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1.
Clin Nucl Med ; 48(2): 143-149, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607363

RESUMO

PURPOSE: To better understand the development of dysphagia in patients with Parkinson disease (PD) and to identify possible neuromodulatory target regions of dysphagia, we studied the striatal dopamine transporter (DAT) availability distribution by subtype of dysphagia. METHODS: In this retrospective cross-sectional study, patients with PD who underwent videofluoroscopic swallowing study and N-(3-[18F]fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane (18F-FP-CIT) PET at intervals of less than 1 month were analyzed. The 14 binarized subitem scores of the Videofluoroscopic Dysphagia Scale were analyzed using a voxel-wise Firth's penalized binary logistic regression model, adjusting for age and disease duration at videofluoroscopic swallowing study. RESULTS: Sixty-five patients with PD were finally included. Striatal mapping showed association of decreased DAT availability with 5 subitems with 1 or more clusters surviving the statistical threshold: 1 oral phase and 4 pharyngeal phase subitems. The overlap maps created by superimposing clusters for all 5 statistically significant subitems revealed associations of dysphagia in PD with decreased DAT availability in the bilateral ventral striatum. Of these, 4 subitems belonging to the pharyngeal phase-specific dysphagia were additionally found to be related to dopaminergic degeneration of the bilateral anterior-to-posterior caudate and ventral striatum. CONCLUSIONS: These findings suggest that subitem/phase-specific striatal subregional dopaminergic depletion may explain the dysphagia of PD. This dopaminergic degeneration of striatal subregions specific to the phases of dysphagia may serve as a potential target for neuromodulatory brain stimulation through stimulation of cortices functionally connected.


Assuntos
Transtornos de Deglutição , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Estudos Retrospectivos , Estudos Transversais , Transtornos de Deglutição/complicações , Transtornos de Deglutição/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Tropanos , Tomografia Computadorizada de Emissão de Fóton Único
2.
Vitam Horm ; 121: 355-393, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36707140

RESUMO

Alkaloids derived from natural sources have been shown to have substantial antioxidant activity, suggesting that these natural-product-inspired bioactive entities may have major beneficial influence on human health and food processing sector. The primary process intricates in the etiology of several disorders such as neurodegenerative, inflammatory cardiovascular, and other chronic diseases appear to be either oxidative injury or a cellular damage caused by reactive oxygen species (ROS) or free-radicals. The alkaloid class of bio-heterocycles have been divided into numerous groups based on their biosynthetic precursor and heterocyclic ring systems i.e., piperidine, imidazole, purine, pyrrolizidine, indole, quinolozidine, isoquinoline, tropane, and pyrrolidine alkaloids. Distinct biological properties have been attributed to various compounds belonging to this chemical groups, including antirheumatic, cardiovascular, antispasmodic, anti-ulcer, anti-inflammatory, antibacterial, antinociceptive etc. For many years, natural products and their analogs have been recognized as a possible source of medicinal agents. Recently, research has been concentrated on the synthesis, separation/purification, and identification of new alkaloids derived from a variety of natural sources. This book chapter aims to summarize on the latest developments on the current knowledge on the relationship between the structural features of promising class of bioactive alkaloids with their antioxidant activities.


Assuntos
Alcaloides , Produtos Biológicos , Humanos , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Alcaloides/farmacologia , Alcaloides/química , Relação Estrutura-Atividade , Tropanos
3.
Toxins (Basel) ; 14(12)2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36548758

RESUMO

The presence of cyanotoxins and its bioaccumulation in the food chain is an increasingly common problem worldwide. Despite the toxic effects produced by Anatoxin-a (ATX-a), this neurotoxin has been less studied compared to microcystins (MCs) and cylindrospermopsin (CYN). Studies conducted under laboratory conditions are of particular interest because these provide information which are directly related to the effects produced by the toxin. Currently, the World Health Organization (WHO) considers the ATX-a toxicological database inadequate to support the publication of a formal guideline reference value. Therefore, the aim of the present work is to compile all of the in vitro and in vivo toxicological studies performed so far and to identify potential data gaps. Results show that the number of reports is increasing in recent years. However, more in vitro studies are needed, mainly in standardized neuronal cell lines. Regarding in vivo studies, very few of them reflect conditions occurring in nature and further studies with longer periods of oral exposure would be of interest. Moreover, additional toxicological aspects of great interest such as mutagenicity, genotoxicity, immunotoxicity and alteration of hormonal balance need to be studied in depth.


