RESUMEN

Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are common food additives for human consumption. We examined multi-organ toxicity of both compounds on Wistar rats orally exposed for 90 days. Rats were divided into three groups: (1) control (saline solution), (2) E171-exposed, and (3) ZnO NPs-exposed. Histological examination was performed with hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Ceramide (Cer), 3-nitrotyrosine (NT), and lysosome-associated membrane protein 2 (LAMP-2) were detected by immunofluorescence. Relevant histological changes were observed: disorganization, inflammatory cell infiltration, and mitochondrial damage. Increased levels of Cer, NT, and LAMP-2 were observed in the liver, kidney, and brain of E171- and ZnO NPs-exposed rats, and in rat hearts exposed to ZnO NPs. E171 up-regulated Cer and NT levels in the aorta and heart, while ZnO NPs up-regulated them in the aorta. Both NPs increased LAMP-2 expression in the intestine. In conclusion, chronic oral exposure to metallic NPs causes multi-organ injury, reflecting how these food additives pose a threat to human health. Our results suggest how complex interplay between ROS, Cer, LAMP-2, and NT may modulate organ function during NP damage.

Asunto(s)

Ceramidas , Nanopartículas del Metal , Ratas Wistar , Titanio , Óxido de Zinc , Animales , Óxido de Zinc/toxicidad , Titanio/toxicidad , Titanio/efectos adversos , Ratas , Ceramidas/metabolismo , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Masculino , Administración Oral , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología

RESUMEN

Tumor heterogeneity leads to drug resistance in cancer treatment with the crucial role of sphingolipids in cell fate and stress signaling. We analyzed sphingolipid metabolism and autophagic flux to study chemotherapeutic interactions on the A549 lung cancer model. Loaded cells with fluorescent sphingomyelin analog (BODIPY) and mCherry-EGFP-LC3B were used to track autophagic flux and assess cytotoxicity when cells are exposed to chemotherapy (epirubicin, cisplatin, and paclitaxel) together with sphingolipid pathway inhibitors and autophagy modulators. Our cell model approach employed fluorescent sphingolipid biosensors and a Gaussian Mixture Model of cell heterogeneity profiles to map the influence of chemotherapy on the sphingolipid pathway and infer potential synergistic interactions. Results showed significant synergy, especially when combining epirubicin with autophagy inducers (rapamycin and Torin), reducing cell viability. Cisplatin also synergized with a ceramidase inhibitor. However, paclitaxel often led to antagonistic effects. Our mapping model suggests that combining chemotherapies with autophagy inducers increases vesicle formation, possibly linked to ceramide accumulation, triggering cell death. However, the in silico model proposed ceramide accumulation in autophagosomes, and kinetic analysis provided evidence of sphingolipid colocalization in autophagosomes. Further research is needed to identify specific sphingolipids accumulating in autophagosomes. These findings offer insights into potential strategies for overcoming chemotherapy resistance by targeting the sphingolipid pathway.

Asunto(s)

Neoplasias Pulmonares , Esfingolípidos , Humanos , Esfingolípidos/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Cisplatino/farmacología , Epirrubicina , Cinética , Ceramidas/farmacología , Ceramidas/metabolismo , Paclitaxel/farmacología

RESUMEN

SARS-CoV-2 infection triggers distinct patterns of disease development characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SLs) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n = 55), COVID-19 patients (n = 204), and convalescent individuals (n = 77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, a predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, and neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) species (d18:1/24:1) and (d18:1/24:0)were associated with increased risk. Moreover, we observed the enhanced expression of key enzymes involved in the SL pathway in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.

