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https://www.readbyqxmd.com/read/29222480/a-tyrosinase-mtyr-cnk-that-is-functionally-available-as-a-monophenol-monooxygenase
#1
Hyunsu Do, Eungsu Kang, Byeongseon Yang, Hyung Joon Cha, Yoo Seong Choi
Tyrosinase efficiently catalyzes the ortho-hydroxylation of monophenols and the oxidation of diphenols without any additional cofactors. Although it is of significant interest for the biosynthesis of catechol derivatives, the rapid catechol oxidase activity and inactivation of tyrosinase have hampered its practical utilization as a monophenol monooxygenase. Here, we prepared a functional tyrosinase that exhibited a distinguished monophenolase/diphenolase activity ratio (V max mono/ V max di = 3.83) and enhanced catalytic efficiency against L-tyrosine (k cat  = 3...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29220863/a-small-dose-of-apomorphine-counteracts-the-deleterious-effects-of-middle-cerebral-artery-occlusion-in-different-models
#2
F Mastroiacovo, A Gaglione, C L Busceti, L Ryskalin, G Bozza, F Nicoletti, F Orzi, F Fornai
The present manuscript investigates in two animal species by using two different experimental models of middle cerebral artery occlusion (permanent and transient), the neuroprotective effects of the dopamine receptor agonist apomorphine. These effects were evaluated by measuring the infarct volume and by counting muscle strength at different time points following the ischemic insult. Apomorphine at the dose of 3 mg/Kg when adminsitered at two hours following the occlusion of the middle cerebral artery was able to reduce significantly the infarct volume in the cortex of mice and the ischemic volume of the basal ganglia perfused by the perforant branches of the middle cerebral artery in the rat...
September 1, 2017: Archives Italiennes de Biologie
https://www.readbyqxmd.com/read/29219207/motor-complications-in-parkinson-s-disease-striatal-molecular-and-electrophysiological-mechanisms-of-dyskinesias
#3
REVIEW
Barbara Picconi, Ledia F Hernández, Jose A Obeso, Paolo Calabresi
Long-term levodopa (l-dopa) treatment in patients with Parkinson´s disease (PD) is associated with the development of motor complications (ie, motor fluctuations and dyskinesias). The principal etiopathogenic factors are the degree of nigro-striatal dopaminergic loss and the duration and dose of l-dopa treatment. In this review article we concentrate on analysis of the mechanisms underlying l-dopa-induced dyskinesias, a phenomenon that causes disability in a proportion of patients and that has not benefited from major therapeutic advances...
December 8, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29217686/synaptic-regulator-%C3%AE-synuclein-in-dopaminergic-fibers-is-essentially-required-for-the-maintenance-of-subependymal-neural-stem-cells
#4
Ana Perez-Villalba, Mª Salomé Sirerol-Piquer, Germán Belenguer, Raúl Soriano-Cantón, Ana Belén Muñoz-Manchado, Javier Villadiego, Diana Alarcón-Arís, Federico N Soria, Benjamin Dehay, Erwan Bezard, Miquel Vila, Analía Bortolozzi, Juan José Toledo-Aral, Francisco Pérez-Sánchez, Isabel Fariñas
Synaptic protein α-synuclein (α-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in Parkinson's disease. Here, we report that α-SYN present in dopaminergic nigral afferents is essential for the normal cycling and maintenance of neural stem cells (NSCs) in the brain subependymal zone of adult male and female mice. We also show that premature senescence of adult NSCs into non-neurogenic astrocytes in mice lacking α-SYN resembles the effects of dopaminergic fiber degeneration resulting from chronic exposure to MPTP or intranigral inoculation of aggregated toxic α-SYN...
December 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29214211/targeted-kinase-inhibition-relieves-slowness-and-tremor-in-a-drosophila-model-of-lrrk2-parkinson-s-disease
#5
Amy C Cording, Nicolas Shiaelis, Stavroula Petridi, C Adam Middleton, Laurence G Wilson, Christopher J H Elliott
In a number of Drosophila models of genetic Parkinson's disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, "arousal", central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER). This is attractive because the PER has a simple, well-identified reflex neural circuit, in which sucrose sensing neurons activate a pair of "command interneurons", and thence motoneurons whose activity contracts the proboscis muscle...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/29213160/isotope-effects-in-mechanistic-studies-of-l-tyrosine-halogen-derivatives-hydroxylation-catalyzed-by-tyrosinase
#6
Małgorzata Pająk, Marianna Kańska
The kinetic (KIE) and solvent (SIE) isotope effect methods were used to investigate the mechanism of enzymatic hydroxylation of halogenated derivatives of l-tyrosine to l-DOPA catalyzed by the enzyme tyrosinase (EC 1.14.18.1). The values of deuterium KIE and SIE were obtained using the non-competitive method with spectrophotometric measurements. The Lineweaver-Burk plots were used for determination of the inhibition mode of 3'-iodo-l-tyrosine. Based upon kinetic effects values the mechanism of action of enzyme tyrosinase was proposed...