Assuntos
Toxinas Bacterianas , Toxinas Bacterianas/toxicidade , Tropanos/toxicidade , Microcistinas/toxicidade , Neurotoxinas , Mutagênicos/toxicidade
4.
Hell J Nucl Med ; 25(3): 247-252, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36507880

RESUMO

OBJECTIVE: This study aimed to explore the availability of striatal dopamine transporter (DAT) after deep brain stimulation (DBS) by single photon emission computed tomography (SPECT) using technetium-99m-labeled tropane derivative (99mTc-Trodat-1). SUBJECTS AND METHODS: In this cohort, 28 patients with PD were enrolled (including 18 males and 10 females). Among these patients, the age range was 55-75 years. All patients referred for optimized DBS programming were recruited for 99mTc-Trodat-1 imaging and symptom assessment. Dopamine transporter SPECT was performed under medication-off state before DBS and at the 6th month after DBS, respectively. The clinical scales including Unified Parkinson Disease Rating Scale (UPDRS), Modified Hoehn & Yahr Scale (MHYS) and Ability of Daily Life Scale (ADLS) were carried out before DBS and at 6 months after DBS under medication-on and medication-off, respectively. Dopamine transporter availability was assessed based on DAT SPECT. In addition, the correlation between DAT availability and clinical scales was investigated. The data were analyzed using SPSS 23.0. RESULTS: The mean UPDRS total, MHYS and ADLS scores were 62.36, 2.23 and 42.07 under medication-on, respectively. The medication improvement rate of UPDRS total, MHYS and ADLS scores were 27.55%, 21.88% and 54.19%, respectively. Interestingly, we found PD patients with MHYS grade I usually presented unilateral symptoms, but DAT imaging showed that DAT uptake of the bilateral striatum was lower than that of the normal and the S-value of the contralateral side was significantly lower than that of the ipsilateral side. Furthermore, we found that DBS can improve the laterality of symptoms. The DBS improvement rate of UPDRS total scores, ADLS scores and DAT S-value were 37.65%, 72.51% and 18.21%, respectively. The symptom laterality was significantly correlated with the DAT S-value at baseline and at 6 months after DBS (r=0.63, 0.69 and 0.66, 0.75). The dosage of levodopa was 696.43±146.52 and was 455.36±107.44 before DBS surgery and at DBS-on, respectively. CONCLUSION: Deep brain stimulation can significantly improve the symptom of PD. Dopamine transporter S-value was well correlated with the change of symptoms laterality. Therefore, DAT imaging can be used to diagnose PD in the early stage and to evaluate the curative effect of DBS. However, the validation of this result requires further study.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/terapia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Estimulação Encefálica Profunda/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Levodopa , Tropanos
5.
Toxins (Basel) ; 14(11)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36356028

RESUMO

The paper presents the first proof of planktonic cyanoprokaryote genus Cuspidothrix as an anatoxin A (ATX) producer in Bulgarian wetlands. The results from polymerase chain reaction (PCR) obtained from two summer sampling campaigns in 26 selected lakes and reservoirs demonstrated presence of the anaC gene, responsible for ATX production in 21 strains of the genus. They were found in three waterbodies sampled in 2018 (coastal lake Vaya, coastal reservoir Poroy, inland reservoir Sinyata Reka) and in four waterbodies sampled in 2019 (inland reservoirs Duvanli, Koprinka, Plachidol 2, Sinyata Reka). The detected genetic diversity generally corresponds to the observations conducted by conventional light microscopy, by which we distinguished three species of Cuspidothrix (Cuspidothrix issatschenkoi, Cuspidothrix elenkinii and Cuspidothrix tropicalis, the latter considered alien in the country). Eleven strains showed high similarity to two sequences of C. issatschenkoi available from the National Centre for Biotechnology Information (NCBI). Ten other strains assembled in a group, which-in lack of available from NCBI genetic sequences-were presumed related to C. tropicalis and C. elenkinii after comparison with the results from light microscopy. Cuspidothrix strains found in Bulgarian waterbodies showed high genetic similarity to those isolated and sequenced from Asia (Japan, China) and Northern Europe (Norway, Finland).


