RESUMEN
As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.
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Sleepiness is a multicausal condition, and previous research has highlighted associations between this symptom and the circadian timing system, specifically concerning social jetlag and sleep variability. Recent inquiries have shown that the effects of social jetlag on sleepiness can be confounded with the consequences of sleep debt. In light of the current evidence, we aimed to assess the effects of social jetlag and sleep variability on sleepiness and the potential mediating role of sleep debt. We used data from the EPISONO study, a cross-sectional population-based study with a sample size of 1042 participants, representative of the city of Sao Paulo, Brazil. Participants completed the UNIFESP Sleep Questionnaire (self-reported bedtime and get-up time) and the Epworth Sleepiness Scale (subjective daytime sleepiness). Subsequently, sleep-corrected mid-sleep time (chronotype), total sleep time, social jetlag (absolute difference between the mid-sleep time on workdays and mid-sleep time on free days), sleep variability (standard deviation of mid-sleep time), and sleep debt (difference between total sleep time on workdays and free days) were calculated. Generalised linear models were used to test whether social jetlag and sleep variability affected sleepiness. Mediation models were used to determine if any observed significant effects were mediated by sleep debt. The prevalence of social jetlag was 23% for >1 h and 12% for >2 h. The mean sleep variability was 41 ± 30 min. Social jetlag had a significant effect on the Epworth Sleepiness Scale scores. This association was no longer statistically significant after controlling for age, sex, body mass index, work schedule, and chronotype. A significant indirect effect of social jetlag on sleep debt and subsequently on the Epworth Sleepiness Scale scores was found. No effect of sleep variability on sleepiness could be identified. In conclusion, the association between social jetlag and sleepiness was mediated by sleep debt but was not independent of demographic, work, and chronotype variables. This study provides new evidence on the importance of circadian misalignment and sleep debt for sleep health on a population level.
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Ritmo Circadiano , Privación de Sueño , Humanos , Somnolencia , Estudios Transversales , Brasil/epidemiología , Sueño , Síndrome Jet Lag/epidemiología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) affects nearly 1 billion people globally, and has established links with cardiovascular and neurocognitive complications. Although it has some limitations, the apnea-hypopnea index (AHI) is commonly used to gauge OSA severity and therapeutic response. Homocysteine (Hcy) metabolism, when impaired, can elicit cellular senescence mechanisms that may be shared with OSA. Hence, our objective was to explore the role of Hcy concentrations both as a predictor of AHI values and as a potential risk factor for OSA. METHODS: Involving 1042 volunteers aged 20 to 80 years, the initial study (2007) included polysomnographic evaluations, questionnaires on sleep and general health, as well as biochemical analyses. After an 8-year interval, 715 participants from the initial study were invited for a follow-up assessment in 2015. RESULTS: Our findings showed that Hcy was a predictor for an increased AHI, and AHI increased over time. Individuals with plasma Hcy concentrations ≥ 15 µmol/L experienced an average AHI increase of 7.43 events/hour ([beta coefficient] ß = 7.43; 95%CI 2.73 to 12.13) over time, compared to those with plasma concentrations < 10 µmol/L. A similar trend was apparent in those with plasma Hcy concentrations between 10 ≥ and < 15 µmol/L, who had an AHI increase with an average beta coefficient of 3.20 events/hour (95%CI 1.01 to 5.39) compared to those with plasma Hcy concentrations < 10 µmol/L. CONCLUSIONS: In summary, our study suggests that increased plasma Hcy concentrations could be considered a risk factor for the development of OSA. These findings highlight that elevated plasma Hcy concentrations can predict the severity of OSA, underscoring their correlation with the AHI.
