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1.
Acta Psychol (Amst) ; 246: 104236, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38613854

RESUMEN

Languages can express grammatical gender through different ortho-phonological regularities present in nouns (e.g., the cues "-o" and "-a" for the masculine and the feminine respectively in Italian, Portuguese, or Spanish). The term "gender transparency" was coined to describe these regularities (Bates et al., 1995). In gendered languages, we can hence distinguish between transparent nouns, i.e., those displaying form regularities; opaque nouns, i.e., those with ambiguous endings; and irregular nouns, i.e., those that display the typical form regularities but are associated with the opposite gender. Following a descriptive analysis of such regularities, languages have been recently classified according to their degree of gender transparency, which seems relevant in regard to gender acquisition and processing. Yet, there are certain inconsistencies in determining which languages are overall transparent and which are opaque. In particular, it is not clear whether some other complex regularities such as derivational suffixes are also "transparent" cues for gender, what really constitutes an "opaque" noun, or which role orthography and morphology have in transparency. Given the existing inconsistencies in classifying languages as transparent or opaque, this work introduces a proposal to assess gender transparency systematically. Our methodology adapts the standardized factors proposed by Audring (2019) to analyse the relative complexity of gender systems. Such factors are adapted to gender transparency on the basis of the literature on gender acquisition and processing. To support the feasibility of such a proposal, the concepts have been instantiated in a quantitative model to obtain for the first time an objective measure of gender transparency using European Portuguese and Dutch as instances of target languages. Our results coincide with the theoretically expected outcome: European Portuguese obtains a high value of gender transparency while Dutch obtains a moderately low one. Future adaptations of this model to the gender systems of other languages could allow the continuum of gender transparency to sustain robust predictions in studies on gender processing and acquisition.


Asunto(s)
Lenguaje , Humanos , Psicolingüística/normas , Femenino , Masculino , Identidad de Género , Señales (Psicología)
2.
Healthcare (Basel) ; 12(5)2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38470707

RESUMEN

BACKGROUND: Guatemala remains one of the poorest countries in Central America and suffers from high rates of social inequality and violence. In addition to the negative impact that two years without attending school has had on Guatemalan children due to the consequences of the COVID-19 pandemic, this unfavourable socioeconomic context poses a risk to children's emotional and cognitive development. This work presents a protocol for implementing a cognitive and emotional stimulation program aimed at increasing the academic performance of these children and consequently improving their quality of life. METHODS: The protocol proposes the implementation of a randomized controlled trial to assess the efficacy of a 24-session-long stimulation program. It targets the cognitive functions of attention, language, executive functions, and social cognition, using the digital neurorehabilitation platform NeuronUP. The participants (n = 480) will be randomly assigned to an Experimental or Control group. Pre- and post-intervention assessments will be carried out, together with a follow-up in the next academic year, in which both groups will change roles. Results will be compared for the first and second years, looking for differences in academic and cognitive performance between groups. DISCUSSION: Mid- and long-term outcomes are still unknown, but effective interventions based on this protocol are expected to facilitate the following benefits for participants: (1) improved cognitive and emotional development; (2) improved academic performance; (3) improved well-being. We expect to create a validated neuropsychological stimulation program that could be applied in similar socioeconomically disadvantaged contexts around the world to help these children improve their life chances.

3.
FASEB J ; 38(1): e23331, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38031991

RESUMEN

Adequate and timely delivery of iron is essential for brain development. The uptake of transferrin-bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H-ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1- and Tf-bound iron. In the present study, we used C57BL/6J male and female mice at a developing (post-natal day (PND) 15) and adult age (PND 85). In developing mice, ID results in increased iron delivery from both FTH1 and Tf for both males and females. The amount of iron uptake from FTH1 was higher than the Tf and this difference between the iron delivery was much greater in females. In contrast, in the adult model, ID was associated with increased brain iron uptake by both FTH1 and Tf but only in the males. There was no increased uptake from either protein in the females. Moreover, transferrin receptor expression on the microvasculature as well as whole brain iron, and H and L ferritin levels revealed the male brains became iron deficient but not the female brains. Last, under normal dietary conditions, 55 Fe uptake was higher in the developing group from both delivery proteins than in the adult group. These results indicate that there are differences in iron acquisition between the developing and adult brain for FTH1 and Tf during nutritional ID and demonstrate a level of regulation of brain iron uptake that is age and sex-dependent.