Assuntos
Toxinas de Cianobactérias , Lagos , Bulgária , Tropanos
6.
Proc Natl Acad Sci U S A ; 119(49): e2215372119, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36442128

RESUMO

Tropane alkaloids (TAs) are heterocyclic nitrogenous metabolites found across seven orders of angiosperms, including Malpighiales (Erythroxylaceae) and Solanales (Solanaceae). Despite the well-established euphorigenic properties of Erythroxylaceae TAs like cocaine, their biosynthetic pathway remains incomplete. Using yeast as a screening platform, we identified and characterized the missing steps of TA biosynthesis in Erythroxylum coca. We first characterize putative E. coca polyamine synthase- and amine oxidase-like enzymes in vitro, in yeast, and in planta to show that the first tropane ring closure in Erythroxylaceae occurs via bifunctional spermidine synthase/N-methyltransferases and both flavin- and copper-dependent amine oxidases. We next identify a SABATH family methyltransferase responsible for the 2-carbomethoxy moiety characteristic of Erythroxylaceae TAs and demonstrate that its coexpression with methylecgonone reductase in yeast engineered to express the Solanaceae TA pathway enables the production of a hybrid TA with structural features of both lineages. Finally, we use clustering analysis of Erythroxylum transcriptome datasets to discover a cytochrome P450 of the CYP81A family responsible for the second tropane ring closure in Erythroxylaceae, and demonstrate the function of the core coca TA pathway in vivo via reconstruction and de novo biosynthesis of methylecgonine in yeast. Collectively, our results provide strong evidence that TA biosynthesis in Erythroxylaceae and Solanaceae is polyphyletic and that independent recruitment of unique biosynthetic mechanisms and enzyme classes occurred at nearly every step in the evolution of this pathway.


Assuntos
Amina Oxidase (contendo Cobre) , Coca , Cocaína , Solanaceae , Saccharomyces cerevisiae , Tropanos , Solanaceae/genética , Aminas
7.
Toxins (Basel) ; 14(10)2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36287919

RESUMO

This work presents an optimized methodology based on the miniaturization of the original QuEChERS (µ-QuEChERS) followed by liquid chromatography coupled to mass spectrometry (HPLC-MS/MS) for the determination of tropane alkaloids (TAs), atropine, and scopolamine in leafy vegetable samples. The analytical methodology was successfully validated, demonstrating quantitation limits (MQL) ≤ 2.3 ng/g, good accuracy, and precision, with recoveries between 90-100% and RSD ≤ 13% for both analytes. The method was applied to the analysis of TA-producing plants (Brugmansia versicolor, Solandra maxima, and Convolvulus arvensis). High concentrations of scopolamine were found in flowers (1771 mg/kg) and leaves (297 mg/kg) of B. versicolor. The highest concentration of atropine was found in flowers of S. maxima (10.4 mg/kg). Commercial mixed leafy vegetables contaminated with B. versicolor and S. maxima were analysed to verify the efficacy of the method, showing recoveries between 82 and 110% for both analytes. Finally, the method was applied to the analysis of eighteen samples of leafy vegetables, finding atropine in three samples of mixed leafy vegetables, with concentrations of 2.7, 3.2, and 3.4 ng/g, and in nine samples with concentrations ≤MQL. In turn, scopolamine was only found in a sample of chopped Swiss chard with a concentration ≤MQL.


Assuntos
Espectrometria de Massas em Tandem , Verduras , Cromatografia Líquida de Alta Pressão , Verduras/química , Espectrometria de Massas em Tandem/métodos , Tropanos/análise , Atropina , Escopolamina/análise , Folhas de Planta/química
8.
Anal Bioanal Chem ; 414(28): 8107-8124, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36183043

RESUMO

1,2-Unsaturated pyrrolizidine alkaloids (PA), their corresponding N-oxides (PANO), and tropane alkaloids (TA) are toxic secondary plant metabolites. Their possible transfer into the milk of dairy cows has been studied in feeding trials; however, only few data on the occurrence of these toxins in milk are available. In this study, the development of a sensitive analytical approach for the simultaneous detection and quantification of a broad range of 54 PA/PANO as well as of the TA atropine and scopolamine in milk of dairy cows is presented. The method optimisation focused on sensitivity and separation of PA/PANO isomers. Milk samples were extracted using liquid-liquid extraction with aqueous formic acid and n-hexane, followed by a cation-exchange solid-phase extraction for purification. Reversed phase liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was performed using alkaline solvent conditions. Validation proved low limits of detection and quantification of 0.005 to 0.054 µg/L and of 0.009 to 0.123 µg/L, respectively. For 51 of the 54 tested PA/PANO and both TA, the recovery rates ranged from 64 to 127% with repeatability (RSDr) values below 15% at concentration levels of 0.05 and 0.50 µg/L and below 8% at a concentration level of 3.00 µg/L. Only three PANO did not match the validation criteria and were therefore regarded as semiquantitative. The final method was applied to 15 milk samples obtained from milk vending stations at farms and from local marketers in Bavaria, Germany. In three of the milk samples, traces of PA were detected.


