scholarly journals New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

2021 ◽  
Vol 14 (11) ◽  
pp. 1147
Author(s):  
Milena Mlakić ◽  
Tena Čadež ◽  
Danijela Barić ◽  
Ivana Puček ◽  
Ana Ratković ◽  
...  
Keyword(s):  
Docking Studies ◽  
New Class ◽  
Nerve Signal ◽  
Central Nervous Systems ◽  
Cns Activity ◽  
High Yields ◽  
Further Development ◽  
The Brain ◽  
Very High ◽  
Inhibited Enzyme

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight trans,anti- and trans,syn-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

2020 ◽  
Vol 20 (14) ◽  
pp. 1714-1721
Author(s):  
Hatem A. Abuelizz ◽  
El Hassane Anouar ◽  
Mohamed Marzouk ◽  
Mizaton H. Hasan ◽  
Siti R. Saleh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Kojic Acid ◽  
Docking Studies ◽  
Breast Adenocarcinoma ◽  
Amino Acid Residues ◽  
New Class ◽  
Structure Activity ◽  
Tyrosinase Inhibitors ◽  
Mcf 7

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

Physiology and pathophysiology of the RANKL/RANK system

2010 ◽  
Vol 391 (12) ◽  
Author(s):  
Reiko Hanada ◽  
Toshikatsu Hanada ◽  
Josef M. Penninger
Keyword(s):  
Body Temperature ◽  
Mammary Gland Development ◽  
Basal Body Temperature ◽  
Central Nervous Systems ◽  
Rank System ◽  
Functional Relevance ◽  
Rank Signaling ◽  
Gland Development ◽  
The Brain ◽  
Node Formation

Abstract The TNF family molecule RANKL and its receptor RANK are key regulators of bone remodeling, lymph node formation, and mammary gland development during pregnancy. RANKL and RANK are also expressed in the central nervous systems (CNS). However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Recently, our group reported that the RANKL/RANK signaling pathway has an essential role in the central regulation of body temperature via the prostaglandin axis. This review discusses novel aspects of the RANKL/RANK system as key regulators of fever and female basal body temperature in the CNS.

scholarly journals Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Helge Thisgaard ◽  
Joel Kumlin ◽  
Niels Langkjær ◽  
Jansen Chua ◽  
Brian Hook ◽  
...  
Keyword(s):  
Radiochemical Purity ◽  
High Yield ◽  
Clinical Use ◽  
Automated Production ◽  
Automated Method ◽  
Gallium 68 ◽  
High Yields ◽  
High Level ◽  
Mev Protons ◽  
Very High

Abstract Background With increasing clinical demand for gallium-68, commercial germanium-68/gallium-68 ([68Ge]Ge/[68Ga]Ga) generators are incapable of supplying sufficient amounts of the short-lived daughter isotope. In this study, we demonstrate a high-yield, automated method for producing multi-Curie levels of [68Ga]GaCl3 from solid zinc-68 targets and subsequent labelling to produce clinical-grade [68Ga]Ga-PSMA-11 and [68Ga]Ga-DOTATATE. Results Enriched zinc-68 targets were irradiated at up to 80 µA with 13 MeV protons for 120 min; repeatedly producing up to 194 GBq (5.24 Ci) of purified gallium-68 in the form of [68Ga]GaCl3 at the end of purification (EOP) from an expected > 370 GBq (> 10 Ci) at end of bombardment. A fully automated dissolution/separation process was completed in 35 min. Isolated product was analysed according to the Ph. Eur. monograph for accelerator produced [68Ga]GaCl3 and found to comply with all specifications. In every instance, the radiochemical purity exceeded 99.9% and importantly, the radionuclidic purity was sufficient to allow for a shelf-life of up to 7 h based on this metric alone. Fully automated production of up to 72.2 GBq [68Ga]Ga-PSMA-11 was performed, providing a product with high radiochemical purity (> 98.2%) and very high apparent molar activities of up to 722 MBq/nmol. Further, manual radiolabelling of up to 3.2 GBq DOTATATE was performed in high yields (> 95%) and with apparent molar activities (9–25 MBq/nmol) sufficient for clinical use. Conclusions We have developed a high-yielding, automated method for the production of very high amounts of [68Ga]GaCl3, sufficient to supply proximal radiopharmacies. The reported method led to record-high purified gallium-68 activities (194 GBq at end of purification) and subsequent labelling of PSMA-11 and DOTATATE. The process was highly automated from irradiation through to formulation of the product, and as such comprised a high level of radiation protection. The quality control results obtained for both [68Ga]GaCl3 for radiolabelling and [68Ga]Ga-PSMA-11 are promising for clinical use.

