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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 265: 120385, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34536885

RESUMO

In this work, a strong blue-emitting fluorescent biosensor based on graphite carbon nitride nanoparticles (GCNNs) (Ex = 340 nm and Em = 435 nm) was synthesized by a facile one-step hydrothermal method. With the aid of hydrogen peroxide and horseradish peroxidase, pyrocatechol structure of dopamine (DA) was oxidized to o-quinone structure of polydopamine (PDA) by hydroxyl radical. PDA was able to rapidly and significantly quench fluorescence of GCNNs. In the meanwhile, oxidative self-polymerization from DA to PDA would be blocked by antioxidants, such as glutathione (GSH) and ascorbic acid (AA). Thus, the fluorescence of GCNNs@DA sensor would be recovered owing to the decrease of o-quinone. Based on above-mentioned dual recognition strategy of "turn-off" and "turn off-on", a fast, simple and ultrasensitive method was developed to measure DA and antioxidants. Under the optimal experimental conditions, the detection limits of DA, GSH and AA were 0.064 µmol L-1, 0.11 µmol L-1 and 0.16 µmol L-1 with relative standard deviations of 1.7%, 9.3% and 8.0%, respectively. As one of metal-free quantum dots, our GCNNs-based sensors were also successfully applied to the determination of DA as well as GSH and AA in human serum. The recoveries for the spiked samples were in the range of 93.8%-109% and 95.0%-110% of DA and antioxidants, which shows great promise to clinicalapplication.


Assuntos
Grafite , Pontos Quânticos , Antioxidantes , Carbono , Dopamina , Humanos , Limite de Detecção , Nitrilas , Soro
2.
Talanta ; 237: 122986, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34736705

RESUMO

A highly sensitive cationic polyfluorinated azobenzene/reduced graphene oxide (C3F7-azo+/RGO) nanocomposite electrochemical sensor for simultaneous detection of dopamine (DA), ascorbic acid (AA) and uric acid (UA) was successfully synthesized using a facile exfoliation/restacking method. The nanocomposite is self-assembled from oppositely charged graphene oxide nanosheets (GO) and polyfluorinated azobenzene cations (C3F7-azo+), and then obtained by electrochemical reduction. The structure and electrochemical properties were characterized by X-ray diffraction (XRD), energy dispersive spectrometer analysis (EDS), transmission electron microscope (TEM) and scanning electron microscope (SEM). The electrochemical property of C3F7-azo+/RGO was characterized by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). It can be clearly seen from experimental results that C3F7-azo+/RGO-modified electrode (C3F7-azo+/RGO/GCE) can detect DA, AA and UA simultaneously, and has good stability and anti-interference performance. The detection limits are 65 nM, 8 nM and 11 nM for DA, AA and UA in the ranges 57.28-134.28 µM, 0.04-6.01 µM, 9.23-23.45 µM, respectively.


Assuntos
Grafite , Ácido Úrico , Ácido Ascórbico , Compostos Azo , Cátions , Dopamina , Técnicas Eletroquímicas , Eletrodos
3.
Rev. colomb. anestesiol ; 49(4): e200, Oct.-Dec. 2021. tab, graf
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1341236

RESUMO

Abstract Introduction Vasopressors are essential in the management of various types of shock. Objective To establish the trend of vasopressors use in the intensive care units (ICU) in a population of patients affiliated with the Colombian Health System, 2010-2017. Methods Observational trial using a population database of patients hospitalized in eleven ICUs in various cities in Colombia. The drugs dispensed to hospitalized patients over 18 years old, from January 2010 until December 2017 were considered. A review and analysis of the vasopressors dispensed per month was conducted, taking into account sociodemographic and pharmacological variables (vasopressor used and daily doses defined per 100/beds/day (DBD). Results 81,348 dispensations of vasopressors, equivalent to 26,414 treatments in 19,186 patients receiving care in 11 hospitals from 7 cities were reviewed. The mean age of patients was 66.3±18.1 years and 52.6 % were males. Of the total number of treatments recorded, 17,658 (66.8 %) were with just one vasopressor. Norepinephrine was the most frequently prescribed drug (75.9 % of the prescriptions dispensed; 60.5 DBD), followed by adrenaline (26.6 %; 41.6 DBD), dopamine (19.4%), dobutamine (16.0 %), vasopressin (8.5 %) and phenylephrine (0.9 %). The use of norepinephrine increased from 2010 to 2017 (+6.19 DBD), whilst the use of other drugs decreased, particularly the use of adrenaline (-60.6 DBD) and dopamine (-10.8 DBD). Conclusions Norepinephrine is the most widely used vasopressor showing a growing trend in terms of its use during the study period, which is supported by evidence in favor of its effectiveness and safety in patients with shock.


