RESUMEN
Society in eusocial insects is based on the reproductive division of labor, with a small number of reproductive individuals supported by a large number of nonreproductive individuals. Because inclusive fitness of all colony members depends on the survival and fertility of reproductive members, sterile members provide royals with special treatment. Here, we show that termite kings and queens each receive special food of a different composition from workers. Sequential analysis of feeding processes demonstrated that workers exhibit discriminative trophallaxis, indicating their decision-making capacity in allocating food to the kings and queens. Liquid chromatography tandem-mass spectrometry analyses of the stomodeal food and midgut contents revealed king- and queen-specific compounds, including diacylglycerols and short-chain peptides. Desorption electrospray ionization mass spectrometry imaging analyses of 13C-labeled termites identified phosphatidylinositol and acetyl-l-carnitine in the royal food. Comparison of the digestive tract structure showed remarkable differences in the volume ratio of the midgut-to-hindgut among castes, indicating that digestive division of labor underlies reproductive division of labor. Our demonstration of king- and queen-specific foods in termites provides insight into the nutritional system that underpins the extraordinary reproduction and longevity of royals in eusocial insects.
RESUMEN
As an important neurotransmitter, glutamate acts in over 90% of excitatory synapses in the human brain. Its metabolic pathway is complicated, and the glutamate pool in neurons has not been fully elucidated. Tubulin polyglutamylation in the brain is mainly mediated by two tubulin tyrosine ligase-like (TTLL) proteins, TTLL1 and TTLL7, which have been indicated to be important for neuronal polarity. In this study, we constructed pure lines of Ttll1 and Ttll7 knockout mice. Ttll knockout mice showed several abnormal behaviors. Matrix-assisted laser desorption/ionization (MALDI) Imaging mass spectrometry (IMS) analyses of these brains showed increases in glutamate, suggesting that tubulin polyglutamylation by these TTLLs acts as a pool of glutamate in neurons and modulates some other amino acids related to glutamate.
Asunto(s)
Ácido Glutámico , Tubulina (Proteína) , Animales , Humanos , Ratones , Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Ratones Noqueados , Neuronas/metabolismo , Procesamiento Proteico-Postraduccional , Tubulina (Proteína)/metabolismoRESUMEN
Cancer tissues reflect a greater number of pathological characteristics of cancer compared to cancer cells, so the evaluation of cancer tissues can be effective in determining cancer treatment strategies. Mass spectrometry imaging (MSI) can evaluate cancer tissues and even identify molecules while preserving spatial information. Cluster analysis of cancer tissues' MSI data is currently used to evaluate the phenotype heterogeneity of the tissues. Interestingly, it has been reported that phenotype heterogeneity does not always coincide with genotype heterogeneity in HER2-positive breast cancer. We thus investigated the phenotype heterogeneity of luminal breast cancer, which is generally known to have few gene mutations. As a result, we identified phenotype heterogeneity based on lipidomics in luminal breast cancer tissues. Clusters were composed of phosphatidylcholine (PC), triglycerides (TG), phosphatidylethanolamine, sphingomyelin, and ceramide. It was found that mainly the proportion of PC and TG correlated with the proportion of cancer and stroma on HE images. Furthermore, the number of carbons in these lipid class varied from cluster to cluster. This was consistent with the fact that enzymes that synthesize long-chain fatty acids are increased through cancer metabolism. It was then thought that clusters containing PCs with high carbon counts might reflect high malignancy. These results indicate that lipidomics-based phenotype heterogeneity could potentially be used to classify cancer for which genetic analysis alone is insufficient for classification.
