RESUMEN
OBJECTIVE: Skin microbiomes vary across individuals. They are known to play essential roles in maintaining homeostasis and preventing infectious pathogens. In recent years, cosmetic product development has begun to focus on the relationship between skin microbiomes and skin conditions. However, the statistical methods used in many studies include the standard t-test and small-scale correlation analysis, which do not take into account the internal correlation structure in data on skin microbiomes and skin features. In this study, we aimed to understand the relationship between skin microbiomes and skin features by analysing complex microbiomes and skin data. METHODS: We obtained data on 19 skin characteristics and skin microbiomes based on 16s ribosomal RNA (16S rRNA) gene analysis of 276 healthy Japanese women. We then performed the principal component analysis (PCA), a method that takes into account the internal correlation structure, on 234 panels of them that did not contain outliers or missing values. We confirmed the relationship between skin microbiomes and skin features with principal component regression analysis and hierarchical clustering analysis (HCA). RESULTS: The principal component regression analysis showed strong relationships between skin microbiomes and sebum-related skin characteristics and skin pH. In the HCA, the female panel was classified into two major groups based on the skin microbiome. Furthermore, there were significant differences in sebum-related skin characteristics and the way skin condition changes with ageing between those groups, suggesting the possibility of measuring skin condition and age-related skin risk based on microbiome data. In addition, sebum-related characteristics differed significantly among middle-aged participants, suggesting a strong relationship between skin microbiomes and sebum-related characteristics. CONCLUSION: Analysis of skin condition and skin microbiome in Japanese women, taking into account the correlation between variables, showed that skin microbiome was significantly related to the number of pores and the amount of sebum. Furthermore, it was suggested that the skin condition and the way the skin condition changes with ageing may differ depending on the type of skin microbiome. The finding of a relationship between skin condition and skin microbiome suggests the possibility of proposing a new beauty method focusing on the skin microbiome in the future.
OBJECTIF: Les microbiomes de la peau varient selon les individus. Ils sont connus pour jouer des rôles essentiels dans le maintien de l'homéostasie et la prévention des agents pathogènes infectieux. Ces dernières années, le développement de produits cosmétiques a commencé à se concentrer sur la relation entre les microbiomes cutanés et les conditions de la peau. Cependant, les méthodes statistiques utilisées dans de nombreuses études comprennent le t-test standard et l'analyse de corrélation à petite échelle, qui ne tiennent pas compte de la structure de corrélation interne dans les données sur les microbiomes cutanés et les caractéristiques de la peau. Dans cette étude, nous avons cherché à comprendre la relation entre les microbiomes cutanés et les caractéristiques de la peau en analysant des données complexes sur les microbiomes et la peau. MÉTHODES: Nous avons obtenu des données sur 19 caractéristiques de la peau et sur les microbiomes cutanés à partir de l'analyse du gène de l'ARNr 16S (16S rRNA) de 276 femmes japonaises en bonne santé. Nous avons ensuite effectué l'analyse en composantes principales (PCA: principal component analysis), une méthode qui prend en compte la structure de corrélation interne, sur 234 d'entre elles qui ne contenaient pas de valeurs aberrantes ou manquantes. Nous avons confirmé la relation entre les microbiomes cutanés et les caractéristiques de la peau à l'aide d'une analyse de régression en composantes principales et d'une analyse de regroupement hiérarchique (HCA: hierarchical clustering analysis). RÉSULTATS: L'analyse de régression en composantes principales a montré des relations fortes entre les microbiomes cutanés et les caractéristiques de la peau liées au sébum et au pH de la peau. Dans l'étude HCA, le panel de femmes a été classé en deux grands groupes sur la base du microbiome cutané. En outre, il y avait des différences significatives dans les caractéristiques de la peau liées au sébum et dans la façon dont l'état de la peau change avec l'âge entre ces groupes, ce qui suggère la possibilité de mesurer l'état de la peau et le risque cutané lié à l'âge à partir des données du microbiome. En outre, les caractéristiques liées au sébum différaient de manière significative chez les participants d'âge moyen, ce qui suggère une forte relation entre les microbiomes cutanés et les caractéristiques liées au sébum. CONCLUSION: L'analyse de l'état de la peau et du microbiome cutané chez les femmes japonaises, en tenant compte de la corrélation entre les variables, a montré que le microbiome cutané était significativement lié au nombre de pores et à la quantité de sébum. En outre, il a été suggéré que l'état de la peau et la façon dont l'état de la peau évolue avec le vieillissement peuvent différer en fonction du type de microbiome cutané. La découverte d'une relation entre l'état de la peau et le microbiome cutané suggère la possibilité de proposer à l'avenir une nouvelle méthode de beauté axée sur le microbiome cutané.