Resumen Introducción Los fármacos vasopresores son fundamentales en el manejo de los diferentes tipos de choque. Objetivo Determinar la tendencia de utilización de fármacos vasopresores en unidades de cuidados intensivos (UCI) en una población de pacientes afiliados al Sistema de Salud de Colombia, 2010-2017. Métodos Estudio observacional, a partir de una base de datos poblacional con pacientes hospitalizados en once UCI de diferentes ciudades de Colombia. Se obtuvieron las dispensaciones de pacientes mayores de 18 años hospitalizados desde enero de 2010 hasta diciembre de 2017. Se hizo revisión y análisis de la dispensación mensual de vasopresores. Se consideraron variables sociodemográficas y farmacológicas (medicamento vasopresor usado y dosis diarias definidas por 100 camas/día [DCD]). Resultados Se revisaron 81.348 dispensaciones de vasopresores, equivalentes a 26.414 terapias en 19.186 pacientes atendidos en 11 hospitales de 7 ciudades, cuya edad promedio fue 66,3±18,1 años y el 52,6 % eran hombres. Del total de terapias registradas, 17.658 (66,8 %) fueron con un solo vasopresor. La norepinefrina fue el más comúnmente prescrito (75,9 % de las dispensaciones; 60,5 DCD), seguido por adrenalina (26,6 %; 41,6 DCD), dopamina (19,4 %), dobutamina (16,0 %), vasopresina (8,5 %) y fenilefrina (0,9 %). El uso de norepinefrina se incrementó de 2010 a 2017 (+6,19 DCD), mientras que el de otros fármacos disminuyó, especialmente adrenalina (-60,6 DCD) y dopamina (-10,8 DCD). Conclusiones La norepinefrina es el fármaco vasopresor más utilizado y el que ha demostrado una tendencia de uso incremental durante el periodo de estudio, lo cual está respaldado por evidencia a favor de su efectividad y seguridad en pacientes con choque.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Choque , Vasoconstritores , Vasopressinas , Unidades de Terapia Intensiva , Fenilefrina , Preparações Farmacêuticas , Dopamina , Epinefrina , Norepinefrina , Dobutamina , Uso de Medicamentos , Dosagem , Prescrições
4.
Anal Chim Acta ; 1187: 339124, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34753568

RESUMO

Dopamine is an important neurotransmitter involved in many human biological processes as well as in different neurodegenerative diseases. Monitoring the concentration of dopamine in biological fluids, i.e., blood and urine is an effective way of accelerating the early diagnosis of these types of diseases. Electrochemical sensors are an ideal choice for real-time screening of dopamine as they can achieve fast, portable inexpensive and accurate measurements. In this work, we present electrochemical dopamine sensors based on reduced graphene oxide coupled with Au or Pt nanoparticles. Sensors were developed by co-electrodeposition onto a flexible substrate, and a systematic investigation concerning the electrodeposition parameters (concentration of precursors, deposition time and potential) was carried out to maximize the sensitivity of the dopamine detection. Square wave voltammetry was used as an electrochemical technique that ensured a high sensitive detection in the nM range. The sensors were challenged against synthetic urine in order to simulate a real sample detection scenario where dopamine concentrations are usually lower than 600 nM. Our sensors show a negligible interference from uric and ascorbic acids which did not affect sensor performance. A wide linear range (0.1-20 µm for gold nanoparticles, 0.1-10 µm for platinum nanoparticles) with high sensitivity (6.02 and 7.19 µA µM-1 cm-2 for gold and platinum, respectively) and a low limit of detection (75 and 62 nM for Au and Pt, respectively) were achieved. Real urine samples were also assayed, where the concentrations of dopamine detected aligned very closely to measurements undertaken using conventional laboratory techniques. Sensor fabrication employed a cost-effective production process with the possibility of also being integrated into flexible substrates, thus allowing for the possible development of wearable sensing devices.


