Pashirova TN

General

Full name : Pashirova Tatiana N

First name : Tatiana

Mail : A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences , 8 Arbuzov Street, Kazan 420088

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Country : Russia

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References (9)

Title : Activation\/Inhibition of Cholinesterases by Excess Substrate: Interpretation of the Phenomenological b Factor in Steady-State Rate Equation - Mukhametgalieva_2023_Int.J.Mol.Sci_24_
Author(s) : Mukhametgalieva AR , Nemtarev AV , Sykaev VV , Pashirova TN , Masson P
Ref : Int J Mol Sci , 24 : , 2023
Abstract : Cholinesterases (ChEs) display a non-michaelian behavior with positively charged substrates. In the steady-state rate equation, the b factor describes this behavior: if b > 1 there is substrate activation, if b < 1 there is substrate inhibition. The mechanistic significance of the b factor was investigated to determine whether this behavior depends on acylation, deacylation or on both steps. Kinetics of human acetyl- (AChE) and butyryl-cholinesterase (BChE) were performed under steady-state conditions and using a time-course of complete substrate hydrolysis. For the hydrolysis of short acyl(thio)esters, where acylation and deacylation are partly rate-limiting, steady-state kinetic analysis could not decide which step determines b. However, the study of the hydrolysis of an arylacylamide, 3-(acetamido)-N,N,N-trimethylanilinium (ATMA), where acetylation is rate-limiting, showed that b depends on the acylation step. The magnitude of b and opposite b values between AChE and BChE for the hydrolysis of acetyl(thio)- versus benzoyl-(thio) esters, then indicated that the productive adjustment of substrates in the active center at high concentration depends on motions of both the and the acyl-binding loops. Benzoylcholine was shown to be a poor substrate of AChE, and steady-state kinetics showed a sudden inhibition at high concentration, likely due to the non-dissociation of hydrolysis products. The poor catalytic hydrolysis of this bulky ester by AChE illustrates the importance of the fine adjustment of substrate acyl moiety in the acyl-binding pocket. Molecular modeling and QM/MM simulations should definitively provide evidence for this statement.
ESTHER : Mukhametgalieva_2023_Int.J.Mol.Sci_24_
PubMedSearch : Mukhametgalieva_2023_Int.J.Mol.Sci_24_
PubMedID: 37445649

Title : Therapeutic nanoreactors for detoxification of xenobiotics: Concepts, challenges and biotechnological trends with special emphasis to organophosphate bioscavenging - Pashirova_2021_Chem.Biol.Interact__109577
Author(s) : Pashirova TN , Bogdanov A , Masson P
Ref : Chemico-Biological Interactions , :109577 , 2021
Abstract : The introduction of enzyme nanoreactors in medicine is relatively new. However, this technology has already been experimentally successful in cancer treatments, struggle against toxicity of reactive oxygen species in inflammatory processes, detoxification of drugs and xenobiotics, and correction of metabolic and genetic defects by using encapsulated enzymes, acting in single or cascade reactions. Biomolecules, e.g. enzymes, antibodies, reactive proteins capable of inactivating toxicants in the body are called bioscavengers. In this review, we focus on enzyme-containing nanoreactors for in vivo detoxification of organophosphorous compounds (OP) to be used for prophylaxis and post-exposure treatment of OP poisoning. A particular attention is devoted to bioscavenger-containing injectable nanoreactors operating in the bloodstream. The nanoreactor concept implements single or multiple enzymes and cofactors co-encapsulated in polymeric semi-permeable nanocontainers. Thus, the detoxification processes take place in a confined space containing highly concentrated bioscavengers. The article deals with historical and theoretical backgrounds about enzymatic detoxification of OPs in nanoreactors, nanoreactor polymeric enveloppes, realizations and advantages over other approaches using bioscavengers.
ESTHER : Pashirova_2021_Chem.Biol.Interact__109577
PubMedSearch : Pashirova_2021_Chem.Biol.Interact__109577
PubMedID: 34274336