Asunto(s)
Deficiencias de Hierro , Hierro , Ratones , Masculino , Animales , Femenino , Hierro/metabolismo , Ratones Endogámicos C57BL , Encéfalo/metabolismo , Transferrina , Hierro de la Dieta/metabolismo
4.
J Neurochem ; 167(2): 248-261, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37667496

RESUMEN

Excessive brain iron accumulation is observed early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-ß disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-ß stimulates iron transport from endothelial cells and induces changes in iron transport pathway proteins. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes, which in turn increases levels of apo-transferrin in the amyloid-ß conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease that can lead to iron accumulation. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation.

5.
Water Res ; 243: 120386, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37494741

RESUMEN

Identifying sources of pollutants in watersheds is critical to accurately predicting stormwater quality. Many existing software used to model stormwater quality rely on decades-old data sets which may not represent current runoff quality in the United States. Because of environmental regulations promulgated at the federal level over previous decades, there is a need to understand long-term trends (and potential shifts) in runoff quality to better parameterize models. Pollutant event mean concentrations (EMCs) from the National Stormwater Quality Database (NSQD) were combined with those from recent sources to understand if untreated stormwater quality has changed over the past 40 years. A significant decreasing monotonic trend (i.e., continually decreasing in a nonuniform fashion) was observed for total suspended solids (TSS), total phosphorus (TP), total Kjeldahl nitrogen (TKN), total copper (Cu), total lead (Pb), and total zinc (Zn) in the resultant database, suggesting that runoff quality has become less polluted with time. Median EMCs decreased from 99.2 to 42 mg/L, 0.34 to 0.26 mg/L, 1.27 to 1.03 mg/L, 40 to 6.8 µg/L, 110 to 3.7 µg/L, and 375 to 53.3 µg/L for TSS, TP, TN, Cu, Pb, and Zn, respectively, from the 1980s to the 2010s. These significant reductions often aligned temporally with advancements in clean manufacturing, amendments of the Clean Air Act, and other source control efforts which impact pollutant bioavailability and atmospheric deposition. Results suggest environmental regulations not specifically targeting stormwater management have had a positive impact on stormwater quality and that temporal fluctuations should be considered in modeling.


Asunto(s)
Contaminantes Ambientales , Contaminantes Químicos del Agua , Estados Unidos , Contaminantes Químicos del Agua/análisis , Plomo , Zinc/análisis , Fósforo , Monitoreo del Ambiente/métodos , Lluvia , Movimientos del Agua
6.
bioRxiv ; 2023 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-37292926

RESUMEN

Excessive brain iron accumulation is observed in early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-ß disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-ß stimulates iron transport from endothelial cells and induces changes in iron transport pathway protein levels. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes which in turn increases levels of apo-transferrin in the amyloid-ß conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease to detrimental ends. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation. Significance Statement: Excessive brain iron accumulation is hallmark pathology of Alzheimer's disease that occurs early in the disease staging and before widespread proteinopathy deposition. This overabundance of brain iron has been implicated to contribute to disease progression, thus understandingthe mechanism of early iron accumulation has significant therapeutic potential to slow to halt disease progression. Here, we show that in response to low levels of amyloid-ß exposure, astrocytes increase their mitochondrial activity and iron uptake, resulting in iron deficient conditions. Elevated levels of apo (iron free)-transferrin stimulate iron release from endothelial cells. These data are the first to propose a mechanism for the initiation of iron accumulation and the misappropriation of iron transport signaling leading to dysfunctional brain iron homeostasis and resultant disease pathology.

