Martínez Cáceres, Carlos Manuel

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Martínez Cáceres, Carlos Manuel

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Martínez Cáceres, Carlos Manuel

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Anatomía y Anatomía Patológica Comparadas

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Open Access
CD14 release induced by P2X7 receptor restrict inflammation and increases survival during sepsis
(eLife Sciences Publications, 2020-11-26) Alarcón-Vila, Cristina; Baroja-Mazo, Alberto; Torre-Minguela, Carlos de; Martínez-García, Juan J.; Martínez-Banaclocha, Helios; Gracia-Palenciano, Carlos; Martínez Cáceres, Carlos Manuel; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
P2X7 receptor activation induces the release of different cellular proteins, such as CD14, a glycosylphosphatidylinositol (GPI)-anchored protein to the plasma membrane important for LPS signaling via TLR4. Circulating CD14 has been found at elevated levels in sepsis, but the exact mechanism of CD14 release in sepsis has not been established. Here we show for first time that P2X7 receptor induces the release of CD14 in extracellular vesicles, resulting in a net reduction in macrophage plasma membrane CD14 that functionally affects LPS, but not monophosphoryl lipid A, pro-inflammatory cytokine production. Also, we found that during a murine model of sepsis, P2X7 receptor activity is important for maintaining elevated levels of CD14 in biological fluids and a decrease in its activity results in higher bacterial load and exacerbated organ damage, ultimately leading to premature deaths. Our data reveal that P2X7 is a key receptor for helping to clear sepsis because it maintains elevated concentrations of circulating CD14 during infection.
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TWEAK and NT-proBNP levels predict exercise capacity in hypertrophic cardiomyopathy
(Wiley, 2015-02) Jover, Eva; Andreu Cayuelas, José M.; Romero Aniorte, Ana I.; Casas, Teresa; Cánovas López, Sergio; Montero Argudo, José A.; Valdés, Mariano; Morena, Gonzalo de la; Marín, Francisco; Martínez Cáceres, Carlos Manuel; Orenes-Piñero, Esteban; Hernández Romero, Diana; Cirugía, Pediatría y Obstetricia y Ginecología
Background Hypertrophic cardiomyopathy (HCM) is characterized by inappropriate hypertrophy, myocyte disarray and increased interstitial fibrosis. The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a cell surface cytokine with biological activities including stimulation of cell growth, induction of inflammatory cytokines and stimulation of apoptosis. There are controversial data about the potential role of TWEAK in different cardiovascular pathologies. NT-proBNP is an established biomarker of myocardial wall stress, associated with poor functional class in HCM. We hypothesized that effort capacity in patients with HCM could be related to serum levels of these biomarkers. Materials and methods We included 40 haemodynamic stable HCM patients and 53 healthy controls with similar sex and age. We studied exercise capacity by maximal oxygen consumption in a limited treadmill exercise test. TWEAK and NT-proBNP were assayed by ELISA method and automated Elecsys® platform, respectively. We obtained 46 samples of myocardial tissues by septal myectomy in patients with HCM and evaluated myocardial fibrosis, immunoreaction with TWEAK antibody and apoptosis with TUNEL assay. Results We found raised TWEAK and NT-proBNP serum levels in patients when compared with control levels (both P < 0·001). In a multivariate analysis, TWEAK and NT-proBNP levels, as well as sex, remained independently associated with the effort capacity (all P < 0·05). We found an association between immunoreaction degree and the degree of myocardial fibrosis (P = 0·021), as well as apoptosis (P = 0·002) in the tissue samples from patients undergoing septal myectomy. Conclusions TWEAK and NT-proBNP levels are biomarkers of disease severity independently associated with the effort capacity in patients with HCM.