Assuntos
Grafite , Nanopartículas Metálicas , Ácido Ascórbico , Dopamina , Técnicas Eletroquímicas , Eletrodos , Ouro , Humanos , Platina , Ácido Úrico
5.
Adv Exp Med Biol ; 1344: 57-69, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34773226

RESUMO

Rhythmic gene expression is found throughout the central nervous system. This harmonized regulation can be dependent on- and independent of- the master regulator of biological clocks, the suprachiasmatic nucleus (SCN). Substantial oscillatory activity in the brain's reward system is regulated by dopamine. While light serves as a primary time-giver (zeitgeber) of physiological clocks and synchronizes biological rhythms in 24-h cycles, nonphotic stimuli have a profound influence over circadian biology. Indeed, reward-related activities (e.g., feeding, exercise, sex, substance use, and social interactions), which lead to an elevated level of dopamine, alters rhythms in the SCN and the brain's reward system. In this chapter, we will discuss the influence of the dopaminergic reward pathways on circadian system and the implication of this interplay on human health.


Assuntos
Ritmo Circadiano , Núcleo Supraquiasmático , Relógios Biológicos , Dopamina , Humanos , Recompensa
6.
Am J Case Rep ; 22: e933995, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34776506

RESUMO

BACKGROUND Multiple system atrophy cerebellar type (MSA-C) is a subtype of MSA that presents with predominant ataxia along with lesser signs of parkinsonism and autonomic dysfunction. Previous studies have shown benefits from carbidopa/levodopa therapy for the MSA parkinsonian subtype but few studies have focused on the MSA-C subtype. We present a video case of MSA-C that demonstrated significant improvement with carbidopa/levodopa therapy. CASE REPORT A right-handed 61-year-old man with a past medical history of chronic microvascular ischemia, mild lower extremity neuropathy, and lumbar and cervical stenosis status after decompression presented with progressive worsening gait changes over several months with acute deterioration before admission. The initial neurological workup demonstrated bilateral cogwheel rigidity; difficulty with movement initiation. including standing up from a seated position; slow saccadic eye movements; masked facies (hypomimia); right ankle clonus; bilateral upper and left lower limb ataxia; and hyperreflexia. A follow-up workup was negative for metabolic, infectious, and paraneoplastic causes, but magnetic resonance imaging demonstrated cerebellar atrophy along with a "hot cross bun sign" suggestive of probable MSA-C according to consensus criteria, and the patient was started on carbidopa-levodopa. He subsequently demonstrated improvement in key motor domains, including his cogwheel rigidity and gait testing, and was discharged shortly thereafter. CONCLUSIONS Through this case report, we highlight a significant response to L-dopa therapy beyond what is normally expected according to diagnostic criteria for MSA. MSA treatment responsiveness can vary significantly across patients, which warrants additional studies into appropriate treatment choices for patients with Parkinson's disease and MSA.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Cerebelo , Dopamina , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/tratamento farmacológico
7.
Artigo em Inglês | MEDLINE | ID: mdl-34770047

RESUMO

Alcohol and other substance use disorders share comorbidity with other RDS disorders, i.e., a reduction in dopamine signaling within the reward pathway. RDS is a term that connects addictive, obsessive, compulsive, and impulsive behavioral disorders. An estimated 2 million individuals in the United States have opioid use disorder related to prescription opioids. It is estimated that the overall cost of the illegal and legally prescribed opioid crisis exceeds one trillion dollars. Opioid Replacement Therapy is the most common treatment for addictions and other RDS disorders. Even after repeated relapses, patients are repeatedly prescribed the same opioid replacement treatments. A recent JAMA report indicates that non-opioid treatments fare better than chronic opioid treatments. Research demonstrates that over 50 percent of all suicides are related to alcohol or other drug use. In addition to effective fellowship programs and spirituality acceptance, nutrigenomic therapies (e.g., KB220Z) optimize gene expression, rebalance neurotransmitters, and restore neurotransmitter functional connectivity. KB220Z was shown to increase functional connectivity across specific brain regions involved in dopaminergic function. KB220/Z significantly reduces RDS behavioral disorders and relapse in human DUI offenders. Taking a Genetic Addiction Risk Severity (GARS) test combined with a the KB220Z semi-customized nutrigenomic supplement effectively restores dopamine homeostasis (WC 199).