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Homocisteína , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/epidemiología , Homocisteína/sangre , Masculino , Persona de Mediana Edad , Adulto , Femenino , Anciano , Estudios Longitudinales , Factores de Riesgo , Anciano de 80 o más Años , Polisomnografía , Adulto Joven , Índice de Severidad de la Enfermedad , Biomarcadores/sangreRESUMEN
Methionine is a precursor of s-adenosylmethionine, the main donor of methyl radicals for methylation of DNA and other compounds. Previous studies have shown that reduced availability of methyl radicals during pregnancy/lactation decreased offspring perigonadal white adipose tissue (PWAT) and body weight. Therefore, we aimed to evaluate the effects of methionine supplementation during early development, a time of great ontogenic plasticity, by assessing the biometric, biochemical and behavioural parameters of the offspring of adult Swiss female mice supplemented with 1 % methionine in water 1 month before pregnancy, during pregnancy or pregnancy/lactation. After birth, the offspring were distributed into three groups: control (CT), methionine supplementation during pregnancy (SP) and methionine supplementation during pregnancy and lactation (SPL), and were followed until postnatal day (PND) 300. No changes were observed in offspring birth weight in both sexes. At PND 5, 28 and 90, no differences in body weight were found in females; however, at PND 300, SP and SPL females showed an increase in body weight when compared with the control group. This increase in body weight was accompanied by a total and relative increase in PWAT, and a decrease in locomotor activity in these groups. No differences in the body and organ weights were found in male offspring. In conclusion, the increased availability of methyl radicals during pregnancy and lactation impacted long-term body composition and locomotor activity in female offspring.
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Lactancia , Metionina , Animales , Peso Corporal , Suplementos Dietéticos , Femenino , Locomoción , Masculino , Metionina/farmacología , Ratones , EmbarazoRESUMEN
PURPOSE: The identification of subgroups of obstructive sleep apnea (OSA) is critical to understand disease outcome and treatment response and ultimately develop optimal care strategies customized for each subgroup. In this sense, we aimed to perform a cluster analysis to identify subgroups of individuals with OSA based on clinical parameters in the Epidemiological Sleep Study of São Paulo city (EPISONO). We aimed to analyze whether or not subgroups remain after 8 years, since there is not any evidence showing if these subtypes of clinical presentation of OSA in the same population can change overtime. METHODS: We used data derived from EPISONO cohort, which was followed over 8 years after baseline evaluation. All individuals underwent polysomnography, answered questionnaires, and had their blood collected for biochemical examinations. OSA was defined according to AHI ≥ 15 events/h. Cluster analysis was performed using latent class analysis (LCA). RESULTS: Of the 1042 individuals in the EPISONO cohort, 68% agreed to participate in the follow-up study (n = 712), and 704 were included in the analysis. We were able to replicate the OSA 3-cluster solution observed in previous studies: disturbed sleep, minimally symptomatic and excessively sleepy in both baseline (36%, 45% and 19%, respectively) and follow-up studies (42%, 43%, and 15%, respectively). The optimal cluster solution for our sample based on Bayesian information criterion (BIC) was 2 cluster for baseline (disturbed sleep and excessively sleepy) and 3 clusters for follow-up (disturbed sleep, minimally symptomatic, and excessively sleepy). A total of 45% of the participants migrated clusters between the two evaluations (and the factor associated with this was a greater delta-AHI (B = - 0.033, df = 1, p = 0.003). CONCLUSIONS: The results replicate and confirm previously identified clinical clusters in OSA which remain in the longitudinal analysis, with some percentage of migration between clusters.
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Apnea Obstructiva del Sueño , Teorema de Bayes , Brasil , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Reproducibilidad de los ResultadosRESUMEN
V-ATPases are part of the membrane components of pathogen-containing vacuoles, although their function in intracellular infection remains elusive. In addition to organelle acidification, V-ATPases are alternatively implicated in membrane fusion and anti-inflammatory functions controlled by ATP6V0d2, the d subunit variant of the V-ATPase complex. Therefore, we evaluated the role of ATP6V0d2 in the biogenesis of pathogen-containing vacuoles using ATP6V0d2 knock-down macrophages infected with the protozoan parasite Leishmania amazonensis. These parasites survive within IFNγ/LPS-activated inflammatory macrophages, multiplying in large/fusogenic parasitophorous vacuoles (PVs) and inducing ATP6V0d2 upregulation. ATP6V0d2 knock-down decreased macrophage cholesterol levels and inhibited PV enlargement without interfering with parasite multiplication. However, parasites required ATP6V0d2 to resist the influx of oxidized low-density lipoprotein (ox-LDL)-derived cholesterol, which restored PV enlargement in ATP6V0d2 knock-down macrophages by replenishing macrophage cholesterol pools. Thus, we reveal parasite-mediated subversion of host V-ATPase function toward cholesterol retention, which is required for establishing an inflammation-resistant intracellular parasite niche.