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Tetrameriosis in feral pigeons from Murcia, Southeastern Spain
(Elsevier, 2009-08) Martínez-Carrasco Pleite, Carlos; Ruiz de Ybáñez Carnero, María del Rocío; Espigares, David; Tizzani, Paolo; Alonso, Francisco D.; Martínez Cáceres, Carlos Manuel; Sanidad Animal
A total of 165 adult feral pigeons (Columba livia) were captured in 7 different parks of the municipality of Murcia, Southeastern Spain. Birds were evaluated clinically and subsequently necropsied. All birds appeared to be in good physical condition and no apparent signs of disease were observed. However, 17.6% of the pigeons were parasitized by Tetrameres (Petrowimeres) fissispina. The nematode burden in the proventriculus ranges from 5 to 64 specimens (median: 19); the median of female and male nematodes was 17 (range: 4–54) and 3 (range: 0–12), respectively. Despite the absence of detectable signs of disease, lesions induced by T. (P.) fissispina were evident. The histopathologic analysis revealed a pressure atrophy of the proventricular glands and a light inflammatory infiltrate surrounding the papillae. Pigeons captured in parks with soil had significantly higher T. (P.) fissispina prevalence compared with those captured in paved areas.
Embargo
Cell volume regulation modulates NLRP3 inflammasome activation
(Elsevier, 2012-09-21) Compan, Vincent; Baroja Mazo, Alberto; López Castejón ∙, Gloria; Gómez, Ana I.; Angosto, Diego; Montero, María T.; Herranz, Antonio S.; Bazán, Eulalia; Reimers, Diana; Martínez Cáceres, Carlos Manuel; Mulero Méndez, Victoriano Francisco; Pelegrín Vivancos, Pablo; Anatomía y Anatomía Patológica Comparadas
Cell volume regulation is a primitive response to alterations in environmental osmolarity. The NLRP3 inflammasome is a multiprotein complex that senses pathogen- and danger-associated signals. Here, we report that, from fish to mammals, the basic mechanisms of cell swelling and regulatory volume decrease (RVD) are sensed via the NLRP3 inflammasome. We found that a decrease in extracellular osmolarity induced a K+-dependent conformational change of the preassembled NLRP3-inactive inflammasome during cell swelling, followed by activation of the NLRP3 inflammasome and caspase-1, which was controlled by transient receptor potential channels during RVD. Both mechanisms were necessary for interleukin-1β processing. Increased extracellular osmolarity prevented caspase-1 activation by different known NLRP3 activators. Collectively, our data identify cell volume regulation as a basic conserved homeostatic mechanism associated with the formation of the NLRP3 inflammasome and reveal a mechanism for NLRP3 inflammasome activation.
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Characterization of a murine model of intranasal infection suitable for testing vaccines against C. abortus
(Elsevier, 2007-01-15) Nicolás, L.; Gallego, M. C.; Sánchez, J.; Caro, M. R.; Salinas, J.; Martínez Cáceres, Carlos Manuel; Navarro Cámara, José Antonio; Ortega Hernández, Nieves; Buendía Marín, Antonio Julián; Anatomía y Anatomía Patológica Comparadas
Mouse models have been widely used to test candidate vaccines against Chlamydophila abortus infection in mice. Although the induction of a systemic infection by endogenous or intraperitoneal inoculation is a useful tool for understanding the immune mechanism involved in the protection conferred by the vaccination, a different approach is necessary to understand other factors of the infection, such as mucosal immunity or the colonization of target organs. To test whether C. abortus intranasal model of infection in mice is a useful tool for testing vaccines in a first group of experiments mice, were infected intranasally with C. abortus to characterize the model of infection. When this model was used to test vaccines, two inactivated experimental vaccines, one of them adjuvated with QS-21 and another with aluminium hydroxide, and a live attenuated vaccine (strain 1B) were used. Non-vaccinated control mice died within the first 8 days, after displaying substantial loss of weight. Histologically, the mice showed lobar fibrinopurulent bronchointerstitial pneumonia. Prior immunization with QS-21 adjuvated vaccine or 1B vaccine presented mortality and the recipients showed a greater number of T cells in the lesions, especially CD8+ T cells, than the control mice and mice immunized with vaccine adjuvated with aluminium hydroxide. The results confirm that the C. abortus intranasal model of infection in mice is a useful tool for testing vaccines