Assuntos
Alcaloides de Pirrolizidina , Animais , Cromatografia Líquida/métodos , Alcaloides de Pirrolizidina/análise , Leite/química , Espectrometria de Massas em Tandem/métodos , Tropanos/análise , Cromatografia Líquida de Alta Pressão
9.
Environ Sci Technol ; 56(19): 13837-13844, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36125920

RESUMO

Toxic benthic cyanobacterial mats are increasingly reported worldwide as being responsible for animal mortalities due to their production of the potent neurotoxin anatoxin-a (ATX) and its analogues. Improved analytical methods for anatoxins are needed to address public health and watershed management challenges arising from extremely high spatial and temporal variability within impacted systems. We present the development, validation, and application of a direct analysis in real-time-high-resolution tandem mass spectrometry (DART-HRMS/MS) method for analysis of anatoxins in cyanobacterial field samples, including a simplified sample preparation approach. The method showed excellent sensitivity and selectivity for ATX, homoanatoxin-a, and dihydroanatoxin-a. Isotopically labeled ATX was used as an internal standard for all three analogues and successfully corrected for the matrix effects observed (86 ± 16% suppression). The limit of detection and recovery for ATX was estimated as 5 ng/g and 88%, respectively, using spiked samples. The total analysis time was ∼2 min, and excellent agreement was observed with results from a liquid chromatography-HRMS reference method. Finally, the DART-HRMS/MS method was applied to a set of 45 Microcoleus-dominated benthic cyanobacterial mat samples from the Wolastoq near Fredericton, Canada, demonstrating its power and applicability in enabling broad-scale field studies of ATX distribution.


Assuntos
Cianobactérias , Espectrometria de Massas em Tandem , Animais , Cianobactérias/química , Toxinas de Cianobactérias , Neurotoxinas , Rios/química , Tropanos
10.
Toxins (Basel) ; 14(9)2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36136559

RESUMO

The cereal grains, which represent the cultivated grasses fruits, supply almost half of the total caloric requirements for humans and provide more nourishment compared with any other class of the food. Out of many cereals used for food, maize, rice, and wheat are the most important food resources for humans, representing 94% of the total cereals consumption. According to the data of the Republic Institute of Statistics for the year 2018, the harvested areas of corn amount to 906,753 hectares. The production of about 7 million tons was achieved with an average yield of 7.7 t/ha according to the Ministry of Agriculture of the Republic of Serbia. Serbia is still among the ten largest exporters of wheat and corn in the world for the period of 2014/15-2017/18. More precisely, it ranks seventh in the export of corn. Utilization of maize products for food animal nutrition (1000 t) is 491,48, and for industrial processing (1000 t) 278,862 expressed as the total consumption (1000 t) is 769,910. Therefore, a total of 103 samples of maize products were analyzed for the presence of toxins, i.e., tropane alkaloids (TAs). The samples were collected from the retail stores in the Republic of Serbia in 2021 and analyzed for the presence of atropine and scopolamine (33 corn grits, 39 polenta, and 31 semolina samples). Therefore, the Recommendation 2015/976/EU on the monitoring of TAs in food was adopted by the EU Commission to obtain more occurrence data on TAs in food. The monitoring extent, however, is restricted because reliable analytical methods and appropriate sensitivity are limited. There was a limit of 1 g/kg for each atropine and scopolamine in cereals containing millet, sorghum, buckwheat, or their derivatives. All the samples were analyzed by the LC-MS/MS. The LOQ was set at 1.0 µg/kg. Out of the total 103 tested samples, 32 samples (31.1%) were contaminated with atropine and scopolamine in concentrations above the LOQ. The highest concentrations of the studied TAs were observed in a semolina sample-atropine: 58.80 µg/kg, scopolamine: 10.20 µg/kg. The obtained results indicate that the TAs concentrations are above the LOQ which can be considered potential human and animal health hazards.


