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1.
Pharmaceutics ; 16(6)2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38931934

RESUMO

In the treatment of experimental neurodegeneration with disaccharide trehalose, various regimens are used, predominantly a 2% solution, drunk for several weeks. We studied the effects of different regimens of dietary trehalose treatment in an amyloid-ß (Aß) 25-35-induced murine model of Alzheimer's disease (AD). Aß-treated mice received 2% trehalose solution daily, 4% trehalose solution daily (continuous mode) or every other day (intermittent mode), to drink for two weeks. We revealed the dose-dependent effects on autophagy activation in the frontal cortex and hippocampus, and the restoration of behavioral disturbances. A continuous intake of 4% trehalose solution caused the greatest activation of autophagy and the complete recovery of step-through latency in the passive avoidance test that corresponds to associative long-term memory and learning. This regimen also produced an anxiolytic effect in the open field. The effects of all the regimens studied were similar in Aß load, neuroinflammatory response, and neuronal density in the frontal cortex and hippocampus. Trehalose successfully restored these parameters to the levels of the control group. Thus, high doses of trehalose had increased efficacy towards cognitive impairment in a model of early AD-like pathology. These findings could be taken into account for translational studies and the development of clinical approaches for AD therapy using trehalose.

2.
Behav Brain Res ; 454: 114651, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37657512

RESUMO

Animal models of Alzheimer's disease (AD) induced by intracerebroventricular (ICV) or intrahippocampal (IH) administration of amyloid-beta (Aß) are widely used in current research. It remains unclear whether these models provide similar outcomes or mimic pathological mechanisms of AD equally. The aim of the work was to compare two models induced by ICV or IH administration of Aß25-35 oligomers to C57BL/6 mice. Parameters characterizing cognitive function (passive avoidance test), protein expression (IBA1, Aß, LC3-II) and expression of genes for neuroinflammation (Aif1, Lcn2, Nrf2), autophagy (Atg8, Becn1, Park2), or markers of neurodegeneration (Cst3, Insr, Vegfa) were analyzed. Сognitive deficits, amyloid accumulation, and neuroinflammatory response in the brain evaluated by the microglial activation were similar in both models. Thus, both ways of Aß administration appear to be equally suitable for modelling AD-like pathology in mice. Our findings strongly support the key role of Aß load and neuroinflammatory response in the hippocampus and frontal cortex for the progression of AD-like pathology and development of cognitive deficits. There were certain minor differences between the models in the mRNA level of genes involved in the processes of neuroinflammation, neurodegeneration, and autophagy. Modulating effects of the central administration of Aß25-35 on the mRNA expression of Aif1, Lcn2, Park2, and Vegfa genes in different brain structures were revealed. The effects occurred to be more pronounced with the ICV method compared with the IH method. These findings give insight into the processes at initial stages of Aß-induced pathology depending on a primary location of Aß oligomers in the brain.


Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Inflamação , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias
3.
Molecules ; 28(18)2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37764390

RESUMO

In this study, determination of the inorganic and organic forms of tin in waters of different salinities is considered. The possibility of the separation of speciations of tin using liquid-liquid extraction (LLE); precipitation with fluorides, iodides, ammonia, and iron (III) chloride; and sorption of organotin compounds (OTCs) was studied. The LLE and analyte precipitation methods proved to be ineffective. Inorganic and organic forms of tin were separated by the sorption of OTCs using silica gel sorbent Diapak C18. Under optimized conditions, a technique for the separate determination of the forms of tin in natural waters was developed. The technique combines hydride generation and microwave mineralization of solutions followed by ICP spectrometry. The inorganic forms of tin were determined after their solid-phase separation from organotin compounds. The lower limits of analyte quantification were 0.03 µg/L (ICP-MS) and 0.05 µg/L (ICP-OES), which provide separate determinations of inorganic and organic forms of tin in waters with different salinities. The content of OTCs in water was determined by subtracting the inorganic concentration from the total concentration of tin. The technique will allow a comprehensive assessment of the toxicological impact of tin speciations on the aquatic ecosystem.