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Molecular mechanisms of postoperative atrial fibrillation in patients with obstructive sleep apnea
(Wiley, 2023-04-28) López Gálvez, Raquel; Rivera Caravaca, José Miguel; Mandaglio Collados, Darío; Lahoz, Álvaro; Carpes, Marina; Arribas, José María; Cánovas López, Sergio; Lip, Gregory Y. H.; Marín, Francisco; Martínez Cáceres, Carlos Manuel; Orenes-Piñero, Esteban; Hernández Romero, Diana; Cirugía, Pediatría y Obstetricia y Ginecología
Obstructive sleep apnea (OSA) promotes atrial remodeling and fibrosis, providing a substrate for atrial fibrillation (AF). Herein, we investigate the pathophysiological mechanisms of AF in association with OSA in a cohort of cardiac surgery patients. A prospective study including patients undergoing cardiac surgery. Biomarkers reflective of AF pathophysiology (interleukin [IL-6], C-reactive protein [CRP], von Willebrand factor [vWF], N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity Troponin T [hs-TnT], and Galectin-3 [Gal-3]) was assessed by functional or immunological assays. miRNAs involved in AF were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Using atrial tissue samples, fibrosis was assessed by Masson's trichrome. Connexin 40 and 43 (Cx40; Cx43) were evaluated by immunolabeling. Fifty-six patients (15 with OSA and 41 non-OSA) were included in this hypothesis-generating pilot study. OSA group had a higher incidence of postoperative AF (POAF) (46.7% vs. 19.5%; p = .042), presented an increased risk of POAF (OR 3.61, 95% CI 1.01–12.92), and had significantly higher baseline levels of NT-proBNP (p = .044), vWF (p = .049), Gal-3 (p = .009), IL-6 (p = .002), and CRP (p = .003). This group presented lower levels of miR-21 and miR-208 (both p < .05). Also, lower Cx40 levels in POAF and/or OSA patients (50.0% vs. 81.8%, p = .033) were found. The presence of interstitial fibrosis (according to myocardial collagen by Masson's trichrome) was raised in OSA patients (86.7% vs. 53.7%, p = .024). Several biomarkers and miRNAs involved in inflammation and fibrosis were dysregulated in OSA patients, which together with a higher degree of interstitial fibrosis, altered miRNA, and Cxs expression predisposes to the development of a substrate that increases the AF risk.
Open Access
Melatonin as an agent for direct pulp-capping treatment
(MDPI, 2020-02-06) Guerrero Gironés, Julia; Alcaina Lorente, Antonia; Ortiz Ruiz, Clara; Ortiz Ruiz, Eduardo; Pecci Lloret, María P.; Rodríguez Lozano, Francisco Javier; Ortiz Ruiz, Antonio José; Martínez Cáceres, Carlos Manuel; Dermatología, Estomatología, Radiología y Medicina Física
Melatonin plays an essential role in the regulation of bone growth. The actions that melatonin exerts on odontoblasts may be similar to its action on osteoblasts. This research aimed to evaluate the pulp response to melatonin used for direct pulp capping to evaluate the antioxidant effect of melatonin administered orally and its influence on dental pulp. Direct pulp capping was performed on the upper molars of Sprague Dawley rats using melatonin or Mineral Trioxide Aggregate (MTA). The study groups were: MTA; Melatonin; MTA + Melatonin administered orally; and Melatonin + Melatonin administered orally. In the latter two groups, the animals drank water dosed with melatonin ad libitum (10 mg/100 mL). After 30 days, the animals were sacrificed, and 5 ml of blood, the kidneys, and the liver were extracted in order to evaluate oxidative stress using thiobarbituric acid reactive substances testing (TBARS). Fragments of the maxilla containing the study molars were prepared for histological evaluation. The degree of pulp inflammation and pulp necrosis, the presence of reparative dentin and dentin bridging the pulp chamber, the presence and regularity of the odontoblastic layer, and the presence of pulp fibrosis were evaluated. No significant differences were found between the four study groups for any of the studied histological variables. The oral administration of melatonin did not modify the local effects of MTA or melatonin on dental pulp, or reduce basal-level oxidative stress. The effect of melatonin on pulp is similar to that of MTA and may be used as an agent for direct pulp capping.
