RESUMEN
Carbon nitrides can form coordination compounds or metallic oxides in the presence of transition metals, depending on the reaction conditions. By adjusting the pH to basic levels for mild synthesis with metals, composites like g-C3N4-M(OH)x (where M represents metals) were obtained for nickel (II) and manganese (II), while copper (II) yielded coordination compounds such as Cu-g-C3N4. These materials underwent spectroscopic and electrochemical characterization, revealing their photocatalytic potential to generate superoxide anion radicals-a feature consistent across all metals. Notably, the copper coordination compound also produced significant hydroxyl radicals. Leveraging this catalytic advantage, with band gap energy in the visible region, all compounds were activated to disinfect E. coli bacteria, achieving total disinfection with Cu-g-C3N4. The textural properties influence the catalytic performance, with copper's stabilization as a coordination compound enabling more efficient activity compared to the other metals. Additionally, the determination of radicals generated under light in the presence of dicloxacillin supported the proposed mechanism and highlighted the potential for degrading organic molecules with this new material, alongside its disinfectant properties.
RESUMEN
There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which might contribute to the identification of new therapeutic targets. In this study, we investigated the presence of SARS-CoV-2 in postmortem lung, kidney, and liver samples of patients who died with coronavirus disease (COVID-19) and its relationship with host factors involved in virus spread and pathogenesis, using microscopy-based methods. The cases analyzed showed advanced stages of diffuse acute alveolar damage and fibrosis. We identified the SARS-CoV-2 nucleocapsid (NC) in a variety of cells, colocalizing with mitochondrial proteins, lipid droplets (LDs), and key host proteins that have been implicated in inflammation, tissue repair, and the SARS-CoV-2 life cycle (vimentin, NLRP3, fibronectin, LC3B, DDX3X, and PPARγ), pointing to vimentin and LDs as platforms involved not only in the viral life cycle but also in inflammation and pathogenesis. SARS-CoV-2 isolated from a patient´s nasal swab was grown in cell culture and used to infect hamsters. Target cells identified in human tissue samples included lung epithelial and endothelial cells; lipogenic fibroblast-like cells (FLCs) showing features of lipofibroblasts such as activated PPARγ signaling and LDs; lung FLCs expressing fibronectin and vimentin and macrophages, both with evidence of NLRP3- and IL1ß-induced responses; regulatory cells expressing immune-checkpoint proteins involved in lung repair responses and contributing to inflammatory responses in the lung; CD34+ liver endothelial cells and hepatocytes expressing vimentin; renal interstitial cells; and the juxtaglomerular apparatus. This suggests that SARS-CoV-2 may directly interfere with critical lung, renal, and liver functions involved in COVID-19-pathogenesis.
Asunto(s)
COVID-19 , Humanos , COVID-19/patología , Fibronectinas , Vimentina , SARS-CoV-2 , Células Endoteliales , Proteína con Dominio Pirina 3 de la Familia NLR , PPAR gamma , Pulmón , Inflamación/patología , Riñón , HígadoRESUMEN
An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in "remission" and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of "at-risk phenotypes" such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.
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Diabetes Mellitus , Pie Diabético , Hiperglucemia , Humanos , Cicatriz/patología , Úlcera/patología , Pie Diabético/patología , Extremidad Inferior/patología , Hiperglucemia/patología , Recurrencia , Diabetes Mellitus/patologíaRESUMEN
INTRODUCTION: Heart failure in patients with non-valvular atrial fibrillation (NVAF) is two to three times more common than in individuals without NVAF. OBJECTIVE: To identify cardiometabolic risk factors (CMRF) and antithrombotic treatment in patients with NVAF and heart failure with reduced ejection fraction (HFrEF), and to determine if there were differences according to gender. METHODS: CMRF, pro-thrombotic risk, bleeding risk, and antithrombotic therapy were globally analyzed and according to gender. RESULTS: Out of 1,423 patients with NVAF, 336 had HFrEF. On average, females were older than males. There was no difference between genders with regard to the type of NVAF or direct oral anticoagulants use. Hypertension was more common in women. History of transient ischemic attack was reported in 3.6% of the patients and cerebrovascular event in 10%, without differences in terms of gender. The percentage of men with elevated embolic risk was higher, but without antithrombotic treatment, in comparison with women. CONCLUSIONS: Significant differences were found according to gender in patients with NVAF and HFrEF, both in CMRF and some comorbidities, as well as in antithrombotic treatment according to embolic and bleeding risk.