4.
Molecules ; 28(16)2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37630219

RESUMO

This paper considers the features of determining the total tin content in waters with different salinity. Direct ICP-spectrometric analysis of sea waters with a salinity of more than 6‱ significantly reduced the analytical signal of tin by 70% (ICP-MS) and 30% (ICP-OES). The matrix effect of macrocomponents was eliminated by generating hydrides using 0.50 M sodium borohydride and 0.10 M hydrochloric acid. The effect of transition metals on the formation of tin hydrides was eliminated by applying L-cysteine at a concentration of 0.75 g/L. The total analyte concentrations, considering the content of organotin compounds, were determined after microwave digestion of sample with oxidizing mixtures based on nitric acid. The generation of hydrides with the ICP-spectrometric determination of tin leveled the influence of the sea water matrix and reduced its detection limit from 0.50 up to 0.05 µg/L for all digestion schemes. The developed analysis scheme made it possible to determine the total content of inorganic and organic forms of tin in sea waters. The total content of tin was determined in the waters of the Azov and Black seas at the levels of 0.17 and 0.24 µg/L, respectively.

5.
Pharmacol Res ; 183: 106373, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35907433

RESUMO

Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.


Assuntos
Doenças Neurodegenerativas , Trealose , Animais , Autofagia , Dissacarídeos/farmacologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Terapias em Estudo , Trealose/farmacologia , Trealose/uso terapêutico
6.
Pharmacol Biochem Behav ; 217: 173406, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35609863

RESUMO

Alzheimer's disease (AD) is associated with amyloid-ß (Aß) accumulation that might be hindered by autophagy. There are two ways to induce autophagy: through mTOR-dependent and mTOR-independent pathways (here, by means of rapamycin and trehalose, respectively). The aim of this study was to evaluate the contribution of these pathways and their combination to the treatment of experimental AD. Mice were injected bilaterally intracerebroventricularly with an Aß fragment (25-35) to set up an AD model. Treatment with rapamycin (10 mg/kg, every other day), trehalose consumption with drinking water (2 mg/mL, ad libitum), or their combination started 2 days after the surgery and lasted for 2 weeks. Open-field, plus-maze, and passive avoidance tests were used for behavioral phenotyping. Neuronal density, Aß accumulation, and the expression of autophagy marker LC3-II and neuroinflammatory marker IBA1 were measured in the frontal cortex and hippocampus. mRNA levels of autophagy genes (Atg8, Becn1, and Park2) were assessed in the hippocampus. Trehalose but not rapamycin caused pronounced prolonged autophagy induction and transcriptional activation of autophagy genes. Both drugs effectively prevented Aß deposition and microglia activation. Autophagy inhibitor 3-methyladenine significantly attenuated autophagy activation and disturbed the effect of the inducers on Aß load. The inducers substantially reversed behavioral and neuronal deficits in Aß-injected mice. In many cases, the best outcomes were achieved with the combined treatment. Thus, trehalose alone or combined autophagy activation by the two inducers may be a promising treatment approach to AD-like neurodegeneration. Some aspects of interaction between mTOR-dependent and mTOR-independent pathways of autophagy are discussed.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Autofagia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Terapias em Estudo , Trealose/farmacologia , Trealose/uso terapêutico
7.
Cells ; 10(10)2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34685538

RESUMO

Autophagy attenuation has been found in neurodegenerative diseases, aging, diabetes mellitus, and atherosclerosis. In experimental models of neurodegenerative diseases, the correction of autophagy in the brain reverses neuronal and behavioral deficits and hence seems to be a promising therapy for neuropathologies. Our aim was to study the effect of an autophagy inducer, trehalose, on brain autophagy and behavior in a genetic model of diabetes with signs of neuronal damage (db/db mice). A 2% trehalose solution was administered as drinking water during 24 days of the experiment. Expressions of markers of autophagy (LC3-II), neuroinflammation (IBA1), redox state (NOS), and neuronal density (NeuN) in the brain were assessed by immunohistochemical analysis. For behavioral phenotyping, the open field, elevated plus-maze, tail suspension, pre-pulse inhibition, and passive avoidance tests were used. Trehalose caused a slight reduction in increased blood glucose concentration, considerable autophagy activation, and a decrease in the neuroinflammatory response in the brain along with improvements of exploration, locomotor activity, anxiety, depressive-like behavior, and fear learning and memory in db/db mice. Trehalose exerted some beneficial peripheral and systemic effects and partially reversed behavioral alterations in db/db mice. Thus, trehalose as an inducer of mTOR-independent autophagy is effective at alleviating neuronal and behavioral disturbances accompanying experimental diabetes.