Asunto(s)

COVID-19 , Esfingomielinas , Humanos , Pronóstico , SARS-CoV-2/metabolismo , Ceramidas/metabolismo , Esfingolípidos/metabolismo , Biomarcadores

RESUMEN

In the last 2 years, different pharmacological agents have been indicated as potential inhibitors of SARS-CoV-2 in vitro. Specifically, drugs termed as functional inhibitors of acid sphingomyelinase (FIASMAs) have proved to inhibit the SARS-CoV-2 replication using different types of cells. Those therapeutic agents share several chemical structure characteristics and some well-known representatives are fluoxetine, escitalopram, fluvoxamine, and others. Most of the FIASMAs are primarily used as effective therapeutic agents to treat different pathologies, therefore, they are natural drug candidates for repositioning strategy. In this review, we summarize the two main proposed mechanisms mediating acid sphingomyelinase (ASM) inhibition and how they can explain the inhibition of SARS-CoV-2 replication by FIASMAs. The first mechanism implies a disruption in the lysosomal pH fall as the endosome-lysosome moves toward the interior of the cell. In fact, changes in cholesterol levels in endosome-lysosome membranes, which are associated with ASM inhibition is thought to be mediated by lysosomal proton pump (ATP-ase) inactivation. The second mechanism involves the formation of an extracellular ceramide-rich domain, which is blocked by FIASMAs. The ceramide-rich domains are believed to facilitate the SARS-CoV-2 entrance into the host cells.

Asunto(s)

COVID-19 , SARS-CoV-2 , Esfingomielina Fosfodiesterasa , Humanos , Ceramidas/metabolismo , Fluoxetina/farmacología , SARS-CoV-2/efectos de los fármacos , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Esfingomielina Fosfodiesterasa/metabolismo

RESUMEN

In rodents, sphingomyelins (SMs) species with very-long-chain polyunsaturated fatty acid (VLCPUFA) are required for normal spermatogenesis. Data on the expression of enzymes with roles in their biosynthesis and turnover during germ cell differentiation and on possible effects on such expression of testosterone (Tes), known to promote this biological process, were lacking. Here we quantified, in isolated pachytene spermatocytes (PtS), round spermatids (RS), and later spermatids (LS), the mRNA levels from genes encoding ceramide (Cer), glucosylceramide (GlcCer), and SM synthases (Cers3, Gcs, Sms1, and Sms2) and sphingomyelinases (aSmase, nSmase) and assessed products of their activity in cells in culture using nitrobenzoxadiazole (NBD)-labeled substrates and [3H]palmitate as precursor. Transcript levels from Cers3 and Gcs were maximal in PtS. While mRNA levels from Sms1 increased with differentiation in the direction PtS→RS→LS, those from Sms2 increased between PtS and RS but decreased in LS. In turn, the nSmase transcript increased in the PtS→RS→LS order. During incubations with NBD-Cer, spermatocytes produced more GlcCer and SM than did spermatids. In total germ cells cultured for up to 25 h with NBD-SM, not only abundant NBD-Cer but also NBD-GlcCer were formed, demonstrating SM→Cer turnover and Cer recycling. After 20 h with [3H]palmitate, PtS produced [3H]SM and RS formed [3H]SM and [3H]Cer, all containing VLCPUFA, and Tes increased their labeling. In total germ cells, Tes augmented in 5 h the expression of genes with roles in VLCPUFA synthesis, decreased the mRNA from Sms2, and increased that from nSmase. Thus, Tes enhanced or accelerated the metabolic changes occurring to VLCPUFA-SM during germ cell differentiation.

Asunto(s)

Espermatogénesis , Espermatozoides , Esfingomielinas , Testosterona , Animales , Masculino , Ratas , Ceramidas/metabolismo , Espermátides/metabolismo , Esfingomielinas/metabolismo , Testosterona/metabolismo , Espermatozoides/citología , Espermatozoides/metabolismo