Assuntos
Atropina , Escopolamina , Animais , Cromatografia Líquida/métodos , Grão Comestível/química , Contaminação de Alimentos/análise , Humanos , Escopolamina/análise , Sérvia , Espectrometria de Massas em Tandem/métodos , Tropanos/análise , Zea mays
11.
Int J Mol Sci ; 23(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36142812

RESUMO

Pinellia ternata (Thunb.) Druce is a traditional medicinal plant containing a variety of alkaloids, which are important active ingredients. Brassinolide (BR) is a plant hormone that regulates plant response to environmental stress and promotes the accumulation of secondary metabolites in plants. However, the regulatory mechanism of BR-induced alkaloid accumulation in P. ternata is not clear. In this study, we investigated the effects of BR and BR biosynthesis inhibitor (propiconazole, Pcz) treatments on alkaloid biosynthesis in the bulbil of P. ternata. The results showed that total alkaloid content and bulbil yield was enhanced by 90.87% and 29.67% under BR treatment, respectively, compared to the control. We identified 818 (476 up-regulated and 342 down-regulated) and 697 (389 up-regulated and 308 down-regulated) DEGs in the BR-treated and Pcz-treated groups, respectively. Through this annotated data and the Kyoto encyclopedia of genes and genomes (KEGG), the expression patterns of unigenes involved in the ephedrine alkaloid, tropane, piperidine, pyridine alkaloid, indole alkaloid, and isoquinoline alkaloid biosynthesis were observed under BR and Pcz treatments. We identified 11, 8, 2, and 13 unigenes in the ephedrine alkaloid, tropane, piperidine, and pyridine alkaloid, indole alkaloid, and isoquinoline alkaloid biosynthesis, respectively. The expression levels of these unigenes were increased by BR treatment and were decreased by Pcz treatment, compared to the control. The results provided molecular insight into the study of the molecular mechanism of BR-promoted alkaloid biosynthesis.


Assuntos
Alcaloides , Pinellia , Alcaloides/metabolismo , Brassinosteroides , Efedrina , Perfilação da Expressão Gênica , Isoquinolinas/metabolismo , Pinellia/genética , Piperidinas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/farmacologia , Piridinas/metabolismo , Esteroides Heterocíclicos , Transcriptoma , Tropanos
12.
Int J Chron Obstruct Pulmon Dis ; 17: 2027-2041, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072610

RESUMO

Purpose: The rationale of this study was to investigate the prevalence of daily and night symptoms and quality of sleep in Greek COPD patients as a means to evaluate their response to treatment with the fixed dose combination of aclidinium/formoterol (administered through the Genuair® device). Patients and Methods: This study was a multicenter, nationwide, non-interventional, observational study in 2105 patients suffering from COPD, who have recently started treatment with aclidinium/formoterol. Patients were attending to two visits, one baseline and a final visit, 3 months later. Different variables have been collected on either the baseline or the final visit or both: demographics, vital sign measurements, COPD-related medical history parameters, comorbidities, COPD assessment test (CAT), COPD severity based on spirometry measurements, COPD stage based on the ABCD assessment approach proposed by the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD), COPD treatment report, and severity of early-morning, daytime and night-time COPD-related symptoms. Reasons for prescribing aclidinium/formoterol, satisfaction of patients to the treatment, as well as their compliance have also been recorded. Results: After 3 months on aclidinium/formoterol, 50.1% of the patients experienced an improvement in their early-morning symptoms. Furthermore, 49.9% of them experienced an improvement in their daily symptoms, 44.9% improved their night-time symptoms and 43.2% reduced the frequency of overnight sleep disruptions due to COPD symptoms. These favorable outcomes apply mainly to GOLD Groups B-D. Treatment with aclidinium/formoterol improved on average the pre-bronchodilation FEV1% pred by 3.18%, the post-bronchodilation FEV1% pred by 2.78% and reduced CAT score by 5.22 points. Satisfaction with using aclidinium/formoterol across patients was high, as well as compliance to therapy. Conclusion: Aclidinium/formoterol provided significant benefits on the quality of life of COPD patients by reducing the morning, daytime and the night-time symptoms and symptom burden in GOLD Groups B-D, and activity impairment under real-life conditions in all GOLD ABCD groups.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Volume Expiratório Forçado , Fumarato de Formoterol , Grécia/epidemiologia , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Qualidade de Vida , Resultado do Tratamento , Tropanos/efeitos adversos
13.
Schizophr Res ; 248: 263-270, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36115191

