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1.
J Nanobiotechnology ; 21(1): 216, 2023 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-37424018

RESUMEN

Evidence suggests that increased level/aggregation of ß-amyloid (Aß) peptide, together with enhanced phosphorylation/aggregation of tau protein, play a critical role in the development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. At present, AD diagnosis is based primarily on cognitive assessment, neuroimaging, and immunological assays to detect altered levels/deposition of Aß peptides and tau protein. While measurement of Aß and tau in the cerebrospinal fluid/blood can indicate disease status, neuroimaging of aggregated Aß and tau protein in the brain using positron emission tomography (PET) enable to monitor the pathological changes in AD patients. With advancements in nanomedicine, several nanoparticles, apart from drug-delivery, have been used as a diagnostic agent to identify more accurately changes in AD patients. Recently, we reported that FDA approved native PLGA nanoparticles can interact with Aß to inhibit its aggregation/toxicity in cellular and animal models of AD. Here, we reveal that fluorescence labelled native PLGA following acute intracerebellar injection can identify majority of the immunostained Aß as well as Congo red labelled neuritic plaques in the cortex of 5xFAD mice. Labelling of plaques by PLGA is apparent at 1 h, peak around 3 h and then start declining by 24 h after injection. No fluorescent PLGA was detected in the cerebellum of 5xFAD mice or in any brain regions of wild-type control mice following injection. These results provide the very first evidence that native PLGA nanoparticles can be used as a novel nano-theragnostic agent in the treatment as well as diagnosis of AD pathology.


Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Ratones , Animales , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Placa Amiloide/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos
2.
Cell Mol Neurobiol ; 42(1): 225-242, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33839994

RESUMEN

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite ß-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.


Asunto(s)
Antidepresivos , Inhibidores de la Monoaminooxidasa , Fármacos Neuroprotectores , Fenelzina , Animales , Antidepresivos/farmacología , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Fenelzina/farmacología , Ratas , Ratas Sprague-Dawley
3.
J Nanobiotechnology ; 20(1): 67, 2022 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-35120558

RESUMEN

Conversion of ß-amyloid (Aß) peptides from soluble random-coil to aggregated protein enriched with ß-sheet-rich intermediates has been suggested to play a role in the degeneration of neurons and development of Alzheimer's disease (AD) pathology. Aggregation of Aß peptide can be prompted by a variety of environmental factors including temperature which can influence disease pathogenesis. Recently, we reported that FDA-approved unconjugated poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles can have beneficial effects in cellular and animal models of AD by targeting different facets of the Aß axis. In this study, using biochemical, structural and spectroscopic analyses, we evaluated the effects of native PLGA on temperature-dependent Aß aggregation and its ability to protect cultured neurons from degeneration. Our results show that the rate of spontaneous Aß1-42 aggregation increases with a rise in temperature from 27 to 40 °C and PLGA with 50:50 resomer potently inhibits Aß aggregation at all temperatures, but the effect is more profound at 27 °C than at 40 °C. It appears that native PLGA, by interacting with the hydrophobic domain of Aß1-42, prevents a conformational shift towards ß-sheet structure, thus precluding the formation of Aß aggregates. Additionally, PLGA triggers disassembly of matured Aß1-42 fibers at a faster rate at 40 °C than at 27 °C. PLGA-treated Aß samples can significantly enhance viability of cortical cultured neurons compared to neurons treated with Aß alone by attenuating phosphorylation of tau protein. Injection of native PLGA is found to influence the breakdown/clearance of Aß peptide in the brain. Collectively, these results suggest that PLGA nanoparticles can inhibit Aß aggregation and trigger disassembly of Aß aggregates at temperatures outside the physiological range and can protect neurons against Aß-mediated toxicity thus validating its unique therapeutic potential in the treatment of AD pathology.


Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Nanopartículas/química , Neuronas , Fragmentos de Péptidos/química , Temperatura
4.
Molecules ; 26(24)2021 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-34946752

RESUMEN

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aß) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aß-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aß induced tau hyperphosphorylation in culture, but were not able to protect cells from Aß induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Modelos Animales de Enfermedad , Neuronas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neuronas/metabolismo , Neuronas/patología , Inhibidores de Proteínas Quinasas/química
6.
Glia ; 65(11): 1728-1743, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28722194

RESUMEN

Amyloid ß (Aß) peptides generated from the amyloid precursor protein (APP) play an important role in the degeneration of neurons and development of Alzheimer's disease (AD). Current evidence indicates that high levels of cholesterol-which increase the risk of developing AD-can influence Aß production in neurons. However, it remains unclear how altered level/subcellular distribution of cholesterol in astrocytes can influence APP metabolism. In this study, we evaluated the effects of cholesterol transport inhibitor U18666A-a class II amphiphile that triggers redistribution of cholesterol within the endosomal-lysosomal (EL) system-on APP levels and metabolism in rat primary cultured astrocytes. Our results revealed that U18666A increased the levels of the APP holoprotein and its cleaved products (α-/ß-/η-CTFs) in cultured astrocytes, without altering the total levels of cholesterol or cell viability. The cellular levels of Aß1-40 were also found to be markedly increased, while secretory levels of Aß1-40 were decreased in U18666A-treated astrocytes. We further report a corresponding increase in the activity of the enzymes regulating APP processing, such as α-secretase, ß-secretase, and γ-secretase as a consequence of U18666A treatment. Additionally, APP-cleaved products are partly accumulated in the lysosomes following cholesterol sequestration within EL system possibly due to decreased clearance. Interestingly, serum delipidation attenuated enhanced levels of APP and its cleaved products following U18666A treatment. Collectively, these results suggest that cholesterol sequestration within the EL system in astrocytes can influence APP metabolism and the accumulation of APP-cleaved products including Aß peptides, which can contribute to the development of AD pathology.


Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Androstenos/farmacología , Anticolesterolemiantes/farmacología , Astrocitos/efectos de los fármacos , Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Transporte Biológico/efectos de los fármacos , Células Cultivadas , Colesterol/metabolismo , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de Membrana de los Lisosomas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Fragmentos de Péptidos/metabolismo , Ratas , Factores de Tiempo
7.
Hum Mol Genet ; 24(24): 7132-50, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26433932

RESUMEN

Amyloid-ß (Aß) peptides originating from ß-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Aß peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Aß metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal-lysosomal system, a major site of Aß production, on APP/Aß metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (α-CTF/ß-CTF) and Aß peptides, but not APP mRNA/protein or soluble APPα/APPß, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of γ-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Aß levels may result from a combination of increased production and decreased turnover. APP-CTFs and Aß peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Aß peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced ß-CTF/Aß levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Aß metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogénicas/metabolismo , Colesterol/metabolismo , Proteínas/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Autofagia , Línea Celular Tumoral , Supervivencia Celular , Endosomas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lisosomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación , Neuronas/metabolismo , Proteína Niemann-Pick C1 , Complejo de la Endopetidasa Proteasomal/metabolismo
8.
Neurodegener Dis ; 15(6): 361-8, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26606591

RESUMEN

BACKGROUND: Amyloid-ß (Aß) peptides are a family of proteins that are considered to be a principal aspect of Alzheimer's disease (AD), the most common cause of senile dementia affecting elderly individuals. These peptides result from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via ß- and x03B3;-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aß levels which, in turn, contribute to neuronal loss and development of AD. OBJECTIVES: In this study, we seek to determine what effect Aß has on APP processing in cultured astrocytes. METHODS: Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Aß1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments αCTF and ßCTF, and Aß1-40. In conjunction with these experiments, we examined the relative levels and activity of ß- and x03B3;-secretases in Aß-treated astrocytes. RESULTS: We report here that Aß1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Aß1-40 in a time-dependent manner. CONCLUSIONS: These results suggest that activated astrocytes can contribute to the development of AD by enhancing levels and processing of APP leading to an increased production/secretion of Aß-related peptides.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Astrocitos/metabolismo , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Células Cultivadas , Humanos
9.
J Biol Chem ; 288(5): 3136-52, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23250759