RESUMEN

Psychiatric disorders affect 970 million people worldwide, representing a significant source of disability. Although the underlying neurobiological traits for these disorders are not fully understood, a complex interplay between psychological, environmental, and biological factors contributes to their outcomes. Recent advances in lipidomic analysis and artificial intelligence algorithms have improved the identification of selective lipid species modulating the susceptibility to mental disorders. Sphingolipids (SLs) and ceramides-related SLs are among the most abundant lipids species in the brain that support major key pathways during neurodevelopment and brain plasticity. High levels of ceramides in plasma and brain contribute to psychiatric illness susceptibility in humans and animal models. However, the neuropathological mechanism regarding the involvement of ceramides in these disorders remain inconclusive. The brain is highly susceptible to nutritional insults, which could lead to functional impairment and influence the development and progression of psychiatric disorders. While the brain relies on glucose metabolism to support its physiological needs, a selective nutrient formula appears to have greater effects on brain health than others. For instance, consumption of high-energy diets is associated with brain anatomical, physiological, and metabolic changes, including ceramides metabolism. Herein, we will address the contribution of ceramides metabolism as a modulator of major psychiatric disorders such as depression, anxiety, bipolar disorder, schizophrenia, and attention deficit-hyperactivity disorder. We will also describe molecular and cellular targets of ceramides metabolism assisting the maintenance and progression of psychiatric disorders and their modulation by dietary formulas as non-pharmacologic treatments.

Asunto(s)

Trastorno Bipolar , Trastornos Mentales , Animales , Humanos , Inteligencia Artificial , Trastornos Mentales/metabolismo , Esfingolípidos/metabolismo , Ceramidas/metabolismo , Trastorno Bipolar/metabolismo

RESUMEN

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and a severe threat to pregnant people and offspring health. The molecular origins of GDM, and in particular the placental responses, are not fully known. The present study aimed to perform a comprehensive characterisation of the lipid species in placentas from pregnancies complicated with GDM using high-resolution MS lipidomics, with a particular focus on sphingolipids and acylcarnitines in a semi-targeted approach. The results indicated that despite no major disruption in lipid metabolism, placentas from GDM pregnancies showed significant alterations in sphingolipids, mostly lower abundance of total ceramides. Additionally, very long-chain ceramides and sphingomyelins with twenty-four carbons were lower, and glucosylceramides with sixteen carbons were higher in placentas from GDM pregnancies. Semi-targeted lipidomics revealed the strong impact of GDM on the placental acylcarnitine profile, particularly lower contents of medium and long-chain fatty-acyl carnitine species. The lower contents of sphingolipids may affect the secretory function of the placenta, and lower contents of long-chain fatty acylcarnitines is suggestive of mitochondrial dysfunction. These alterations in placental lipid metabolism may have consequences for fetal growth and development.

Asunto(s)

Diabetes Gestacional , Placenta , Embarazo , Femenino , Humanos , Placenta/metabolismo , Diabetes Gestacional/metabolismo , Esfingolípidos/metabolismo , Carnitina/metabolismo , Ceramidas/metabolismo

RESUMEN

Acid Sphingomyelinase (ASM) is a human phosphodiesterase that catalyzes the metabolism of sphingomyelin (SM) to ceramide and phosphocholine. ASM is involved in the plasma membrane cell repair and is associated with the lysosomal inner lipid membrane by nonbonding interactions. The disruption of those interaction would result in ASM release into the lysosomal lumen and consequent degradation of its structure. Furthermore, SARS-CoV-2 infection has been linked with ASM activation and with a ceramide domain formation in the outer leaflet of the plasma membrane that is thought to be crucial for the viral particles recognition by the host cells. In this study, we have explored in silico the behavior of fluoxetine and related drugs as potential inhibitors of ASM. Theoretically, these drugs would be able to overpass lysosomal membrane and reach the interactions that sustain ASM structure, breaking them and inhibiting the ASM. The analyses of docking data indicated that fluoxetine allocated mainly in the N-terminal saposin domain via nonbonding interactions, mostly of hydrophobic nature. Similar results were obtained for venlafaxine, citalopram, atomoxetine, nisoxetine and fluoxetine's main metabolite norfluoxetine. In conclusion, it was observed that the saposin allocation may be a good indicative of the drugs inhibition mechanism, once this domain is responsible for the binding of ASM to lysosomal membrane and some of those drugs have previously been reported to inhibit the phosphodiesterase by releasing its structure in the lysosomal lumen. Our MD data also provides some insight about natural ligand C18 sphingomyelin conformations on saposin.Communicated by Ramaswamy H. Sarma.

