Artículos (Bioquímica Médica y Biología Molecular e Inmunología)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10990

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Expression and immunohistochemical localization of leptin in human periapical granulomas
(Medicina oral S L, 2015) Martín González, Jenifer; Carmona-Fernández, Antonio; Pérez Pérez, Antonio; Sánchez Jiménez, Flora; Sánchez Margalet, Víctor; Segura Egea, Juan José; Universidad de Sevilla. Departamento de Estomatología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. CTS941: Patología Dentaria, Operatoria Dental y Endodoncia; Universidad de Sevilla. CTS151: Bioquímica Medica
ackground: Leptin, initially described as an adipocyte-derived hormone to regulate weight control, is expressed in normal and inflamed human dental pulp, being up-regulated during pulp experimental inflammation. Leptin receptor (LER) has been identified in human periapical granulomas. The aim of this study was to analyze and characterize the expression of leptin in human periapical granulomas. Material and methods: Fifteen periapical inflammatory lesions were obtained from extracted human teeth and teeth which underwent periapical surgery. After their morphological categorization as periapical granulomas and gradation of the inflammatory infiltrate, they were examined by immunohistochemistry using human leptin policlonal antibodies. Leptin mRNA expression was also determined by quantitative real-time PCR (qRT-PCR) and the amount of leptin protein was analyzed by immunoblot. Results: All periapical lesions exhibited the characteristic of chronic granulomatous inflammatory process with inflammatory infiltrate grade III. Leptin+ cells were detected in 13 periapical granulomas (86.6%). The median number of Leptin+ cells in periapical granulomas was 1.70 (0.00-7.4). Amongst the inflammatory cells in the periapical granulomas, only macrophages were reactive to leptin antibodies. Western blot analysis revealed the presence in all samples of a protein with apparent molecular weight of approximately 16 kDa, corresponding to the estimated molecular weights of leptin. The expression of leptin mRNA was confirmed by qRT-PCR analysis and the size of the amplified fragment (296 bp for leptin and 194 bp for cyclophilin) was assessed by agarose gel electrophoresis. Conclusions: For the first time, it has been demonstrated that human periapical granuloma expresses the adipokine leptin.
Impact of obesity‑associated myeloid‑derived suppressor cells on cancer risk and progression (Review)
(International journal of oncology; Espandidos Publications Ltd, 2024-06-27) Jiménez Cortegana, Carlos; Gutiérrez-García, Cristian; Sánchez Jiménez, Flora; Vilariño-García, Teresa; Flores-Campos, Rocío; Pérez Pérez, Antonio; Garnacho Montero, Carmen; García-Domínguez, Daniel J.; Cruz Merino, Luis de la; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica; Universidad de Sevilla. Departamento de Medicina; Junta de Andalucía; Universidad de Sevilla. CTS151: Bioquímica Medica; Universidad de Sevilla. CTS229: BioPatología Celular
Abstract. Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abili ties. Obesity associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipo cytes, plays in MDSC driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity related cancer.