Asunto(s)
Lipidómica , Neoplasias , Lipidómica/métodos , Espectrometría de Masas , Análisis por Conglomerados , TriglicéridosRESUMEN
Background: Though various mechanisms have been proposed for the pathophysiology of schizophrenia, the full extent of these mechanisms remains unclear, and little is known about the relationships among them. We carried out trans-omics analyses by comparing the results of the previously reported lipidomics, transcriptomics, and proteomics analyses; all of these studies used common post-mortem brain samples. Methods: We collected the data from three aforementioned omics studies on 6 common post-mortem samples (3 schizophrenia patients and 3 controls), and analyzed them as a whole group sample. Three correlation analyses were performed for each of the two of three omics studies in these samples. In order to discuss the strength of the correlations in a limited sample size, the p-values of each correlation coefficient were confirmed using the Student's t-test. In addition, partial correlation analysis was also performed for some correlations, to verify the strength of the impact of each factor on the correlations. Results: The following three factors were strongly correlated with each other: the lipid level of phosphatidylinositol (PI) (16:0/20:4), the amount of TNC mRNA, and the quantitative signal intensity of APOA1 protein. PI (16:0/20:4) and TNC showed a positive correlation, while PI (16:0/20:4) and APOA1, and TNC and APOA1 showed negative correlations. All of these correlations reached at p < 0.01. PI (16:0/20:4) and TNC were decreased in the prefrontal cortex of schizophrenia samples, while APOA1 was increased. Partial correlation analyses among them suggested that PI (16:0/20:4) and TNC have no direct correlation, but their relationships are mediated by APOA1. Conclusion: The current results suggest that these three factors may provide new clues to elucidate the relationships among the candidate mechanisms of schizophrenia, and support the potential of trans-omics analyses as a new analytical method.
RESUMEN
Mass spectrometry imaging (MSI) allows us to visualize the spatial distribution of molecular components in a sample. A large amount of mass spectrometry data comprehensively provides molecular distributions. In this study, we focus on the information in the obtained data and use the Shannon entropy as a quantity to analyze MSI data. By calculating the Shannon entropy at each pixel on a sample, the spatial distribution of the Shannon entropy is obtained from MSI data. We found that low-entropy pixels in entropy heat maps for kidneys of mice had different structures between two ages (3 months and 31 months). Such changes cannot be visualized by conventional imaging techniques. We further propose a method to find informative molecules. As a demonstration of the proposed scheme, we identified two molecules by setting a region of interest which contained low-entropy pixels and by exploring changes of peaks in the region.
Asunto(s)
Diagnóstico por Imagen , Animales , Ratones , Espectrometría de Masas/métodos , EntropíaRESUMEN
The characteristic patterns of mass spectra in imaging mass spectrometry (IMS) strongly reflect the tissue environment. However, the boundaries formed where different tissue environments collide have not been visually assessed. In this study, IMS and convolutional neural network (CNN), one of the deep learning methods, were applied to the extraction of characteristic mass spectra patterns from training brain regions on rodents' brain sections. CNN produced classification models with high accuracy and low loss rate in any test data sets of mouse coronal sections measured by desorption electrospray ionization (DESI)-IMS and of mouse and rat sagittal sections by matrix-assisted laser desorption (MALDI)-IMS. On the basis of the extracted mass spectra pattern features, the histologically plausible segmentation and classification score imaging of the brain sections were obtained. The boundary imaging generated from classification scores showed the extreme changes of mass spectra patterns between the tissue environments, with no significant buffer zones for the intermediate state. The CNN-based analysis of IMS data is a useful tool for visually assessing the changes of mass spectra patterns on a tissue section, and it will contribute to a comprehensive view of the tissue environment.
Asunto(s)
Aprendizaje Profundo , Animales , Encéfalo , Rayos Láser , Ratas , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosRESUMEN
Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A2 and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs' production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy.
Asunto(s)
Lisofosfatidilcolinas , Microglía , Animales , Encéfalo , Cromatografía Liquida , Inflamación , Ivermectina , Lisofosfolípidos/química , Trastornos de la Memoria , Ratones , Necrosis , Receptores Purinérgicos P2X4 , Espectrometría de Masas en Tándem/métodosRESUMEN
OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is a common genetic disease with diverse morphology, symptoms, and prognosis. Hypertrophied myocardium metabolism has not been explored in detail. We assessed the association between myocardium lipid metabolism and clinical severity of heart failure (HF) in HCM using imaging mass spectrometry (IMS). RESULTS: We studied 16 endomyocardial biopsy (EMB) specimens from patients with HCM. Analysis was conducted using desorption electrospray ionization IMS. The samples were assigned into two cohorts according to the period of heart biopsy (cohort 1, n = 9 and cohort 2, n = 7). In each cohort, samples were divided into two groups according to the clinical severity of HF in HCM: clinically severe and clinically mild groups. Signals showing a significant difference between the two groups were analyzed by volcano plot. In cohort 1, the volcano plot identified four signals; the intensity in the clinically severe group was more than twice that of the mild group. Out of the four signals, docosahexaenoic acid (DHA) showed significant differences in intensity between the two groups in cohort 2 (10,575.8 ± 2750.3 vs. 19,839.3 ± 4803.2, P = 0.025). The intensity of DHA was significantly higher in EMB samples from the clinically severe HCM group than in those from the mild group.