Title : Surface modification of pralidoxime chloride-loaded solid lipid nanoparticles for enhanced brain reactivation of organophosphorus-inhibited AChE: pharmacokinetics in rat - Buzyurova_2020_Toxicology__152578
Author(s) : Buzyurova DN , Pashirova TN , Zueva IV , Burilova EA , Shaihutdinova ZM , Rizvanov IK , Babaev VM , Petrov KA , Souto EB
Ref : Toxicology , :152578 , 2020
Abstract : The nanotechnological approach is an innovative strategy of high potential to achieve reactivation of organophosphorus-inhibited acetylcholinesterase in central nervous system. It was previously shown that pralidoxime chloride-loaded solid lipid nanoparticles (2-PAM-SLNs) are able to protect the brain against pesticide (paraoxon) central toxicity. In the present work, we increased brain AChE reactivation efficacy by PEGylation of 2-PAM-SLNs using PEG-lipid N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt) (DSPE-PEG(2000)) as a surface-modifier of SLNs. To perform pharmacokinetic study, a simple, sensitive (LLOQ 1.0 ng/ml) high-performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization by multiple reaction monitoring mode (HPLC-APCI-MS) was developed. The method was compared to mass spectrometry with electrospray ionization. The method was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. Acetophenone oxime was used as the internal standard for the quantification of 2-PAM in rat plasma and brain tissue after intravenous administration. 2-PAM-DSPE-PEG(2000)-SLNs of mean size about 80 nm (PDI = 0.26), zeta-potential of -55 mV and of high in vitro stability, prolonged the elimination phase of 2-PAM from the bloodstream more than 3 times compared to free 2-PAM. An increase in reactivation of POX-inhibited human brain acetylcholinesterase up to 36.08 +/- 4.3% after intravenous administration of 2-PAM-DSPE-PEG(2000)-SLNs (dose of 2-PAM is 5 mg/kg) was achieved. The result is one of the first examples where this level of brain acetylcholinesterase reactivation was achieved. Thus, the implementation of different approaches for targeting and modifying nanoparticles' surface gives hope for improving the antidotal treatment of organophosphorus poisoning by marketed reactivators.
ESTHER : Buzyurova_2020_Toxicology__152578
PubMedSearch : Buzyurova_2020_Toxicology__152578
PubMedID: 32898602

Title : Bi-functional sterically hindered phenol lipid-based delivery systems as potential multi-target agents against Alzheimer's disease via an intranasal route - Burilova_2020_Nanoscale_12_13757
Author(s) : Burilova EA , Pashirova TN , Zueva IV , Gibadullina EM , Lushchekina SV , Sapunova AS , Kayumova RM , Rogov AM , Evtjugin VG , Sudakov IA , Vyshtakalyuk AB , Voloshina AD , Bukharov SV , Burilov AR , Petrov KA , Zakharova LY , Sinyashin OG
Ref : Nanoscale , 12 :13757 , 2020
Abstract : New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-alpha-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.
ESTHER : Burilova_2020_Nanoscale_12_13757
PubMedSearch : Burilova_2020_Nanoscale_12_13757
PubMedID: 32573587

Title : Delivery nanosystems based on sterically hindered phenol derivatives containing a quaternary ammonium moiety: Synthesis, cholinesterase inhibition and antioxidant activity - Pashirova_2019_Chem.Biol.Interact_13ChEPon_310_108753
Author(s) : Pashirova TN , Burilova EA , Tagasheva RG , Zueva IV , Gibadullina EM , Nizameev IR , Sudakov IA , Vishtakalyk AB , Voloshina AD , Kadirov MK , Petrov KA , Burilov AR , Bukharov SV , Zakharova LY
Ref : Chemico-Biological Interactions , :108753 , 2019
Abstract : Multitarget ligands (MTL) based on sterically hindered phenol and containing a quaternary ammonium moiety (SHP-n-Q) were synthesized. These compounds are inhibitors of cholinesterases with antioxidant properties. The inhibitory selectivity is 10-fold potent for BChE than for AChE. IC50 of SHP-n-Q for BChE is 20muM. SHP-n-Q and their nanosystems exhibit more pronounced antioxidant properties than the synthetic antioxidant (hindered phenol, butylated hydroxytoluene). These compounds display a low hemolytic activity against human red blood cells. The nanotechnological approach was used to increase the bioavailability of SHP-n-Q derivatives. For water soluble SHP-n-Q derivative, the self-assembled structures have a size close to 100nmat critical association concentration (0.01M). Mixed cationic liposomes based on l-alpha-phosphatidylcholine and SHP-n-Q of 100nm diameter were prepared. The stability, encapsulation efficacy and release from liposomes of a model drug, Rhodamine B, depend on the structure of SHP-n-Q. Cationic liposomes based on l-alpha-phosphatidylcholine and SHP-3-Q show a good stability in time (1year) and a sustained release (>65h). They are promising templates for the development of anti-Alzheimer MT-drug delivery systems.
ESTHER : Pashirova_2019_Chem.Biol.Interact_13ChEPon_310_108753
PubMedSearch : Pashirova_2019_Chem.Biol.Interact_13ChEPon_310_108753
PubMedID: 31319075