Ketone Bodies Are Potential Prognostic Biomarkers in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results from the R2-GDP-GOTEL Trial
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-02-05) Fernández-Castillejo, Sara; Badia, Joan; Cruz Merino, Luis de la; Martín Garcia-Sáncho, Alejandro; Carnicero-González, Fernando; Palazón-Carrión, Natalia; Ríos Herranz, Eduardo; Cruz-Vicente, Fátima de la; Rueda-Domínguez, Antonio; Martínez-Banaclocha, Natividad; Sánchez Margalet, Víctor; Jiménez Cortegana, Carlos; Gumà, Josep; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología
Background: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of outcome in patients with R/R-DLBCL. Methods: This study included 69 R/R DLBCL patients from the R2-GDP-GOTEL trial (EudraCT 2014-001620-299). Serum samples were collected at baseline, and the mean length of follow-up was 41 months. Serum metabolites were analyzed by nuclear magnetic resonance (NMR). Metabolites were correlated with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Serum levels of 3-hydroxybutyrate (3OHB) and acetone were significantly (p < 0.001) associated with PFS (3OHB: hazard ratio [HR] 7.7, 95% confidence interval [CI] 2.5–24.1; acetone: HR 9.32, 95% CI 2.75–31.6) and OS (3OHB: HR 9.32, 95% CI 2.75–31.6; acetone: HR 1.92, 95% CI 1.36–2.69). Serum values of 141 µM for 3OHB and 40 µM for acetone were the optimal cutoffs associated with the survival outcomes. Elevated 3OHB levels (>141 μM) were specific to the ABC subtype of DLBCL, while acetone levels were elevated in both types of DLCBL but more pronounced in ABC cases. In a multivariate survival analysis, including the International Prognostic Index (IPI) score and refractoriness status (R/R), 3OHB and acetone remained significant. To aid oncologists employing the R2-GDP regime, we constructed PFS and OS nomograms for R/R-DLBCL risk stratification, incorporating 3OHB levels or acetone levels, IPI score, and refractoriness status. The nomogram with 3OHB and refractoriness status showed a time-dependent AUC of 0.86 for 6-month PFS and 0.84 for 12-month OS. These nomograms provide a comprehensive tool for individualized risk assessment and treatment optimization. Conclusions: The ketone bodies 3OHB and acetone are potential prognostic biomarkers of poor outcome in R/R DLBCL patients treated with the R2-GDP regimen, independently of IPI score and chemorefractoriness status.
Nutritional modulation of leptin expression and leptin action in obesity and obesity-associated complications
(Elsevier Science Inc, 2021) Montserrat de la Paz, Sergio; Pérez Pérez, Antonio; Vilariño-García, Teresa; Jiménez Cortegana, Carlos; Muriana, Francisco Javier G.; Millán Linares , Carmen; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Salud Carlos III; Universidad de Sevilla. CTS151: Bioquímica Medica; Universidad de Sevilla. CTS1074: Inmunonutrición e Inmunometabolismo
In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.
Expression of nutrient transporters in placentas affected by gestational diabetes: role of leptin
(Frontiers Media S.A., 2023-07) Guadix, Pilar; Corrales-Gutiérrez, Isabel; Vilariño García, Teresa; Rodríguez Chacón, Carmen; Sánchez Jiménez, Flora; Jiménez Cortegana, Carlos; Dueñas, José L.; Sánchez Margalet, Víctor; Pérez Pérez, Antonio; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. CTS607: Salud Reproductiva de la Mujer; Universidad de Sevilla. CTS151: Bioquímica Medica
Gestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased nutrient transport in the placenta. Recent studies by our group have demonstrated that leptin is a key hormone in placental physiology, and its expression is increased in placentas affected by GDM. However, the effect of leptin on placental nutrient transport, such as transport of glucose, amino acids, and lipids, is not fully understood. Thus, we aimed to review literature on the leptin effect involved in placental nutrient transport as well as activated leptin signaling pathways involved in the expression of placental transporters, which may contribute to an increase in placental nutrient transport in human pregnancies complicated by GDM. Leptin appears to be a relevant key hormone that regulates placental transport, and this regulation is altered in pathophysiological conditions such as gestational diabetes. Adaptations in the placental capacity to transport glucose, amino acids, and lipids may underlie both under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered due to changes in maternal nutrition or metabolic disease. Implementing new strategies to modulate placental transport may improve maternal health and prove effective in normalizing fetal growth in cases of intrauterine growth restriction and fetal overgrowth. However, further studies are needed to confirm this hypothesis.
Leptin and Leptin Signaling in Multiple Sclerosis: A Narrative Review
(Springer Nature, 2025-02-28) Flores Cordero, Juan Antonio; Aranaz Murillo, Amalia; Vilariño-García, Teresa; Pérez Pérez, Antonio; Izquierdo, Guillermo; Flores-Campos, Rocío; Hontecillas-Prieto, Lourdes; García-Domínguez, Daniel J.; Sánchez Margalet, Víctor; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Junta de Andalucía
Obesity, a pandemic health problem, is now considered as a chronic inflammatory state, related to many autoimmune diseases, such as multiple sclerosis. Thus, adipokines, inflammatory mediators secreted by adipose tissue, play an important role modulating the immune response. In this context, obesity, especially during adolescent age, seems to be a key factor for the development of multiple sclerosis. Leptin, the main pro-inflammatory adipokine secreted by the adipose tissue, has been found increased in patients with multiple sclerosis and is able to regulate the immune system promoting a pro-inflammatory response. Leptin signaling in both innate and adaptative immune cells might have immunomodulatory effects in the context of multiple sclerosis. In this way, leptin has been found to produce a Th1 and Th17 response, increasing M1 macrophages and decreasing regulatory T cells and Th2 response. Moreover, circulating inflammatory adipokines, such as leptin, have been found in people with multiple sclerosis. In the present work, we are reviewing literature to update the body of knowledge regarding the role of obesity and leptin in multiple sclerosis.