Asunto(s)

COVID-19 , Esfingomielina Fosfodiesterasa , Humanos , Esfingomielina Fosfodiesterasa/metabolismo , Fluoxetina/farmacología , SARS-CoV-2/metabolismo , Esfingomielinas , Saposinas , Antidepresivos/farmacología , Ceramidas/metabolismo

RESUMEN

In some dermal diseases with evident skin dehydration and desquamation, the natural ratio of CER[NP]:CER[AP] is altered in the extracellular matrix of the stratum corneum by increasing the concentration of CER[AP]. The extracellular matrix of the stratum corneum is composed of several stacked lipid bilayers. Molecular dynamics simulations were used to investigate the molecular nanostructure of CER[NP], CER[AP], cholesterol and lignoceric acid models of the extracellular matrix of the stratum corneum with a nativelike CER[NP]:CER[AP] 2:1 ratio and a CER[NP]:CER[AP] ratio of 1:2. Despite the very minor chemical difference between CER[NP] and CER[AP], which is only a single OH group, it was possible to observe differences between the structural influence of the two ceramides. In the models with 1:2 ratio, the higher CER[AP] content leads to a larger inclination of the acyl chains and a smaller overlap in the lamellar midplane, with a small increase of the repeat distance compared to the model with higher CER[NP] concentration. Because CER[AP] forms more H-bonds than CER[NP], the total number of hydrogen bonds in the headgroup region is larger in the models with higher CER[AP] concentration, reducing the mobility of the lipids towards the centre of the bilayer and resulting in less overlap and increased tilt angles.

Asunto(s)

Epidermis , Simulación de Dinámica Molecular , Epidermis/química , Piel/química , Membrana Dobles de Lípidos/química , Ceramidas/química

RESUMEN

Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.

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A produção de ceramida ocorre em todo o corpo e desempenha um papel importante na manutenção da fisiologia normal. No entanto, os níveis de ceramidas são alterados em estados de doença, principalmente durante o desenvolvimento de diabetes e dislipidemia. A produção de ceramidas também está associada à instabilidade das placas ateroscleróticas. Estudos recentes revelam que pacientes com doença arterial coronariana instável apresentam níveis plasmáticos aumentados de ceramidas (principalmente C16, C18 e C24:1). Atualmente, são consideradas biomarcadores emergentes nas doenças cardiovasculares, sendo utilizadas na predição de instabilidade da placa aterosclerótica e eventos cardiovasculares adversos de forma independente aos fatores de risco tradicionais. Com o objetivo de descrever e discutir o papel das ceramidas na estratificação das doenças cardiovasculares, o desenvolvimento desta revisão narrativa contextualiza a importância desse biomarcador no cenário atual da cardiologia.

Asunto(s)

Enfermedades Cardiovasculares , Placa Aterosclerótica , Biomarcadores , Enfermedades Cardiovasculares/etiología , Ceramidas , Humanos , Medición de Riesgo , Factores de Riesgo

Asunto(s)

Ceramidas , Esfingolípidos , Humanos

RESUMEN

OBJECTIVE: Psoriasis is a chronic inflammatory skin disorder. Oral or subcutaneous methotrexate (MTX) is a first-line antipsoriatic treatment, whose adverse effects can be observed even at low doses. To minimize systemic side effects, antipsoriatic drugs should be administered topically, since they could permeate the stratum corneum. As liquid crystals with lamellar phase (LP) can be helpful in promoting skin permeation, this work evaluated two MTX-loaded LPs (C1CH and C1CHCE), based on stearic acid, cholesterol and ceramides, like topical treatments for mice with imiquimod-induced psoriasis. METHODS: C1CH and C1CHCE were topically administered to mice with imiquimod-induced psoriasis. Dexamethasone cream was used as positive treatment control. Skin histology and inflammation biomarkers were assessed. KEY FINDINGS: C1CH and C1CHCE exhibited marked immunomodulatory effects and induced extensive microstructural skin remodelling on the epidermis and dermis. These formulations increased keratinization score, epidermis thickness, inflammatory infiltrate, hair follicle hypertrophy and vascular congestion in the dermis. C1CH and C1CHCE also attenuated IL-10 upregulation and upregulated IL-1, IFN-γ, TNF-α and prostaglandin E2 levels, as well as myeloperoxidase, N-acetyl-ß-d-glucosaminidase and cyclooxygenase 2 activity compared with untreated psoriatic animals. CONCLUSION: Although liquid crystals have been reported as good options for carrying topical drugs, they need to be carefully assessed on a case-by-case basis.

