RESUMEN
Mercury (Hg) and vitamin A (VitA) are two environmental factors with potential health impacts, especially during pregnancy and early childhood. Fish and seafood may present elevated levels of methylmercury (MeHg), the major Hg derivative, and VitA. This study aimed to evaluate the transgenerational effects of exposure to MeHg and/or VitA on epigenetic and toxicological parameters in a Wistar rat model. Our findings revealed persistent toxicological effects in generations F1 and F2 following low/mild doses of MeHg and/or VitA exposure during dams' (F0) gestation and breastfeeding. Toxicological effects observed in F2 included chronic DNA damage, bone marrow toxicity, altered microglial content, reduced neuronal signal, and diminished male longevity. Sex-specific patterns were also observed. Co-exposure to MeHg and VitA showed both synergistic and antagonistic effects. Additionally, the study demonstrated that MeHg and VitA affected histone methylation and caused consistent effects in F2. While MeHg exposure has been associated with transgenerational inheritance effects in other organisms, this study provides the first evidence of transgenerational inheritance of MeHg and VitA-induced toxicological effects in rodents. Although the exact mechanism is not yet fully understood, these findings suggest that MeHg and VitA may perpetuate their impacts across generations. The study highlights the need for remedial policies and interventions to mitigate the potential health problems faced by future generations exposed to MeHg or VitA. Further research is warranted to investigate the transgenerational effects beyond F2 and determine the matrilineal or patrilineal inheritance patterns.
Asunto(s)
Mercurio , Compuestos de Metilmercurio , Humanos , Preescolar , Ratas , Animales , Embarazo , Femenino , Masculino , Compuestos de Metilmercurio/toxicidad , Ratas Wistar , Vitamina A , MetilaciónRESUMEN
The gut microbiota is a complex community composed by several microorganisms that interact in the maintenance of homeostasis and contribute to physiological processes, including brain function. The relationship of the taxonomic composition of the gut microbiota with neurological diseases such as autism, Parkinson's, Alzheimer's, anxiety, and depression is widely recognized. The immune system is an important intermediary between the gut microbiota and the central nervous system, being one of the communication routes of the gut-brain axis. Although the complexity of the relationship between inflammation and epilepsy has not yet been elucidated, inflammatory processes are similar in many ways to the consequences of dysbiosis and contribute to disease progression. This study aimed to analyze the taxonomic composition of the gut microbiota of rats treated with prednisolone in a kindling model of epilepsy. Male Wistar rats (90 days, n = 24) divided into four experimental groups: sodium chloride solution 0.9 g%, diazepam 2 mg/kg, prednisolone 1 mg/kg, and prednisolone 5 mg/kg administered intraperitoneally (i.p.) for 14 days. The kindling model was induced by pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. The taxonomic profile was established by applying metagenomic DNA sequencing. There was no change in alpha diversity, and the composition of the gut microbiota between prednisolone and diazepam was similar. The significant increase in Verrucomicrobia, Saccharibacteria, and Actinobacteria may be related to the protective activity against seizures and inflammatory processes that cause some cases of epilepsy. Further studies are needed to investigate the functional influence that these species have on epilepsy and the inflammatory processes that trigger it.
Asunto(s)
Microbioma Gastrointestinal , Pentilenotetrazol , Animales , Masculino , Prednisolona , Ratas , Ratas Wistar , Convulsiones/inducido químicamenteRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of the nigrostriatal dopaminergic neurons that are associated with motor alterations and non-motor manifestations (such as depression). Neuroinflammation is a process with a critical role in the pathogenesis of PD. In this regard, toll-like receptor 4 (TLR4) is a central mediator of immune response in PD. Moreover, there are gender-related differences in the incidence, prevalence, and clinical features of PD. Therefore, we aimed to elucidate the role of TLR4 in the sex-dependent response to dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA) in mice. Female and male adult wildtype (WT) and TLR4 knockout (TLR4-/-) mice were administered with unilateral injection of 6-OHDA in the dorsal striatum, and non-motor and motor impairments were evaluated for 30 days, followed by biochemistry analysis in the substantia nigra pars compacta (SNc), dorsal striatum, and dorsoventral cortex. Early non-motor impairments (i.e., depressive-like behavior and spatial learning deficits) induced by 6-OHDA were observed in the male WT mice but not in male TLR4-/- or female mice. Motor alterations were observed after administration of 6-OHDA in both strains, and the lack of TLR4 was also related to motor commitment. Moreover, ablation of TLR4 prevented 6-OHDA-induced dopaminergic denervation and microgliosis in the SNc, selectively in female mice. These results reinforced the existence of sex-biased alterations in PD and indicated TLR4 as a promising therapeutic target for the motor and non-motor symptoms of PD, which will help counteract the neuroinflammatory and neurodegenerative processes.
