years, an increase in the incidence of cases of OSCC has been observed in adult patients up to 45 years old in several genetic underrepresented and underserved countries. The increase in OSCC cases in young people is very relevant because it shows that OSCC does not make exceptions and hereditarily must play an important role. This fact has not been associated with an evident biological basis, and a large majority of these patients do not present the classic principal risk factors association. OSCC is the result of accumulation of genetic and epigenetic alterations and this information is still fragmented in the literature, mainly in the young group. Conducting studies with a comprehensive analysis of genetic and epigenetic data is crucial, to provide greater understanding of the underlying biology of OSCC, because this information can be decisive to determine targets for therapeutic treatment. We review the main germline and somatic aspects of genetic and genomic variation in OSCC considering the absence of genomic data from developing countries such as Chile and the rest of Hispano-America.Item Immunosensory signaling by carotid body chemoreceptors(2011) Zapata, Patricio; Larraín, Carolina; Reyes, Pablo; Fernández, RicardoInjections of lipopolysaccharide (LPS) have been used to produce the signs of sepsis and study their underlying mechanisms. Intravenous (IV) injections of LPS in anesthetized cats induce tachypnea, tachycardia and hypotension, but ventilatory changes are suppressed after sectioning carotid and aortic nerves. Otherwise. LPS increases the basal frequency of carotid chemosensory discharges, but reduces ventilatory and chemosensory responses to hypoxia and nicotine injections. Increases in cytokines (IL-1 beta, IL-6 and TNF-alpha) are observed in plasma and tissues after injecting LPS. In carotid bodies perfused in vitro. TNF-alpha reduces chemosensory discharges induced by hypoxia. The rat carotid body and its sensory ganglion constitutively express LPS canonical receptor. TLR4, as well as TNF-alpha and its receptors (TNF-R1 and TNF-R2). Increases of TNF-alpha and TNF-R2 expression occur after LPS administration. The activation of peripheral and central autonomic pathways induced by LPS or IL's is partly dependent on intact vagus nerves. Thus, the carotid and vagus nerves provide routes between the immune system and CNS structures involved in systemic inflammatory responses. (C) 2011 Elsevier B.V. All rights reserved.Item Lipopolysaccharide-Induced Ionized Hypocalcemia and Acute Kidney Injury in Carotid Chemo/Baro-Denervated Rats.(Springer International Publishing AG, 2015) Fernández, Ricardo; Cortés, Paula; Del Río, Rodrigo; Acuña-Castillo, Claudio; Reyes, EdisonThe acute kidney injury (AKI) observed during sepsis is due to an uncontrolled release of inflammatory mediators. Septic patients develop electrolytic disturbances and one of the most important is ionized hypocalcemia. AKI adversely affects the function of other organs and hypocalcemia is associated with cardiovascular and respiratory dysfunctions. Since carotid body chemoreceptors modulate the systemic inflammatory response during sepsis syndromes, we used pentobarbitone-anesthetized male Sprague-Dawley rats in control condition (SHAM surgery) and after bilateral carotid neurotomy (carotid chemo/baro-denervated, BCN). We evaluate serum creatinine (CRE), serum neutrophil gelatinase-associated lipocaline (NGAL), ionized calcium (iCa) and cardiac Troponin I (cTnI) 90 min after the IP administration of 15 mg/kg lipopolysaccharide (LPS) or saline. In the SHAM group, LPS failed to induce significant changes CRE, NGAL, or iCa, and increased cTnI. Conversely, in the BCN group LPS increased CRE and NGAL, decreased iCa, and enhanced the increase of cTnI. Our results suggest that carotid chemo/baro-receptors might contribute to the regulation of both renal function and calcemia during sepsis. In addition, results imply that the carotid chemo-baroreceptors serve as an immunosensory organ.Item Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy(Frontiers Research Foundation, 2014) Fernández, Ricardo; Nardocci, Gino; Navarro, Cristina; Reyes, Edison; Acuña-Castillo, Claudio; Cortes, PaulaSepsis progresses