Assuntos
Comportamento Aditivo , Transtornos Relacionados ao Uso de Substâncias , Suicídio , Dopamina , Humanos , Recompensa
8.
Alzheimers Res Ther ; 13(1): 187, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772450

RESUMO

BACKGROUND: Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer's disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course. METHODS: We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D), and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial correlation analysis. Results were deemed significant at p < 0.05, after Bonferroni correction for multiple comparisons. RESULTS: We found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced [123I]FP-CIT binding, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient ≤ 0.25) and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). CONCLUSION: Local- and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.


Assuntos
Doença de Alzheimer , Dopamina , Doença de Alzheimer/diagnóstico por imagem , Humanos , Neuroimagem , Estudos Retrospectivos , Tomografia Computadorizada de Emissão de Fóton Único
9.
Anal Chim Acta ; 1186: 339086, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34756249

RESUMO

Carbon fiber microelectrode arrays based on diazonium salt and single-walled carbon nanotubes composites (DS-SWCNT/CFMEA) have been fabricated, and it developed for the simultaneous monitoring of dopamine (DA) and serotonin (5-HT) with differential pulse voltammary (DPV). The diazonium salt can improve the water-solubility of single-walled carbon nanotubes and show good selectivity to DA, thus DS-SWCNT/CFMEA exhibits enhanced electrocatalytic activity for the oxidation of DA and 5-HT, and well antifouling ability to the other biomolecules. Moreover, DS-SWCNT/CFMEA shows the wider liner range, and the good performance of precision, reproducibility and biocompatibility. The excellent characteristics of the prepared microsensor array make it to be used to monitor the release of DA and 5-HT in the mouse brain striatum of different group over time. Meanwhile, the results of in vivo on line assay further confirmed the pharmacological effects of Uncaria alkaloid extract solution on DA and 5-HT. This research may provide a new method for monitoring the release of neurobiomolecules, and the microsensor array are expected to be a tool for the study of pharmacological and physiological processes on line in vivo.


Assuntos
Dopamina , Nanotubos de Carbono , Animais , Fibra de Carbono , Camundongos , Microeletrodos , Reprodutibilidade dos Testes , Serotonina
10.
Biomed Khim ; 67(5): 402-410, 2021 Sep.
Artigo em Russo | MEDLINE | ID: mdl-34730553

RESUMO

The closed enriched cross maze test was employed as a new experimental model of the attention deficit disorder (ADD) for evaluation of the behavioral and neurochemical effects of the nootropic drug pantogam (100 mg/kg, intraperitoneally) and atomoxetine hydrochloride (3 mg/kg, intraperitoneally) administered subchronically to CD-1 outbred mice. Two subpopulations of rodents differed spontaneously in attention to enriched compartments (ED-Low and ED-High), were estimated on the basis of time spent by the mice in the empty or enriched compartments. The ED-Low and ED-High mice insignificantly differed in parameters associated with anxiety, exploratory efficacy and motor activity. Subchronic administration of both drugs in selected doses produced corrective effect on animal behavior seen as a selective increase in the ED-ratio values in the ED-Low subpopulation. Differences in the distribution of dopamine D2 and GABAB receptors (Bmax) between placebo-treated ED-Low and ED-High mice were found in the prefrontal cortex using the radioligand binding method. The neuroreceptor effects of atomoxetine were seen in prefrontal cortex of ED-Low mice as decrease in the Bmax values of D2 receptors by 14%. Pantogam in the prefrontal cortex of ED-Low subpopulation showed a decrease in the Bmax values of D2 receptors by 22% and an increase for GABAB receptors by 44%. Therefore, subchronic administration of pantogam had a positive corrective effect on the behavior parameters and the density of the studied receptor subtypes in animals with severe attention deficit.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Animais , Cloridrato de Atomoxetina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Dopamina , Camundongos , Ácido Pantotênico/análogos & derivados , Ácido gama-Aminobutírico/análogos & derivados
11.
Transl Vis Sci Technol ; 10(12): 5, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34609478

