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1.
J Lipid Res ; : 100596, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39019344

RESUMO

Membrane lipids extensively modulate the activation gating of voltage-gated potassium channels (KV), however, much less is known about mechanisms of ceramide and glucosylceramide actions including which structural element is the main intramolecular target and whether there is any contribution of indirect, membrane biophysics-related mechanisms to their actions. We used two-electrode voltage-clamp fluorometry capable of recording currents and fluorescence signals to simultaneously monitor movements of the pore domain (PD) and the voltage sensor domain (VSD) of the KV1.3 ion channel after attaching an MTS-TAMRA fluorophore to a cysteine introduced into the extracellular S3-S4 loop of the VSD. We observed rightward shifts in the conductance-voltage (G-V) relationship, slower current activation kinetics and reduced current amplitudes in response to loading the membrane with C16-ceramide (Cer) or C16-glucosylceramide (GlcCer). When analyzing VSD movements, only Cer induced a rightward shift in the fluorescence signal-voltage (F-V) relationship and slowed fluorescence activation kinetics, whereas GlcCer exerted no such effects. These results point at a distinctive mechanism of action with Cer primarily targeting the VSD, while GlcCer only the PD of KV1.3. Using environment-sensitive probes and fluorescence-based approaches, we show that Cer and GlcCer similarly increase molecular order in the inner, hydrophobic regions of bilayers, however, Cer induces a robust molecular reorganization at the membrane-water interface. We propose that this unique ordering effect in the outermost membrane layer in which the main VSD rearrangement involving an outward sliding of the top of S4 occurs, can explain the VSD targeting mechanism of Cer, which is unavailable for GlcCer.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38828630

RESUMO

BACKGROUND: Due to its heterogeneous manifestation an individualized approach to reach therapeutic goals in cervical dystonia (CD) is advantageous. OBJECTIVES: The aim of the current study was to adapt goal attainment scaling (GAS) to drive the management of CD. METHODS: 38 patients with CD, regularly treated with botulinum neurotoxin (BoNT), were involved in the current exploratory observational pilot study. GAS, including domains of motor, pain, disability, and psychiatric features, was applied to set up individualized goals with the calculation of initial GAS T-scores. Following at least 4 BoNT injection cycles, patients were reassessed whether they reached the pre-set goals. RESULTS: The initial GAS T-scores (median: 36.9, range: 22.8-40) significantly improved (P < 0.001) to the end of the study (the median of final GAS T-scores: 50, range: 25.5-63.6). CONCLUSIONS: The applicability of GAS in CD patients was confirmed, but further large-scale studies are needed refining this innovative approach.

3.
Int J Mol Sci ; 24(13)2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37445923

RESUMO

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.


Assuntos
Blefarospasmo , Distúrbios Distônicos , Torcicolo , Adulto , Humanos , Pessoa de Meia-Idade , Hungria , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Blefarospasmo/diagnóstico , Torcicolo/diagnóstico , Torcicolo/genética , Testes Genéticos
4.
Ideggyogy Sz ; 76(1-2): 37-45, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36892297

RESUMO

Background and purpose:

Cervical dys­tonia (CD) is the most common form of focal dystonias, where the identification of the involved muscles, the determination of optimal botulinum neurotoxin A (BoNT-A) dose per muscle injection, and precise tar­ge­ting may be challenging. The aim of the current study is to compare local centre data with international data, enabling the iden­tification of population and me­tho­do­­lo­gical factors behind the differences, there­by further improvement of the care of Hun­ga­rian patients with CD.

. Methods:

The data of all consecutive CD patients, who were injected with BoNT-A at the botulinum neurotoxin outpatient clinic at the Department of Neurology, University of Szeged between 11 August and 21 Sep­tember 2021, were retrospectively col­lected and analysed in a cross-sectional manner. The frequency of the involved muscles, determined by the application of the collum-caput (COL-CAP) concept, and the parameters for the BoNT-A formulations, injected via ultrasound (US)-guidance, were calculated and compared with available international data.