Asunto(s)
Cardiomiopatía Hipertrófica , Insuficiencia Cardíaca , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/metabolismo , Cardiomiopatía Hipertrófica/patología , Ácidos Docosahexaenoicos , Corazón , Insuficiencia Cardíaca/diagnóstico , Humanos , Miocardio/metabolismoRESUMEN
The endocannabinoid 2-arachidonoylglycerol (2AG) is an important modulator of stress responses. Its level in the brain increases in response to stress, but region-specific effects of stress on brain 2AG are not well known yet. Moreover, green nut oil (GNO), oil extracted from the seeds of Plukenetia volubilis has several health benefits, but its effects on brain 2AG levels are unknown. Therefore, we conducted this study to explore the effects of stress and GNO supplementation on 2AG levels in specific brain regions of senescence-accelerated mouse prone 8 (SAMP8). In this study, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) revealed that water-immersion stress for three days significantly increased 2AG levels in several brain regions of SAMP8 mice, including the hypothalamus, midbrain, and hindbrain. No significant change was observed in the relative abundance of brain 2AG in stress given SAMP8 mice after eighteen days of removing stress load compared to control SAMP8 mice. GNO supplementation also increased brain 2AG in SAMP8 mice without stress load. Additionally, GNO supplementation sustained the increased brain 2AG levels in stress given SAMP8 mice after eighteen days of removing stress load. Among all brain regions, a relatively higher accumulation of 2AG was noted in the hypothalamus, midbrain, and hindbrain of GNO-fed SAMP8. Our data explored the potentiality of GNO supplementation to improve brain 2AG levels which might be used to treat anxiety and depressive behaviors.
Asunto(s)
Encéfalo , Nueces , Envejecimiento , Animales , Ácidos Araquidónicos , Suplementos Dietéticos , Endocannabinoides , Glicéridos , Hipotálamo , Mesencéfalo , Ratones , RombencéfaloRESUMEN
The plasma membrane (PM) serves multiple functions to support cell activities with its heterogeneous molecular distribution. Fatty acids (FAs) are hydrophobic components of the PM whose saturation and length determine the membrane's physical properties. The FA distribution contributes to the PM's lateral heterogeneity. However, the distribution of PM FAs is poorly understood. Here, we proposed the FA cluster hypothesis, which suggested that FAs on the PM exist as clusters. By the optogenetic tool translocating the endoplasmic reticulum (ER), we were able to manipulate the distribution of PM FAs. We used time-of-flight combined secondary ion mass spectrometry (TOF-SIMS) to image PM FAs and discovered that PM FAs were presented and distributed as clusters and are also manipulated as clusters. We also found the existence of multi-FA clusters formed by the colocalization of more than one FA. Our optogenetic tool also decreased the clustering degree of FA clusters and the formation probability of multi-FA clusters. This research opens up new avenues and perspectives to study PM heterogeneity from an FA perspective. This research also suggests a possible treatment for diseases caused by PM lipid aggregation and furnished a convenient tool for therapeutic development.
Asunto(s)
Ácidos Grasos , Espectrometría de Masa de Ion Secundario , Ácidos Grasos/metabolismo , Espectrometría de Masa de Ion Secundario/métodos , Optogenética , Membrana Celular/metabolismo , Diagnóstico por ImagenRESUMEN
BACKGROUND: The vermilion of the human lip presents characteristic features and undergoes aging faster than the skin. Therefore, knowledge of the vermilion surface-specific functional molecules is important to understand lip aging and formulate lip care products. Previously, we analyzed the free fatty acids distributions and showed that docosahexaenoic acid highly accumulated in the vermilion's epithelium than in the skin. OBJECTIVE: We aimed to explore the functional molecules other than the free fatty acids on the vermilion's surface. METHODS: Human lip tissues from children and tape-stripped samples from smooth and rough lips of adults were measured by desorption electrospray ionization-mass spectrometry imaging (DESI-MSI). RESULTS: DESI-MSI of children's lip sections revealed a major distribution of five phospholipid species in the viable layer, but not in the superficial area, of both the vermilion and the skin than that in the underlying tissue. Interestingly, a remarkably higher distribution of cholesterol sulfate was observed in the vermilion's superficial area compared to that in the skin in all subjects under this study. Furthermore, DESI-MSI of tape-stripped lip samples showed an overall higher accumulation of cholesterol sulfate in the stratum corneum of the rough lips than that in the smooth lips. CONCLUSION: Our study concluded that cholesterol sulfate has a characteristic distribution to the vermilion's surface and showed an association with the roughness of the lip.