RESUMO

BACKGROUND: Cognitive impairments, the main determinants of functional outcomes in schizophrenia, had limited treatment responses and need a better understanding of the mechanisms. Dysfunctions of the dopamine system and N-methyl-d-aspartate receptor (NMDAR), the primary pathophysiologies of schizophrenia, may impair cognition. This study explored the effects and interactions of striatal dopamine transporter (DAT) and plasma NMDAR-related amino acids on cognitive impairments in schizophrenia. METHODS: We recruited 36 schizophrenia patients and 36 age- and sex-matched healthy controls (HC). All participants underwent cognitive assessments of attention, memory, and executive function. Single-photon emission computed tomography with 99mTc-TRODAT and ultra-performance liquid chromatography were applied to determine DAT availability and plasma concentrations of eight amino acids, respectively. RESULTS: Compared with HC, schizophrenia patients had lower cognitive performance, higher methionine concentrations, decreased concentrations of glutamic acid, cysteine, aspartic acid, arginine, the ratio of glutamic acid to gamma-aminobutyric acid (Glu/GABA), and DAT availability in the left caudate nucleus (CN) and putamen. Regarding memory scores, Glu/GABA and the DAT availability in left CN and putamen exhibited positive relationships, while methionine concentrations showed negative associations in all participants. The DAT availability in left CN mediated the methionine-memory relationship. An exploratory backward stepwise regression analysis for the four biological markers associated with memory indicated that DAT availability in left CN and Glu/GABA remained in the final model. CONCLUSIONS: This study demonstrated the interactions of striatal DAT and NMDAR-related amino acids on cognitive impairments in schizophrenia. Future studies to comprehensively evaluate their complex interactions and treatment implications are warranted.


Assuntos
Disfunção Cognitiva , Esquizofrenia , Humanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Dopamina/metabolismo , Aminoácidos/metabolismo , Ácido Aspártico/metabolismo , Cisteína , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Corpo Estriado/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Metionina , Arginina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Glutamatos/metabolismo , Tropanos
14.
Acta Crystallogr F Struct Biol Commun ; 78(Pt 9): 313-323, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36048081

RESUMO

The affinity and thermodynamic parameters for the interactions of two naturally occurring neurotoxins, (+)-anatoxin-a and (-)-hosieine-A, with acetylcholine-binding protein were investigated using a fluorescence-quenching assay and isothermal titration calorimetry. The crystal structures of their complexes with acetylcholine-binding protein from Aplysia californica (AcAChBP) were determined and reveal details of molecular recognition in the orthosteric binding site. Comparisons treating AcAChBP as a surrogate for human α4ß2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the molecular features involved in ligand recognition and affinity for the protein targets are conserved. The ligands exploit interactions with similar residues as the archetypal nAChR agonist nicotine, but with greater affinity. (-)-Hosieine-A in particular has a high affinity for AcAChBP driven by a favorable entropic contribution to binding. The ligand affinities help to rationalize the potent biological activity of these alkaloids. The structural data, together with comparisons with related molecules, suggest that there may be opportunities to extend the hosieine-A scaffold to incorporate new interactions with the complementary side of the orthosteric binding site. Such a strategy may guide the design of new entities to target human α4ß2 nAChR that may have therapeutic benefit.


Assuntos
Receptores Nicotínicos , Acetilcolina/química , Acetilcolina/metabolismo , Proteínas de Transporte/química , Cristalografia por Raios X , Toxinas de Cianobactérias , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Ligantes , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Tropanos
15.
J AOAC Int ; 105(6): 1730-1740, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-35951765

RESUMO

BACKGROUND: Scopolamine is among the most essential tropane alkaloids used to remedy various nervous system disorders such as urinary incontinence, motion sickness, and spasmodic movements because of its anticholinergic and antispasmodic effects. OBJECTIVE: In this study, an optical nanosensor was fabricated using nano-Dragendorff's reagent to detect and determine scopolamine in different plant parts at different stages of growth. METHOD: For fabrication of the sensing phase, GO-g-PCA/DR was synthesized by encapsulation of Dragendorff's reagent (DR) on the graphene oxide grafted with poly citric acid (GO-g-PCA) with ultrasonication for 15 min and stirred for 80 min at room temperature, and then it was immobilized on a triacetyl cellulose membrane. The kinetic absorption profiles were recorded at 360 nm, which is concerned with the reaction between immobilized GO-g-PCA/DR and different concentrations of scopolamine. RESULTS: The nanosensor showed a rapid, strong, and stable response to the scopolamine solution with changing the absorption spectrum at 360 nm. The reaction was completed in a period of 300 s. The SEM, AFM, and FT-IR analysis of nanocomposites and nanosensors show the successful synthesis of GO-g-PCA/DR and the reaction between nanosensor and scopolamine. All experiments were performed at the wavelength of 360 nm, room temperature, pH 7 (the scopolamine solution pH), and 300 s. The nanosensor had a linear range of 0.65 to 19.63 µg/mL and 0.19 ± 0.025 µg/mL as the limit of detection for scopolamine determination. In order to reuse the designed nanosensor, it was recovered with ethanol, and the color ultimately returned to its original state. CONCLUSIONS: This in situ nanosensor can determine the scopolamine in real samples with easy reversibility, extended lifetime, and reproducibility of the sensing phase response. HIGHLIGHTS: A sensitive, precise, and fast response optical nanosensor is designed for in situ determination of scopolamine in real samples.