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Colesterol/metabolismo , Regulación Enzimológica de la Expresión Génica , Homeostasis , Leishmania/metabolismo , Macrófagos/metabolismo , Regulación hacia Arriba , ATPasas de Translocación de Protón Vacuolares/biosíntesis , Vacuolas/metabolismo , Animales , Lipoproteínas LDL/metabolismo , Macrófagos/parasitología , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Células RAW 264.7 , Vacuolas/parasitología , Vacuolas/patologíaRESUMEN
We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology.
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Anomalías Múltiples/genética , Fosfatasa Ácida/genética , Alopecia/genética , Cerebelo/anomalías , Anomalías Craneofaciales/genética , Secuenciación del Exoma , Trastornos del Crecimiento/genética , Síndromes Neurocutáneos/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/diagnóstico por imagen , Alopecia/patología , Brasil/epidemiología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/patología , Femenino , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/diagnóstico por imagen , Trastornos del Crecimiento/patología , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Síndromes Neurocutáneos/diagnóstico , Síndromes Neurocutáneos/diagnóstico por imagen , Síndromes Neurocutáneos/patología , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Rombencéfalo/diagnóstico por imagen , Rombencéfalo/patología , Nervio Trigémino/diagnóstico por imagen , Nervio Trigémino/metabolismo , Nervio Trigémino/patología , Adulto JovenRESUMEN
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by a mutation in the IDUA gene, which codes α-L-iduronidase (IDUA), a lysosomal hydrolase that degrades two glycosaminoglycans (GAGs): heparan sulfate (HS) and dermatan sulfate (DS). GAGs are macromolecules found mainly in the extracellular matrix and have important signaling and structural roles which are essential to the maintenance of cell and tissue physiology. Nondegraded GAGs accumulate in various cell types, which characterizes MPS I as a multisystemic progressive disease. Many tissues and vital organs have been described in MPS I models, but there is a lack of studies focused on their effects on the reproductive tract. Our previous studies indicated lower sperm production and morphological damage in the epididymis and accessory glands in male MPS I mice, despite their ability to copulate and to impregnate females. Our aim was to improve the testicular characterization of the MPS I model, with a specific focus on ultrastructural observation of the different cell types that compose the seminiferous tubules and interstitium. We investigated the testicular morphology of 6-month-old male C57BL/6 wild-type (Idua+/+) and MPS I (Idua-/-) mice. We found vacuolated cells widely present in the interstitium and important signs of damage in myoid, Sertoli and Leydig cells. In the cytoplasmic region of Sertoli cells, we found an increased number of vesicles with substrates under digestion and a decreased number of electron-dense vesicles similar to lysosomes, suggesting an impaired flux of substrate degradation. Conclusions: Idua exerts an important role in the morphological maintenance of the seminiferous tubules and the testicular interstitium, which may influence the quality of spermatogenesis, having a greater effect with the progression of the disease.
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Glicosaminoglicanos/genética , Enfermedades por Almacenamiento Lisosomal/genética , Mucopolisacaridosis I/genética , Células de Sertoli/patología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Células Intersticiales de Cajal/metabolismo , Células Intersticiales de Cajal/patología , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/patología , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Ratones , Mucopolisacaridosis I/metabolismo , Mucopolisacaridosis I/patología , Mutación/genética , Células de Sertoli/metabolismo , Espermatozoides/metabolismo , Espermatozoides/patologíaRESUMEN
A previous animal study by our group found that sleep deprivation during preimplantation was associated with decreased pregnancy maintenance. Given its impact on human society, we aimed in the current study to assess whether sleep deprivation affects blastocyst gene expression and/or the implantation process. For this, pregnant mice (gestational day 0 [GD 0]) were assigned into paradoxical sleep deprivation (SD, 72 hr; multiple platform method) and, a control (CT) group. Animals were euthanized on GD 3.5 and blood, uterus (embryos) and fallopian tube were collected. Then, 89% of CT presented blastocysts in the uterus versus 25% from SD group. Compared to CT, SD presented lighter relative uterus weight, increased plasma concentrations of corticosterone and testosterone, decreased concentrations of progesterone and luteinizing hormone, but no statistical differences in plasma concentrations of 17ß-estradiol and follicle stimulating hormone. There were no differences in uterus and blastocyst gene expression related to embryo implantation and development, and no alteration in blastocysts global DNA methylation. Considering this, the decreased pregnancy maintenance after sleep deprivation seems not to be associated with implantation losses or developmental problems related to the blastocysts. It is likely that complications in morula development and/or its movement through the fallopian tubes affect the pregnancy rate, since only 25% of SD females presented a blastocyst on the GD 3.5. In fact, three out of four females without blastocysts in the uterus presented morula in the fallopian tubes due to a phase delay. Additionally, we suggest that the observed hormonal changes may play a role in this outcome.