A comprehensive review on the functionality and biological relevance of pectin and the use in the food industry
(Elsevier, 2024-09-26) Barrera Chamorro, Luna; Fernández Prior, África; Rivero Pino, Fernando; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Gobierno de España; Universidad de Sevilla. CTS1074: Inmunonutrición e Inmunometabolismo
Pectin is a natural biopolymer, which can be extracted from food by-products, adding value to raw material, with a structure more complex than that of other polysaccharides. The gelling properties of these molecules, together with the bioactivity that these can exert, make them suitable to be used as ingredients and bioactive agents. In this review, the characterization of pectin (structure, sources, techno-functional, and biological properties), the extraction methods, and their use in the food industry (food packaging, as carriers, and as ingredients) are described. Different by-products can be used as substrates to extract pectin, enhancing a sustainable food system as described by the circular economy principles. Pectin is characterized for their techno-functional and biological properties, such as gelling and thickening properties or modulation of microbiota both in animals and humans. Such properties make these molecules suitable for a wide range of applications within the food chain, serving as packaging or carriers in foodstuff, or for direct use as functional ingredients as fiber. Overall, pectin has been shown to exert as promising components to be introduced in the food system, although further research on scaling-up the production process and feasibility has to be done.
Food-derived vesicles as immunomodulatory drivers: Current knowledge, gaps, and perspectives
(Elsevier, 2024-06-20) Rivero Pino, Fernando; Márquez Parada, Elvira; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Gobierno de España
Extracellular vesicles (EVs) are lipid-bound membrane vesicles released from cells, containing active compounds, which can be found in different foods. In this review, the role of food-derived vesicles (FDVs) as immunomodulatory drivers is summarized, with a focus on sources, isolation techniques and yields, as well as bioavailability and potential health implications. In addition, gaps and perspectives detected in this research field have been highlighted. FDVs have been efficiently extracted from different sources, and differential ultracentrifugation seems to be the most adequate isolation technique, with yields ranging from 108 to 1014 EV particles/mL. Animal studies show promising results in how these FDVs might regulate different pathways related to inflammation. Further investigation on the production of stable components in a cost-effective way, as well as human studies demonstrating safety and health-promoting properties, since scarce information has been reported until now, in the context of modulating the immune system are needed.
Neuroprotective effect of mealworm protein hydrolysate-derived bioactive peptides in human microglial cells
(Brill Academic Publishers, 2024-12-07) González de la Rosa, Teresa; del Valle Alonso, M.A.; Montserrat de la Paz, Sergio; Rivero Pino, Fernando; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología
The larva of Tenebrio molitor, better known as mealworm, is one of the most studied insects today, since it was recently classified as safe for human consumption. Specifically, its high protein content makes it a splendid candidate for the search for bioactive peptides, with properties ranging from anti-inflammatory to neuroprotective. In this study, the effect of a digested hydrolysate on microglia cells (which previously demonstrated high anti-inflammatory activity in intestinal CACO-2 cells) was analysed, specifically on their levels of gene expression of various cytokines, such as IL-6, IL-10, or IL-1β, among others. In addition, four chemically synthesised peptides, selected from this digested hydrolysate based on in silico analysis, including the estimation of the bioactive properties of these peptides, their physicochemical properties and their toxicokinetic, were evaluated in the microglia cells as well. In addition, molecular docking assays of the peptides were performed with two receptors relevant to inflammation. Relevant changes in the expression of IL-6, IL-1β, and BDNF were observed due to the action of the peptides, especially in the case of IYVDAVIN and SLPSLPEPV. These results provide an insight on how specific peptides found in Tenebrio molitor could be used as therapeutics agent in the immunomodulation of brain cells.