Asunto(s)

Metotrexato , Psoriasis , Animales , Ceramidas/efectos adversos , Colesterol , Modelos Animales de Enfermedad , Imiquimod/efectos adversos , Metotrexato/farmacología , Ratones , Ratones Endogámicos BALB C , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Piel , Tensoactivos/farmacología

RESUMEN

Bottlenose dolphins (Tursiops truncatus) are found in coastal and estuarine ecosystems where they are in continuous contact with multiple abiotic and biotic stressors in the environment. Due to their role as predators, they can bioaccumulate contaminants and are considered sentinel organisms for monitoring the health of coastal marine ecosystems. The northern zonal coast of the Yucatan peninsula of Mexico has a high incidence of anthropogenic activities. The principal objectives of this study were two-fold: 1) to determine the presence of trace metals and their correlation with lipids in bottlenose dolphin blubber, and 2) to use a lipidomics approach to characterize their biological responses. Levels of trace elements (Al, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Cd, Pb) were analyzed using ICP-MS and lipids were measured using a targeted lipidomics approach with LC-MS/MS. Spearman correlation analysis was used to identify associations between lipids and trace elements. The influences of gender, stranding codes, presence of stomach content, growth stages and body length were also analyzed. Blubber lipid composition was dominated by triacylglycerols (TAG). Our results demonstrated the presence of heavy-metal elements such as Cd and As, which were correlated with different lipid species, mainly the ceramides and glycerophospholipids, respectively. Organisms with Cd showed lower concentrations of ceramides (CER, HCER and DCER), TAG and cholesteryl esters (CE). Trace elements Cr, Co, As and Cd increased proportionately with body length. This study provides a novel insight of lipidomic characterization and correlations with trace elements in the bottlenose dolphin which might contribute to having a better understanding of the physiological functions and the risks that anthropogenic activities can bring to sentinel organisms from coastal regions.

Asunto(s)

Delfín Mular , Oligoelementos , Contaminantes Químicos del Agua , Animales , Cadmio/análisis , Ceramidas , Cromatografía Liquida , Ecosistema , Monitoreo del Ambiente , Lipidómica , Lípidos , México , Espectrometría de Masas en Tándem , Oligoelementos/análisis , Contaminantes Químicos del Agua/análisis

RESUMEN

The profile of sphingomyelin and its metabolites shows changes in the plasma, organs, and tissues of patients with cardiovascular, renal, and metabolic diseases. The objective of this study was to investigate the effect of empagliflozin on the levels of sphingomyelin and its metabolites, as well as on the activity of acid and neutral sphingomyelinase (aSMase and nSMase) and neutral ceramidase (nCDase) in the plasma, kidney, heart, and liver of streptozotocin-induced diabetic and Angiotensin II (Ang II)-induced hypertension rats. Empagliflozin treatment decreased hyperglycemia in diabetic rats whereas blood pressure remained elevated in hypertensive rats. In diabetic rats, empagliflozin treatment decreased sphingomyelin in the plasma and liver, ceramide in the heart, sphingosine-1-phosphate (S1P) in the kidney, and nCDase activity in the plasma, heart, and liver. In hypertensive rats, empagliflozin treatment decreased sphingomyelin in the plasma, kidney, and liver; S1P in the plasma and kidney; aSMase in the heart, and nCDase activity in the plasma, kidney, and heart. Our results suggest that empagliflozin downregulates the interaction of the de novo pathway and the catabolic pathway of sphingolipid metabolism in the diabetes, whereas in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway.