Title : New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease - Zueva_2019_Neuropharmacol_155_131
Author(s) : Zueva IV , Dias J , Lushchekina SV , Semenov VE , Mukhamedyarov MA , Pashirova TN , Babaev VM , Nachon F , Petrova N , Nurullin LF , Zakharova LY , Ilyin VI , Masson P , Petrov KA
Ref : Neuropharmacology , 155 :131 , 2019
Abstract : Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5mg/kg, i.p) and donepezil (0.75mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action.
ESTHER : Zueva_2019_Neuropharmacol_155_131
PubMedSearch : Zueva_2019_Neuropharmacol_155_131
PubMedID: 31132435
Gene_locus related to this paper: human-ACHE

Title : Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection - Pashirova_2018_J.Control.Release_290_102
Author(s) : Pashirova TN , Braiki A , Zueva IV , Petrov KA , Babaev VM , Burilova EA , Samarkina DA , Rizvanov IK , Souto EB , Jean L , Renard PY , Masson P , Zakharova LY , Sinyashin OG
Ref : J Control Release , 290 :102 , 2018
Abstract : A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160nm and negative zeta potential (-30 to -25mV) were stable for a period of 10months at 4 degrees C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8xLD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.
ESTHER : Pashirova_2018_J.Control.Release_290_102
PubMedSearch : Pashirova_2018_J.Control.Release_290_102
PubMedID: 30308259

Title : Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model - Pashirova_2018_Colloids.Surf.B.Biointerfaces_171_358
Author(s) : Pashirova TN , Zueva IV , Petrov KA , Lukashenko SS , Nizameev IR , Kulik NV , Voloshina AD , Almasy L , Kadirov MK , Masson P , Souto EB , Zakharova LY , Sinyashin OG
Ref : Colloids Surf B Biointerfaces , 171 :358 , 2018
Abstract : New mixed cationic liposomes based on L-alpha-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 mug mL(-1)) and Bacillus cereus (MIC=7.8 mug mL(-1)), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency ( approximately 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 +/- 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.
ESTHER : Pashirova_2018_Colloids.Surf.B.Biointerfaces_171_358
PubMedSearch : Pashirova_2018_Colloids.Surf.B.Biointerfaces_171_358
PubMedID: 30059851

Title : Nanoparticle-Delivered 2-PAM for Rat Brain Protection against Paraoxon Central Toxicity - Pashirova_2017_ACS.Appl.Mater.Interfaces_9_16922
Author(s) : Pashirova TN , Zueva IV , Petrov KA , Babaev VM , Lukashenko SS , Rizvanov IK , Souto EB , Nikolsky EE , Zakharova LY , Masson P , Sinyashin OG
Ref : ACS Appl Mater Interfaces , 9 :16922 , 2017
Abstract : Solid lipid nanoparticles (SLNs) are among the most promising nanocarriers to target the blood-brain barrier (BBB) for drug delivery to the central nervous system (CNS). Encapsulation of the acetylcholinesterase reactivator, pralidoxime chloride (2-PAM), in SLNs appears to be a suitable strategy for protection against poisoning by organophosphorus agents (OPs) and postexposure treatment. 2-PAM-loaded SLNs were developed for brain targeting and delivery via intravenous (iv) administration. 2-PAM-SLNs displayed a high 2-PAM encapsulation efficiency ( approximately 90%) and loading capacity (maximum 30.8 +/- 1%). Drug-loaded particles had a mean hydrodynamic diameter close to 100 nm and high negative zeta potential (-54 to -15 mV). These properties contribute to improve long-term stability of 2-PAM-SLNs when stored both at room temperature (22 degrees C) and at 4 degrees C, as well as to longer circulation time in the bloodstream compared to free 2-PAM. Paraoxon-poisoned rats (2 x LD50) were treated with 2-PAM-loaded SLNs at a dose of 2-PAM of 5 mg/kg. 2-PAM-SLNs reactivated 15% of brain AChE activity. Our results confirm the potential use of SLNs loaded with positively charged oximes as a medical countermeasure both for protection against OPs poisoning and for postexposure treatment.
ESTHER : Pashirova_2017_ACS.Appl.Mater.Interfaces_9_16922
PubMedSearch : Pashirova_2017_ACS.Appl.Mater.Interfaces_9_16922
PubMedID: 28504886