7.
J Biomed Sci ; 30(1): 36, 2023 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-37277838

RESUMEN

BACKGROUND: Apo- (iron free) and holo- (iron bound) transferrin (Tf) participate in precise regulation of brain iron uptake at endothelial cells of the blood-brain barrier. Apo-Tf indicates an iron-deficient environment and stimulates iron release, while holo-Tf indicates an iron sufficient environment and suppresses additional iron release. Free iron is exported through ferroportin, with hephaestin as an aid to the process. Until now, the molecular mechanisms of apo- and holo-Tf influence on iron release was largely unknown. METHODS: Here we use a variety of cell culture techniques, including co-immunoprecipitation and proximity ligation assay, in iPSC-derived endothelial cells and HEK 293 cells to investigate the mechanism by which apo- and holo-Tf influence cellular iron release. Given the established role of hepcidin in regulating cellular iron release, we further explored the relationship of hepcidin to transferrin in this model. RESULTS: We demonstrate that holo-Tf induces the internalization of ferroportin through the established ferroportin degradation pathway. Furthermore, holo-Tf directly interacts with ferroportin, whereas apo-Tf directly interacts with hephaestin. Only pathophysiological levels of hepcidin disrupt the interaction between holo-Tf and ferroportin, but similar hepcidin levels are unable to interfere with the interaction between apo-Tf and hephaestin. The disruption of the holo-Tf and ferroportin interaction by hepcidin is due to hepcidin's ability to more rapidly internalize ferroportin compared to holo-Tf. CONCLUSIONS: These novel findings provide a molecular mechanism for apo- and holo-Tf regulation of iron release from endothelial cells. They further demonstrate how hepcidin impacts these protein-protein interactions, and offer a model for how holo-Tf and hepcidin cooperate to suppress iron release. These results expand on our previous reports on mechanisms mediating regulation of brain iron uptake to provide a more thorough understanding of the regulatory mechanisms mediating cellular iron release in general.


Asunto(s)
Hepcidinas , Transferrina , Humanos , Transferrina/metabolismo , Hepcidinas/metabolismo , Células Endoteliales/metabolismo , Células HEK293
8.
J Neurochem ; 165(5): 625-642, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37000124

RESUMEN

Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H-ferritin is critical. Endothelial cells of the blood-brain barrier are the site of iron transport regulation. The movement of iron through endothelial cells into the brain can be divided into three distinct processes: uptake, transcytosis, and release. Each process possesses external and internal influences on the regulation at each stage. This review discusses the mechanisms of iron uptake, transcytosis, and release at the blood-brain barrier, as well as the elements that contribute to regulation. Additionally, we explore the dysregulation of brain iron in Alzheimer's disease, Parkinson's disease, and restless legs syndrome.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Parkinson , Síndrome de las Piernas Inquietas , Humanos , Células Endoteliales , Encéfalo , Barrera Hematoencefálica , Hierro , Homeostasis/fisiología
9.
J Biol Chem ; 299(2): 102868, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36603765

RESUMEN

Iron is essential for normal brain development and function. Hence, understanding the mechanisms of iron efflux at the blood-brain barrier and their regulation are critical for the establishment of brain iron homeostasis. Here, we have investigated the role of exosomes in mediating the transfer of H-ferritin (FTH1)- or transferrin (Tf)-bound iron across the blood-brain barrier endothelial cells (BBBECs). Our study used ECs derived from human-induced pluripotent stem cells that are grown in bicameral chambers. When cells were exposed to 55Fe-Tf or 55Fe-FTH1, the 55Fe activity in the exosome fraction in the basal chamber was significantly higher compared to the supernatant fraction. Furthermore, we determined that the release of endogenous Tf, FTH1, and exosome number is regulated by the iron concentration of the endothelial cells. Moreover, the release of exogenously added Tf or FTH1 to the basal side via exosomes was significantly higher when ECs were iron loaded compared to when they were iron deficient. The release of exosomes containing iron bound to Tf or FTH1 was independent of hepcidin regulation, indicating this mechanism by-passes a major iron regulatory pathway. A potent inhibitor of exosome formation, GW4869, reduced exosomes released from the ECs and also decreased the Tf- and FTH1-bound iron within the exosomes. Collectively, these results indicate that iron transport across the blood-brain barrier is mediated via the exosome pathway and is modified by the iron status of the ECs, providing evidence for a novel alternate mechanism of iron transport into the brain.