2017: Journal of Radioanalytical and Nuclear Chemistry
https://www.readbyqxmd.com/read/29209553/antidyskinetic-treatment-with-mtep-affects-multiple-molecular-pathways-in-the-parkinsonian-striatum
#7
Jing-Ya Lin, Zhen-Guo Liu, Cheng-Long Xie, Lu Song, Ai-Juan Yan
Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/29206163/frozen-microemulsions-for-maple-immobilization-of-lipase
#8
Valeria Califano, Francesco Bloisi, Giuseppe Perretta, Antonio Aronne, Giovanni Ausanio, Aniello Costantini, Luciano Vicari
Candida rugosa lipase (CRL) was deposited by matrix assisted pulsed laser evaporation (MAPLE) in order to immobilize the enzyme with a preserved native conformation, which ensures its catalytic functionality. For this purpose, the composition of the MAPLE target was optimized by adding the oil phase pentane to a water solution of the amino acid 3-(3,4-dihydroxyphenyl)-2-methyl-l-alanine (m-DOPA), giving a target formed by a frozen water-lipase-pentane microemulsion. Fourier transform infrared (FTIR) spectroscopy and atomic force microscopy (AFM) were used to investigate the structure of MAPLE deposited lipase films...
December 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29201549/l-dopa-carbidopa-intestinal-gel-and-subthalamic-nucleus-stimulation-effects-on-cognition-and-behavior
#9
Francesc Valldeoriola, Pilar Santacruz, José Ríos, Yaroslau Compta, Jordi Rumià, José Esteban Muñoz, María José Martí, Eduardo Tolosa
Objective: In Parkinson's disease (PD), effects on behavior and cognition of levodopa/carbidopa intestinal gel (LCIG) and subthalamic stimulation (STN-DBS) and their practical consequences remain controversial. This study was designed to analyze the possible effects of these therapies on cognition and behavior after 1 year follow-up. Methods: This was an open-label, nonrandomized prospective study for pre- and postintervention analyses. Twenty-four patients were considered eligible to be candidates for complex therapies such as STN-DBS or LCIG; 23 patients treated with standard medication were included as controls...
November 2017: Brain and Behavior
https://www.readbyqxmd.com/read/29200295/fluorous-l-carbidopa-precursors-highly-enantioselective-synthesis-and-computational-prediction-of-bioactivity
#10
Albert Granados, Anna Del Olmo L Oacute Pez, Francesca Peccati, Thierry Billard, Mariona Sodupe, Adelina Vallribera
New fluorous enantiopure (S)-α-aminated β-keto esters were prepared through a highly enantioselective electrophilic α-amination step in the presence of europium triflate and (R,R)-phenyl-pybox. These compounds are precursors of fluorinated analogues of L-Carbidopa, which is known to inhibit DOPA decarboxylase (DDC), a key protein in Parkinson's disease. Fluorination provides better stability for biological applications, which could possibly lead to better DDC inhibitors than L-Carbidopa itself. Induced fit docking computational simulations performed on the newly structures interacting with DDC highlight that for an efficient binding at the DDC site at least one hydroxyl substituent must be present at the aromatic ring of the L-Carbidopa analogues, and point out that the presence of fluorine can further concur to fix the position of the ligand in the active site...
December 4, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29198021/alpha-synuclein-aggregation-ubiquitin-proteasome-system-impairment-and-l-dopa-response-in-zinc-induced-parkinsonism-resemblance-to-sporadic-parkinson-s-disease
#11
Vinod Kumar, Deepali Singh, Brajesh Kumar Singh, Shweta Singh, Namrata Mittra, Rakesh Roshan Jha, Devendra Kumar Patel, Chetna Singh
Alpha-synuclein (α-synuclein) aggregation and impairment of the Ubiquitin proteasome system (UPS) are implicated in Parkinson's disease (PD) pathogenesis. While zinc (Zn) induces dopaminergic neurodegeneration resulting in PD phenotype, its effect on protein aggregation and UPS has not yet been deciphered. The current study investigated the role of α-synuclein aggregation and UPS in Zn-induced Parkinsonism. Additionally, levodopa (L-Dopa) response was assessed in Zn-induced Parkinsonian model to establish its closeness with idiopathic PD...
December 2, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29197517/dpi-289-a-novel-mixed-delta-opioid-agonist-mu-opioid-antagonist-dama-has-l-dopa-sparing-potential-in-parkinson-s-disease
#12
Tom H Johnston, Eboo Versi, Patrick A Howson, Paula Ravenscroft, Susan H Fox, Michael P Hill, Bruce E Reidenberg, Ronald Corey, Jonathan M Brotchie
L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate...
November 29, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29186917/the-design-and-evaluation-of-an-l-dopa-lazabemide-prodrug-for-the-treatment-of-parkinson-s-disease
#13
Monique Hoon, Jacobus P Petzer, Francois Viljoen, Anél Petzer
l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson's disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa's physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa-lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption...