RESUMEN

Cathepsin D is an aspartyl protease that plays a crucial role in normal cellular functions and in a variety of neurodegenerative disorders, including Niemann-Pick type C (NPC) disease, which is characterized by intracellular accumulation of cholesterol and glycosphingolipids in many tissues, including the brain. There is evidence that the level and activity of cathepsin D increased markedly in vulnerable neurons in NPC pathology, but its involvement in neurodegeneration remains unclear. In the present study, using mouse hippocampal cultured neurons, we evaluated the significance of cathepsin D in toxicity induced by U18666A, a class II amphiphile, which triggers cell death by impairing the trafficking of cholesterol, as observed in NPC pathology. Our results showed that U18666A-mediated toxicity is accompanied by an increase in cathepsin D mRNA and enzyme activity but a decrease in the total peptide content. The cytosolic level of cathepsin D, on the other hand, was increased along with cytochrome c and activated caspase-3 in U18666A-treated neurons. The cathepsin D inhibitor, pepstatin A, partially protected neurons against toxicity by attenuating these signaling mechanisms. Additionally, down-regulation of cathepsin D level prevented, whereas overexpression of the protease increased, vulnerability of cultured N2a cells to U18666A-induced toxicity. We also showed that extracellular cathepsin D from U18666A-treated neurons or application of exogenous enzyme can induce neurotoxicity by activating the autophagic pathway. These results suggest that increased release/activation of cathepsin D can trigger neurodegeneration and possibly development of NPC pathology. Thus, targeting cathepsin D level/activity may provide a new therapeutic opportunity for the treatment of NPC pathology.


Asunto(s)
Androstenos/toxicidad , Catepsina D/metabolismo , Neuronas/patología , Enfermedad de Niemann-Pick Tipo C/enzimología , Enfermedad de Niemann-Pick Tipo C/patología , Animales , Proteína 5 Relacionada con la Autofagia , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Catepsina D/antagonistas & inhibidores , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colesterol/metabolismo , Citocromos c/metabolismo , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Fibroblastos/patología , Hipocampo/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/enzimología , Enfermedad de Niemann-Pick Tipo C/etiología , Inhibidores de Proteasas/farmacología , Estaurosporina/farmacología
10.
Hum Mol Genet ; 21(22): 4857-75, 2012 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-22869680

RESUMEN

Niemann-Pick type C (NPC) disease, an autosomal recessive disorder caused primarily by loss-of-function mutations in NPC1 gene, is characterized neuropathologically by intracellular cholesterol accumulation, gliosis and neuronal loss in selected brain regions. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease (AD), including the presence of tau-positive neurofibrillary tangles (NFTs) and ß-amyloid (Aß)-related peptides in vulnerable brain regions. Since enhanced cholesterol level, which acts as a risk factor for AD, can increase Aß production by regulating amyloid precursor protein (APP) metabolism, it is possible that APP overexpression can influence cholesterol-regulated NPC pathology. We have addressed this issue in a novel bigenic mice (ANPC) generated by crossing heterozygous Npc1-deficient mice with mutant human APP transgenic mice. These mice exhibited decreased lifespan, early object memory and motor impairments, and exacerbated glial pathology compared with other littermates. Neurodegeneration observed in the cerebellum of ANPC mice was found to be accelerated along with a selective increase in the phosphorylation/cleavage of tau protein. Additionally, enhanced levels/activity of cytosolic cathepsin D together with cytochrome c and Bcl-2-associated X protein suggest a role for the lysosomal enzyme in the caspase-induced degeneration of neurons in ANPC mice. The reversal of cholesterol accretion by 2-hydroxypropyl-ß-cyclodextrin (2-HPC) treatment increased longevity and attenuated behavioral/pathological abnormalities in ANPC mice. Collectively, our results reveal that overexpression of APP in Npc1-deficient mice can negatively influence longevity and a wide spectrum of behavioral/neuropathological abnormalities, thus raising the possibility that APP and NPC1 may interact functionally to regulate the development of AD and NPC pathologies.


Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Mutación , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/patología , beta-Ciclodextrinas/farmacología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Catepsina D/metabolismo , Colesterol/metabolismo , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Modelos Animales de Enfermedad , Humanos , Trastornos de la Memoria/genética , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Niemann-Pick Tipo C/mortalidad , Fosforilación/efectos de los fármacos , Sinapsis/metabolismo , beta-Ciclodextrinas/administración & dosificación , Proteínas tau/metabolismo
11.
Sci Rep ; 14(1): 144, 2024 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-38167993

RESUMEN

Evidence suggests that beta-amyloid (Aß)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aß and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA nanoparticles without any drug can attenuate Aß aggregation/toxicity in cellular/animal models of AD. In this study, we evaluated the effects of native PLGA on Aß seed-induced aggregation of tau protein using a variety of biophysical, structural and spectroscopic approaches. Our results show that Aß1-42 seeds enhanced aggregation of tau protein in the presence and absence of heparin and the effect was attenuated by native PLGA nanoparticles. Interestingly, PLGA inhibited aggregation of both 4R and 3R tau isoforms involved in the formation of neurofibrillary tangles in AD brains. Furthermore, Aß seed-induced tau aggregation in the presence of arachidonic acid was suppressed by native PLGA. Collectively, our results suggest that native PLGA nanoparticles can inhibit the Aß seed-induced aggregation of different tau protein isoforms highlighting their therapeutic implication in the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Anciano , Animales , Humanos , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Fosforilación
12.
J Psychiatry Neurosci ; 38(1): 6-23, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22894822

RESUMEN

Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid ß peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid ß and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid ß production, but also amyloid ß can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Encéfalo/fisiopatología , Ácido Glutámico/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Memantina/uso terapéutico , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Fosforilación , Membranas Sinápticas/metabolismo , Membranas Sinápticas/fisiología
13.
Neuroscience ; 516: 27-41, 2023 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-36805001

RESUMEN

Kainic acid (KA), an analogue of the excitatory neurotransmitter glutamate, when administered systemically can trigger seizures and neuronal loss in a manner that mirrors the neuropathology of human mesial temporal lobe epilepsy (mTLE), which affects ∼50 million people globally. Evidence suggests that changes in astrocytes which precede neuronal damage play an important role in the degeneration of neurons and/or development of seizures in TLE pathogenesis. Additionally, a role for microtubule associated tau protein, involved in various neurodegenerative diseases including Alzheimer's disease, has also been suggested in the development of seizure and/or neurodegeneration in TLE pathogenesis. At present, possible alterations of different subtypes of astrocytes and their association, if any, with tau protein in TLE remain unclear. In this study, we evaluated alterations of different subtypes of astrocytes and phospho-/cleaved-tau levels in KA-treated rat model of TLE. Our results reveal that levels/expression of various astrocyte markers such as GFAP, vimentin, S100B, Aldh1L1, but not GS, are increased in the hippocampus of KA-treated rats. The levels/expression of both A1(C3+) and A2(S100A10+)-like astrocytes are also increased in KA-treated rats. Concurrently, the total (Tau1 and Tau5) and phospho-tau (AT270 and PHF1) levels are transiently enhanced following KA administration. Furthermore, the level/expression of cleaved-tau, which is apparent in a subset of GFAP-, S100B- and A2-positive astrocytes, are increased in KA-treated rats. These results, taken together, suggest a differential role for various astrocytic subpopulations and tau protein in the development of seizure and/or loss of neurons in KA model of TLE and possibly in human mTLE pathogenesis.