INTRODUCCIÓN: La insuficiencia cardiaca en pacientes con fibrilación auricular no valvular (FANV) es de dos a tres veces más frecuente que en individuos sin FANV. OBJETIVO: Identificar los factores de riesgo cardiometabólico (FRCM) y el tratamiento antitrombótico de pacientes con FANV e insuficiencia cardiaca con fracción de expulsión reducida (IC-FEr), y determinar si existen diferencias conforme al sexo. MÉTODOS: En forma global y de acuerdo con el sexo se analizaron FRCM, riesgo protrombótico, riesgo de sangrado y terapia antitrombótica. RESULTADOS: De 1423 pacientes con FANV, 336 tuvieron IC-FEr. Las mujeres promediaron mayor edad que los hombres. No hubo diferencia entre los sexos respecto al tipo de FANV o uso de anticoagulantes orales directos. La hipertensión arterial sistémica fue más frecuente en mujeres. Un 3.6 % de los pacientes reportó antecedente de ataque isquémico transitorio y 10 % de evento vascular cerebral, sin diferencias en cuanto al sexo. El porcentaje de hombres con riesgo embólico elevado fue mayor, pero sin tratamiento antitrombótico, en comparación con las mujeres. CONCLUSIONES: Se encontraron diferencias significativas de acuerdo con el sexo en pacientes con FANV e IC-FEr, tanto en FRCM y algunas comorbilidades, como en el tratamiento antitrombótico de acuerdo con el riesgo embólico y de sangrado.
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Fibrilación Atrial , Insuficiencia Cardíaca , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Anticoagulantes/efectos adversos , Fibrinolíticos/efectos adversos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Factores de Riesgo Cardiometabólico , Volumen Sistólico , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & controlRESUMEN
Cellular memory is a controversial concept representing the ability of cells to "write and memorize" stressful experiences via epigenetic operators. The progressive course of chronic, non-communicable diseases such as type 2 diabetes mellitus, cancer, and arteriosclerosis, is likely driven through an abnormal epigenetic reprogramming, fostering the hypothesis of a cellular pathologic memory. Accordingly, cultured diabetic and cancer patient-derived cells recall behavioral traits as when in the donor's organism irrespective to culture time and conditions. Here, we analyze the data of studies conducted by our group and led by a cascade of hypothesis, in which we aimed to validate the hypothetical existence and transmissibility of a cellular pathologic memory in diabetes, arteriosclerotic peripheral arterial disease, and cancer. These experiments were based on the administration to otherwise healthy animals of cell-free filtrates prepared from human pathologic tissue samples representative of each disease condition. The administration of each pathologic tissue homogenate consistently induced the faithful recapitulation of: (1) Diabetic archetypical changes in cutaneous arterioles and nerves. (2) Non-thrombotic arteriosclerotic thickening, collagenous arterial encroachment, aberrant angiogenesis, and vascular remodeling. (3) Pre-malignant and malignant epithelial and mesenchymal tumors in different organs; all evocative of the donor's tissue histopathology and with no barriers for interspecies transmission. We hypothesize that homogenates contain pathologic tissue memory codes represented in soluble drivers that "infiltrate" host's animal cells, and ultimately impose their phenotypic signatures. The identification and validation of the actors in behind may pave the way for future therapies.