to multiple organ dysfunction due to the uncontrolled release of inflammatory mediators, and a growing body of evidence shows that neural signals play a significant role in modulating the immune response. Thus, similar toall other physiological systems, the immune system is both connected to and regulated by the central nervous system. The efferent arc consists of the activation of the hypothalamic–pituitary–adrenal axis, sympathetic activation, the cholinergic anti-inflammatory reflex, and the local release of physiological neuromodulators. Immunosensory activity is centered on the production of pro-inflammatory cytokines, signals that are conveyed to the brain through different pathways. The activation of peripheral sensory nerves, i.e., vagal paraganglia by the vagus nerve, and carotid body (CB) chemoreceptors by the carotid/sinus nerve are broadly discussed here. Despite cytokine receptor expression in vagal afferent fibers, pro-inflammatory cytokines have no significant effect on vagus nerve activity. Thus, the CB may be the source of immunosensory inputs and incoming neural signals and, in fact, sense inflammatory mediators, playing a protective role during sepsis. Considering that CB stimulation increases sympathetic activity and adrenal glucocorticoids release, the electrical stimulation of arterial chemoreceptors may be suitable therapeutic approach for regulating systemic inflammation.Item Opening of pannexin- and con nexin-based channels increases the excitability of nodose ganglion sensory neurons(Frontiers Research Foundation, 2014) Retamal, Mauricio; Alcayaga, Julio; Verdugo, Christian; Bultynck, Geert; Leybaert, Luc; Sáez, Pablo; Fernández, Ricardo; León, Luis; Sáez, JuanSatellite glial cells (SGCs) are the main glia in sensory ganglia. They surround neuronal bodies and form a cap that prevents the formation of chemical or electrical synapses between neighboring neurons. SGCs have been suggested to establish bidirectional paracrine communication with sensory neurons. However, the molecular mechanism involved in this cellular communication is unknown. In the central nervous system (CNS), astrocytes present connexin43 (Cx43) hemichannels and pannexin1 (Panx1) channels, and the opening of these channels allows the release of signal molecules, such as ATP and glutamate. We propose that these channels could play a role in glia-neuron communication in sensory ganglia. Therefore, we studied the expression and function of Cx43 and Panx1 in rat and mouse nodose-petrosal-jugular complexes (NPJcs) using confocal immunofluorescence, molecular and electrophysiological techniques. Cx43 and Panx1 were detected in SGCs and in sensory neurons, respectively. In the rat and mouse, the electrical activity of vagal nerve increased significantly after nodose neurons were exposed to a Ca2+/Mg2+-free solution, a condition that increases the open probability of Cx hemichannels. This response was partially mimicked by a cell-permeable peptide corresponding to the last 10 amino acids of Cx43 (TAT-Cx43CT). Enhanced neuronal activity was reduced by Cx hemichannel, Panx1 channel and P2X7 receptor blockers. Moreover, the role of Panx1 was confirmed in NPJc, because in those from Panx1 knockout mice showed a reduced increase of neuronal activity induced by Ca2+/Mg2+-free extracellular conditions. The data suggest that Cx hemichannels and Panx channels serve as paracrine communication pathways between SGCs and neurons by modulating the excitability of sensory neurons.Publication Prevalence Distribution of Chronic Obstructive Pulmonary Disease (COPD) in the City of Osorno (Chile) in 2018, and Its Association with Fine Particulate Matter PM2.5 Air Pollution(2024) Fernández, Ricardo; Peña, Romina; Bravo, Jaime; Maisey, Kevin; Reyes, EdisonOutdoor air pollution and biomass smoke exposure are related to the prevalence of chronic obstructive pulmonary disease (COPD). Since Osorno, Chile, is saturated with fine particulate matter (PM2.5), the aim of this work is to determine the prevalence distribution of COPD patients in the Primary Health Care (PHC) system in the city of Osorno, and its relationship with PM2.5. A cross-sectional descriptive study was carried out on COPD patients enrolled