RESUMO

Purpose: Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via peribulbar, intravitreal, or intraperitoneal injections is not clinically viable, we sought to evaluate ocular penetration and safety of the topically applied dopaminergic prodrug etilevodopa. Methods: The ocular penetration of dopamine and dopaminergic prodrugs (levodopa and etilevodopa) were quantified using an enzyme-linked immunosorbent assay in enucleated porcine eyes after a single topical administration. The pharmacokinetic profile of the etilevodopa was then assessed in rats. A four-week once-daily application of etilevodopa as a topical eye drop was conducted to establish its safety profile. Results: At 24 hours, the studied prodrugs showed increased dopaminergic derivatives in the vitreous of porcine eyes. Dopamine 0.5% (P = 0.0123) and etilevodopa 10% (p = 0.370) achieved significant vitreous concentrations. Etilevodopa 10% was able to enter the posterior segment of the eye after topical administration in rats with an intravitreal half-life of eight hours after single topical administration. Monthly application of topical etilevodopa showed no alterations in retinal ocular coherence tomography, electroretinography, caspase staining, or TUNEL staining. Conclusions: At similar concentrations, no difference in ocular penetration of levodopa and etilevodopa was observed. However, etilevodopa was highly soluble and able to be applied at higher topical concentrations. Dopamine exhibited both high solubility and enhanced penetration into the vitreous as compared to other dopaminergic prodrugs. Translational Relevance: These findings indicate the potential of topical etilevodopa and dopamine for further study as a therapeutic treatment for myopia.


Assuntos
Levodopa , Pró-Fármacos , Animais , Dopamina , Levodopa/análogos & derivados , Levodopa/toxicidade , Penetrância , Pró-Fármacos/toxicidade , Ratos , Retina , Suínos
12.
J Vis Exp ; (176)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34661577

RESUMO

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.


Assuntos
Discinesia Induzida por Medicamentos , Doença de Parkinson , Animais , Dopamina , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Ratos
13.
Chin J Physiol ; 64(5): 218-224, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34708713

RESUMO

Positive feeling or rewarding experience is crucial for individuals to operative their cognitive activities via an outcome evaluation of incentive reinforcement. For a long time, rewarding process or outcome evaluation is assumed greatly influenced by neuronal construct that holds individuals' impulsiveness, a capacity to inhibit unwanted behaviors provoked in a given situation. In the present study, we proposed that the outcome evaluation or rewarding experience can influence the occurrence of impulsiveness too. We hypothesized that animals would be more likely to deliver impulsive action in the place where it was previously associated with reinforcing process, in which central dopamine may play an important role. By employing five-choice serial reaction time task (5-CSRTT), we examined whether one of the five holes where rats made a correct response to get the reward would gain a higher probability to deliver premature or perseverative activities than other holes in the next trial of 5-CSRTT under baseline or longer waiting period condition. The effects of D1 receptor antagonist SCH23390 were also evaluated in the above paradigm. We demonstrated that (i) the influence on motoric impulsive response from previous rewarded experience can be described in a behavioral paradigm such as the 5-CSRTT, (ii) both prematures and perseverations at the hole associated with previous rewarding were about one-fifth of probability, however were statistically not correlated unless the interventions of inter-trial interval = 7 plus SCH23390, and (iii) the hole associated with the positive reinforcement of the 5-CSRTT appears more likely for rats to carry out an intuitive impetus under SCH23390 in a longer waiting condition. Our results may shed some insight toward the role of rewarding process in impulsive behavior.