Assuntos
Autofagia/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Doenças Neuroinflamatórias/tratamento farmacológico , Comportamento Problema/psicologia , Trealose/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Trealose/farmacologia
8.
Pharmacol Biochem Behav ; 177: 1-11, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582934

RESUMO

The neuroprotective effect of autophagy activation by rapamycin and trehalose was studied in a mouse model of Parkinson's disease (PD) induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both rapamycin (10 mg/kg/day, 7 days) and trehalose (2% in drinking water, 7 days) increased the expression of LC3-II (a marker of autophagy activation) in the frontal cortex and striatum of normal C57Bl/6J mice, with signs of an additive effect. Autophagy stimulation in the striatum was confirmed by a lysosomal osmotic test. In the model of MPTP-induced PD, the two drugs were applied starting from the 2nd day after subchronic daily MPTP administration (20 mg/kg/day, 4 days). A marked increase in LC3-II expression in the striatum was detected under the action of trehalose and in the S. nigra after combined treatment with rapamycin and trehalose. The drugs had a positive effect for recovery of dopaminergic neurons and neuroprotection after MPTP-induced PD-like injury. The therapeutic effect was proven by active restoration of tyrosine hydroxylase (TH) content in the striatum and S. nigra and by improved cognition measured by the passive avoidance learning task. The results revealed the additive effect of the combined treatment with rapamycin and trehalose on dopaminergic deficits (according to the levels of TH expression in the nigrostriatal system) but not on the behavioral performance in the mouse PD model. Thus, the autophagy activation through different pathways by the combination of rapamycin and trehalose reverses both neuronal dopaminergic and behavioral deficits in vivo and seems to be a promising therapy for PD-like pathology.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Autofagia/efeitos dos fármacos , Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/farmacologia , Sirolimo/uso terapêutico , Trealose/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Neurotoxinas/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Sirolimo/administração & dosagem , Substância Negra/metabolismo , Trealose/administração & dosagem , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Neurosci Lett ; 672: 140-144, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29203207

RESUMO

Transgenic overexpression of α-synuclein is a common model of Parkinson's disease (PD). Accumulation of А53Т-mutant α-synuclein induces three autophagy cell responses: the inhibition of autophagy caused by the accumulation of α-synuclein, compensatory activation of macroautophagy in response to inhibition of the chaperone-mediated autophagy, and toxic effects of mutant α-synuclein accompanied by the activation of autophagy. The overall effect of long-term overexpression of mutant α-synuclein in vivo remains unclear. Here we evaluated the activity of autophagy in the frontal cortex, striatum and s.nigra of transgenic mice with overexpression of А53Т-mutant α-synuclein. We revealed low autophagic activity in the dopaminergic structures of 5 mo. transgenic B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J mice as compared to controls C57Bl/6J mice. The results were further supported by the data on tyrosine hydroxylase immunostaining that indicated its significant decrease in the striatum but not in s.nigra of transgenic mice and might be more related to earlier damage of dopaminergic neurites than to the somas due to disturbed formation of autophagosomes at the neuron periphery. The results provide evidence of a possible contribution of suppressed autophagy to the development of PD-like condition as an early event at synucleinopathy progression. Activation of autophagy at early stages of PD seems to be a promising therapeutic tool while B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J mice are suggested as a suitable and adequate model for studying the neuroprotective potential and value of this approach.


Assuntos
Autofagia/genética , Corpo Estriado/metabolismo , Lobo Frontal/metabolismo , Doença de Parkinson/genética , Substância Negra/metabolismo , alfa-Sinucleína/genética , Animais , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/metabolismo , Camundongos , Camundongos Transgênicos , Doença de Parkinson/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
10.
Transl Oncol ; 8(2): 97-105, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25926075

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non-small cell lung carcinoma (NSCLC) cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1) was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549) were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6). In A549 cells, STAT3 activity enhanced the level of MMP-1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6-stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs.

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