in the six PHC centers (PHCCs) of the city to assess the adjusted prevalence (population over 40 years). Gender- and territory-associated odds ratios (ORs) were also determined. In addition, an urban analysis of the distribution of PM2.5 and an exploratory analysis of the spatial behavior of enrolled COPD patients through featured binning were carried out. In 2018, the city of Osorno had 809 enrolled COPD patients in the PHC system (55.1% female), with a 1.3% age-adjusted prevalence (inhabitants over 40 years old), which was 11.7% after underdiagnosis correction. The COPD patients were mainly between 70 and 79 years old (34.3%). The urban area under the administration of the PHCC Rahue Alto (PHCC-RA) had a higher OR (1.98 [1.73–2.26]) compared to the situation of the city. Also, air pollution (PM2.5) was the highest in the PHCC-RA area, which could account for the observed prevalence. The number of COPD patients in this area is the highest in the commune, which increases the risk of complications derived from the disease and air pollution. Thus, territories with the highest COPD prevalence have the largest OR, which could complicate patients’ condition due to the high levels of outdoor air pollution.Item Sepsis progression to multiple organ dysfunction in carotid chemo/baro-denervated rats treated with lipopolysaccharide(Elsevier B.V., 2015) Nardocci, Gino; Martín, Aldo; Abarzúa, Sebastián; Rodríguez, Jorge; Simon, Felipe; Reyes, Edison; Acuña-Castillo, Claudio; Navarro, Cristina; Cortés, Paula; Fernández, RicardoSepsis progresses to multiple organ dysfunction (MOD) due to the uncontrolled release of inflammatory mediators. Carotid chemo/baro-receptors could play a protective role during sepsis. In anesthetized male rats, we measured cardiorespiratory variables and plasma TNF-α, glucocorticoids, epinephrine, and MOD marker levels 90min after lipopolysaccharide (LPS) administration in control (SHAM surgery) and bilateral carotid chemo/baro-denervated (BCN) rats. BCN prior to LPS blunted the tachypneic response and enhanced tachycardia and hypotension. BCN-LPS rats also showed blunted plasma glucocorticoid responses, boosted epinephrine and TNF-α responses, and earlier MOD onset with a lower survival time compared with SHAM-LPS rats. Consequently, the complete absence of carotid chemo/baro-sensory function modified the neural, endocrine and inflammatory responses to sepsis. Thus, carotid chemo/baro-receptors play a protective role in sepsis.Item SPINK7 expression changes accompanied by HER2, P53 and RB1 can be relevant in predicting oral squamous cell carcinoma at a molecular level(2021) Pennacchiotti, Gina; Valdés, Fabio; González, Wilfredo; Federico, Héctor; Parra, Judith; Guida, Valeria; Gómez, Silvina; Guerrero, Martin; Fernández, Juan Manuel; Felipe, Carlos; Carón, Rubén; Ezquer, Marcelo; Fernández, Ricardo; Bruna, FlaviaThe oral squamous cell carcinoma (OSCC), which has a high morbidity rate, affects patients worldwide. Changes in SPINK7 in precancerous lesions could promote oncogenesis. Our aim was to evaluate SPINK7 as a potential molecular biomarker which predicts OSCC stages, compared to: HER2, TP53, RB1, NFKB and CYP4B1. This study used oral biopsies from three patient groups: dysplasia (n = 33), less invasive (n = 28) and highly invasive OSCC (n = 18). The control group consisted of clinically suspicious cases later to be confirmed as normal mucosa (n = 20). Gene levels of SPINK7, P53, RB, NFKB and CYP4B1 were quantified by qPCR. SPINK7 levels were correlated with a cohort of 330 patients from the TCGA. Also, SPINK7, HER2, TP53, and RB1, were evaluated by immunohistofluorescence. One-way Kruskal-Wallis test and Dunn's post-hoc with a p < 0.05 significance was used to analyze data. In OSCC, the SPINK7 expression had down regulated while P53, RB, NFKB and CYP4B1 had up regulated (p < 0.001). SPINK7 had also diminished in TCGA patients (p = 2.10e-6). In less invasive OSCC, SPINK7 and HER2 proteins had decreased while TP53 and RB1 had increased with respect to the other groups (p < 0.05). The changes of SPINK7 accompanied by HER2, P53 and RB1 can be used to classify the molecular stage of OSCC lesions allowing a diagnosis at molecular and histopathological levels.