Asunto(s)
Ésteres del Colesterol/análisis , Labio/química , Piel/química , Femenino , Humanos , Lactante , Masculino , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Dementia is a major public health concern nowadays. Reduced levels of brain docosahexaenoic acid (DHA) and DHA-phosphatidylcholines (DHA-PCs) in dementia patients were reported previously. Recently, we have reported that supplementation of green nut oil (GNO) or DHA improves memory function and distribution levels of brain DHA in senescence accelerated mice P8 (SAMP8). GNO is extracted from Plukenetia volubilis seeds, and SAMP8 is a well-known model mouse of dementia. In this current study, we examined the results of GNO or DHA supplementation in the distribution levels of brain DHA-PCs in same model mouse of dementia using desorption electrospray ionization (DESI) mass spectrometry imaging (MSI). We observed significantly decreased distribution of brain DHA-PCs, PC (16:0_22:6), and PC (18:0_22:6) in SAMP8 mice compared to wild type mice, and GNO or DHA treatment restored the decreased distribution levels of PC (16:0_22:6) and PC (18:0_22:6) in the brain of SAMP8 mice. These results indicate that GNO or DHA supplementation can ameliorate the decreased distribution of brain DHA-PCs in dementia, and could be potentially used for the prevention and treatment of dementia.
RESUMEN
Hericium erinaceus has been recognized as medical mushroom since ancient time, but its scientific evidence for human health has been still uncertain. In this study, we tested a randomized, double-blind, placebo-controlled parallel-group comparative study to evaluate the improvement of the cognitive functions by taking supplements containing fruiting body of H. erinaceus for 12 weeks. We performed three kinds of tests: Mini Mental State Examination (MMSE), Benton visual retention test, and Standard verbal paired-associate learning test (S-PA). MMSE alone showed that oral intake of H. erinaceus significantly improved cognitive functions and prevented from the deterioration. We speculate that various chemical compounds, including hericenones, in the mushroom have multiple effects to the brain neural networks and improve cognitive functions. Oral intake of H.erinaceus is safe and convenient method for dementia prevention so far.
Asunto(s)
Agaricales , Cognición , Demencia , Suplementos Dietéticos , Red Nerviosa/fisiopatología , Anciano , Demencia/fisiopatología , Demencia/prevención & control , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
At the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling and 3D wing morphogenesis are coordinated. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally within both dorsal and ventral wing epithelia during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning/differentiation, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia and the spatial distribution of BMP signaling are tightly coupled, revealing that 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.
Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Morfogénesis/fisiología , Transducción de Señal , Alas de Animales/crecimiento & desarrollo , Alas de Animales/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epitelio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Morfogénesis/genética , Alas de Animales/anatomía & histologíaRESUMEN
Membrane vesicles (MVs) of Porphyromonas gingivalis are regarded as an offensive weapon of the bacterium, leading to tissue deterioration in periodontal disease. Therefore, isolation of highly purified MVs is indispensable to better understand the pathophysiological role of MVs in the progression of periodontitis. MVs are generally isolated by a conventional method based on ultracentrifugation of the bacterial culture supernatant. However, the resulting MVs are often contaminated with co-precipitating bacterial appendages sheared from the live bacteria. Here, we report an intriguing property of P. gingivalis MVs--their ability to bind superparamagnetic beads coated with epoxy groups (SB-Epoxy). Analysis of fractions collected during the purification revealed that all MVs of five tested P. gingivalis stains bound to SB-Epoxy. In contrast, free fimbriae in the crude MV preparation did not bind to the SB-Epoxy. The SB-Epoxy-bound MVs were easily dissociated from the SB-Epoxy using a mild denaturation buffer. These results suggest that the surface chemistry conferred by epoxy on the beads is responsible for the binding, which is mediated by noncovalent bonds. Both the structural integrity and purity of the isolated MVs were confirmed by electron microscopy. The isolated MVs also caused cell detachment from culture dishes at a physiologically relevant concentration. Assays of competitive binding between the SB-Epoxy and mixtures of MVs from five bacterial species demonstrated that only P. gingivalis MVs could be selectively eliminated from the mixtures. We suggest that this novel approach enables efficient purification and selective elimination of P. gingivalis MVs.