Asunto(s)
Encéfalo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Factores Sexuales , Receptor Toll-Like 4/metabolismo , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Hidroxidopaminas/farmacología , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Degeneración Nerviosa/inducido químicamente , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/genética , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/genéticaRESUMEN
Piracanjunba (Brycon orbignyanus) is an endangered South American fish, and ovarian tissue cryopreservation is an alternative method for preserving maternal germplasm and genetic diversity. Therefore, our aim was to test a vitrification protocol for ovarian tissue containing primary growth (PG) oocytes of B. orbignyanus as a strategy to avoid the threat of extinction. Two vitrification solutions were evaluated (VS1: 1.5 M methanol + 4.5 M propylene glycol and VS2: 1.5 M methanol + 5.5 M Me2SO) and compared using control/fresh ovarian tissue. After vitrification, the following factors were analyzed: membrane integrity using trypan blue, morphology using a histological assessment, oxidative stress (total reactive antioxidant potential (TRAP) and reduced thiol [-SH]), mitochondrial activity using MTT, and DNA damage using a comet assay. The vitrified oocytes (VS1 = 24.3 ± 0.49% and VS2 = 24.8 ± 0.69%) showed higher DNA damage than the control group (control = 20.7 ± 1.03%) (P = 0.004). In contrast, in most evaluations (membrane integrity, membrane damage, oxidative stress, and mitochondrial activity), there were no discernible differences between the control group and the vitrified samples. In addition, oocyte (P = 0.883) and nuclear diameter (P = 0.118) did not change after vitrification. VS2 treatment resulted in higher nuclear damage (15.7 ± 1.45%) than in the control treatment (3.5 ± 1.19%); however, VS1 treatment did not result in significantly more damage (9.5 ± 3.01%) than in the control (P = 0.015). Therefore, the protocol for ovarian tissue vitrification tested in this study resulted in high maintenance of PG oocyte cell integrity, making it a promising alternative for B. orbignyanus maternal genome preservation.
Asunto(s)
Characiformes , Vitrificación , Animales , Criopreservación/métodos , Femenino , Oocitos , OvarioRESUMEN
Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-ß peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.
Asunto(s)
Astrocitos/patología , Microglía/patología , Enfermedades Neurodegenerativas/patología , Schistosoma mansoni/aislamiento & purificación , Esquistosomiasis mansoni/complicaciones , Acetilcisteína/farmacología , Animales , Antihelmínticos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Deferoxamina/farmacología , Modelos Animales de Enfermedad , Depuradores de Radicales Libres/farmacología , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiología , Praziquantel/farmacología , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/metabolismo , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/patología , Sideróforos/farmacologíaRESUMEN
BACKGROUND: The construction sector is one of the most stable growth industries in the world. However, many studies have suggested an association between occupational exposure in civil construction and lung cancer risk. Thus, this study aims to assess lung cancer risk in civil construction workers occupationally exposed to physical and chemical agents through a systematic review and meta-analysis. METHODS/DESIGN: Studies will be identified by searching PUBMED, Embase, SCOPUS, WEB OF SCIENCE and the reference list of included articles. Eligible study designs will be cohort, cross-sectional, and case-control studies that report occupational exposure to physical or chemical agents and lung cancer risk through mortality or incidence outcomes. A meta-analysis will be used to combine odds ratios (ORs) from case-control studies and relative risks (RR) from cohort studies. Two reviewers will independently screen articles, extract data, and assess scientific quality using standardized forms and ROBINS-E tool if available. Otherwise, the New-Castle Ottawa rating scale will be used. Any of those will also be used in combination with the GRADE approach for quality of evidence. Overall risk estimates and their corresponding 95% confidence intervals (CIs) will be obtained using the random-effects model meta-analysis. This systematic review and meta-analysis will be conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. DISCUSSION: This review will identify and synthesize studies investigating the association between occupational exposure in the construction industry and lung cancer. The findings will help governmental entities and researchers with evidence-based decision-making because they will integrate and validate the evidence on construction workers' health effects due to occupational exposure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020164209.