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Implantación del Embrión , Mórula/metabolismo , Reproducción , Privación de Sueño , Útero/fisiología , Animales , Biomarcadores , Blastocisto/metabolismo , Peso Corporal , Metilación de ADN , Epigénesis Genética , Trompas Uterinas/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica , Hormonas/metabolismo , Ratones , Factores de TiempoRESUMEN
BACKGROUND: Bacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children. The Hcy pathway controls bioavailability of methyl, and its homeostasis can be modulated by vitamin B12, a cofactor of the methionine synthase enzyme. Herein, the neuroprotective potential and the underlying mode of action of vitamin B12 adjuvant therapy were assessed in an infant rat model of BM. METHODS: Eleven-day old rats were intracysternally infected with Streptococcus pneumoniae serotype 3, or saline, treated with B12 or placebo, and, 24 h after infection, their hippocampi were analyzed for apoptosis in the dentate gyrus, sulfur amino acids content, global DNA methylation, transcription, and proximal promoter methylation of candidate genes. Differences between groups were compared using 2-way ANOVA followed by Bonferroni post hoc test. Correlations were tested with Spearman's test. RESULTS: B12 attenuated BM-induced hippocampal apoptosis in a Hcy-dependent manner (r = 0.80, P < 0.05). BM caused global DNA hypomethylation; however, B12 restored this parameter. Accordingly, B12 increased the methylation capacity of hippocampal cells from infected animals, as inferred from the ratio S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) in infected animals. BM upregulated selected pro-inflammatory genes, and this effect was counteracted by B12, which also increased methylation of CpGs at the promoter of Ccl3 of infected animals. CONCLUSION: Hcy is likely to play a central role in hippocampal damage in the infant rat model of BM, and B12 shows an anti-inflammatory and neuroprotective action through methyl-dependent epigenetic mechanisms.
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Apoptosis/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Hipocampo/efectos de los fármacos , Meningitis Neumocócica/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Vitamina B 12/uso terapéutico , Animales , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Meningitis Neumocócica/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Regiones Promotoras Genéticas/efectos de los fármacos , Ratas , Ratas Wistar , Streptococcus pneumoniae , Vitamina B 12/administración & dosificaciónRESUMEN
Gomez-López-Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.
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Anomalías Múltiples/tratamiento farmacológico , Anomalías Múltiples/genética , Alopecia/genética , Cerebelo/anomalías , Anomalías Craneofaciales/tratamiento farmacológico , Anomalías Craneofaciales/genética , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/genética , Misoprostol/uso terapéutico , Síndromes Neurocutáneos/tratamiento farmacológico , Síndromes Neurocutáneos/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Alopecia/diagnóstico por imagen , Alopecia/tratamiento farmacológico , Alopecia/patología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/patología , Femenino , Trastornos del Crecimiento/diagnóstico por imagen , Trastornos del Crecimiento/patología , Humanos , Imagen por Resonancia Magnética , Síndromes Neurocutáneos/diagnóstico por imagen , Síndromes Neurocutáneos/patología , Fenotipo , Rombencéfalo/diagnóstico por imagen , Rombencéfalo/patología , Nervio Trigémino/diagnóstico por imagen , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/patologíaRESUMEN
NEW FINDINGS: What is the central question of this study? What is the effect in male and female offspring of a protein-deficient diet producing intrauterine growth restriction (IUGR) in maternal mice on morphometric, metabolic and behavioural parameters before and after a challenge with a fat diet? What is the main finding and its importance? Male and female mice presented different growth trajectories after birth. IUGR favoured increased adiposity in male mice, and high-fat diet-induced anxiety-like behaviour in female mice. ABSTRACT: As there is sexual dimorphism in the response to maternal manipulations, we aimed to analyse the effects of intrauterine growth restriction (IUGR) in both sexes on morphometric, metabolic and behavioural parameters throughout postnatal development, and after challenge with a hyperlipidic diet. Female Swiss mice (n = 59) were distributed into two groups (SD: standard diet, n = 26; and PDD: isocaloric protein-deficient diet, n = 33), 2 weeks before mating and during the gestational period. After birth, offspring from SD and PDD dams were cross-fostered and nurtured by SD dams until postnatal day (PND) 28. At PND 60 all animals were challenged with a hypercaloric diet for 4 weeks. Offspring birth weight was significantly reduced in the PDD group compared to the SD group (P = 0.0001), but only male offspring presented a rapid catch-up during the first 21 days of development. Although no differences in body weight were observed between groups after the challenge with the hyperlipidic diet, an increase in the relative perigonadal white adipose tissue (P = 0.009) and a decrease in gross gastrocnemius muscle weight (P = 0.010) were observed in the PDD males. In relation to behavioural tests, there was an increase in locomotion in both sexes (P = 0.0001), and a decrease in female grooming (P = 0.006) in the PDD group. Additionally, females from the PDD group showed increased hyperlipidic food intake. In conclusion, IUGR affected both sexes, with females showing prominent behavioural modifications and males presenting altered body composition elicited by a hyperlipidic diet.