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Diabetes Mellitus Tipo 2 , Enfermedad Arterial Periférica , Animales , Humanos , Neovascularización PatológicaRESUMEN
Lower-extremity arterial disease is a major health problem with increasing prevalence, often leading to non-traumatic amputation, disability and mortality. The molecular mechanisms underpinning abnormal vascular wall remodeling are not fully understood. We hypothesized on the existence of a vascular tissue memory that may be transmitted through soluble signaling messengers, transferred from humans to healthy recipient animals, and consequently drive the recapitulation of arterial wall thickening and other vascular pathologies. We examined the effects of the intralesional infiltration for 6 days of arteriosclerotic popliteal artery-derived homogenates (100 µg of protein) into rats' full-thickness wounds granulation tissue. Animals infiltrated with normal saline solution or healthy brachial arterial tissue homogenate obtained from traumatic amputation served as controls. The significant thickening of arteriolar walls was the constant outcome in two independent experiments for animals receiving arteriosclerotic tissue homogenates. This material induced other vascular morphological changes including an endothelial cell phenotypic reprogramming that mirrored the donor's vascular histopathology. The immunohistochemical expression pattern of relevant vascular markers appeared to match between the human tissue and the corresponding recipient rats. These changes occurred within days of administration, and with no cross-species limitation. The identification of these "vascular disease drivers" may pave novel research avenues for atherosclerosis pathobiology.
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Arteriosclerosis/metabolismo , Tejido de Granulación/metabolismo , Arteria Poplítea/lesiones , Proteínas/administración & dosificación , Lesiones del Sistema Vascular/inducido químicamente , Anciano , Animales , Arteriosclerosis/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Lesiones del Sistema Vascular/patologíaRESUMEN
BACKGROUND/AIMS: Microglia are the dynamic motile phagocytes of the brain considered the first line of defense against threats or disturbances to the Central Nervous System (CNS). Microglia help orchestrate the immunological response by interacting with others immune cells. Mast cells (MCs) are effector cells of the innate immune system distributed in all organs and vascularized tissues, brain included. Several molecular mechanisms for potential interactions between MCs and microglia have been determined. However, the effect of MCs on regulated exocytosis and phagocytic clearance in microglia has not been explored. METHODS: Cocktails of MCs mediators (MCM) obtained at 37°C and 53°C were used to induce microglia activation. Changes in intracellular calcium [Ca2+]i and ATP release were studied by calcium and quinacrine fluorescence imaging. Fluorescent latex beads were used to assay phagocytosis in microglia after MCM treatment and compared to that measured in the presence of histamine, ATP and lipopolysaccharide (LPS). Iba-1 expression and area were quantified by immunofluorescence and histamine levels evaluated by ELISA techniques. RESULTS: Local application onto microglia of the MC mediator cocktail elicited Ca2+ transients and exocytotic release associated with quinacrine dye de-staining. Ca2+ signals were mimicked by histamine and blocked by the H1 receptor (H1R) antagonist, cetirizine. Hydrolysis of ATP by apyrase also affected Ca2+ transients to a lesser extent. Iba-1 fluorescence, cell area and phagocytosis were enhanced by histamine through H1R. However, ATP prevented iba-1 expression and microglial phagocytosis. MCM showed combined effects of histamine and ATP, increasing the number of internalized microbeads per cell and area without raising iba1 expression. CONCLUSION: Our results highlight the relevance of MC-derived histamine and ATP in the modulation of secretory and phagocytic activities that would explain the heterogeneity of microglial responses in different pathological contexts.