Asunto(s)
Barrera Hematoencefálica , Exosomas , Hierro , Humanos , Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Exosomas/metabolismo , Hierro/metabolismo , Transferrina/metabolismo , Transporte Biológico
10.
Res Sq ; 2023 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-36711476

RESUMEN

Background : Apo- (iron free) and holo- (iron bound) transferrin (Tf) participate in precise regulation of brain iron uptake at endothelial cells of the blood-brain barrier. Apo-Tf indicates an iron deficient environment and stimulates iron release, while holo-Tf indicates an iron sufficient environment and suppresses additional iron release. Free iron is exported through ferroportin, with hephaestin as an aid to the process. Until now, the molecular mechanism of apo- and holo-Tf's influence on iron release was largely unknown. Methods : Here we use a variety of cell culture techniques, including co-immunoprecipitation and proximity ligation assay, in iPSC-derived endothelial cells and HEK 293 cells to investigate the mechanism of apo- and holo-Tf's influence over iron release. We placed our findings in physiological context by further deciphering how hepcidin played a role in this mechanism as well. Results : We demonstrate that holo-Tf induces the internalization of ferroportin through the established ferroportin degradation pathway. Furthermore, holo-Tf directly binds to ferroportin, whereas apo-Tf directly binds to hephaestin. Only pathological levels of hepcidin disrupt the interaction between holo-Tf and ferroportin, and no amount of hepcidin disrupts the interaction between apo-Tf and hephaestin. The disruption of the holo-Tf and ferroportin interaction by hepcidin is due to hepcidin's ability to rapidly internalize ferroportin compared to holo-Tf. Conclusions : These novel findings provide a molecular mechanism for apo- and holo-Tf regulation of iron release from endothelial cells. They further demonstrate how hepcidin impacts these protein-protein interactions, and offer a model for how holo-Tf and hepcidin corporate to suppress iron release. We have established a more thorough understanding of the mechanisms behind iron release regulation with great clinical impact for a variety of neurological conditions in which iron release is dysregulated.

11.
bioRxiv ; 2023 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-36712094

RESUMEN

Background: Apo- (iron free) and holo- (iron bound) transferrin (Tf) participate in precise regulation of brain iron uptake at endothelial cells of the blood-brain barrier. Apo-Tf indicates an iron deficient environment and stimulates iron release, while holo-Tf indicates an iron sufficient environment and suppresses additional iron release. Free iron is exported through ferroportin, with hephaestin as an aid to the process. Until now, the molecular mechanism of apo- and holo-Tf's influence on iron release was largely unknown. Methods: Here we use a variety of cell culture techniques, including co-immunoprecipitation and proximity ligation assay, in iPSC-derived endothelial cells and HEK 293 cells to investigate the mechanism of apo- and holo-Tf's influence over iron release. We placed our findings in physiological context by further deciphering how hepcidin played a role in this mechanism as well. Results: We demonstrate that holo-Tf induces the internalization of ferroportin through the established ferroportin degradation pathway. Furthermore, holo-Tf directly binds to ferroportin, whereas apo-Tf directly binds to hephaestin. Only pathological levels of hepcidin disrupt the interaction between holo-Tf and ferroportin, and no amount of hepcidin disrupts the interaction between apo-Tf and hephaestin. The disruption of the holo-Tf and ferroportin interaction by hepcidin is due to hepcidin's ability to rapidly internalize ferroportin compared to holo-Tf. Conclusions: These novel findings provide a molecular mechanism for apo- and holo-Tf regulation of iron release from endothelial cells. They further demonstrate how hepcidin impacts these protein-protein interactions, and offer a model for how holo-Tf and hepcidin corporate to suppress iron release. We have established a more thorough understanding of the mechanisms behind iron release regulation with great clinical impact for a variety of neurological conditions in which iron release is dysregulated.