Asunto(s)
Industria de la Construcción , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/mortalidad , Metaanálisis como Asunto , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/mortalidad , Revisiones Sistemáticas como Asunto , Femenino , Humanos , Incidencia , Masculino , Obreros Metalúrgicos , Exposición Profesional/análisis , Factores de RiesgoRESUMEN
People with large amounts of adipose tissue are more vulnerable and more likely to develop diseases where oxidative stress and inflammation play a pivotal role, than persons with a healthy weight. Atmospheric contamination is a reality to which a large part of the worldwide population is exposed. Half of today's global electrical energy is derived from coal. Each organism, in its complexity, responds in different ways to dietary compounds and air pollution. The objective of this study was to investigate the effects of obesity and coal ash inhalation within the parameters of oxidative damage and inflammation in different regions of the brain of rats. A diet containing high-fat concentration was administered chronically to rats, along with exposure to coal ash, simulating the contamination that occurs daily throughout human life. High-resolution transmission electron microscopy was performed to identify the particles present in coal ash samples. Our results demonstrated that obese rats exposed to coal ash inhalation were more affected by oxidative damage with subsequent systemic inflammation in the hippocampus. Since there is an inflammatory predisposition caused by obesity, the inhalation of nanoparticles increases the levels of free radicals, resulting in systemic inflammation and oxidative damage, which can lead to chronic neurodegeneration.
Asunto(s)
Ceniza del Carbón/toxicidad , Hipocampo/efectos de los fármacos , Inflamación/metabolismo , Exposición por Inhalación , Obesidad/metabolismo , Estrés Oxidativo/efectos de los fármacos , Contaminantes Atmosféricos/toxicidad , Animales , Catalasa/metabolismo , Dieta Alta en Grasa , Glutatión Peroxidasa/metabolismo , Inflamación/inducido químicamente , Masculino , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Maple Syrup Urine Disease (MSUD) is an inborn error of the metabolism caused by defects in the branched a-ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of branched chain amino acids (BCAAs) (leucine, isoleucine and valine). Patients with MSUD present a series of neurological dysfunction. Recent studies have been associated the brain damage in the MSUD with inflammation and immune system activation. MSUD patients die within a few months of life due to recurrent metabolic crises and neurologic deterioration, often precipitated by infection or other stresses. In this regard, our previous results showed that the inflammatory process, induced by lipopolysaccharide (LPS), associated with high levels of BCAAs causes blood-brain barrier (BBB) breakdown due to hyperactivation of MMPs. Thus, we hypothesize that the synergistic action between high concentrations of BCAAs (H-BCAAs) and LPS on BBB permeability and hyperactivation of MMPs could be through an increase in the production of cytokines and RAGE protein levels. We observed that high levels of BCAA in infant rats are related to increased brain inflammation induced by LPS administration. In addition, BCAA exposure led to an increase on brain RAGE expression of young rats. The brain inflammation was characterized by enhanced levels of interleukin 1 ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and Interferon- γ (IFN-γ), and decreased content of interleukin-10 (IL-10). Therefore, MSUD is associated with a more intense neuroinflammation induced by LPS infection.
Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Barrera Hematoencefálica/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inflamación/inducido químicamente , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Corteza Cerebral/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Inflamación/metabolismo , Lipopolisacáridos , Masculino , Metaloproteinasas de la Matriz/metabolismo , Permeabilidad , Ratas , Ratas Wistar , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
OBJECTIVE: Some factors related to lifestyle, including stress and high-fat diet (HFD) consumption, are associated with higher prevalence of obesity. These factors can lead to an imbalance between ROS production and antioxidant defenses and to mitochondrial dysfunctions, which, in turn, could cause metabolic impairments, favoring the development of obesity. However, little is known about the interplay between these factors, particularly at early ages, and whether long-term sex-specific changes may occur. Here, we evaluated whether social isolation during the prepubertal period only, associated or not with chronic HFD, can exert long-term effects on oxidative status parameters and on mitochondrial function in the whole hypothalamus, in a sex-specific manner. METHODS: Wistar male and female rats were divided into two groups (receiving standard chow or standard chow + HFD), that were subdivided into exposed or not to social isolation during the prepubertal period. Oxidative status parameters, and mitochondrial function were evaluated in the hypothalamus in the adult age. RESULTS: Regarding antioxidant enzymes activities, HFD decreased GPx activity in the hypothalamus, while increasing SOD activity in females. Females also presented increased total thiols; however, non-protein thiols were lower. Main effects of stress and HFD were observed in TBARS levels in males, with both factors decreasing this parameter. Additionally, HFD increased complex IV activity, and decreased mitochondrial mass in females. Complex I-III activity was higher in males compared to females. CONCLUSION: Stress during the prepubertal period and chronic consumption of HFD had persistent sex-specific effects on oxidative status, as well as on its consequences for the cell and for mitochondrial function. HFD had more detrimental effects on females, inducing oxidative imbalance, which resulted in damage to the mitochondria. This HFD-induced imbalance may be related to the development of obesity.
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Dieta Alta en Grasa/efectos adversos , Hipotálamo/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo/fisiología , Caracteres Sexuales , Estrés Psicológico/metabolismo , Animales , Femenino , Masculino , Potenciales de la Membrana/fisiología , Ratas , Ratas Wistar , Maduración Sexual/fisiología , Estrés Psicológico/psicologíaRESUMEN
Fish consumption and ubiquitous methylmercury (MeHg) exposure represent a public health problem globally. Micronutrients presented in fish affects MeHg uptake/distribution. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. The present study aimed to examine the effects of both MeHg and retinyl palmitate administered to pregnant and lactating rats. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/Kg/day) and retinyl palmitate (7500 µg RAE1/Kg/day), either individually or in combination from the gestational day 0 to weaning. In dams, maternal behavior was scored. In neonatal and infant offspring, associative learning and neurodevelopment were evaluated. Further periadolescent male and female pups were assessed for open field, habituation and object recognition using episodic-like memory paradigm. Maternal and offspring redox parameters were evaluated. Our results showed no effects of MeHg-VitA co-administration in the quality of maternal care but showed subtle alterations in the pro-oxidant response of the hippocampus. In offspring, MeHg-VitA co-exposure affected early associative learning in neonatal pups, with no further modifications in neurodevelopment, and no locomotor or exploratory alterations in later developmental stages. Habituation was altered in a sex-dependent manner, but no overall memory disturbances were encountered. Finally, MeHg-VitA co-administration reduced lipoperoxidation in male offspring hippocampus. In conclusion, VitA co-administration in dams, under our exposure protocol, can counteract the deleterious neurodevelopmental effects solely attributed to low-dose MeHg in a tissue-specific mechanism, suggesting a protective effect of VitA against MeHg-induced oxidative damage in the central nervous system, especially in the offspring. Further work is needed to confirm our findings and elucidate the molecular mechanisms of MeHg-VitA modulation. Pre-clinical assays are necessary to demonstrate the potential therapeutical use of VitA in populations directly or indirectly exposed to MeHg.