Asunto(s)
Microbiota/fisiología , Sebo/microbiología , Piel/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Recent developments of molecular biology have revealed diverse mechanisms of skin diseases, and precision medicine considering these mechanisms requires the frequent objective evaluation of skin phenotypes. Transepidermal water loss (TEWL) is commonly used for evaluating skin barrier function; however, direct measurement of TEWL is time-consuming and is not convenient for daily clinical practice. Here, we propose a new skin barrier assessment method using skin images with topological data analysis (TDA). TDA enabled efficient identification of structural features from a skin image taken by a microscope. These features reflected the regularity of the skin texture. We found a significant correlation between the topological features and TEWL. Moreover, using the features as input, we trained machine-learning models to predict TEWL and obtained good accuracy (R2 = 0.524). Our results suggest that assessment of skin barrier function by topological image analysis is promising.
Asunto(s)
Análisis de Datos , Procesamiento de Imagen Asistido por Computador , Piel/anatomía & histología , Piel/diagnóstico por imagen , HumanosRESUMEN
GABAA receptors containing α5 subunits (GABAAα5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAAα5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABAAα5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABAAα5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl-N-[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human α5-containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAAα5 NAM activity for GABA-induced Cl- channel activity with a maximum 44.4% inhibition and an EC50 of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1-20 mg/kg) dose-dependently occupied hippocampal GABAAα5 in a range of 40%-90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABAAα5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.
Asunto(s)
Cognición/efectos de los fármacos , Imidazoles/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Piridinas/farmacología , Receptores de GABA-A/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Células HEK293 , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Imidazoles/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Piridinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
Senescence-accelerated mice are known to display a variety of deficits and signs of accelerated aging, but the specific mechanisms involved in this process are still unclear. In this study, we examined the expression levels of antioxidant enzymes, transcription factors responsible for the regulation of expression of these enzymes, and mitochondrial proteins in the liver of SAMP10 and SAMR1 mice at 3 and 12â¯months of age using western blotting analysis. To investigate the amount of oxidative damage to DNA, levels of 8-OHdG were measured in the liver of these mice. At 3â¯months of age, the levels of catalase, Mn-SOD, GPx, UQCRC2 and COXIV were significantly upregulated in SAMP10 mice compared with that in SAMR1 mice. However, NDUFS3 levels were not significantly different at this young age. In contrast, the expression level of catalase was significantly lower, and the levels of phosphorylated FoxO-1a and UQCRC2 were significantly higher in SAMP10 mice compared to those in SAMR1 mice; however, at 12â¯months of age, there were no significant differences in Mn-SOD, GPx, total -FoxO-1a, COXIV, and NDUFS3 expression between the two groups of mice. The levels of 8-OHdG in the liver were markedly higher in 12-month-old SAMP10 mice than those in 3-month-old SAMP10 and SAMR1 mice. These results suggest that an increase in number of mitochondria or a collapse in the balance between the levels of complexes I and III results in an increase in the amount of ROS and induces the expression of antioxidant enzymes in the liver of SAMP10 mice at 3â¯months of age. Although young SAMP10 mice produce a large amount of ROS, they also produce suitable levels of antioxidant enzymes that decompose ROS; consequently accelerated aging does not occur in young SAMP10 mice. In addition to excessive ROS production which is an important cause of aging, the level of catalase was significantly lower in SAMP10 than that in SAMR1 mice. These results suggested that overexpression of ROS and a decrease in the levels of catalase resulted in the accelerated aging observed in older SAMP10 mice. Moreover, the level of phosphorylated FoxO-1a was increased in SAMP10 compared to that in SAMR1 mice though the total amount of FoxO-1a was not significantly different between the two groups in old age. These results suggest that some impairment in the regulation mechanism of FoxO-1a phosphorylation is responsible for abnormal catalase expression and that a significant decrease in the level of catalase with aging decisively affects the metabolic balance of ROS; thus, ROS that cannot be metabolized contributes to the accelerated aging of SAMP10 mice.
Asunto(s)
Envejecimiento/metabolismo , Antioxidantes/metabolismo , Hígado/enzimología , Animales , Western Blotting , Catalasa/metabolismo , Modelos Animales de Enfermedad , Proteína Forkhead Box O1/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Ratones , Ratones Mutantes , Fosforilación , Superóxido Dismutasa/metabolismo , Regulación hacia ArribaRESUMEN
PURPOSE: Oral mucositis induced by radiotherapy impacts quality of life. Previous studies have reported on the use of the hamster as a model for radiation-induced oral mucositis; however, details regarding factors such as radiation dose response, effects on myeloperoxidase (MPO) activity and related histopathological changes remain unclear. In the present study using the hamster, we evaluated the dose dependency of radiation-induced oral mucositis and the effects of keratinocyte growth factor (palifermin). METHODS: Oral mucositis was induced in the cheek pouch by X-irradiation using single doses in the range 20-50 Gy. To evaluate the protective effect of palifermin, administration was carried out (5 mg/kg) on days 1, 2 and 3 or on days 9, 10 and 11 after single irradiation at a dose of 40 Gy. RESULTS: The oral mucositis score, MPO activity and histopathological findings of inflammation increased in a dose dependent manner. Palifermin treatment stimulated the proliferation of mucosal epithelial cells. Additionally, palifermin when administered on days 1, 2 and 3 after irradiation (40 Gy) reduced the severity of oral mucositis. CONCLUSIONS: The hamster was found to be a suitable model for radiation-induced oral mucositis, with excellent results regarding the evaluation of radiation dose response and drug reactivity.