12.
Sci Total Environ ; 862: 160827, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36509280

RESUMEN

Urban stormwater is a substantial source of non-point source pollution. Despite considerable monitoring efforts, little is known about stormwater quality in certain geographic regions. These spatial gaps induce uncertainty when extrapolating data and reduce model calibration capabilities, thereby limiting pollutant load reduction strategies. In this study, stormwater quality was monitored from 15 watersheds to characterize pollutant event mean concentrations (EMCs) and loads as a function of urban and forested (i.e., surrogates for pre-development) land use and land covers (LULCs) and rainfall patterns from a geographic region where these data are sparse. Residential and heavy industrial, heavy industrial, and industrial and commercial LULCs, respectively, were the primary generators of nutrients, total suspended solids (TSS), and heavy metals. Increased rainfall intensities (average and peak) significantly increased the EMCs of all particulate bound pollutants. Pollutant loads increased with rainfall depth and, in general, did not follow the same LULC trends as EMCs, suggesting loads were influenced substantially by watershed hydrologic responses. Mean annual urban loads of total phosphorus, total nitrogen, TSS, and zinc (Zn) ranged from 0.4 (low density residential [LDR]) to 1.5 (heavy industrial), 3.2 (single family residential [SFR]) to 11.5 (heavy industrial), 122.6 (SFR) to 1219.9 (heavy industrial), and 0.1 (LDR) to 0.7 (commercial) kg/ha/yr, respectively. Annual urban loads of TSS were 3.5 to 34 and - 1.5 to 6.8-fold greater than annual loads from forested and agricultural watersheds, respectively. Mean annual loads of heavy metals from urban LULCs were substantially greater than loads produced by forested and agricultural watersheds (e.g., 8.6 to 92 and 6.8 to 73-fold greater, respectively, for Zn), while loads of nutrients were generally similar between urban and agricultural watersheds. Findings herein suggest non-point source pollution will continue to threaten surface water quality as land is developed; results can help guide the development of cost-efficient stormwater management strategies.


Asunto(s)
Contaminantes Ambientales , Metales Pesados , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente , Lluvia , Zinc , Movimientos del Agua
14.
Am Ann Deaf ; 167(5): 644-671, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38661777

RESUMEN

Few studies exist on the reading habits of the deaf population, and most of those that do were published more than 20 years ago. Hence, changes in reading habits due to the availability to the deaf population of online reading material and portable electronic devices have likely occurred. Additionally, in the hearing population, confinement causes changes in reading habits. We used an online questionnaire to compare the reading habits of 102 deaf and hard of hearing adult residents of Spain both before and during COVID-19 confinement. In general, more reading occurred during confinement, although not all participants showed this pattern: Regular readers read more during lockdown. Motivations for reading were largely unaffected by confinement. Furthermore, the time spent reading was not related to the availability of books at home: More was read in digital format during confinement.


Asunto(s)
COVID-19 , Sordera , Hábitos , Personas con Deficiencia Auditiva , Lectura , Humanos , Adulto , Masculino , Femenino , Personas con Deficiencia Auditiva/psicología , COVID-19/epidemiología , Persona de Mediana Edad , Sordera/psicología , España , SARS-CoV-2 , Encuestas y Cuestionarios , Adulto Joven , Anciano , Motivación , Cuarentena/psicología
15.
Front Psychol ; 13: 994399, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36389522

RESUMEN

Diet directly affects children's physical and mental development. Nonetheless, how food insecurity and household food consumption impact the cognitive performance of children at risk of social exclusion remains poorly understood. In this regard, children in Guatemala face various hazards, mainly related to the socioeconomic difficulties that thousands of families have in the country. The main objective of this study was to analyze the differences in cognitive performance considering food insecurity and household food consumption in a sample of rural and urban Guatemalan children and adolescents at risk of social exclusion. Child cognitive performance was assessed in 134 children and adolescents (age M = 11.37; SD = 3.54) from rural and urban settings. Language, attention, and executive functions were assessed using neuropsychological tasks. Differences in cognitive performance in each level of food insecurity and household diet consumption were compared using the Mann-Whitney U test. A stepwise multivariate regression analysis was conducted to determine which factors may influence cognitive scores. The results showed that rural and urban groups did not differ in terms of food insecurity. However, considering just rural areas, differences were found between groups with food security and insecurity in attention and executive function tasks. Moreover, differences were found in food consumption for certain groups of food (e.g., meat, U = 1,146, p < 0.001, g = 0.72). Regarding regressions, protein food consumption (e.g., meat and fish), which is related to having a more balanced diet, was a relevant factor in executive performance. Contrary to what we expected, performance in attentional tasks was not related to the consumption of any food group. These findings could help politicians and decision-makers to select actions focused on improving diet balance and food security in families at risk of social exclusion. It is necessary to carry out more specific studies on the factors related to diet that affect the cognitive development of minors at risk of social exclusion. In addition, it is necessary to study the implementation of alternative interventions that include low-cost nutrients, thus ensuring that minors have access to a more balanced diet.