Asunto(s)
Lactancia/efectos de los fármacos , Locomoción/efectos de los fármacos , Compuestos de Metilmercurio/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Vitamina A/análogos & derivados , Animales , Anticarcinógenos/administración & dosificación , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Diterpenos , Combinación de Medicamentos , Femenino , Lactancia/fisiología , Locomoción/fisiología , Masculino , Compuestos de Metilmercurio/toxicidad , Odorantes , Estrés Oxidativo/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Ésteres de Retinilo , Vitamina A/administración & dosificaciónRESUMEN
Microbiota alterations are observed in pathological conditions, and their regulation is a subject of great interest. Gut microbes are affected by diet, and plant polyphenols may have positive effect on gut microbiota; however, plant-derived extracts may have toxic effects. Guarana (Paullinia cupana Mart.) is a nontraditional medicinal plant applied worldwide. Guarana yields an alkaloid and polyphenol-rich seed with antimicrobial, antioxidant, and anti-inflammatory properties, where caffeine is the major compound. We evaluated the effects of guarana seed powder (GSP) and purified caffeine on gut microbial composition and redox and inflammatory parameters in Wistar rats after 21 days of treatment. Fecal microbiota was analyzed utilizing 16S rDNA sequencing. Antioxidant enzymes activities from liver, kidney, and colon, as well as oxidative damage markers, were evaluated. Total nonenzymatic antioxidant potential was also evaluated. Microbiota was altered by both treatments, GSP and caffeine, without loss of diversity. In the liver, the kidney, and the colon, we observed a decrease in the antioxidant enzymes activities in the GSP group with no increase in the expression of oxidative damage markers, although some enzymes were also regulated by caffeine. Taken together, these results suggested that GSP ameliorates redox parameters but negatively affected gut microbiota, partially via caffeine.
Asunto(s)
Cafeína/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Teobromina/farmacología , Teofilina/farmacología , Animales , Antioxidantes/farmacología , Cafeína/química , Disbiosis/inducido químicamente , Disbiosis/microbiología , Disbiosis/patología , Masculino , Oxidación-Reducción/efectos de los fármacos , Paullinia/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Ratas , Ratas Wistar , Semillas , Teobromina/química , Teofilina/químicaRESUMEN
The genes of the NFκB pathway are involved in the control of a plethora of biological processes ranking from inhibition of apoptosis to metastasis in cancer. It has been described that Gliobastoma multiforme (GBM) patients carry aberrant NFκB activation, but the molecular mechanisms are not completely understood. Here, we present a NFκB pathway analysis in tumor specimens of GBM compared to non-neoplasic brain tissues, based on the different kind of cycles found among genes of a gene co-expression network constructed using quantized data obtained from the microarrays. A cycle is a closed walk with all vertices distinct (except the first and last). Thanks to this way of finding relations among genes, a more robust interpretation of gene correlations is possible, because the cycles are associated with feedback mechanisms that are very common in biological networks. In GBM samples, we could conclude that the stoichiometric relationship between genes involved in NFκB pathway regulation is unbalanced. This can be measured and explained by the identification of a cycle. This conclusion helps to understand more about the biology of this type of tumor.
Asunto(s)
Retroalimentación Fisiológica , Glioblastoma/genética , FN-kappa B/metabolismo , Transducción de Señal/genética , Ciclo Celular/genética , Ciclo Celular/fisiología , Curaduría de Datos , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiología , Glioblastoma/fisiopatología , Humanos , Análisis por Micromatrices , FN-kappa B/genética , Transducción de Señal/fisiologíaRESUMEN
Glioma cells release cytokines to stimulate inflammation that facilitates cell proliferation. Here, we show that Lipopolysaccharide (LPS) treatment could induce glioma cells to proliferate and this process was dependent on nucleotide receptor activation as well as interleukin-8 (IL-8/CXCL8) secretion. We observed that extracellular nucleotides controlled IL-8/CXCL8 and monocyte chemoattractant protein 1 (MCP-1/CCL2) release by U251MG and U87MG human glioma cell lines via P2X7 and P2Y6 receptor activation. The LPS-induced release of these cytokines was also modulated by purinergic receptor activation since IL-8 and MCP-1 release was decreased by the nucleotide scavenger apyrase as well as by the pharmacological P2Y6 receptor antagonists suramin and MRS2578. In agreement with these observations, the knockdown of P2Y6 expression decreased LPS-induced IL-8 release as well as the spontaneous release of IL-8 and MCP-1, suggesting an endogenous basal release of nucleotides. Moreover, high millimolar concentrations of ATP increased IL-8 and MCP-1 release by the glioma cells stimulated with suboptimal LPS concentration which were blocked by P2X7 and P2Y6 antagonists. Altogether, these data suggest that extracellular nucleotides control glioma growth via P2 receptor-dependent IL-8 and MCP-1 secretions.