Assuntos
Comportamento Impulsivo , Recompensa , Animais , Dopamina , Ratos , Tempo de Reação
14.
Mater Sci Eng C Mater Biol Appl ; 130: 112468, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34702543

RESUMO

The high near infrared (NIR) absorption displayed by reduced graphene oxide (rGO) nanostructures renders them a great potential for application in cancer photothermal therapy. However, the production of this material often relies on the use of hydrazine as a reductant, leading to poor biocompatibility and environmental-related issues. In addition, to improve rGO colloidal stability, this material has been functionalized with poly(ethylene glycol). However, recent studies have reported the immunogenicity of poly(ethylene glycol)-based coatings. In this work, the production of rGO, by using dopamine as the reducing agent, was optimized considering the size distribution and NIR absorption of the attained materials. The obtained results unveiled that the rGO produced by using a 1:5 graphene oxide:dopamine weight ratio and a reaction time of 4 h (termed as DOPA-rGO) displayed the highest NIR absorption while retaining its nanometric size distribution. Subsequently, the DOPA-rGO was functionalized with thiol-terminated poly(2-ethyl-2-oxazoline) (P-DOPA-rGO), revealing suitable physicochemical features, colloidal stability and cytocompatibility. When irradiated with NIR light, the P-DOPA-rGO could produce a temperature increase (ΔT) of 36 °C (75 µg/mL; 808 nm, 1.7 W/cm2, 5 min). The photothermal therapy mediated by P-DOPA-rGO was capable of ablating breast cancer cells monolayers (viability < 3%) and could reduce heterotypic breast cancer spheroids' viability to just 30%. Overall, P-DOPA-rGO holds a great potential for application in breast cancer photothermal therapy.


Assuntos
Grafite , Neoplasias , Dopamina , Neoplasias/tratamento farmacológico , Fototerapia , Terapia Fototérmica , Poliaminas
16.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638579

RESUMO

Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin-proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Cevanas/farmacologia , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , alfa-Sinucleína/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Degeneração Neural/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Substância Negra/metabolismo , Ubiquitina/metabolismo
17.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639047

RESUMO

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.


Assuntos
Dopamina/metabolismo , Epinefrina/metabolismo , Norepinefrina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Catecolaminas/química , Catecolaminas/metabolismo , Dopamina/química , Epinefrina/química , Humanos , Drogas Ilícitas/metabolismo , Inativação Metabólica , Redes e Vias Metabólicas , Modelos Biológicos , Norepinefrina/química , Transtornos Relacionados ao Uso de Substâncias/etiologia
18.
Anal Chim Acta ; 1182: 338949, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34602205

RESUMO

Novel porous boron-doped diamond (BDDporous)-based materials have attracted lots of research interest due to their enhanced detection ability and biocompatibility, favouring them for use in neuroscience. This study reports on morphological, spectral, and electrochemical characterisation of three BDDporous electrodes of different thickness given by a number of deposited layers (2, 3 and 5). These were prepared using microwave plasma-enhanced chemical vapour deposition on SiO2 nanofiber-based scaffolds. Further, the effect of number of layers and poly-l-lysine coating, commonly employed in neuron cultivation experiments, on sensing properties of the neurotransmitter dopamine in a pH 7.4 phosphate buffer media was investigated. The boron doping level of ∼2 × 1021 atoms cm-3 and increased content of non-diamond (sp2) carbon in electrodes with more layers was evaluated by Raman spectroscopy. Cyclic voltammetric experiments revealed reduced working potential windows (from 2.4 V to 2.2 V), higher double-layer capacitance values (from 405 µF cm-2 to 1060 µF cm-2), enhanced rates of electron transfer kinetics and larger effective surface areas (from 5.04 mm2 to 7.72 mm2), when the number of porous layers increases. For dopamine, a significant boost in analytical performance was recognized with increasing number of layers using square-wave voltammetry: the highest sensitivity of 574.1 µA µmol-1 L was achieved on a BDDporous electrode with five layers and dropped to 35.9 µA µmol-1 L when the number of layers decreased to two. Consequently, the lowest detection limit of 0.20 µmol L-1 was obtained on a BDDporous electrode with five layers. Moreover, on porous electrodes, enhanced selectivity for dopamine detection in the presence of ascorbic acid and uric acid was demonstrated. The application of poly-l-lysine coating on porous electrode surface resulted in a decrease in dopamine peak currents by 17% and 60% for modification times of 1 h and 15 h, respectively. Hence, both examined parameters, the number of deposited porous layers and the presence of poly-l-lysine coating, were proved to considerably affect the characteristics and performance of BDDporous electrodes.