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Ansiedad/fisiopatología , Composición Corporal/fisiología , Dieta Alta en Grasa/efectos adversos , Retardo del Crecimiento Fetal/fisiopatología , Adiposidad/fisiología , Animales , Femenino , Masculino , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Ratones , Obesidad/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by a deficiency of the lysosomal hydrolase, α-L-iduronidase (IDUA). IDUA degrades heparan and dermatan sulfates, two types of glycosaminoglycan (GAG), important signalling and structural molecules of the extracellular matrix. Because many cell types store GAGs, MPS I has been investigated in human and animal models. Enzyme replacement therapy is available for MPS I patients and has improved their life expectancy, allowing them to achieve reproductive age. The aim of this study was to evaluate epididymal and sperm morphology and function in a murine model of MPS I. We used C57BL Idua+/+ and Idua-/- adult male mice (6 months old) to investigate epididymal morphology, sperm ultrastructure, GAG characterisation and mating competence. Epithelial GAG storage, especially in the cauda epididymidis, was seen in Idua-/- mice. Regardless of the morphologic change and GAG storage found in the cauda epididymis, sperm morphology and motility were normal, similar to wild types. In the interstitium, vacuolated cells were found in addition to deposits of GAGs. Mating was not impaired in Idua-/- males and litter sizes were similar between groups. At the time point of the disease evaluated, the deficiency in IDUA affected the morphology of the epididymis in male Idua-/- mice, whereas sperm appearance and motility and the male's capacity to mate and impregnate females were preserved.
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Colágeno/metabolismo , Epidídimo/metabolismo , Glicosaminoglicanos/metabolismo , Mucopolisacaridosis I/metabolismo , Motilidad Espermática , Espermatozoides/metabolismo , Animales , Supervivencia Celular , Modelos Animales de Enfermedad , Epidídimo/ultraestructura , Fertilización , Iduronidasa/deficiencia , Iduronidasa/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/patología , Espermatozoides/ultraestructuraRESUMEN
Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of ß-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration.
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Precursor de Proteína beta-Amiloide/metabolismo , Catepsina B/metabolismo , Corteza Cerebral/metabolismo , Mucopolisacaridosis I/metabolismo , Células Piramidales/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/metabolismo , Astrocitos/patología , Catepsina B/genética , Corteza Cerebral/patología , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Lisosomas/metabolismo , Lisosomas/patología , Ratones , Ratones Noqueados , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/patología , Células Piramidales/patologíaRESUMEN
We assessed levels of plasma selenium (Se), selenoproteins and their change after Se supplementation in patients with mucopolysaccharidosis (MPS) types I, II and VI. This was done in a retrospective study of the medical records of 30 patients with MPS I (n=13), MPS II (n=9) and MPS VI (n=8) who were being treated with enzyme replacement therapy. As part of routine nutritional monitoring, Se levels were measured, revealing that 28 patients (93.3%) had values below the normal range. Therefore, they received supplementation for 12 months, and Se was measured after 6 and 12 months. Glutathione peroxidase (GPx) activity, total glutathione (GSHt), oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured at baseline and 6 months after Se supplementation. The mean GSHt at baseline was 7.90 ± 2.36 µmol/g Hb, and after Se supplementation it was 5.76 ± 1.13 µmol/g Hb; GSH/GSSG was 2.3 ± 1.16 at baseline and 0.58 ± 0.38 after supplementation. GPx activity was 16.46 ± 3.31 U/g Hb at baseline and 4.53 ± 4.92 U/g Hb after Se supplementation. The difference was shown to be statistically significant by paired t-test. In conclusion, our study demonstrated that oxidative stress parameters were altered by Se supplementation in patients with MPS I, II and VI who were previously deficient in Se.