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Adenosina Trifosfato/metabolismo , Señalización del Calcio , Comunicación Celular , Histamina/metabolismo , Mastocitos/metabolismo , Microglía/metabolismo , Animales , Ratas , Ratas WistarRESUMEN
BACKGROUND: Mast cells (MCs) in the brain can respond to environmental cues and relay signals to neurons that may directly influence neuronal electrical activity, calcium signaling, and neurotransmission. MCs also express receptors for neurotransmitters and consequently can be activated by them. Here, we developed a coculture model of peritoneal MCs, incubated together with dissociated hippocampal neurons for the study of cellular mechanisms involved in the mast cell-neuron interactions. METHODS: Calcium imaging was used to simultaneously record changes in intracellular calcium [Ca2+]i in neurons and MCs. To provide insight into the contribution of MCs on neurotransmitter release in rat hippocampal neurons, we used analysis of FM dye release, evoked by a cocktail of mediators from MCs stimulated by heat. RESULTS: Bidirectional communication is set up between MCs and hippocampal neurons. Neuronal depolarization caused intracellular calcium [Ca2+]i oscillations in MCs that produced a quick response in neurons. Furthermore, activation of MCs with antigen or the secretagogue compound 48/80 also resulted in a neuronal [Ca2+]i response. Moreover, local application onto neurons of the MC mediator cocktail elicited Ca2+ transients and a synaptic release associated with FM dye destaining. Neuronal response was partially blocked by D-APV, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and was inhibited when the cocktail was pre-digested with chondroitinase ABC, which induces enzymatic removal of proteoglycans of chondroitin sulfate (CS). CONCLUSIONS: MC-hippocampal neuron interaction affects neuronal [Ca2+]i and exocytosis signaling through a NMDAR-dependent mechanism.
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Comunicación Celular/fisiología , Hipocampo/metabolismo , Mastocitos/metabolismo , Neuronas/metabolismo , Proteoglicanos/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Técnicas de Cocultivo , Hipocampo/química , Hipocampo/citología , Mastocitos/química , Neuronas/química , Proteoglicanos/análisis , RatasRESUMEN
Proteolysis as mediated by one of the major cellular protein degradation pathways, the ubiquitin-proteasome system (UPS), plays an essential role in learning and memory formation. However, the functional relevance of immunoproteasomes in the healthy brain and especially their impact on normal brain function including processes of learning and memory has not been investigated so far. In the present study, we analyzed the phenotypic effects of an impaired immunoproteasome formation using a ß5i/LMP7-deficient mouse model in different behavioral paradigms focusing on locomotor activity, exploratory behavior, innate anxiety, startle response, prepulse inhibition, as well as fear and safety conditioning. Overall, our results demonstrate no strong effects of constitutive ß5i/LMP7-deficiency on gross locomotor abilities and anxiety-related behavior in general. However, ß5i/LMP7-deficient mice expressed more anxiety after mild stress and increased cued fear after fear conditioning. These findings indicate that the basal proper formation of immunoproteasomes and/or at least the expression of ß5i/LMP7 in healthy mice seem to be involved in the regulation of anxiety and cued fear levels.
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Complejo de la Endopetidasa Proteasomal/metabolismo , Estrés Psicológico/metabolismo , Animales , Ansiedad/metabolismo , Señales (Psicología) , Modelos Animales de Enfermedad , Miedo/fisiología , Femenino , Masculino , Memoria/fisiología , Ratones , Ratones Noqueados , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/inmunología , Complejo de la Endopetidasa Proteasomal/fisiología , Proteolisis , Reflejo de Sobresalto/fisiología , Estrés Psicológico/inmunologíaRESUMEN
Diabetic foot ulcer is one of the most frightened diabetic complications leading to amputation disability and early mortality. Diabetic wounds exhibit a complex networking of inflammatory cytokines, local proteases, and reactive oxygen and nitrogen species as a pathogenic polymicrobial biofilm, overall contributing to wound chronification and host homeostasis imbalance. Intralesional infiltration of epidermal growth factor (EGF) has emerged as a therapeutic alternative to diabetic wound healing, reaching responsive cells while avoiding the deleterious effect of proteases and the biofilm on the wound's surface. The present study shows that intralesional therapy with EGF is associated with the systemic attenuation of pro-inflammatory markers along with redox balance recovery. A total of 11 diabetic patients with neuropathic foot ulcers were studied before and 3 weeks after starting EGF treatment. Evaluations comprised plasma levels of pro-inflammatory, redox balance, and glycation markers. Pro-inflammatory markers such as erythrosedimentation rate, C-reactive protein, interleukin-6, soluble FAS, and macrophage inflammatory protein 1-alpha were significantly reduced by EGF therapy. Oxidative capacity, nitrite/nitrate ratio, and pentosidine were also reduced, while soluble receptor for advanced glycation end-products significantly increased. Overall, our results indicate that the local intralesional infiltration of EGF translates in systemic anti-inflammatory and antioxidant effects, as in attenuation of the glycation products' negative effects.