The Role of Bioactive Compounds in Immunonutrition
(MDPI, 2024-10-10) Rivero Pino, Fernando; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Gobierno de España
The link between diet and immune function is a growing area of interest, recognized not only by the scientific community but also by global health organizations, such as the World Health Organization (WHO). As research continues to unveil the complex interactions between nutrients, bioactive compounds, and the immune system, it is becoming increasingly clear that what we consume plays a pivotal role in shaping our body’s defense mechanisms. This Special Issue, “The Role of Bioactive Compounds in Immunonutrition”, explores these intricate relationships and highlights the potential of dietary components in modulating immune responses, reducing inflammation, and improving health outcomes across various disease states. This Special Issue features a total of twelve papers, including three systematic reviews, one narrative review, and eight original research articles, which collectively explore the diverse sources and effects of bioactive compounds derived from food, mainly plants, on immune function. (extract)
Nutritional composition and biological activity of narrow-leafed lupins (Lupinus angustifolius L.) hydrolysates and seeds
(Elsevier, 2023-04-03) Lemus Conejo, Ana; Rivero Pino, Fernando; Montserrat de la Paz, Sergio; Millán Linares, María del Carmen; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Junta de Andalucía
Lupins are an interesting source of nutrients, part of the Fabaceae family. More specifically, narrow-leafed lupin (Lupinus angustifolius L.) is a legume, largely produced in Australia, which is used both for human food and animal fodder. There is a growing interest in plant proteins-derived products due to benefits for the ecosystem and lower production costs compared to traditional animal sources of protein. This review aimed to summarize major and minor chemical components in Lupinus angustifolius L., and potential health benefits of this plant and product thereof. In particular, the protein fraction of Lupinus and their biological properties are described. L. angustifolius seed and proteins by-products can be used as a valuable source of high value-added compounds for diverse food products with the goal to maximize its economic value.
GPETAFLR, an octapeptide isolated from Lupinus angustifolius L. protein hydrolysate, promotes the skewing to the M2 phenotype in human primary monocytes
(Royal Society of Chemistry, 2019-04-23) Montserrat de la Paz, Sergio; Lemus Conejo, Ana; Toscano Sánchez, María del Rocío; Pedroche, Justo; Millán, Francisco; Millán Linares, María del Carmen; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla; Gobierno de España
The present study aimed to test the mechanisms by which GPETAFLR, released from the enzymatic hydrolysis of lupine protein, may modulate the inflammatory response and plasticity in human primary monocytes. Human circulating monocytes and mature macrophages were used to analyze the effects of GPETAFLR on plasticity and inflammatory response using biochemical, flow cytometry, quantitative real-time PCR, and ELISA assays. GPETAFLR skewed the monocyte plasticity towards the anti-inflammatory non-classical CD14+CD16++ monocyte subset and reduced the inflammatory competence of LPS-treated human monocytes diminishing IL-1β, IL-6, and TNF-α and increasing IL-10 production and gene expression. Results showed that GPETAFLR decreased the frequency of the LPS-induced activated monocyte population (CD14++CD16−), diminished monocyte activation involved down-regulation of CCR2 mRNA expression and protein expression, and decreased gene expression of the LPS-induced chemoattractant mediator CCL2. Our findings imply a new understanding of the mechanisms by which GPETAFLR favor a continuous and gradual plasticity process in the human monocyte/macrophage system and offer novel benefits derived from the consumption of Lupinus angustifolius L. in the prevention of inflammatory-related diseases.