RESUMEN
Obstructive sleep apnoea (OSA) is positively associated with cardiometabolic diseases; however, high levels of physical activity could decrease the incidence of OSA and associated comorbidities.In this study we aimed to examine the incidence of OSA in relation to physical activity, and its role as a protective factor in individuals with OSA on the incidence of cardiometabolic diseases, in an 8-9-year follow-up study. We analysed data of 658 volunteers from the São Paulo Epidemiologic Sleep Study (EPISONO), a cohort study of individuals aged 20-80â years, collected through polysomnography, the International Physical Activity Questionnaire and an assessment of cardiometabolic profile.Active subjects had a lower risk of developing OSA compared with nonactive subjects (relative risk 0.877, 95% CI 0.296-0.855) and there was a reduced risk of developing type 2 diabetes mellitus in active/apnoeic subjects (relative risk 0.493, 95% CI 0.252-0.961) compared with nonactive subjects. Metabolic equivalent was negatively associated to cardiometabolic markers, such as C-reactive protein (exp(B)=0.720; p=0.001), interleukin-6 (exp(B)=0.991; p=0.03), insulin (exp(B)=0.982; p=0.03), triglycerides (exp(B)=0.997; p<0.001), homeostasis model assessment for insulin resistance (exp(B)≤0.946; p<0.024), quantitative insulin sensitivity check index (exp(B)=992.4; p<0.001) and mean arterial pressure (exp(B)=0.987; p=0.001).Physical activity was a protective factor against type 2 diabetes mellitus in apnoeic individuals; moreover, being active reduced the risk of developing OSA and was associated with a better cardiometabolic profile.
Asunto(s)
Biomarcadores/sangre , Diabetes Mellitus Tipo 2/prevención & control , Ejercicio Físico , Apnea Obstructiva del Sueño/terapia , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/prevención & control , Comorbilidad , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Resistencia a la Insulina , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/prevención & control , Persona de Mediana Edad , Polisomnografía , Estudios Prospectivos , Apnea Obstructiva del Sueño/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: This article aimed to identify the influence of high serum homocysteine (Hcy) and cysteine (Cys) levels, alone or in conjunction, on changes in anthropometric parameters in children and adolescents over a 12-month follow-up period. METHODS: This is a cohort study involving 483 boys and girls 7-15 years of age. The outcome variables were body mass index (BMI)-for-age and waist circumference (WC) and the principal exposure variables were serum Hcy and Cys levels, alone or in conjunction. A generalized estimating equation (GEE) approach was used to identify longitudinal changes in the outcome variables. RESULTS: Irrespective of age, sex, socioeconomic conditions, dietary intake, or the practice of physical activity, the children and adolescents in the fifth quintile of distribution of Hcy levels had a z-score increase of 0.50 (p < 0.01) and a 3.62 cm increase (p < 0.01) in mean BMI-for-age and WC, respectively, over the period of the study. In individuals with Cys values above the fifth quintile, a z-score increase of 0.59 (p < 0.01) and a 5 cm increase (p < 0.01) were found in BMI-for-age and WC, respectively. When serum Hcy and Cys levels were both above the fifth quintile of distribution, a z-score increase of 0.87 (p < 0.01) and a 6.57 cm increase (p < 0.01) were found in mean BMI-for-age and WC, respectively, over the 12-month follow-up. CONCLUSION: High serum Hcy and Cys levels contributed to an increase in BMI-for-age and WC in children and adolescents over a 12-month follow-up period, with these increases being even greater when these 2 biochemical parameters were simultaneously high.