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Neoplasias Encefálicas/metabolismo , Proliferación Celular , Quimiocina CCL2/metabolismo , Glioma/metabolismo , Interleucina-8/metabolismo , Receptores Purinérgicos/fisiología , Secuencia de Bases , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Cartilla de ADN , Glioma/patología , Humanos , Reacción en Cadena de la Polimerasa , Receptores Purinérgicos/genética , Receptores Purinérgicos/metabolismo , Transducción de SeñalRESUMEN
Chemoreception is among the most important sensory modalities in animals. Organisms use the ability to perceive chemical compounds in all major ecological activities. Recent studies have allowed the characterization of chemoreceptor gene families. These genes present strikingly high variability in copy numbers and pseudogenization degrees among different species, but the mechanisms underlying their evolution are not fully understood. We have analyzed the functional networks of these genes, their orthologs distribution, and performed phylogenetic analyses in order to investigate their evolutionary dynamics. We have modeled the chemosensory networks and compared the evolutionary constraints of their genes in Mus musculus, Homo sapiens, and Rattus norvegicus. We have observed significant differences regarding the constraints on the orthologous groups and network topologies of chemoreceptors and signal transduction machinery. Our findings suggest that chemosensory receptor genes are less constrained than their signal transducing machinery, resulting in greater receptor diversity and conservation of information processing pathways. More importantly, we have observed significant differences among the receptors themselves, suggesting that olfactory and bitter taste receptors are more conserved than vomeronasal receptors.
Asunto(s)
Células Quimiorreceptoras/metabolismo , Evolución Molecular , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genética , Análisis de Varianza , Animales , Análisis por Conglomerados , Biología Computacional , Ontología de Genes , Humanos , Ratones , Modelos Genéticos , Filogenia , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Especificidad de la EspecieRESUMEN
Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Neuroblastoma/genética , Neuroblastoma/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Línea Celular Tumoral , Análisis por Conglomerados , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Modelos Biológicos , Neuroblastoma/metabolismo , Neuroblastoma/mortalidad , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Satureja hortensis L. is an aromatic plant with antibacterial and antibiofilm activities against periodontopathogens. Here, we attempted to find out whether the antioxidant properties of S. hortensis L. essential oil (EO) could be used to inhibit matrix metalloproteinase (MMP) activities and prevent the induction of cell death by a pro-oxidant insult. First, a landscape analysis of MMP and REDOX/nitric oxide (NO)-related genes was performed (MRN model), and array data from periodontitis patients were plotted over the newly developed model. Thereafter, the antigelatinolytic activity of S. hortensis L. EO and its preventive effect against hydrogen peroxide (H2 O2 )-induced cell death were tested in vitro (HaCaT cells). Up-regulation of MMP genes in the MRN network (except for MMP-10, -15, -16, -20, -25, and -26) and differential expression of genes coding for antioxidant enzymes were found among others in periodontitis samples. MMP2 and MMP9 were central genes in the MRN network model. Moreover, treatments with 1 and 5â µl/ml of S. hortensis L. EO inhibited both MMP-2 and MMP-9 activities, and H2 O2 -induced cell death in vitro. We concluded that S. hortensis L. EO could be a promising host-modulating agent, since oxidative stress and excessive MMP expression/activity are typical hallmarks of periodontal pathogenesis.