Asunto(s)

Diabetes Mellitus Experimental , Hipertensión , Animales , Compuestos de Bencidrilo , Ceramidas/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Glucósidos , Humanos , Hipertensión/tratamiento farmacológico , Ratas , Esfingolípidos/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas

RESUMEN

Enzymes related to sphingolipids metabolism has been suggested as altered in oral squamous cell carcinoma (OSCC). However, clinical relevance of diverse sphingolipids in OSCC is not fully known. Here, we evaluated sphingolipidomics in plasma and tumor tissues as a tool for diagnosis/prognosis in OSCC patients. Plasma was obtained from 58 controls and 56 OSCC patients, and paired tumor and surgical margin tissues (n = 42). The levels of 28 sphingolipids molecules were obtained by mass spectrometry. Furthermore, sphingolipids were analyzed with clinical and pathological characteristics to search the potential for diagnosis and prognosis. Lower levels of 17 sphingolipids was found in the plasma of OSCC patients compared to controls while four were elevated in tumor tissues. C18:0 dyhidroceramide and C24:0 lactosylceramide in plasma were associated with perineural invasion, while tissue levels of ceramide and dyhidroceramide were associated with advanced tumor stage and perineural invasion. High plasma levels of C24:0 ceramide (HR = 0.10, p = 0.0036) and C24:1 glucosylceramide (HR = 6.62, p = 0.0023), and tissue levels of C24:0 dyhidroceramide (HR = 3.95, p = 0.032) were identified as independent prognostic factors. Moreover, we identified signatures composed by i) sphinganine-1-phosphate and C16 ceramide-1-phosphate in plasma with significant diagnostic accuracy, while ii) C24:0 ceramide, C24:0 dyhidroceramide, and C24:1 glucosylceramide plasma levels, and iii) C24:0 dyhidrosphingomyelin and C24:0 ceramide tissue levels showed value to predict survival in patients aged 60 years or older. We proposed the sphingolipids signatures in plasma and tumor tissues as biomarkers candidates to diagnosis and prognosis in OSCC.

Asunto(s)

Metabolismo de los Lípidos/genética , Pronóstico , Esfingolípidos/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Adulto , Anciano , Ceramidas/sangre , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glucosilceramidas/sangre , Humanos , Masculino , Persona de Mediana Edad , Esfingolípidos/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Transcriptoma/genética

Asunto(s)

Síndrome Coronario Agudo , Enfermedades Cardiovasculares , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Ceramidas , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Fosfatidilcolinas , Fosfolípidos , Factores de Riesgo

RESUMEN

Emerging research has linked psychological well-being with many physiological markers as well as morbidity and mortality. In this analysis, the relationship between components of eudaimonic well-being and serum sphingolipids levels was investigated using data from a large national survey of middle-aged American adults (Midlife in the United States). Health behaviors (i.e., diet, exercise, and sleep) were also examined as potential mediators of these relationships. Serum levels of total ceramides-the main molecular class of sphingolipids previously associated with several disease conditions-were inversely linked with environmental mastery. In addition, significant correlations were found between specific ceramide, dihydroceramide, and hexosylceramides species with environmental mastery, purpose in life, and self-acceptance. Using hierarchical regression and mediation analyses, health behaviors appeared to mediate these associations. However, the link between ceramides and environmental mastery was partially independent of health behaviors, suggesting the role of additional mediating factors. These findings point to sphingolipid metabolism as a novel pathway of health benefits associated with psychological well-being. In particular, having a sense of environmental mastery may promote restorative behaviors and benefit health via improved blood sphingolipid profiles.

Asunto(s)

Ceramidas/sangre , Esfingolípidos/sangre , Población Blanca , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Depresión/tratamiento farmacológico , Depresión/epidemiología , Dislipidemias/tratamiento farmacológico , Dislipidemias/epidemiología , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Control Interno-Externo , Estilo de Vida , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Autonomía Personal , Calidad de Vida , Autoimagen , Autoeficacia , Sueño , Estados Unidos/epidemiología , Población Blanca/psicología

RESUMEN

Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.