. Results:

In the current study, 58 patients (19 males and 39 females) were involved with mean age of 58.4 (± SD 13.6, range 24-81) years. The most common subtype was torticaput (29.3%). Tremor affected 24.1% of patients. The most injected muscles were trapezius (56.9% of all cases), followed by the levator scapulae (51.7%), splenius capitis (48.3%), sternocleidomastoid (32.8%), and semispinalis capitis (22.4%). The injected mean doses per patient were 117 ± SD 38.5 (range: 50-180) units for onaBoNT-A, 118 ± SD 29.8 (range: 80-180) units for incoBoNT-A, and 405 ± SD 162 (range: 100-750 units) for aboBoNT-A.

. Conclusion:

Although there were several similarities between the results of the current and the multicentre studies, all were carried out using the COL-CAP concept and US-guided BoNT-A injections, authors should pay attention to better distinction of torti-forms and the more frequent injection of especially the obliquus capitis inferior, mainly in cases with no-no tremor.

.


Assuntos
Toxinas Botulínicas Tipo A , Torcicolo , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Torcicolo/diagnóstico por imagem , Torcicolo/tratamento farmacológico , Estudos Transversais , Estudos Retrospectivos , Toxinas Botulínicas Tipo A/uso terapêutico , Ultrassonografia de Intervenção
5.
Front Cell Dev Biol ; 9: 647300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912562

RESUMO

Although the largely positive intramembrane dipole potential (DP) may substantially influence the function of transmembrane proteins, its investigation is deeply hampered by the lack of measurement techniques suitable for high-throughput examination of living cells. Here, we describe a novel emission ratiometric flow cytometry method based on F66, a 3-hydroxiflavon derivative, and demonstrate that 6-ketocholestanol, cholesterol and 7-dehydrocholesterol, saturated stearic acid (SA) and ω-6 γ-linolenic acid (GLA) increase, while ω-3 α-linolenic acid (ALA) decreases the DP. These changes do not correlate with alterations in cell viability or membrane fluidity. Pretreatment with ALA counteracts, while SA or GLA enhances cholesterol-induced DP elevations. Furthermore, ALA (but not SA or GLA) increases endo-lysosomal escape of penetratin, a cell-penetrating peptide. In summary, we have developed a novel method to measure DP in large quantities of individual living cells and propose ALA as a physiological DP lowering agent facilitating cytoplasmic entry of penetratin.

6.
Sci Rep ; 6: 39602, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28004767

RESUMO

Speleothem deposits are among the most valuable continental formations in paleoclimate research, as they can be dated using absolute dating methods, and they also provide valuable climate proxies. However, alteration processes such as post-depositional mineralogical transformations can significantly influence the paleoclimatic application of their geochemical data. An innovative sampling and measurement protocol combined with scanning and transmission electron microscopy, X-ray diffraction and Fourier transform infrared spectroscopy is presented, demonstrating that carbonate precipitating from drip water in caves at ~10 °C contains amorphous calcium carbonate (ACC) that later transforms to nanocrystalline calcite. Stable oxygen isotope fractionations among calcite, ACC and water were also determined, proving that ACC is 18O-depleted (by >2.4 ± 0.8‰) relative to calcite. This, in turn, has serious consequences for speleothem-based fluid inclusion research as closed system transformation of ACC to calcite may induce a negative oxygen isotope shift in fluid inclusion water, resulting in deterioration of the original compositions. ACC formation increases the speleothems' sensitivity to alteration as its interaction with external solutions may result in the partial loss of original proxy signals. Mineralogical analysis of freshly precipitating carbonate at the studied speleothem site is suggested in order to determine the potential influence of ACC formation.

7.
Acta Biol Hung ; 66(4): 464-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26616378

RESUMO

The present work is the first phytochemical investigation of Euphorbia davidii Subils. After multistep separation process, three flavonoid glycosides were obtained from the ethyl acetate soluble fraction of the methanol extract of the whole plant. The structures of the isolated compounds were determined as kaempferol 3-O-rhamnoside, myricetin 3-O-rhamnoside, and quercetin 3-O-rhamnoside. Aqueous and organic extracts of the plant were screened in vitro for antiproliferative activity against HeLa (cervix epithelial adenocarcinoma), A431 (skin epidermoid carcinoma), A2780 (ovarian carcinoma) and MCF7 (breast epithelial adenocarcinoma) cells, using the MTT assay. n-Hexane and chloroform extracts demonstrated moderately dose-dependent cell growth inhibitory activity against all four cell lines.


Assuntos
Euphorbia/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Células HeLa , Humanos , Compostos Fitoquímicos/química , Extratos Vegetais/química
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