Microbiota-derived extracellular vesicles: current knowledge, gaps, and challenges in precision nutrition
(Frontiers media SA, 2025-02-20) Márquez Paradas, Elvira; Torrecillas-López, M; Barrera Chamorro, Luna; del Rio-Vazquez, Jose L.; Montserrat de la Paz, Sergio; González de la Rosa, Teresa; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); Universidad de Sevilla. CTS1074: Inmunonutrición e Inmunometabolismo
The gut microbiota has co-evolved with its host, profoundly shaping the development and functioning of the immune system. This co-evolution has led to a dynamic relationship where microbial metabolites and molecular signals influence immune maturation, tolerance, and defense mechanisms, highlighting its essential role in maintaining host health. Recently, bacterial extracellular vesicles (BEVs), membrane nanoparticles produced by bacteria, have emerged as important players in gut balance and as potent immune modulators. These vesicles reflect the characteristics of the bacterial membrane and contain nucleic acids, proteins, lipids, and metabolites. They can regulate immune processes and are involved in neurological and metabolic diseases due to their ability to distribute both locally in the gut and systemically, affecting immune responses at both levels. This review provides a comprehensive overview of the characteristics and functional profile of BEVs, detailing how nutrition influences the production and function of these vesicles, how antibiotics can disrupt or alter their composition, and how these factors collectively impact immunity and disease development. It also highlights the potential of BEVs in the development of precision nutritional strategies through dietary modulation, such as incorporating prebiotic fibers to enhance beneficial BEV production, reducing intake of processed foods that may promote harmful BEVs, and tailoring probiotic interventions to influence specific microbial communities and their vesicular outputs.
Evaluation of immunomodulatory properties of phenolic extracts from olive mill by-products using Caco-2 cells and molecular docking analysis
(Elsevier, 2024-12) Barrera Chamorro, Luna; Fernández Prior, África; González de la Rosa, Teresa; Rivero Pino, Fernando; Claro Cala, Carmen María; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Union (UE); Universidad de Sevilla. CTS1074: Inmunonutrición e Inmunometabolismo
The bioactive potential of phenolic extracts derived from olive mill solid by-product (OMSbP), also called alperujo, and olive mill water (OMW), remains a topic of significant interest due to the amount of these, espe- cially in Mediterranean regions, and their potential health benefits. In this study, the antioxidant and immu- nomodulatory properties of phenolic extracts obtained from OMSbP and OMW (OMSbP-P and OMW-P, respectively) in intestinal cells were evaluated. Initially, phenol-rich extracts were prepared by ethanol/ethyl acetate extraction and were characterized by HPLC-DAD analyses. The in vitro antioxidant activity showed potent bioactivities for all extracts evaluated. Toxicity assays did not reveal adverse effects on Caco-2 cell viability at concentrations relevant to immunomodulatory activity. Subsequently, the immunomodulatory effects of these extracts were assessed by measuring gene expression of pro- and anti-inflammatory cytokines. The results demonstrate that both OMSbP-P and OMW-P exhibit significant immunomodulatory activities, as evidenced by modulated cytokine gene expression in intestinal cells. Furthermore, molecular docking analyses of the identified phenols with the TLR4/MD2 receptor showed binding affinity, increasing the evidence that these extracts could exert immunomodulatory activity. Overall, our findings suggest that OMSbP-P and OMW-P possess promising immunomodulatory properties in intestinal cells, thus emphasizing their potential as natural therapeutic agents for managing immune-related disorders and promoting gut health. Further elucidation of the molecular mech- anisms underlying these effects and in vivo studies are warranted to fully exploit the therapeutic potential of these extracts.
Role of fibroblasts in chronic inflammatory signalling in chronic rhinosinusitis with nasal polyps-a systematic review
(MDPI, 2023-05-04) Palacios-García, José María; Porras González, Cristina; Moreno-Luna, Ramón; Maza Solano, Juan Manuel; Polo Padillo, Juan; Muñoz-Bravo, José Luis; Sánchez Gómez, Serafín; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Medicina Preventiva y Salud Pública; Consejeria de Salud y Familias; Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades de la Junta de Andalucia; Universidad de Sevilla. CTS-312: Análisis de la demanda sanitaria
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the nose and paranasal sinuses characterized by the presence of nasal polyps. The symptoms produced by the presence of nasal polyps such as nasal obstruction, nasal discharge, facial pain, headache, and loss of smell cause a worsening in the quality of life of patients. The source of the nasal polyps remains unclear, although it seems to be due to a chronic inflammation process in the sinonasal mucosa. Fibroblasts, the main cells in connective tissue, are intimately involved in the inflammation processes of various diseases; to this end, we carried out a systematic review to evaluate their inflammatory role in nasal polyps. Thus, we evaluated the main cytokines produced by nasal polyp-derived fibroblasts (NPDF) to assess their involvement in the production of nasal polyps and their involvement in different inflammatory pathways. The results of the review highlight the inflammatory role of NPDF through the secretion of various cytokines involved in the T1, T2, and T3 inflammatory pathways, as well as the ability of NPDF to be stimulated by a multitude of substances. With these findings, the fibroblast is positioned as a new potential therapeutic target in the treatment of CRSwNP.