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Pie Diabético/tratamiento farmacológico , Factor de Crecimiento Epidérmico/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Anciano , Arginina/análogos & derivados , Arginina/sangre , Biomarcadores/sangre , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , Quimiocina CCL3/sangre , Citocinas/sangre , Femenino , Humanos , Inyecciones Intralesiones , Lisina/análogos & derivados , Lisina/sangre , Masculino , Persona de Mediana Edad , Nitratos/sangre , Nitritos/sangre , Receptor para Productos Finales de Glicación Avanzada/sangre , Cicatrización de Heridas , Receptor fas/sangreRESUMEN
To ensure normal immune function, mast cells employ different pathways to release mediators. Here, we report a thus far unknown capacity of mast cells to recycle and reuse secretory granules after an antigen-evoked degranulation process under physiological conditions; this phenomenon involves the existence of a recycling secretory granule pool that is available for release in a short time scale. Rapid endocytic modes contributed to the recycling of â¼60% of the total secretory granule population, which involved kiss-and-run and cavicapture mechanisms, causing retention of the intragranular matrix. We found the presence of normal-size granules and giant actomyosin- and dynamin-dependent granules, which were characterized by large quantal content. These large structures allowed the recovered mast cells to release a large amount of 5-HT, compensating for the decrease in the number of exocytosed secretory granules. This work uncovers a new physiological role of the exo-endocytosis cycle in the immunological plasticity of mast cells and reveals a new property of their biological secretion.
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Degranulación de la Célula , Inmunoglobulina E/metabolismo , Mastocitos/fisiología , Fusión de Membrana , Vesículas Secretoras/metabolismo , Actinas/metabolismo , Animales , Antígenos/metabolismo , Calcimicina/farmacología , Degranulación de la Célula/efectos de los fármacos , Dinaminas/metabolismo , Técnicas Electroquímicas , Endocitosis/efectos de los fármacos , Exocitosis/efectos de los fármacos , Mastocitos/efectos de los fármacos , Fusión de Membrana/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Biológicos , Miosina Tipo II/metabolismo , Vesículas Secretoras/efectos de los fármacos , Serotonina/metabolismoRESUMEN
Hypertrophic scars (HTS) and keloids are forms of aberrant cutaneous healing with excessive extracellular matrix (ECM) deposition. Current therapies still fall short and cause undesired effects. We aimed to thoroughly evaluate the ability of growth hormone releasing peptide 6 (GHRP6) to both prevent and reverse cutaneous fibrosis and to acquire the earliest proteome data supporting GHRP6's acute impact on aesthetic wound healing. Two independent sets of experiments addressing prevention and reversion effects were conducted on the classic HTS model in rabbits. In the prevention approach, the wounds were assigned to topically receive GHRP6, triamcinolone acetonide (TA), or vehicle (1% sodium carboxy methylcellulose [CMC]) from day 1 to day 30 post-wounding. The reversion scheme was based on the infiltration of either GHRP6 or sterile saline in mature HTS for 4 consecutive weeks. The incidence and appearance of HTS were systematically monitored. The sub-epidermal fibrotic core area of HTS was ultrasonographically determined, and the scar elevation index was calculated on haematoxylin/eosin-stained, microscopic digitised images. Tissue samples were collected for proteomics after 1 hour of HTS induction and treatment with either GHRP6 or vehicle. GHRP6 prevented the onset of HTS without the untoward reactions induced by the first-line treatment triamcinolone acetonide (TA); however, it failed to significantly reverse mature HTS. The preliminary proteomic study suggests that the anti-fibrotic preventing effect exerted by GHRP6 depends on different pathways involved in lipid metabolism, cytoskeleton arrangements, epidermal cells' differentiation, and ECM dynamics. These results enlighten the potential success of GHRP6 as one of the incoming alternatives for HTS prevention.