Asunto(s)
Epilepsia del Lóbulo Temporal , Ácido Kaínico , Humanos , Adulto , Ratas , Animales , Astrocitos/metabolismo , Proteínas tau/metabolismo , Hipocampo/metabolismo , Convulsiones/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Modelos Animales de Enfermedad
14.
Int J Soc Psychiatry ; 69(3): 646-652, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36326007

RESUMEN

BACKGROUND: In recent years there has been significant coverage of mental health in Indian newspapers; the media can play a significant role in perpetuating as well as reducing stigma towards people with mental illness. This paper analyses the content, context and type of newspaper coverage of various mental health disorders in English language newspapers in India between 2016 and 2021. METHODS: A detailed analysis was performed on a sample of articles about mental illness in a range of English language Indian newspapers. RESULTS: Depression was the most prevalent topic amongst the articles followed by anxiety, schizophrenia and bipolar disorder. Our study describes a wide range of use of mental health disorders in various newspapers. All diagnoses were generally described in a criminal context like homicide, sexual assault and other crimes. Over time newspaper coverage of mental illness has become less stigmatising. Further exploration of non-English medium newspapers is required to fully understand the extent of the role of print media in perpetuating unhelpful stereotypes of people with mental illness in India.


Asunto(s)
Trastornos Mentales , Estereotipo , Humanos , Salud Mental , Estudios Retrospectivos , Trastornos Mentales/psicología , India
15.
Int J Biol Macromol ; 219: 1180-1196, 2022 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-36030976

RESUMEN

Biodegradable poly(lactic-co-glycolic acid)(PLGA) nanoparticles have been used extensively in delivering drugs to target tissues due to their excellent biocompatibility. Evidence suggests that PLGA-conjugated drugs/agents can attenuate pathology in cellular/animal models of Alzheimer's disease (AD), which is initiated by increased level/aggregation of amyloid ß (Aß) peptide generated from amyloid precursor protein (APP). The beneficial effects were attributed to conjugated-drugs rather than to PLGA nanoparticles. Interestingly, we recently reported that PLGA without any drug/agent (native PLGA) can suppress Aß aggregation/toxicity. However, very little is known about the internalization, subcellular localization or effects of PLGA in neurons. In this study, using primary mouse cortical neurons, we first showed that native PLGA is internalized by an energy-mediated clathrin-dependent/-independent pathway and is localized in endosomal-lysosomal-autophagic vesicles. By attenuating internalization, PLGA can protect neurons against Aß-mediated toxicity. Additionally, PLGA treatment altered expression profiles of certain AD-associated genes and decreased the levels of APP, its cleaved products α-/ß-CTFs and Aß peptides in mouse as well as iPSC-derived neurons from control and AD patients. Collectively, these results suggest that native PLGA not only protects neurons against Aß-induced toxicity but also influences the expression of AD-related genes/proteins - highlighting PLGA's implication in normal and AD-related pathology.


Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Clatrina , Ratones , Neuronas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacología
16.
Bioact Mater ; 17: 506-525, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36330076

RESUMEN

Alzheimer's disease (AD) is believed to be triggered by increased levels/aggregation of ß-amyloid (Aß) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeutic potential of FDA-approved native poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles on Aß aggregation and in cellular/animal models of AD. Our results showed that native PLGA can not only suppress the spontaneous aggregation but can also trigger disassembly of preformed Aß aggregates. Spectroscopic studies, molecular dynamics simulations and biochemical analyses revealed that PLGA, by interacting with the hydrophobic domain of Aß1-42, prevents a conformational shift towards the ß-sheet structure, thus precluding the formation and/or triggering disassembly of Aß aggregates. PLGA-treated Aß samples can enhance neuronal viability by reducing phosphorylation of tau protein and its associated signaling mechanisms. Administration of PLGA can interact with Aß aggregates and attenuate memory deficits as well as Aß levels/deposits in the 5xFAD mouse model of AD. PLGA can also protect iPSC-derived neurons from AD patients against Aß toxicity by decreasing tau phosphorylation. These findings provide unambiguous evidence that native PLGA, by targeting different facets of the Aß axis, can have beneficial effects in mouse neurons/animal models as well as on iPSC-derived AD neurons - thus signifying its unique therapeutic potential in the treatment of AD pathology.