scholarly journals Production of radioisotopes within a plasma focus device

2005 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Ergisto Angeli ◽  
Agostino Tartari ◽  
Michele Frignani ◽  
Vincenzo Molinari ◽  
Domiziano Mostacci ◽  
...  
Keyword(s):  
Cross Section ◽  
Cross Sections ◽  
Plasma Focus ◽  
Reaction Rates ◽  
Experimental Production ◽  
Endogenous Production ◽  
The Us ◽  
Further Development ◽  
Radio Isotopes ◽  
Very High

In recent years, research conducted in the US and in Italy has demonstrated production of radioisotopes in plasma focus devices, and particularly, on what could be termed "endogenous" production, to wit, production within the plasma it self, as opposed to irradiation of tar gets. This technique relies on the formation of localized small plasma zones characterized by very high densities and fairly high temperatures. The conditions prevailing in these zones lead to high nuclear reaction rates, as pointed out in previous work by several authors. Further investigation of the cross sections involved has proven necessary to model the phenomena involved. In this paper, the present status of research in this field is re viewed, both with regards to cross section models and to experimental production of radio isotopes. Possible out comes and further development are discussed.

scholarly journals Kinetics of a nucleoside release from lactide-caprolactone and lactide-glycolide polymers in vitro.

2000 ◽  
Vol 47 (1) ◽  
pp. 59-64
Author(s):  
T Kryczka ◽  
P Grieb ◽  
M Bero ◽  
J Kasperczyk ◽  
P Dobrzynski
Keyword(s):  
Formation Rate ◽  
Local Treatment ◽  
Extracellular Fluid ◽  
Brain Extracellular Fluid ◽  
Artificial Cerebrospinal Fluid ◽  
Fluid Formation ◽  
Further Development ◽  
Kinetics Of ◽  
The Brain

We assessed the rate of release of a model nucleoside (adenosine, 5%, w/w) from nine different lactide-glycolide or lactide-caprolactone polymers. The polymer discs were eluted every second day with an artificial cerebrospinal fluid at the elution rate roughly approximating the brain extracellular fluid formation rate. Adenosine in eluate samples was assayed by HPLC. Three polymers exhibited a relatively constant release of adenosine for over four weeks, resulting in micromolar concentrations of nucleoside in the eluate. This points to the necessity of further development of polymers of this types as intracerebral nucleoside delivery systems for local treatment of brain tumors.

scholarly journals Construction of a novel quinoxaline as a new class of Nrf2 activator

2019 ◽  
Author(s):  
Murugesh Kandasamy ◽  
Kit-Kay Mak ◽  
Thangaraj Devadoss ◽  
Punniyakoti Veeraveedu Thanikachalam ◽  
Raghavendra Sakirolla ◽  
...  
Keyword(s):  
Docking Studies ◽  
Metabolic Stability ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
New Class ◽  
Ic50 Value ◽  
Kelch Domain ◽  
Anti Inflammatory ◽  
Nrf2 Activator

Abstract The transcription factor Nuclear factor erythroid-2-related factor 2 (NRF2) and its principal repressive regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the regulation of inflammation, as well as maintenance of homeostasis. Thus, NRF2 activation provides cytoprotection against numerous inflammatory disorders. N-nicotinoylquinoxaline-2-carbohdyrazide (NQC) was designed by combining the important pharmacophoric features of bioactive compounds reported in the literature. NQC was synthesised and characterised using spectroscopic techniques. The compound was tested for its anti-inflammatory effect using LPSEc induced inflammation in mouse macrophages (RAW 264.7 cells). The effect of NQC on inflammatory cytokines was measured using ELISA. The Nrf2 activity of the compound NQC was determined using ‘Keap1:Nrf2 Inhibitor Screening Assay Kit’. To obtain the insights on NQC’s activity on Nrf2, molecular docking studies were performed using Schrodinger suite. The metabolic stability of NQC was determined using mouse, rat and human microsomes. NQC was found to be non-toxic until the dose of 50 µM on RAW 264.7 cells. The NQC showed potent anti-inflammatory effect in an in vitro model of Lipopolysaccharide (LPS) stimulated murine macrophages (RAW 264.7 cells) with an IC50 value 26.13 ± 1.17 µM. The NQC dose-dependently down regulated the pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α) and inflammatory mediator, prostaglandin E2 (PGE2) with IC50 values 13.27 ± 2.37, 10.13 ± 0.58, 14.41 ± 1.83 and 15.23 ± 0.91 µM respectively. Molecular docking studies confirmed the favourable binding of NQC at Kelch domain of Keap-1. It disrupts the Nrf2 interaction with kelch domain of keap 1 and its IC50 value was 4.21 ± 0.89 µM. The metabolic stability studies of NQC in human, rat and mouse liver microsomes revealed that it is quite stable with half-life values; 59.78 ± 6.73, 52.93 ± 7.81, 28.43 ± 8.13 minutes; microsomal intrinsic clearance values; 22.1 ± 4.31, 26.0 ± 5.17 and 47.13 ± 6.34 µL/min/mg protein; respectively. So, rat has comparable metabolic profile with human, thus, rat could be used for predicting the pharmacokinetics and metabolism of NQC in human. NQC is a new class of NRF2 activator with potent in vitro anti-inflammatory activity and good metabolic stability.