Regulation of RhoA/ROCK and sustained arterial contraction by low cytosolic Ca2+ levels during prolonged depolarization of arterial smooth muscle
(Elsevier, 2017-08) Porras González, Cristina; Ordóñez Fernández, José Antonio; Castellano Orozco, Antonio Gonzalo; Ureña López, Juan; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España
The role of L-type Ca2 + channels (LTCCs) and RhoA/Rho kinase (ROCK) on depolarization-induced sustained arterial contraction lasting several minutes is already known. However, in vivo, vascular smooth muscle cells can be depolarized for longer periods, inducing substantial inactivation of LTCCs and markedly reducing Ca2 + influx into the myocytes. We have examined, in femoral arterial rings, the role of LTCCs and RhoA/ROCK during long-lasting depolarization. Our results reveal a new vasoreactive response after 20–30 min of depolarization in 2.5 mM external Ca2 + that has not been identified previously with shorter stimuli. Prolonged depolarization-induced arterial contraction was permanently abolished when arterial rings were treated with 100 nM external Ca2 + or 20 nM nifedipine. However, when Ca2 + influx was restricted, applying ~ 7 μM external Ca2 + solution or 3 nM nifedipine, vasorelaxation was transient, and isometric force slowly increased after 30 min and maintained its level until the end of the stimulus. Under these conditions, arterial contraction showed the same temporal course of RhoA activity and was sensitive to fasudil, nifedipine and cyclopiazonic acid. Ca2 +-response curve in β-escin permeabilized arteries was also sensitive to ROCK inhibitors. Thus, although long-lasting depolarization inactivates LTCCs, the reduced Ca2 + entry can induce a detectable arterial contraction via RhoA/ROCK activation.
Contribution of L-type Ca2+ channel-sarcoplasmic reticulum coupling to depolarization-induced arterial contraction in spontaneously hypertensive rats
(Springer Nature, 2018-07-27) Porras González, Cristina; Castellano Orozco, Antonio Gonzalo; Ureña López, Juan; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Instituto de Salud Carlos III
Evidence has shown that vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs) are depolarized and that the expression of L-type Ca2+ channels (LTCCs) and the sarcoplasmic reticulum (SR) Ca2+ buffering system are upregulated. Arterial rings exposed to high K+ solutions develop a contraction with two components, namely, an initial or phasic component and a sustained or tonic component. Because LTCCs and SR have different functions in the phasic and tonic components of depolarization-induced contraction, this study investigated the role of LTCC-SR coupling in depolarized arterial rings of SHRs. In the absence of extracellular Ca2+, high external K+ or LTCC agonists elicited a transitory contraction, which was sensitive to nifedipine and was potentiated in SHRs. In the presence of extracellular Ca2+, cyclopiazonic acid (CPA), an SR Ca2+-ATPase (SERCA) inhibitor, evoked a transient contraction that was significantly increased in SHRs. Although the phasic and tonic components were markedly increased in depolarized arterial rings of SHRs, they showed different voltage-dependence and sensitivity to SERCA inhibition. The tonic component was more sensitive to moderate depolarizations, and CPA selectively reduced the tonic component to the level observed in WKY rats. These results suggested that LTCC-SR coupling is potentiated in the sustained contraction of hypertensive VSMCs.
HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-01-18) Pérez Castro, Miguel Ángel; Hernández Rasco, Francisco; Alonso Bellido, Isabel María; Letrán Sánchez, María S.; Pérez Villegas, Eva María; Vitallé, Joana; Real Navarrete, Luis Miguel; Ruiz Mateos, Ezequiel; Venero Recio, José Luis; Tabares, Lucía; Carrión, Ángel Manuel; Armengol, José Ángel; Bachiller, Sara; Ruiz Laza, Rocío; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Ministerio de Economía y Competitividad (MINECO). España
The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function.