Embargo
Natural killer (NK) cells play a critical role in the early innate immune response to Chlamydophila abortus infection in mice
(Elsevier, 2004-01) Río, L. del; Caro, M. R.; Gallego, M. C.; Sánchez, J.; Cuello, F.; Salinas, J.; Martínez Cáceres, Carlos Manuel; Navarro Cámara, José Antonio; Ortega Hernández, Nieves; Buendía Marín, Antonio Julián; Anatomía y Anatomía Patológica Comparadas
Chlamydophila abortus, the aetiological agent of ovine enzootic abortion, induces a strong inflammatory reaction that leads to the T helper cell (Th1) specific immune response necessary for the clearance of infection. Because the role of natural killer (NK) cells during the first stages of this response has received little attention, this study focused on determining the function of these cells in a mouse model of infection. The location of NK cells in the liver and spleen of infected mice was examined immunohistochemically with an anti-Ly49G monoclonal antibody. The number of NK cells increased during the infection both in spleen and liver. In subsequent experiments, an anti-asialo GM1 polyclonal antibody was injected to deplete the NK cells. NK-depleted mice showed a substantial increase in their susceptibility to C. abortus infection, with high mortality rates and an increased burden of bacteria in the liver. Histopathological studies showed that inflammatory foci, composed mainly of neutrophils, were greater in size and number in depleted mice, while numerous chlamydial inclusions were associated with the foci. Serum concentrations of IFN-gamma, a key cytokine in the control of C. abortus infection, were substantially reduced in the NK-depleted mice. To establish the relationship between NK cells and other components of the innate immune response, neutrophils were depleted with the RB6-8C5 antibody. These cells were shown to be crucial in the recruitment of NK cells to the inflammatory foci.
Open Access
Gender differences in the renal changes induced by a prolonged high-fat diet in rats altered renal developmet
(2021-08) Moreno, Juan Manuel; De Jódar, Carlos; Reverte, Virginia; Bernabé, Antonio; Salazar, Francisco Javier; Llinás Más, María Teresa; Martínez Cáceres, Carlos Manuel; Fisiología
he mechanisms involved in renal dysfunction induced by high-fat diet (HFD) in subjects with altered renal development (ARDev) are understudied. The objective of this study is to examine whether there are sex-dependent differences in the mechanisms involved in the hypertension and deterioration of renal function in SD rats with prolonged HFD and ARDev. The role of angiotensin II (Ang II) in the arterial pressure (AP) increments, the renal hemodynamic sensitivity to Ang II, glomerular damage and changes in fat abdominal volume, plasma adipokine levels, renal NADPHp67phox expression, and renal infiltration of immune cells were examined. Hypertension and deterioration of renal function were enhanced (P < 0.05) in both sexes of rats with HFD and ARDev. The decrease (P < 0.05) of AP elicited by candesartan in hypertensive rats was similar to that induced by the simultaneous administration of candesartan and apocynin. The greater (P < 0.05) renal vasoconstriction induced by Ang II in both sexes of rats with HFD and ARDev was accompanied by an enhanced (P < 0.05) infiltration of CD-3 cells and macrophages in the renal cortex and renal medulla. The increments (P < 0.05) in the renal expression of NADPHp67phox and glomeruloesclerosis were greater (P < 0.05) in males than in females with HFD and ARDev. Our results suggest that the hypertension and deterioration of renal function induced by HFD in rats with ARDev are Ang II-dependent and mediated by increments in oxidative stress and immune system activation. Sex-dependent increments in oxidative stress and glomerular damage may contribute to the deterioration of renal function in these rats.
Open Access
The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
(Nature, 2014) Baroja-Mazo, Alberto; Gomez, Ana I.; Amores-Iniesta, Joaquín; Compan, Vincent; Barberá-Cremades, María; Yagüe, Jordi; Ruiz-Ortiz, Estibaliz; Antón, Jordi; Buján, Segundo; Couillin, Isabelle; Brough, David; Arostegui, Juan I.; Martínez Cáceres, Carlos Manuel; Martín Sánchez, María Rosario Fátima; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
NLRP3 inflammasome assembly activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β, and thereby plays a central role in the inflammatory response and in diverse human diseases. Here we report that upon caspase-1 activation oligomerized NLRP3-inflammasome particles are released from macrophages. Recombinant oligomeric protein particles composed of the adapter protein ASC or the cryopyrin-associated periodic syndromes (CAPS) mutant NLRP3 p.D303N, stimulate further caspase-1 activation extracellularly, and also intracellularly upon phagocytosis by surrounding macrophages. ASC oligomeric particles were found in the serum of patients with active CAPS, but not in patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3-inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.