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Aumento de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cicatriz Hipertrófica/tratamiento farmacológico , Cicatriz/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Cicatrización de Heridas/efectos de los fármacos , Administración Cutánea , Animales , Modelos Animales de Enfermedad , Humanos , Proteómica , ConejosRESUMEN
For 15 years, from 2001, we began to apply Heberprot-P®, an injectable Epidermal Growth Factor (0.75 µg) created in the Center of Biotechnology, in Havana, Cuba. More than 159,000 patients were treated around the world, from 25 countries, with, with only 9-11% high-level amputations. In this paper, we discuss our experience in the treatment of the most complex diabetic foot ulcers cases for the last 15 years.
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Pie Diabético , Factor de Crecimiento Epidérmico , Cicatrización de Heridas/efectos de los fármacos , Administración Tópica , Antiulcerosos/administración & dosificación , Antiulcerosos/efectos adversos , Cuba , Pie Diabético/diagnóstico , Pie Diabético/terapia , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas/métodos , Factor de Crecimiento Epidérmico/administración & dosificación , Factor de Crecimiento Epidérmico/efectos adversos , Humanos , Inyecciones Intralesiones , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
Humans and animals are able to associate an environmental cue with the feeling of relief from an aversive event, a phenomenon called relief learning. Relief from an aversive event is rewarding and a relief-associated cue later induces an attenuation of the startle magnitude or approach behavior. Previous studies demonstrated that the nucleus accumbens is essential for relief learning. Here, we asked whether accumbal cannabinoid type 1 (CB1) receptors are involved in relief learning. In rats, we injected the CB1 receptor antagonist/inverse agonist SR141716A (rimonabant) directly into the nucleus accumbens at different time points during a relief learning experiment. SR141716A injections immediately before the conditioning inhibited relief learning. However, SR141716A injected immediately before the retention test was not effective when conditioning was without treatment. These findings indicate that accumbal CB1 receptors play an important role in the plasticity processes underlying relief learning.
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Aprendizaje/fisiología , Memoria/fisiología , Núcleo Accumbens/fisiología , Receptor Cannabinoide CB1/fisiología , Animales , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Reflejo de Sobresalto , RimonabantRESUMEN
The key role of mast cells (MC), either in development of inflammatory pathologies or in response to environmental stress, has been widely reported in recent years. Previous studies have described the effects of corticotropin-releasing hormone (CRH), which is released from inflamed tissues by cellular stress signals, on MC degranulation, a process possibly driven by selective secretion of mediators (piecemeal degranulation). In this study, we introduce a novel granular exo-endocytic pathway induced by CRH on peritoneal MC. We found that CRH triggers substantial exocytosis, which is even stronger than that induced by Ag stimulation and is characterized by large quantal size release events. Membrane fluorescence increases during stimulation in the presence of FM1-43 dye, corroborating the strength of this exocytosis, given that discrete upward fluorescence steps are often observed and suggesting that secretory granules are preferentially released by compound exocytosis. Additionally, the presence of a depot of large tubular organelles in the cytoplasm suggests that the exocytotic process is tightly coupled to a fast compound endocytosis. This CRH-stimulated mechanism is mediated through activation of adenylate cyclase and an increase of cAMP and intracellular Ca(2+), as evidenced by the fact that the effect of CRH is mimicked by forskolin and 8-bromo-cAMP. Thus, these outcomes constitute new evidence for the critical role of MC in pathophysiological conditions within a cellular stress environment and an alternative membrane trafficking route mediated by CRH.