Assuntos
Boro , Dopamina , Eletrodos , Porosidade , Dióxido de Silício
19.
J Biotechnol ; 342: 28-35, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34648893

RESUMO

The dopamine transporter (DAT) is targeted in substance use disorders (SUDs), and "non-classical"" DAT inhibitors with low abuse potential are therapeutic candidates. Lobinaline, from Lobelia cardinalis, is an atypical DAT inhibitor lead. Chemical synthesis of lobinaline is challenging; thus, "target-directed evolution" was used for lead optimization. A target protein is expressed in plant cells, and a mutant cell population is selected under conditions where target protein functional inhibition confers a survival advantage. Surviving mutants are "mined" for the targeted activity. Applied to a mutant L. cardinalis cell population expressing the human DAT, we identified 20 mutants overproducing DAT inhibitors. Microanalysis prioritized novel lobinaline derivatives, and we first investigated the more water-soluble lobinaline N-oxide. It inhibited rat synaptosomal [3H]DA uptake with an IC50 similar to lobinaline. Against repeated DA microinjections into the rat striatum, lobinaline produced transient DA clearance reductions. In contrast, lobinaline N-oxide prolongingly increased DA peak amplitudes, particularly in the ventral striatum. Lobinaline N-oxide also produced complex changes in post-peak DA clearance inconsistent with simple DAT inhibition. This unusual DAT interaction may prove therapeutically useful for treating SUDs. This study demonstrates the value of target-directed evolution of plant cells for optimizing lead compounds difficult to synthesize chemically.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Lobelia , Animais , Corpo Estriado , Dopamina , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Lobelia/genética , Ratos , Sinaptossomos
20.
ACS Chem Neurosci ; 12(22): 4336-4349, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34704733

RESUMO

Metabolomic reprogramming plays a crucial role in the activation of several regulatory mechanisms including neuronal responses of the host. In the present study, alterations at physiological and biochemical levels were initially assessed to monitor the impact of the candidate pathogen Cronobacter sakazakii on the nematode host Caenorhabditis elegans. The abnormal behavioral responses were observed in infected worms in terms of hyperosmolarity and high viscous chemicals. The microscopic observations indicated reduction in egg laying and internal hatching of larvae in the host. An increased level of total reactive oxygen species and reduction in antioxidant agents such as glutathione and catalase were observed. These observations suggested the severe effect of C. sakazakii infection on C. elegans. To understand the small molecules which likely mediated neurotransmission, the whole metabolome of C. elegans during the infection of C. sakazakii was analyzed using liquid chromatography-mass spectrometry. A decrease in the quantity of methyl dopamine and palmitoyl dopamine and an increase in hydroxyl dopamine suggested that reduction in dopamine reuptake and dopamine neuronal stress. The disordered dopaminergic transmission during infection was confirmed using transgenic C. elegans by microscopic observation of Dat-1 protein expression. In addition, reduction in arachidonic acid and short-chain fatty acids revealed their effect on lipid droplet formation as well as neuronal damage. An increase in the quantity of stearoyl CoA underpinned the higher accumulation of lipid droplets in the host. On the other hand, an increased level of metabolites such as palmitoyl serotonin, citalopram N-oxide, and N-acyl palmitoyl serotonin revealed serotonin-mediated potential response for neuroprotection, cytotoxicity, and cellular damage. Based on the metabolomic data, the genes correspond to small molecules involved in biosynthesis and transportation of candidate neurotransmitters were validated through relative gene expression.


Assuntos
Caenorhabditis elegans , Cronobacter sakazakii , Animais , Animais Geneticamente Modificados , Dopamina , Serotonina
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