Asunto(s)
Fimbrias Bacterianas/metabolismo , Técnicas Microbiológicas/métodos , Periodontitis/microbiología , Porphyromonas gingivalis/metabolismo , Proteínas Bacterianas/metabolismo , Unión Competitiva , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Membrana Celular/metabolismo , Humanos , Magnetismo , Microscopía , Microscopía Electrónica , Especificidad de la Especie , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Neutrophils play an essential role in the innate immune response. To understand neutrophil activity, the development of a new technique to observe neutrophils in situ is required. Here, we report the development of a non-invasive technique for the in vivo imaging of neutrophils labeled with quantum dots, up to 100 µm below the skin surface of mice. Upon inflammation neutrophils began to extravasate from blood vessels and locomoted in interstitial space. Most intriguingly, the quantum dots were endocytosed into vesicles in the neutrophils, allowing us to track the vesicles at 12.5 msec/frame with 15-24 nm accuracy. The vesicles containing quantum dots moved as "diffuse-and-go" manner and were transported at higher speed than the in vitro velocity of a molecular motor such as kinesin or dynein. This is the first report in which non-invasive techniques have been used to visualize the internal dynamics of neutrophils.
Asunto(s)
Rastreo Celular/métodos , Inflamación/patología , Imagen Molecular , Neutrófilos/fisiología , Puntos Cuánticos , Piel/metabolismo , Vesículas Transportadoras/fisiología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Transporte Biológico , Dineínas/metabolismo , Femenino , Cinesinas/metabolismo , Ratones , Ratones SCID , Microscopía ConfocalRESUMEN
To investigate the force generation properties of Chlamydomonas axonemal inner-arm dyneins in response to external force, we analyzed microtubule gliding on dynein-coated surfaces under shear flow. When inner-arm dynein c was used, microtubule translocation in the downstream direction accelerated with increasing flow speed in a manner that depended on the dynein density and ATP concentration. In contrast, the microtubule translocation velocity in the upstream direction was unaffected by the flow speed. The number of microtubules on the glass surface was almost constant with and without flow, suggesting that gliding acceleration was not simply caused by weakened dynein-microtubule binding. With other inner-arm dynein species, the microtubule gliding velocity was unaffected by the flow regardless of the flow direction or nucleotide concentration. The flow-generated force acting on a single dynein was estimated to be as small as approximately 0.03 pN/dynein. These results indicate that dynein c possesses a ratchetlike property that allows acceleration only in one direction by a very small external force. This property should be important for slow- and fast-moving dyneins to function simultaneously within the axoneme.
Asunto(s)
Chlamydomonas/citología , Chlamydomonas/enzimología , Chlamydomonas/metabolismo , Dineínas/metabolismo , Microtúbulos/metabolismo , Animales , Transporte Biológico , CinéticaRESUMEN
Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of retinal ganglion cells (RGCs) and optic nerves. Although glaucoma is often associated with elevated intraocular pressure, recent studies have shown a relatively high prevalence of normal tension glaucoma (NTG) in glaucoma patient populations. In the mammalian retina, glutamate/aspartate transporter (GLAST) is localized to Müller glial cells, whereas excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs. Since the loss of GLAST or EAAC1 leads to retinal degeneration similar to that seen in NTG, we examined the effects of interleukin-1 (IL-1) on RGC death in GLAST- and EAAC1-deficient mice. IL-1 promoted increased glutamate uptake in Müller cells by suppressing intracellular Na(+) accumulation, which is necessary to counteract Na(+)-glutamate cotransport. The observed trends for the glutamate uptake increase in the wild-type (WT), GLAST- and EAAC1-deficient mice were similar; however, the baseline glutamate uptake and intracellular Na(+) concentration in the GLAST-deficient mice were significantly lower than those in the wild-type mice. Consistently, pretreatment with IL-1 exhibited no beneficial effects on glutamate-induced RGC degeneration in the GLAST-deficient mice. In contrast, IL-1 significantly increased glutamate uptake by Müller cells and the number of surviving RGCs in the wild-type and EAAC1-deficient mice. Our findings suggest that the use of IL-1 for enhancing the function of glutamate transporters may be useful for neuroprotection in retinal degenerative disorders including NTG.