17.
Pharmacol Rep ; 74(4): 696-708, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35792967

RESUMEN

BACKGROUND: Diabetes is an independent risk factor of stroke and previous studies have confirmed that diabetic patients and animals experience poorer clinical outcomes following stroke. In this study, we aim to determine the effect of chronic exposure of the first-line antidiabetic agent, metformin, to restore euglycemia and to impact brain cell death following stroke in a new type-2 diabetes, NONcNZO10/LtJ (RCS-10) mouse model of stroke. METHODS: Male RCS-10 mice received a moderate (11%) fat diet post-weaning, at 4 weeks of age, and became diabetic by 12-14 weeks, thus resembling human maturity-onset diabetes. The mice received either metformin or vehicle for 4 weeks before undergoing a hypoxic/ischemic (HI) insult. Blood samples were collected pre-, post-treatment, and post HI for glucose and lipid measurements, and brains were analyzed for infarct size, glial activation, neuronal cell death, and metformin-mediated adenosine monophosphate-activated protein kinase (AMPK) signaling at 48 h post HI. RESULTS: Pretreatment with metformin maintained euglycemia for 4 weeks but did not change body weight or lipid profile. Metformin treatment significantly enhanced the microglial Bfl-1 mRNA expression and showed a non-significant increase in GFAP mRNA, however, GFAP protein levels were reduced. Metformin treatment slightly increased neuronal NeuN and MAP-2 protein levels and significantly reduced overall mortality post HI but did not elicit any significant change in infarct size. CONCLUSION: The study suggests that the prolonged effect of metformin-induced euglycemia promoted the microglial activation, reduced neuronal cell death, and improved the overall survival following stroke, without any change in infarct size.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Accidente Cerebrovascular , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Infarto , Lípidos , Masculino , Metformina/farmacología , Metformina/uso terapéutico , Ratones , ARN Mensajero , Accidente Cerebrovascular/tratamiento farmacológico
18.
Fluids Barriers CNS ; 19(1): 49, 2022 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-35689283

RESUMEN

BACKGROUND: The brain requires iron for a number of processes, including energy production. Inadequate or excessive amounts of iron can be detrimental and lead to a number of neurological disorders. As such, regulation of brain iron uptake is required for proper functioning. Understanding both the movement of iron into the brain and how this process is regulated is crucial to both address dysfunctions with brain iron uptake in disease and successfully use the transferrin receptor uptake system for drug delivery. METHODS: Using in vivo steady state infusions of apo- and holo-transferrin into the lateral ventricle, we demonstrate the regulatory effects of brain apo- and holo-transferrin ratios on the delivery of radioactive 55Fe bound to transferrin or H-ferritin in male and female mice. In discovering sex differences in the response to apo- and holo-transferrin infusions, ovariectomies were performed on female mice to interrogate the influence of circulating estrogen on regulation of iron uptake. RESULTS: Our model reveals that apo- and holo-transferrin significantly regulate iron uptake into the microvasculature and subsequent release into the brain parenchyma and their ability to regulate iron uptake is significantly influenced by both sex and type of iron delivery protein. Furthermore, we show that cells of the microvasculature act as reservoirs of iron and release the iron in response to cues from the interstitial fluid of the brain. CONCLUSIONS: These findings extend our previous work to demonstrate that the regulation of brain iron uptake is influenced by both the mode in which iron is delivered and sex. These findings further emphasize the role of the microvasculature in regulating brain iron uptake and the importance of cues regarding iron status in the extracellular fluid.


Asunto(s)
Hierro , Transferrina , Animales , Apoferritinas , Transporte Biológico , Encéfalo/metabolismo , Femenino , Hierro/metabolismo , Masculino , Ratones , Transferrina/metabolismo
20.
Australas J Dermatol ; 63(3): 376-379, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35506161

RESUMEN

Immunoglobulin type gamma 4-related disease (IgG4-RD) is a fibroinflammatory condition that can have systemic and/or cutaneous manifestations. The most common cutaneous features are erythematous papules, nodules and/or plaques, typically involving the head and neck (J Am Acad Dermatol. 2016;75:197). We report a case of IgG4-RD presenting with eruptive cherry angiomas, a novel cutaneous presentation.


Asunto(s)
Exantema , Hemangioma , Enfermedad Relacionada con Inmunoglobulina G4 , Enfermedades de la Piel , Hemangioma/complicaciones , Humanos , Inmunoglobulina G , Piel
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