Tungstate activates BK channels in a β subunit- and Mg2+-dependent manner: relevance for arterial vasodilatation
(Oxford University Press, 2012-07-01) Fernández Mariño, María Isabel; Porras González, Cristina; González Rodríguez, Patricia; Selent, Jana; Pastor, Manuel; Ureña López, Juan; Castellano Orozco, Antonio Gonzalo; Valverde, Miguel A.; Fernández Fernández, José M.; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Fondo de Investigacion Sanitaria; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Generalitat de Catalunya; Gobierno de España; Ministerio de Ciencia e Innovación (MICIN). España
Aims: Tungstate reduces blood pressure in experimental animal models of both hypertension and metabolic syndrome, although the underlying mechanisms are not fully understood. Given that the large-conductance voltage- and Ca(2+)-dependent K(+) (BK) channel is a key element in the control of arterial tone, our aim was to evaluate whether BK channel modulation by tungstate can contribute to its antihypertensive effect. Methods and results: Patch-clamp studies of heterologously expressed human BK channels (α + β(1-4) subunits) revealed that cytosolic tungstate (1 mM) induced a significant left shift (∼20 mV) in the voltage-dependent activation curve only in BK channels containing αβ(1) or αβ(4) subunits, but reduced the amplitude of K(+) currents through all BK channels tested. The β(1)-dependent activation of BK channels by tungstate was enhanced at cytosolic Ca(2+) levels reached during myocyte contraction, and prevented either by removal of cytosolic Mg(2+) or by mutations rendering the channel insensitive to Mg(2+). A lower concentration of tungstate (0.1 mM) induced voltage-dependent activation of the vascular BKαβ(1) channel without reducing current amplitude, and consistently exerted a vasodilatory action on wild-type but not on β(1)-knockout mouse arteries pre-contracted with endothelin-1. Conclusion: Tungstate activates BK channels in a β subunit- and Mg(2+)-dependent manner and induces vasodilatation only in mouse arteries that express the BK β(1) subunit.
Tonic arterial contraction mediated by L-type Ca2+ channels requires sustained Ca2+ influx, G protein-associated Ca2+ release, and RhoA/ROCK activation
(Elsevier, 2012-12-15) Fernández Tenorio, Miguel; Porras González, Cristina; Castellano Orozco, Antonio Gonzalo; López Barneo, José; Ureña López, Juan; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Andalucía; Fundación Botín; European Union (UE); Ministerio de Sanidad, Servicios Sociales e Igualdad. España
KCl-evoked sustained contraction requires L-type Ca2+ channel activation, metabotropic Ca2+ release from the sarcoplasmic reticulum (mechanism denoted Calcium Channel-Induced Ca2+ Release) and RhoA/Rho associated kinase activation. Although high K+ solutions are used to depolarize myocytes, these solutions can stimulate other signaling pathways such as those triggered by the activation of muscarinic and purinergic receptors. The present study examines the functional role of Calcium Channel-Induced Ca2+ Release under pharmacological activation of L-type Ca2+ channel without significant membrane depolarization. It also analyzes the role of the “steady-state” Ca2+ influx through L-type Ca2+ channels on myocyte sustained contraction. Measurement of contractility in arterial rings was done on a vessel myograph. Membrane potential was measured by fluorescence techniques loading intact myocytes with a membrane potential sensitive dye, and a reversible permeabilization method was used to load myocytes in intact arteries with GDPβS and Cav1.2 siRNA. Application of an L-type Ca2+ channel agonist, without effect on membrane potential, evoked sustained contraction via G-protein induced Ca2+ release from the sarcoplasmic reticulum and RhoA/Rho associated kinase activation. Tonic myocyte contractions mediated by L-type Ca2+ channel activation required sustained Ca2+ influx through the channels and Ca2+ uptake by the sarcoplasmic reticulum. Because L-type Ca2+ channels participate in numerous pathophysiological processes mediated by maintained arterial contraction, our data could help to optimize therapeutic treatment of arterial vasospasm.

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