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Antioxidantes/química , Inhibidores de la Metaloproteinasa de la Matriz/química , Metaloproteinasas de la Matriz/química , Óxido Nítrico/metabolismo , Aceites Volátiles/química , Periodontitis/metabolismo , Satureja/química , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular , Redes Reguladoras de Genes , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/toxicidad , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/química , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Aceites Volátiles/farmacología , Oxidación-Reducción , Periodontitis/tratamiento farmacológico , Periodontitis/patología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Bipolar disorder (BD) is a chronic major mental illness characterized by extreme mood episodes, cognitive impairment, and high rates of disability. Several lines of evidence suggest that BD may be associated with abnormalities in mitochondrial function. Here we critically review findings from brain imaging and from preclinical studies that investigated markers of energy metabolism in BD. Research with postmortem brain and peripheral tissue revealed changes in size and distribution of mitochondria, as well as decreased mitochondrial electron transport chain function, increased oxidative stress, and increased lipid and protein damage. PET imaging studies revealed decreased glucose metabolism in sub-areas of the prefrontal cortex, amygdala, and hippocampus structures in BD. On the other hand, increased lactate levels in BD have been found in cerebrospinal fluid and in gray matter by magnetic resonance spectroscopy, which suggest that distinct pathophysiological processes may be region-specific. Resting state fMRI studies have demonstrated decreased functional connectivity between fronto-limbic circuits. In conclusion, these results support the hypothesis of mitochondrial dysfunction in BD and suggest that BD is associated with decreased energy production and a shift towards anaerobic glycolysis. Such changes in energy metabolism can potentially decrease cell plasticity and ultimately disrupt brain circuits associated with mood and cognitive control.
El trastorno bipolar (TB) es una enfermedad mental crónica grave caracterizada por episodios de ánimo extremo, trastornos cognitivos y altas tasas de discapacidad. Varias líneas de evidencia sugieren que el TB puede estar asociado con anormalidades en la función mitocondrial. Aquí analizamos críticamente los hallazgos de las imágenes cerebrales y de los estudios preclínicos que han investigado los marcadores del metabolismo de energía en TB. Las investigaciones post mórtem basadas en tejidos cerebrales y tejidos periféricos revelaron cambios en el tamaño y en la distribución de las mitocondrias, además de una disminución en la funcionalidad de la cadena de transporte de electrones de las mitocondrias, un mayor estrés oxidativo y mayores daños lipídicos y proteínicos. Estudios con imágenes TEP revelan un metabolismo de glucosa disminuido en las subáreas de la corteza prefrontal, la amígdala y el hipocampo en TB. Por otro lado, se han hallado concentraciones mayores de lactato en TB en el líquido cefalorraquídeo cerebral y en la materia gris utilizando la espectroscopia con resonancia magnética, lo cual sugiere que los procesos fisiopatológicos individuales pueden ser específicos de las distintas regiones. Los estudios con resonancias magnéticas funcionales han demostrado una menor conectividad funcional entre los circuitos frontolímbicos. En conclusión, estos resultados apoyan la hipótesis de una disfunción mitocondrial en el TB y sugieren que el TB está asociado con una menor producción de energía y un cambio hacia la glicólisis anaeróbica. Estos cambios en el metabolismo energético pueden disminuir potencialmente la plasticidad celular y, en últimas, perturbar los circuitos cerebrales asociados con el estado de ánimo y el control cognitivo.
RESUMEN
BACKGROUND: Some of the postulated molecular mechanisms of sepsis progression are linked with the imbalance between reactive oxygen species (ROS) production and its degradation by cellular antioxidant pathways. Some studies have correlated plasma oxidative stress, inflammatory markers, and clinical markers of organ failure, but none performed this in a systematic way, determining in situ oxidative and inflammatory markers and correlating these with markers of organ failure. MATERIALS AND METHODS: Rats subjected to cecal ligation and puncture (CLP) were treated with basic support or antioxidants and killed 12 h after to determine thiobarbituric acid reactive species (as an index of oxidative damage), superoxide dismutase (SOD), catalase (CAT), and myeloperoxidase (MPO) (as an index of neutrophil infiltration) in the kidney and lung. In addition, protein content in bronchoalveolar lavage fluid (as an index of lung alveolo-capillary dysfunction) and plasma urea (as an index of kidney injury) were measured at the same time. RESULTS: In the CLP group, we found a positive correlation between thiobarbituric acid reactive species (TBARS) and markers of organ injury in lung and kidney. Oxidative damage is correlated with an increase in SOD/CAT ratio only in the lung. In contrast, oxidative damage is correlated with MPO activity in the kidney, but not lung, suggesting different sources of oxidative damage depending on the analyzed organ. These reflect differences on the effects of basic support and antioxidants on organ dysfunction after sepsis. CONCLUSION: Despite the general occurrence of oxidative damage in different organs during sepsis development and a positive correlation between oxidative markers and organ injury, antioxidant effects seemed to depend not only on the diminution of oxidative damage but also on its anti-inflammatory activity.