Asunto(s)
Mejilla/patología , Modelos Animales de Enfermedad , Factor 7 de Crecimiento de Fibroblastos/administración & dosificación , Traumatismos por Radiación/patología , Traumatismos por Radiación/prevención & control , Estomatitis/patología , Estomatitis/prevención & control , Animales , Mejilla/efectos de la radiación , Cricetinae , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Humanos , Mesocricetus , Dosis de Radiación , Tolerancia a Radiación/efectos de los fármacos , Protectores contra Radiación/administración & dosificación , Resultado del TratamientoRESUMEN
Short time exposure (STE) test is a cytotoxicity test in SIRC cells (rabbit corneal cell line) that assesses eye irritation potential following a 5-min chemical exposure. This validation study assessed transferability, intra- and inter-laboratory reproducibility, and predictive capacity of STE test in five laboratories (supported by Japanese Society for Alternatives to Animal Experiments). Sodium lauryl sulfate, calcium thioglycolate, and Tween 80 were evaluated, in triplicate, using 5%, 0.5%, and 0.05% concentrations in physiological saline, to confirm transferability. Good transferability was noted when similar mean relative viabilities and rank classifications were obtained in all five laboratories and were comparable to data from test method developing laboratory. Good intra- and inter-laboratory reproducibility was obtained with four assay controls (three solvents and one positive control), and four assay controls and 25 chemicals, respectively. STE irritation category based on relative viability of a 5% solution of 25 blinded test chemicals showed good correlation with Globally Harmonized System (GHS) categories (NI; I: Cat. 1 and 2). The STE prediction model, using relative viability of the 5% and 0.05% solutions, provided an irritation rank (1, 2, or 3) that had a good correlation (above 80%), or predictive capacity, with GHS irritation ranks in all laboratories. Based on these findings, the STE test is a promising alternative eye irritation test that could be easily standardized.
Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Córnea/efectos de los fármacos , Pruebas de Toxicidad/métodos , Animales , Línea Celular , Polisorbatos/toxicidad , Conejos , Reproducibilidad de los Resultados , Dodecil Sulfato de Sodio/toxicidad , Tioglicolatos/toxicidad , Factores de TiempoRESUMEN
Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP(+)) or rotenone and proteasome inhibition causes the appearance of alpha-synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP(+)- or rotenone-induced dopaminergic neuronal death. MPP(+) elevated proteasome activity, dephosphorylated mitogen-activating protein kinase (MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.
Asunto(s)
Acetilcisteína/análogos & derivados , Cisteína Endopeptidasas/fisiología , Dopaminérgicos/metabolismo , Dopamina/metabolismo , Complejos Multienzimáticos/antagonistas & inhibidores , Complejos Multienzimáticos/fisiología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , 1-Metil-4-fenilpiridinio/farmacología , Acetilcisteína/farmacología , Animales , Encéfalo/metabolismo , Caspasa 3 , Inhibidores de Caspasas , Caspasas/metabolismo , Cisteína Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Herbicidas/farmacología , Immunoblotting , Inmunohistoquímica , Iones , L-Lactato Deshidrogenasa/metabolismo , Leupeptinas/farmacología , Sistema de Señalización de MAP Quinasas , Masculino , Mitocondrias/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Complejos Multienzimáticos/metabolismo , Neuronas/patología , Fosforilación , Complejo de la Endopetidasa Proteasomal , Ratas , Ratas Wistar , Rotenona/metabolismo , Rotenona/farmacología , Sinucleínas , Factores de Tiempo , Ubiquitina/metabolismo , alfa-SinucleínaRESUMEN
The prevalence of Parkinson's disease is higher in males than in females. Although the reason for this gender difference is not clear, the level of female steroid hormones or their receptors may be involved in the pathogenesis. The estrogen receptor subtype expressed in the midbrain is limited to the novel beta subtype, whose role in the central nervous system has not been resolved. We demonstrated that ligand-activated estrogen receptor beta suppressed dopaminergic neuronal death in an in vitro Parkinson's disease model which uses 1-methyl-4-phenylpyridinium ions (MPP(+)). MPP(+) treatment caused the upregulation of c-Jun amino-terminal kinase (JNK) and dopaminergic neuronal death, the latter being blocked by curcumin, an inhibitor of the c-Jun/AP-1 cascade. 17alpha- and 17beta-estradiol both protected dopaminergic neurons from MPP(+)-induced neuronal death and this was blocked by a pure antagonist of the estrogen receptor, ICI 182,780, but not by an inhibitor of estrogen receptor dimerization, YP537. These data indicated that the neuroprotection provided by 17alpha-estradiol was via inhibitory transcriptional regulation at the activator protein-1 (AP-1) site mediated by estrogen receptor beta. Thus, 17alpha-estradiol is a suitable candidate for neuroprotective therapy of Parkinson's disease because it is associated with few undesirable feminizing effects.