Assuntos
Hyoscyamus , Escopolamina/análise , Reprodutibilidade dos Testes , Parassimpatolíticos , Espectroscopia de Infravermelho com Transformada de Fourier , Tropanos , Antagonistas Colinérgicos , Extratos Vegetais , Etanol , Ácido Cítrico , Celulose
16.
Nat Commun ; 13(1): 4994, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008484

RESUMO

Tropane alkaloids such as hyoscyamine and cocaine are of importance in medicinal uses. Only recently has the hyoscyamine biosynthetic machinery become complete. However, the cocaine biosynthesis pathway remains only partially elucidated. Here we characterize polyketide synthases required for generating 3-oxo-glutaric acid from malonyl-CoA in cocaine biosynthetic route. Structural analysis shows that these two polyketide synthases adopt distinctly different active site architecture to catalyze the same reaction as pyrrolidine ketide synthase in hyoscyamine biosynthesis, revealing an unusual parallel/convergent evolution of biochemical function in homologous enzymes. Further phylogenetic analysis suggests lineage-specific acquisition of polyketide synthases required for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae species, respectively. Overall, our work elucidates not only a key unknown step in cocaine biosynthesis pathway but also, more importantly, structural and biochemical basis for independent recruitment of polyketide synthases in tropane alkaloid biosynthesis, thus broadening the understanding of conservation and innovation of biosynthetic catalysts.


Assuntos
Cocaína , Hiosciamina , Filogenia , Policetídeo Sintases/metabolismo , Tropanos/metabolismo
17.
Am J Otolaryngol ; 43(5): 103552, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35932690

RESUMO

PURPOSE: Comparison of audiometric measurements of commercially available smartphone audiogram application thresholds as compared to gold standard audiometric evaluation. MATERIALS AND METHODS: A single-institution, original contribution. Ninety consecutive adult patients presenting to a tertiary care auditory clinic with auditory complaints were evaluated using standard audiometric testing and an application-based hearing test. Correlation between app results and standard audiogram for air conduction pure tone thresholds was evaluated. RESULTS: Mimi™ (Berlin, Germany) results for audiometric thresholds were moderately correlated with standard audiogram (r = 0.51-0.68) depending on severity. The percentage of patients whose hearing loss severity on formal audiometry results were accurately reflected in the Mimi™ (app-based hearing test: ABHT)1 results ranged from 18.2 to 80 %. Among patients whose results were at the extremes of hearing performance, app and standard audiogram results were similar. ABHT yielded an overall sensitivity of 35.5 % and specificity of 97.1 % for normal hearing, and an overall sensitivity of 80 % and specificity of 96 % for severe hearing loss. CONCLUSIONS: Results from an audiometric smart phone application showed accurate categorization of hearing loss at the high and extremes as compared to standard audiometry. However, correlation of pure tone values was more variable and dependent on hearing level.


Assuntos
Surdez , Perda Auditiva , Aplicativos Móveis , Adulto , Audiometria , Audiometria de Tons Puros/métodos , Limiar Auditivo , Perda Auditiva/diagnóstico , Humanos , Smartphone , Tropanos
18.
J Lipid Res ; 63(9): 100261, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35934110

RESUMO

Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models. Here, we aimed to determine if IBAT inhibition with SC-435 is protective in Cyp2c70 KO mice. As compared to WT mice, we found male and female Cyp2c70 KO mice exhibited increased levels of serum liver injury markers, and our evaluation of liver histology revealed increased hepatic inflammation, macrophage infiltration, and biliary cell proliferation. We demonstrate serum and histologic markers of liver damage were markedly reduced with SC-435 treatment. Additionally, we show hepatic gene expression in pathways related to immune cell activation and inflammation were significantly upregulated in Cyp2c70 KO mice and reduced to levels indistinguishable from WT with IBAT inhibition. In Cyp2c70 KO mice, the liver BA content was significantly increased, enriched in chenodeoxycholic acid, and more hydrophobic, exhibiting a hydrophobicity index value and red blood cell lysis properties similar to human liver BAs. Furthermore, we determined IBAT inhibition reduced the total hepatic BA levels but did not affect overall hydrophobicity of the liver BAs. These findings suggest that there may be a threshold in the liver for pathological accretion of hydrophobic BAs and reducing hepatic BA accumulation can be sufficient to alleviate liver injury, independent of BA pool hydrophobicity.