Asunto(s)
Índice de Masa Corporal , Cisteína/sangre , Homocisteína/sangre , Circunferencia de la Cintura/fisiología , Adolescente , Antropometría , Brasil , Niño , Femenino , Humanos , Estudios Longitudinales , MasculinoRESUMEN
Tryptophan is the only precursor of serotonin and mediates serotonergic activity in the brain. Previous studies have shown that the administration of tryptophan or tryptophan depletion significantly alters cognition, mood and anxiety. Nevertheless, the neurobiological alterations that follow these changes have not yet been fully investigated. The aim of this study was to verify the effects of a tryptophan-enriched diet on immunoreactivity to Fos-protein in the rat brain. Sixteen male Wistar rats were distributed into two groups that either received standard chow diet or a tryptophan-enriched diet for a period of thirty days. On the morning of the 31st day, animals were euthanized and subsequently analyzed for Fos-immunoreactivity (Fos-ir) in the dorsal and median raphe nuclei and in regions that receive serotonin innervation from these two brain areas. Treatment with a tryptophan-enriched diet increased Fos-ir in the prefrontal cortex, nucleus accumbens, paraventricular hypothalamus, arcuate and ventromedial hypothalamus, dorsolateral and dorsomedial periaqueductal grey and dorsal and median raphe nucleus. These observations suggest that the physiological and behavioral alterations that follow the administration of tryptophan are associated with the activation of brain regions that regulate cognition and mood/anxiety-related responses.
Asunto(s)
Afecto/efectos de los fármacos , Antidepresivos de Segunda Generación/administración & dosificación , Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Triptófano/administración & dosificación , Animales , Ansiedad/metabolismo , Encéfalo/metabolismo , Dietoterapia/métodos , Suplementos Dietéticos , Inmunohistoquímica , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Wistar , Reproducibilidad de los Resultados , Serotonina/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disease caused by alpha-L-iduronidase deficiency in which heparan and dermatan sulfate degradation is compromised. Besides primary lysosomal glycosaminoglycan accumulation, further changes in cellular functions have also been described in several murine MPS models. Herein, we evaluated alterations in hematopoiesis and its implications on the production of mature progeny in a MPS I murine model. Despite the significant increase in hematopoietic stem cells, a reduction in common myeloid progenitors and granulocyte-macrophage progenitor cells was observed in Idua -/- mice bone marrow. Furthermore, no alterations in number, viability nor activation of cell death mechanisms were observed in Idua -/- mice mature macrophages but they presented higher sensitivity to apoptotic induction after staurosporine treatment. In addition, changes in Ca(2+) signaling and a reduction in phagocytosis ability were also found. In summary, our results revealed significant intracellular changes in mature Idua -/- macrophages related to alterations in Idua -/- mice hematopoiesis, revealing a disruption in cell homeostasis. These results provide new insights into physiopathology of MPS I.
Asunto(s)
Hematopoyesis/fisiología , Homeostasis/fisiología , Macrófagos/metabolismo , Monocitos/metabolismo , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/metabolismo , Animales , Muerte Celular/genética , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Homeostasis/genética , Lisosomas/metabolismo , Macrófagos/citología , Ratones Endogámicos C57BL , Monocitos/citologíaRESUMEN
B lymphocytes are immune cells crucial for the maintenance and viability of the humoral response. Sleep is an essential event for the maintenance and integrity of all systems, including the immune system (IS). Thus, sleep deprivation (SD) causes problems in metabolism and homeostasis in many cell systems, including the IS. In this study, our goal was to determine changes in B lymphocytes from the bone marrow (BM) and spleen after SD. Three-month-old male Swiss mice were used. These mice were sleep deprived through the modified multiple platform method for different periods (24, 48, and 72 h), whereas another group was allowed to sleep for 24 h after 72 h of SD (rebound group) and a third group was allowed to sleep normally during the entire experiment. After this, the spleen and BM were collected, and cell analyses were performed. The numbers of B lymphocytes in the BM and spleen were reduced by SD. Additionally, reductions in the percentage of lymphocyte progenitors and their ability to form colonies were observed. Moreover, an increase in the death of B lymphocytes from the BM and spleen was associated with an increase in oxidative stress indicators, such as DCFH-DA, CAT, and mitochondrial SOD. Rebound was not able to reverse most of the alterations elicited by SD. The reduction in B lymphocytes and their progenitors by cell death, with a concomitant increase in oxidative stress, showed that SD promoted a failure in B lymphopoiesis.