scholarly journals Expedient Microwave-Assisted Synthesis of Bis(n)-lophine Analogues as Selective Butyrylcholinesterase Inhibitors: Cytotoxicity Evaluation and Molecular Modelling

2021 ◽  
Author(s):  
Viktor Câmara ◽  
Ana Julia Soares ◽  
Brunella Biscussi ◽  
Ana Paula Murray ◽  
Isabella Guedes ◽  
...  
Keyword(s):  
Ammonium Acetate ◽  
Docking Studies ◽  
Microwave Assisted Synthesis ◽  
One Pot ◽  
Cytotoxic Effects ◽  
One Step ◽  
The Brain ◽  
Micromolar Range ◽  
Potent Inhibitory Activity

In the brain of patients with chronic Alzheimer’s disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)‑lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC50) 32.25-0.03 μM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.

scholarly journals State of the art olfactometers. Different types

2021 ◽  
Keyword(s):  
Human Beings ◽  
Pathological Conditions ◽  
New Concepts ◽  
Different Types ◽  
Clinical Diagnoses ◽  
Human Use ◽  
The Brain ◽  
Very High ◽  
Human Olfaction

The complexity of human olfaction is very high and the importance of being able to measure it directly, objectively and qualitatively has led experts to search for mechanisms that can be applied. Human beings use this sense, which is one of the oldest, to recognize danger and distinguish between pleasant and unpleasant odors. Smells are mixtures of molecules that, at different concentrations in the inhaled air, stimulate the olfactory area and are recognized at the brain level. Therefore, there is a coding and decoding system. Human olfactometer techniques use equipment designed to be able to measure its intensity and quality of volatile substances. If we are able to measure this sense, we will be able to know its variations and be able to make clinical diagnoses in normal and pathological conditions and diagnose the losses that occur in certain infectious, degenerative diseases, traumatic processes and other variants. For many years, systems have been developed that can measure subjective olfaction in humans, as well as objective forms, but it is also true that there is no equipment available that is fast, simple handling and that can be applied in daily clinical services. Aim of the Study Present the recent achievements in olfactometer technology; Elaborate the scientific articles about olfactometry published mainly in the last 10 years; To gather the information published in the last years in relation to the usefulness, existence in the market and purposes of equipment that can measure the odors, what we will call the Smell-o-meter or olfactometer for human use. Material and Methods: In the first part of this research we will gather most of the information existing so far in international bibliography, as well as the achievements and utilities obtained to date. Following, we will analyze all the new concepts related to smell-o-meters devices that exist on the market and assess the possibility, based on what has been done so far, to seek new practical systems for application in the medical field.

scholarly journals Glucose status in cerebrospinal fluid (CSF) in different meningitic children in a hospital in Chittagong, Bangladesh

2013 ◽  
Vol 6 (1-2) ◽  
pp. 41-49
Author(s):  
Sharmistha Mitra ◽  
Robiul Hasan Bhuiyan ◽  
Md Arifuzzaman ◽  
Mohammad Sayedul Islam ◽  
Mahmood A Chowdhury ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Glucose Level ◽  
Viral Meningitis ◽  
Pyogenic Meningitis ◽  
Detailed Medical History ◽  
Different Types ◽  
The Brain ◽  
Very High ◽  
Potential Tool ◽  
Glucose Status

Meningitis is referred to as an inflammatory process of the leptomeninges and cerebrospinal fluid (CSF) within the sub-arachnoid space of the brain. We have investigated glucose status in CSF in different types of meningitis together with detailed medical history in children. In addition, we have also carried out the detailed cytological and microbiological examinations. A total of 40 subjects were investigated. We observed that the glucose level was significantly decreased (<20 mg/dl) in 65%, moderately decreased (20-40 mg/dl) in 20% and mildly decreased (40-50mg/dl) in 15% of the patients in our study. Patients with Pyogenic meningitis had tremendously reduced glucose level (9.0 mg/dl) in their CSF whereas in viral meningitis the CSF glucose level is highly variable (10 to 65 mg/dl). Furthermore, 5 (12.5%) patients showed high lymphocyte counts and 34 (85%) patients showed high neutrophil counts. Interestingly, in Pyogenic meningitis, the neutrophil count was very high compared to that in viral meningitis. The present study clearly demonstrates that biochemical parameters such as glucose level in CSF might be a potential tool for detecting meningitis and as well as differentiation of the different types of meningitis. DOI: http://dx.doi.org/10.3329/cujbs.v6i1-2.17080 The Chittagong Univ. J. B. Sci.,Vol. 6(1&2):41-49, 2011

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