Assuntos
Colestase , Fígado , Animais , Ácidos e Sais Biliares/metabolismo , Proteínas de Transporte , Ácido Quenodesoxicólico/metabolismo , Colestase/metabolismo , Óxidos N-Cíclicos , Feminino , Humanos , Inflamação/metabolismo , Fígado/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Tropanos
19.
J Appl Clin Med Phys ; 23(8): e13723, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35833589

RESUMO

OBJECTIVE: To evaluate the quantitative accuracy of clinical brain dopamine transporters (DAT) investigations utilizing 99m Tc-TRODAT-1 single-photon emission computed tomography (SPECT)/computed tomography (CT) in experimental and clinical settings. MATERIALS AND METHODS: The study used an experimental phantom evaluation and a clinical dataset. Three-dimensional-ordered subsets expectation-maximization reconstructed the original and resampled datasets using attenuation correction, scatter correction, and resolution recovery. The reconstructed data were analyzed and reported as percentage difference, standardized uptake value reference (SUVr), and a coefficient of variation (CoV). The Taguchi method tested the impact of the three different parameters on signal-to-noise ratio (SNR) and SUVr, including number iteration, Poisson resampling, and phantom setup, with and without the plaster of Paris (POP). Six 99m Tc-TRODAT-1 SPECT/CT scans were acquired in healthy subjects for verification purposes. RESULTS: The percentage activity difference between the phantom with and without POP is 20% and 5%, respectively. The SUVr reveals a 10% underestimate for both with and without POP. When it comes to the influence of Poisson resampling, the SUVr value for 75% Poisson resampling indicates 10% underestimation on both sides of the caudate and putamen area, with and without POP. When 25% of Poisson resampling is applied, the SUVr value is overestimated (±35%). In the Taguchi analysis, iteration numbers were the most dominant factor with the F-value of 9.41 and the contribution rate of 52.66% (p < 0.05) for SNR. In comparison, F-value of 9.1 for Poisson resampled with contribution rate of 58.91% (p < 0.05) for SUVr. Reducing counts by 25% from the original dataset resulted in a minimal bias in SUVr, compared to 50% and 75%. CONCLUSION: The optimal absolute SPECT/CT quantification of brain DAT studies using 99m Tc-TRODAT-1 appears achievable with at least 4i10s and SUVr as the surrogate parameter. In clinical investigations, it is possible to reduce the recommended administered dose by up to 25% while maintaining accurate measurement.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Tropanos , Encéfalo/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Compostos de Organotecnécio , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X
20.
Anal Chem ; 94(30): 10857-10864, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35853613

RESUMO

Algal blooms that contaminate freshwater resources with cyanotoxins constitute, nowadays, a global concern. To deal with this problem, a variety of analytical methods, including immunochemical assays, are available for the main algal toxins, for example, microcystins, nodularins, and saxitoxins, with the remarkable exception of anatoxin-a. Now, for the first time, highly sensitive, enantioselective immunoassays for anatoxin-a have been validated using homemade monoclonal antibodies. Two competitive enzyme-linked immunosorbent assays were developed in different formats, with detection limits for (+)-anatoxin-a of 0.1 ng/mL. Excellent recovery values between 82 and 117%, and coefficients of variation below 20%, were observed using environmental water samples fortified between 0.5 and 500 ng/mL. In addition, a lateral-flow immunochromatographic assay was optimized for visual and instrumental reading of results. This test showed a visual detection limit for (+)-anatoxin-a of 4 ng/mL. Performance with a reader was validated in accordance with the European guidelines for semiquantitative rapid methods for small chemical contaminants. Thus, at a screening target concentration of 2 ng/mL, the probability of a blank sample to be classified as "suspect" was as low as 0.2%. Finally, the optimized direct enzyme immunoassay was validated by comparison with high-performance liquid chromatography-tandem mass spectroscopy data and showed a good correlation (r = 0.995) with a slope of 0.94. Moreover, environmental water samples containing more than 2 ng/mL of anatoxin-a were detected by the developed dipstick assay. These results provide supplementary and complementary strategies for monitoring the presence of anatoxin-a in water.


Assuntos
Toxinas Bacterianas , Cianobactérias , Toxinas Bacterianas/química , Cianobactérias/química , Toxinas de Cianobactérias , Monitoramento Ambiental/métodos , Toxinas Marinhas/análise , Microcistinas/análise , Tropanos/análise , Água/análise
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