17.
Radiat Oncol ; 17(1): 77, 2022 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-35428301

RESUMEN

BACKGROUND: There is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40-1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 109 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions. MATERIALS AND METHODS: We used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival after X-ray exposure in normal fibroblast and radioresistant patient- derived GBM stem cells. RESULTS: Oxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 min and pathological hypoxia for up to 24 h after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 min post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522B cells compared to the conventional dose rate protons suggesting an important impact of these extremely high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.1 and 2.5 ± 0.1 respectively for the AG01522B and patient-derived GBM stem cells for X-ray irradiation using our hypoxia chambers. CONCLUSION: We demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after exposure to laser-driven protons at ultra-high dose, conventional protons and X-rays. Suitable levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects. The data obtained provided indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays.


Asunto(s)
Protones , Radiobiología , ADN/efectos de la radiación , Humanos , Hipoxia , Rayos Láser , Oxígeno
18.
Dis Model Mech ; 14(10)2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34524402

RESUMEN

Amyloid ß (Aß) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aß-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence the function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol increases exosome secretion, from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-C-terminal fragments, soluble APP, APP secretases and Aß1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aß production or by neutralizing exosomal Aß peptide with an anti-Aß antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aß peptides and influencing neuronal viability in the affected regions of the AD brain.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Colesterol/metabolismo , Exosomas/metabolismo , Péptidos beta-Amiloides/metabolismo , Androstenos/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/ultraestructura , Autofagia/efectos de los fármacos , Catepsina D/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Exosomas/efectos de los fármacos , Exosomas/ultraestructura , Femenino , Proteína 1 de la Membrana Asociada a los Lisosomas , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Lisosomas/ultraestructura , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas
19.
Bioact Mater ; 6(12): 4491-4505, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34027236

RESUMEN

Evidence suggests that increased level/aggregation of beta-amyloid (Aß) peptides initiate neurodegeneration and subsequent development of Alzheimer's disease (AD). At present, there is no effective treatment for AD. In this study, we reported the effects of gold nanoparticles surface-functionalized with a plant-based amino acid mimosine (Mimo-AuNPs), which is found to cross the blood-brain barrier, on the Aß fibrillization process and toxicity. Thioflavin T kinetic assays, fluorescence imaging and electron microscopy data showed that Mimo-AuNPs were able to suppress the spontaneous and seed-induced Aß1-42 aggregation. Spectroscopic studies, molecular docking and biochemical analyses further revealed that Mimo-AuNPs stabilize Aß1-42 to remain in its monomeric state by interacting with the hydrophobic domain of Aß1-42 (i.e., Lys16 to Ala21) there by preventing a conformational shift towards the ß-sheet structure. Additionally, Mimo-AuNPs were found to trigger the disassembly of matured Aß1-42 fibers and increased neuronal viability by reducing phosphorylation of tau protein and the production of oxyradicals. Collectively, these results reveal that the surface-functionalization of gold nanoparticles with mimosine can attenuate Aß fibrillization and neuronal toxicity. Thus, we propose Mimo-AuNPs may be used as a potential treatment strategy towards AD-related pathologies.

20.
Sci Rep ; 11(1): 699, 2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436708

RESUMEN

Developing compact ion accelerators using intense lasers is a very active area of research, motivated by a strong applicative potential in science, industry and healthcare. However, proposed applications in medical therapy, as well as in nuclear and particle physics demand a strict control of ion energy, as well as of the angular and spectral distribution of ion beam, beyond the intrinsic limitations of the several acceleration mechanisms explored so far. Here we report on the production of highly collimated ([Formula: see text] half angle divergence), high-charge (10s of pC) and quasi-monoenergetic proton beams up to [Formula: see text] 50 MeV, using a recently developed method based on helical coil targetry. In this concept, ions accelerated from a laser-irradiated foil are post-accelerated and conditioned in a helical structure positioned at the rear of the foil. The pencil beam of protons was produced by guided post-acceleration at a rate of [Formula: see text] 2 GeV/m, without sacrificing the excellent beam emittance of the laser-driven proton beams. 3D particle tracing simulations indicate the possibility of sustaining high acceleration gradients over extended helical coil lengths, thus maximising the gain from such miniature accelerating modules.

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