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Hormona Liberadora de Corticotropina/farmacología , Endocitosis/efectos de los fármacos , Exocitosis/efectos de los fármacos , Mastocitos/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Adenilil Ciclasas/metabolismo , Animales , Calcio/metabolismo , Degranulación de la Célula/efectos de los fármacos , Células Cultivadas , Colforsina/farmacología , AMP Cíclico/metabolismo , Activación Enzimática/efectos de los fármacos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Mastocitos/fisiología , Ratones Endogámicos C57BL , Microscopía Confocal , Compuestos de Piridinio/metabolismo , Compuestos de Amonio Cuaternario/metabolismo , Ratas Wistar , Vesículas Secretoras/metabolismoRESUMEN
The diabetic foot ulcer (DFU) is the leading cause of lower extremity amputation worldwide and is directly associated with comorbidity, disability and mortality. Oxidative stress mechanisms have been implicated in the pathogenesis of these wounds. Intra-lesional infiltration of epidermal growth factor has emerged as a potential therapeutic alternative to allow for physiological benefit while avoiding the proteolytic environment at the centre of the wound. The aim of this study was to characterise the response of patients with DFUs to epidermal growth factor treatment in terms of redox status markers. Experimental groups included patients with DFUs before and 3-4 weeks after starting treatment with epidermal growth factor; compensated and non-compensated diabetic patients without ulcers; and age-matched non-diabetic subjects. Evaluations comprised serum levels of oxidative stress and antioxidant reserve markers. Patients with DFUs exhibited the most disheveled biochemical profile, with elevated oxidative stress and low antioxidant reserves, with respect to non-ulcerated diabetic patients and to non-diabetic subjects. Epidermal growth factor intra-lesional administration was associated with a significant recovery of oxidative stress and antioxidant reserve markers. Altogether, our results indicate that epidermal growth factor intra-ulcer therapy contributes to restore systemic redox balance in patients with DFUs.
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Pie Diabético/tratamiento farmacológico , Factor de Crecimiento Epidérmico/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Cuba , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Nocturnal enuresis is a common clinical problem affecting 5% to 10% of school-age children. Etiology is not known but a diminished functional bladder capacity it has been proposed as a predisposing factor. There exist only a few studies evaluating it by ultrasound. OBJECTIVE: To identify if there is a difference of the functional bladder capacity measured by ultrasound between nocturnal enuresis group and healthy children. PATIENTS AND METHOD: A cross-sectional study from February 2014 to May 2015 including two groups, nocturnal enuresis and a control group of 40 patients each, 5 to 15 years old. A single blinded operator measured the functional bladder capacity by ultrasound with an Acuson S2000 SiemensTM 3.5 and 5 MHz transducer. Analytics and descriptive statistics were performed using IBM SPSS 20TM software. RESULTS: Patients with enuresis showed a decreased functional bladder capacity vs. controls (171.7 ml vs 225.5 ml; p = 0.025). A history of first-degree relative with enuresis increased the risk of having enuresis OR = 2.81 (95% CI: 1.06-7.42), a second-degree relative presented OR = 4.0 (95% CI: 1.48-10.78). Functional bladder capacity presented a weak correlation with the bladder capacity estimated by Kaefers formula. CONCLUSION: The functional bladder capacity is lower in the patients with nocturnal enuresis when compared to control group. There is little correlation between functional bladder capacity and Kaefers formula to determine the normal bladder capacity. We reaffirmed that the family history with enuresis strongly increases the risk of developing nocturnal enuresis.
Asunto(s)
Enuresis Nocturna/etiología , Enfermedades de la Vejiga Urinaria/diagnóstico por imagen , Vejiga Urinaria/fisiopatología , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , Enuresis Nocturna/diagnóstico por imagen , Enuresis Nocturna/fisiopatología , Método Simple Ciego , Ultrasonografía , Vejiga Urinaria/diagnóstico por imagen , Enfermedades de la Vejiga Urinaria/complicaciones , Enfermedades de la Vejiga Urinaria/fisiopatologíaRESUMEN
5-hydroxytriptamine (5-HT, serotonin) storage and release in mast cell (MC) secretory granules (SG) are dependent on serglycin proteoglycans (PG). This notion is based on the studies of MC of the connective tissue subtype that predominantly contain PG of the heparin type, whereas intestinal mucosal MC, which contain predominantly chondroitin sulfate, have been poorly explored. In the present study, we addressed the possibility that PG contents may differently affect the storage and release of preformed mediators in these two MC subclasses and explain in part their different functional properties. Rat peritoneal (PMC) and intestinal mast cells (IMC) were isolated and purified using a percoll gradient, and the efflux of 5-HT from each SG was measured by amperometric detection. IMC exhibited a â¼34% reduction in the release of 5-HT compared with PMC because of a lower number of exocytotic events, rather than a lower secretion per single exocytotic event. Amperometric spikes from IMC exhibited a slower decay phase and increased half-width but a similar ascending phase and foot parameters, indicating that the fusion pore kinetics are comparable in both MC subclasses. We conclude that both PG subtypes are equally efficient systems, directly involved in serotonin accumulation, and play a crucial role in regulating the kinetics of exocytosis from SG, providing specific secretory properties for the two cellular subtypes.