Asunto(s)
Antioxidantes/uso terapéutico , Catalasa/metabolismo , Insuficiencia Multiorgánica/prevención & control , Infiltración Neutrófila/fisiología , Estrés Oxidativo/fisiología , Sepsis/complicaciones , Superóxido Dismutasa/metabolismo , Acetilcisteína/uso terapéutico , Animales , Deferoxamina/uso terapéutico , Modelos Animales de Enfermedad , Riñón/metabolismo , Pulmón/metabolismo , Masculino , Insuficiencia Multiorgánica/metabolismo , Insuficiencia Multiorgánica/microbiología , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Urea/sangreRESUMEN
There is a growing body of evidence showing that vitamin A induces toxic effects in several experimental models and in human beings. In the present work, we have investigated the effects of short-term vitamin A supplementation on the adult rat liver redox status. We have found that vitamin A at therapeutic doses induces a hepatic oxidative insult. Furthermore, we have observed increased antioxidant enzyme activity in the liver of vitamin-A-treated rats. Additionally, some mitochondrial dysfunction was found since superoxide anion production was increased in vitamin-A-treated rat liver submitochondrial particles, which may be the result of impaired mitochondrial electron transfer chain activity, as assessed here. We have also isolated rat liver mitochondria and challenged it with 75 muM CaCl2, a non-oxidant agent that is able to induce mitochondrial oxidative stress indirectly. We have found that mitochondria isolated from vitamin-A-treated rat liver are more sensitive to CaCl2 than control mitochondria regarding the redox status. Importantly, vitamin A seems to alter mitochondrial redox status independently of the participation of the mitochondrial permeability transition pore, which is activated by Ca2+ ions since cyclosporin A did not prevent the oxidative insult elicited by Ca2+ addition. Overall, we show here that mitochondria are a target of vitamin-A-associated toxicity also in vivo.
Asunto(s)
Calcio/metabolismo , Mitocondrias Hepáticas , Oxidorreductasas/metabolismo , Vitamina A , Animales , Calcio/farmacología , Ciclosporina/farmacología , Transporte de Electrón , Metabolismo Energético/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Homeostasis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/ultraestructura , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Poro de Transición de la Permeabilidad Mitocondrial , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Partículas Submitocóndricas/metabolismo , Superóxidos/metabolismo , Vitamina A/administración & dosificación , Vitamina A/efectos adversosRESUMEN
Even though retinoids are widely used as adjuvant in chemotherapeutic interventions to improve cancer cell death, their mechanism(s) of action involves multiple overlapping pathways that remain unclear. We have previously shown that vitamin A, the natural precursor of the retinoids, induces oxidative-dependent cytochrome c release from isolated mitochondria, suggesting a putative mechanism for apoptosis activation. Using Sertoli cells in culture, we show that retinol causes mitochondrial-dependent apoptosis, involving oxidative stress. Apoptosis was evaluated by nuclear morphology, DNA fragmentation, and caspase-3/7 activity. Retinol induced oxidant- and time-dependent imbalance of several mitochondrial parameters, cytochrome c release and caspase-3/7 activation, leading cells to commit apoptosis. All parameters tested were attenuated or blocked by trolox co-administration, suggesting that retinol induces apoptosis through oxidative damage, which mitochondria plays a pivotal role.