November 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29185545/movement-disorders-and-chronic-psychosis-five-new-things
#14
Davide Martino, Francesca Morgante
Purpose of review: To discuss selected peer-reviewed research articles published between 2014 and 2016 and highlight 5 clinically relevant messages related to hyperkinetic and hypokinetic movement disorders in patients with chronic psychosis. Recent findings: A recent population-based study complemented data from clinical trials in showing increased risk of developing extrapyramidal symptoms with antipsychotic use. A community service-based longitudinal study showed that dopamine transporter imaging could help identify subgroups of patients with parkinsonism associated with antipsychotics with a progressive course, potentially manageable with l-dopa...
April 2017: Neurology. Clinical Practice
https://www.readbyqxmd.com/read/29180132/the-effect-of-intravitreal-cholinergic-drugs-on-motor-control
#15
Gregory L Willis, Christopher B Freelance
The retina bears embryological, neurochemical and functional similarities to the circadian and dopamine systems of the brain. Recent studies have shown that the intravitreal injection of minute quantities of L-dopa and of the melatonin receptor antagonist ML-23 have anti-Parkinsonian potential. Furthermore, it has been suggested that light therapy may be potentially useful in treating some aspects of Parkinson's disease (PD) and it is hypothesized that this treatment works via the circadian system. Given that little is known about the mechanism by which such treatments work the present study was designed to examine the role of the acetyl cholinergic system of the retina in gross bodily movement...
November 24, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29180052/evaluation-of-thiazolidinone-derivatives-as-a-new-class-of-mushroom-tyrosinase-inhibitors
#16
Mehrnaz Rezaei, Hamed Taj Mohammadi, Atiyeh Mahdavi, Mostafa Shourian, Hossein Ghafoori
Tyrosinase (EC 1.14.18.1) is a key copper-containing metalloenzyme widely distributed in nature and plays determinant role in melanin biosynthesis. The enzyme manifests two unusual catalytic properties including oxidase and monooxygenase activities. Its inhibitors may be applied to efficiently treat of hyperpigmentation and widely used in pharmaceutical and cosmetic products, as well as food supplements and insecticides. The present study aims to evaluate the inhibitory effects of some novel azo-hydrazone tautomeric dyes (4a-e) including bioactive thiazolidinone moiety on the activity of the mushroom tyrosinase...
November 24, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29178365/levodopa-a-new-look-at-an-old-friend
#17
REVIEW
C Warren Olanow, Fabrizio Stocchi
Levodopa is the most effective antiparkinsonian agent, but chronic treatment is associated with the development of motor complications in the majority of patients with PD. Recent scientific and clinical advances are improving this situation. Long-term, double-blind studies demonstrate that dose is an important risk factor for the development of both motor fluctuations and dyskinesia, and suggest that it is best to use low doses of l-dopa when possible. Inhaled l-dopa and sublingual apomorphine are now being developed as rescue therapies that permit rapid and predictable reversal of off periods...
November 27, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29174366/dnajc12-deficiency-a-new-strategy-in-the-diagnosis-of-hyperphenylalaninemias
#18
REVIEW
Nenad Blau, Aurora Martinez, Georg F Hoffmann, Beat Thöny
Patients with hyperphenylalaninemia (HPA) are detected through newborn screening for phenylketonuria (PKU). HPA is known to be caused by deficiencies of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4). Current guidelines for the differential diagnosis of HPA would, however, miss a recently described DNAJC12 deficiency. The co-chaperone DNAJC12 is, together with the 70kDa heat shock protein (HSP70), responsible for the proper folding of PAH. All DNAJC12-deficient patients investigated to date responded to a challenge with BH4 by lowering their blood phenylalanine levels...
November 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29159466/efficacy-and-safety-of-perampanel-in-parkinson-s-disease-a-systematic-review-with-meta-analysis
#19
REVIEW
Simona Lattanzi, Elisabetta Grillo, Francesco Brigo, Mauro Silvestrini
BACKGROUND: L-Dopa represents the mainstay of therapy of Parkinson's disease (PD), but its effectiveness is reduced with continued treatment and disease progression. Accordingly, there remains a need to explore novel treatment strategies to manage the signs and symptoms of the later disease stages. The aim of the study was to evaluate the efficacy and safety of adjunctive perampanel (PER) in patients with PD through a meta-analysis of existing trials. METHODS: Randomized, placebo-controlled, double- or single-blind, add-on studies of PER in patients with PD were identified through a systematic literature search...
November 20, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/29157902/interaction-of-catecholamine-precursor-l-dopa-with-lysozyme-a-biophysical-insight
#20
Saima Nusrat, Aiman Masroor, Masihuz Zaman, Mohd Khursheed Siddiqi, Mohammad Rehan Ajmal, Nida Zaidi, Ali Saber Abdelhameed, Rizwan Hasan Khan
The current study comprises of an inclusive biophysical study, enlightening the binding of L-3, 4-dihydroxyphenylalanine (L-Dopa) with human lysozyme (HL) and hen egg white lysozyme (HEWL). Spectroscopic and molecular docking tools have been utilized to study the interaction of L-Dopa with both HL and HEWL. Spectrofluorimetric measurements exhibited that L-Dopa quenched the HL and HEWL intrinsic fluorescence. A binding constant (Kb) of ∼10(4)M(-1) for both HL and HEWL was obtained, asserting a significant binding...
November 17, 2017: International Journal of Biological Macromolecules
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