Asunto(s)
Mucosa Intestinal/metabolismo , Intestinos/citología , Mastocitos/metabolismo , Peritoneo/citología , Peritoneo/metabolismo , Serotonina/metabolismo , Animales , Células Cultivadas , Exocitosis/fisiología , Cinética , Mastocitos/citología , Tasa de Depuración Metabólica , Especificidad de Órganos/fisiología , Ratas , Ratas WistarRESUMEN
Under the umbrella of pediatric-acquired demyelinating syndromes, there is a multitude of disorders, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica spectrum disorders (NMOSD). Due to overlapping clinical and magnetic resonance imaging (MRI) features, it can be challenging to provide an accurate diagnosis. In view of therapeutic and prognostic implications, an early and reliable diagnosis is however of utmost importance. Recent studies of myelin oligodendrocyte glycoprotein (MOG) identify MOG, as a promising target for antibody-mediated demyelination and a biomarker for a relatively benign and non-MS disease course. We describe the clinical and MRI presentation of five children presenting with an acute, severe central nervous system inflammatory disease involving the brain and spinal cord, all of whom were positive for MOG-IgG antibody. Encephalopathy was uncommon at presentation and all had quick resolution of symptoms with intravenous steroid and intravenous immunoglobulin (IVIG) treatment. All patients recovered well, and have been treated with IVIG to potentially prevent relapses.
Asunto(s)
Autoanticuerpos/inmunología , Encéfalo/diagnóstico por imagen , Enfermedades Desmielinizantes/fisiopatología , Glicoproteína Mielina-Oligodendrócito/inmunología , Médula Espinal/diagnóstico por imagen , Niño , Preescolar , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/inmunología , Encefalomielitis Aguda Diseminada/diagnóstico por imagen , Encefalomielitis Aguda Diseminada/tratamiento farmacológico , Encefalomielitis Aguda Diseminada/inmunología , Encefalomielitis Aguda Diseminada/fisiopatología , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Metilprednisolona/uso terapéutico , Mielitis Transversa/diagnóstico por imagen , Mielitis Transversa/tratamiento farmacológico , Mielitis Transversa/inmunología , Mielitis Transversa/fisiopatología , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/fisiopatología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the risk of stroke and bleeding using the CHA2DS2-VASc and HAS-BLED scores in Mexican patients with atrial fibrillation and to analyze whether the risk score obtained determined treatment decisions regarding antithrombotic therapy. METHODS: This is an observational, retrospective study in Mexican patients recently diagnosed with atrial fibrillation. The risk of stroke was assessed using the CHA2DS2-VASc scores. The bleeding risk was evaluated using the HAS-BLED score. The frequency of use of antithrombotic therapy was calculated according to the results of the score risk assessment. RESULTS: A total of 350 patients with non-valvular atrial fibrillation were analyzed. A 92.9% of patients had a high risk (score ≥ 2) of stroke according to the CHA2DS2-VASc score and only 17.2% were treated with anticoagulants. A high proportion of patients with atrial fibrillation (72.5%) showed both a high risk of stroke and a high risk of bleeding based on HAS-BLED score. CONCLUSIONS: In this group of patients with atrial fibrillation, from Northeast Mexico, there is a remarkably underutilization of anticoagulation despite the high risk of stroke of these patients.