Asunto(s)

Ceramidas/metabolismo , Metabolismo Energético/fisiología , Ácidos Grasos/fisiología , Animales , Ceramidas/fisiología , Dieta Alta en Grasa/efectos adversos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos/metabolismo , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiología , Resistencia a la Insulina/fisiología , Leptina/metabolismo , Lisofosfolípidos/metabolismo , Obesidad/metabolismo , Transducción de Señal/fisiología , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo

RESUMEN

The control of skin permeability to specific substances (e.g., medications, vitamins, and nutrients) through stratum corneum is a challenge. Iontophoresis is an option in spite of the lack of a detailed understanding of the underlying molecular mechanism. In the present work, the simulations concerning application of an external continuous electric field to stratum corneum, in a range of low intensity (0-24 mV nm-1), were carried out using the coarse-grained molecular dynamics approach. Using a set of random seed replicas of the starting configuration, we observed that in the range of electric field intensity of 22-23 mV nm-1, water-rich lipid vesicles were formed in 20% of cases. Pores appeared in the remaining 80%. We argue that lipids undergo fast re-orientations under electric field inducing mechanical instability, which originates the pores. We presented a simple electrostatic model to interpret the results where the mismatch between electrical permittivities of the membrane and external media and the gradient of the local electric field in the membrane surface, govern the time scales and electric fields for vesicle formation. Our results indicate that just 10% difference between electrical permittivities of the membrane and external media decreases 1/6 the minimal time required for vesicle formation. The minimal electric field required decreases 10 times. The control and tunning of formation of biologically compatible vesicles, capable of transporting substances under low-intensity electric fields, has a promising application in fields such as drug therapy and dermo-cosmetics allowing the use of hydrophilic substances in dermal applications.

Asunto(s)

Membrana Celular/metabolismo , Agua/metabolismo , Transporte Biológico , Membrana Celular/química , Ceramidas/química , Colesterol/química , Epidermis/química , Ácidos Grasos/química , Iontoforesis , Simulación de Dinámica Molecular , Electricidad Estática , Agua/química

RESUMEN

Snakebite envenomation causes > 81,000 deaths and incapacities in another 400,000 people worldwide every year. Snake venoms are complex natural secretions comprised of hundreds of different molecules with a wide range of biological functions that after injection cause local and systemic manifestations. Although several studies have investigated snake venoms, the majority have focused on the protein portion (toxins), without significant attention paid to the lipid fraction. Therefore, an untargeted lipidomic approach based on liquid chromatography with high-resolution mass spectrometry (LC-HRMS) was applied to investigate the lipid constituents of venoms of the snake species Crotalus durissus terrificus and Bothrops moojeni. Phosphatidylcholines (PC), Lyso-PCs, phosphatidylethanolamines (PE), Lyso-PE, phosphatidylserine (PS), phosphatidylinositol (PI), ceramides (Cer), and sphingomyelin (SM) species were detected in the analyzed snake venoms. The identified lipids included bioactive compounds such as platelet-activating factor (PAF) precursor, PAF-like molecules, plasmalogens, ceramides, and sphingomyelins with long fatty acid chain lengths, which may be associated with the systemic responses triggered by C. d. terrificus and B. moojeni envenomation. These responses include platelet aggregation, activation of intercellular adhesion molecule 1 (ICAM1), apoptosis, as well as the production of pro-inflammatory lipid mediators, cytokines, and reactive species. The newly proposed lipidomics strategy provided valuable information regarding the lipid profiles of viperid venoms, which could lead to increased understanding of the complex pathology promoted by snakebite envenomation.

Asunto(s)

Bothrops , Ceramidas/metabolismo , Venenos de Crotálidos/metabolismo , Crotalus , Lipidómica , Fosfolípidos/metabolismo , Mordeduras de Serpientes , Esfingomielinas/metabolismo , Animales , Ceramidas/toxicidad , Cromatografía Líquida de Alta Presión , Venenos de Crotálidos/toxicidad , Fosfolípidos/toxicidad , Esfingomielinas/toxicidad , Espectrometría de Masas en Tándem