Asunto(s)
Transportador 1 de Aminoácidos Excitadores/deficiencia , Transportador 3 de Aminoácidos Excitadores/deficiencia , Interleucina-1/metabolismo , Retina/fisiopatología , Degeneración Retiniana/fisiopatología , Células Ganglionares de la Retina/fisiología , Animales , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 3 de Aminoácidos Excitadores/genética , Transportador 3 de Aminoácidos Excitadores/metabolismo , Glaucoma/fisiopatología , Ácido Glutámico/metabolismo , Espacio Intracelular/metabolismo , Presión Intraocular , Ratones , Ratones Noqueados , Neuroglía/fisiología , Sodio/metabolismoRESUMEN
Optic neuritis is an acute inflammatory demyelinating syndrome of the central nervous system (CNS) that often occurs in multiple sclerosis (MS). Since it can cause irreversible visual loss, especially in the optic-spinal form of MS or neuromyelitis optica (NMO), the present study was conducted to assess the effects of geranylgeranylacetone (GGA) on optic neuritis in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Myelin oligodendrocyte glycoprotein-induced EAE mice received oral administration of GGA at 500 mg/kg or vehicle once daily for 22 days. The effects of GGA on the severity of optic neuritis were examined by morphological analysis on day 22. Visual functions were measured by the multifocal electroretinograms (mfERG). In addition, the effects of GGA on severity of myelitis were monitored both on clinical signs and morphological aspects. The visual function, as assessed by the second-kernel of mfERG, was significantly improved in GGA-treated mice compared with vehicle-treated mice. GGA treatment decreased the number of degenerating axons in the optic nerve and prevented cell loss in the retinal ganglion cell layer. However, the severity of demyelination in the spinal cord remained unaffected with the treatment of GGA. These results suggest that oral GGA administration has beneficial effect on the treatment for optic neuritis in the EAE mouse model of MS.
Asunto(s)
Diterpenos/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Neuritis Óptica/tratamiento farmacológico , Animales , Axones/efectos de los fármacos , Axones/patología , Electrorretinografía , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas de la Mielina , Glicoproteína Asociada a Mielina , Glicoproteína Mielina-Oligodendrócito , Nervio Óptico/efectos de los fármacos , Nervio Óptico/patología , Neuritis Óptica/inducido químicamente , Neuritis Óptica/patología , Neuritis Óptica/fisiopatologíaRESUMEN
The beating of eukaryotic cilia and flagella is controlled by multiple species of inner-arm and outer-arm dyneins. To clarify the regulation on axonemal beating by nucleotide conditions and central-pair microtubules, microtubule sliding in disintegrating Chlamydomonas axonemes of various mutants and in vitro microtubule gliding by isolated axonemal dyneins were examined. In the in vitro motility assays with outer-arm dyneins (alphabeta and gamma), microtubule translocation velocity decreased at high concentrations of ATP, while this inhibition was canceled by the simultaneous presence of ADP or ribose-modified analogues, mantATP/ADP. In contrast, motility of inner-arm dyneins was rather insensitive to these nucleotides. The velocity of sliding disintegration in axonemes lacking the central pair was less than that in wild-type axonemes at high ATP concentrations, but was overcome by the presence of ADP or mantATP/ADP. While these nucleotides did not activate the sliding velocity in other mutant axonemes, they increased the extent of sliding, except for axonemes lacking outer-arm dynein. Experiments with axonemes lacking inner-arm dynein f using casein kinase 1 inhibitor suggest that the regulation of outer-arm dynein by the central pair is effected through the activation of inner-arm dynein f, and possibly by other interactions. These results indicate that the central pair activates outer-arm dyneins on specific outer-doublet, resulting in amplification of the axonemal bending force.