scholarly journals Bioconversion of Corticosterone into Corticosterone-Glucoside by Glucosyltransferase

Molecules ◽  
2018 ◽  
Vol 23 (7) ◽  
pp. 1783 ◽  
Author(s):  
Tokutaro Yamaguchi ◽  
Joo-Ho Lee ◽  
A-Rang Lim ◽  
Joon-Soo Sim ◽  
Eun-Ji Yu ◽  
...  
Keyword(s):  
High Resolution Mass Spectrometry ◽  
Hydroxyl Group ◽  
Oxygen Species ◽  
Neuroprotective Agents ◽  
Neuroprotective Effects ◽  
The Difference ◽  
First Time ◽  
Resolution Mass

Glucosylation of the 21-hydroxyl group of glucocorticoid changes its solubility into hydrophilicity from hydrophobicity and, as with glucocorticoid glucuronides as a moving object in vivo, it is conceivable that it exhibits the same behavior. Therefore, glucosylation to the 21-hydroxyl group while maintaining the 11β-hydroxyl group is particularly important, and glucosylation of corticosterone was confirmed by high-resolution mass spectrometry and 1D (1H and 13C) and 2D (COSY, ROESY, HSQC-DEPT and HMBC) NMR. Moreover, the difference in bioactivity between corticosterone and corticosterone 21-glucoside was investigated in vitro. Corticosterone 21-glucoside showed greater neuroprotective effects against H2O2-induced cell death and reactive oxygen species (ROS) compared with corticosterone. These results for the first time demonstrate that bioconversion of corticosterone through the region-selective glucosylation of a novel compound can present structural potential for developing new neuroprotective agents.

scholarly journals AZP2006, a new promising treatment for Alzheimer’s and related diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
N. Callizot ◽  
C. Estrella ◽  
S. Burlet ◽  
A. Henriques ◽  
C. Brantis ◽  
...  
Keyword(s):  
Therapeutic Application ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Potential Therapeutic Application ◽  
Promising Treatment ◽  
Central Synapses ◽  
First Time ◽  
Pgrn Level

AbstractProgranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

In vitro and in vivo metabolism of 3-quinuclidinyl benzilate by high-resolution mass spectrometry

2020 ◽  
Vol 190 ◽  
pp. 113519
Author(s):  
Martin Uher ◽  
Martin Mžik ◽  
Jana Žďárová Karasová ◽  
David Herman ◽  
Lenka Čechová ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
High Resolution Mass Spectrometry ◽  
In Vivo Metabolism ◽  
High Resolution Mass ◽  
Resolution Mass ◽  
Quinuclidinyl Benzilate

scholarly journals The Difference in Cytotoxic Activity between Two Optical Isomers of Gelsemine from Gelsemium elegans Benth. on PC12 Cells

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 2004
Author(s):  
Li Lin ◽  
Yan-Chun Liu ◽  
Zhao-Ying Liu
Keyword(s):  
Cytotoxic Activity ◽  
Pc12 Cells ◽  
High Resolution Mass Spectrometry ◽  
Optical Isomers ◽  
Cytotoxic Potential ◽  
Whole Plant ◽  
Ic50 Value ◽  
The Difference ◽  
Resolution Mass

Two optical isomers, +/− gelsemine (1, 2), together with one known compound were isolated from the whole plant of G. elegans. The structures of the separated constituents were elucidated on 1D and 2D (1H-1H COSY, HMBC, HSQC) NMR spectroscopy and high-resolution mass spectrometry (HRMS). The isolated alkaloids were tested in vitro for cytotoxic potential against PC12 cells by the MTT assay. As a result, (+) gelsemine (compound 1) exhibited cytotoxic activity against PC12 cells with an IC50 value of 31.59 μM, while (−) gelsemine (compound 2) was not cytotoxic.

scholarly journals PGI synthase overexpression protects against bleomycin-induced mortality and is associated with increased Nqo 1 expression

2011 ◽  
Vol 301 (4) ◽  
pp. L615-L622 ◽  
Author(s):  
Weisong Zhou ◽  
Dustin R. Dowell ◽  
Mark W. Geraci ◽  
Timothy S. Blackwell ◽  
Robert D. Collins ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Death Rate ◽  
Treatment Strategies ◽  
Oxygen Species ◽  
In Vitro Experiments ◽  
Wild Type ◽  
Potential Therapeutic Target ◽  
First Time

The mortality rate for acute lung injury (ALI) is reported to be between 35–40%, and there are very few treatment strategies that improve the death rate from this condition. Previous studies have suggested that signaling through the prostaglandin (PG) I2 receptor may protect against bleomycin-induced ALI in mice. We found that mice that overexpress PGI synthase (PGIS) in the airway epithelium were significantly protected against bleomycin-induced mortality and had reduced parenchymal consolidation, apoptosis of lung tissue, and generation of F2-isoprostanes compared with littermate wild-type controls. In addition, we show for the first time in both in vivo and in vitro experiments that PGI2 induced the expression of NADP (H): quinoneoxidoreductase 1 (Nqo 1), an enzyme that prevents the generation of reactive oxygen species. PGI2 induction of Nqo 1 provides a possible novel mechanism by which this prostanoid protects against bleomycin-induced mortality and identifies a potential therapeutic target for human ALI.

scholarly journals Reactive Oxygen Species Registration in Planarian Regeneration

2015 ◽  
Vol 7 (6) ◽  
pp. 13 ◽  
Author(s):  
Kh. P. Tiras ◽  
S. V. Gudkov ◽  
V. I. Emelyanenko ◽  
K. B. Aslanidi
Keyword(s):  
Reactive Oxygen Species ◽  
Physiological State ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Planarian Regeneration ◽  
The Difference ◽  
Dying Cells ◽  
First Time ◽  
Kinetics Of

<p class="1Body">Reactive oxygen species (ROS) are directly involved in cell proliferation, differentiation and apoptosis in a variety of organisms. We studied kinetics of own luminescence induced by changes of ROS in early stages of planarian regeneration. Kinetics of chemiluminescence were measured in intact planarians and the same individuals after decapitation within 15 hours. We analyzed the traumatic fluorescent signal obtained as the difference between kinetics of intact and decapitated planarians. It was found that regeneration is accompanied by changes in the content of ROS correlated with the energy-intensive process in regenerating planarians. Oxidative stress was caused by damage to cell membranes in the dissection of the planarian and it was accompanied by a drop in the intensity of luminescence with a time constant of about 3.6 hours. Phagocytosis of dying cells by neoblasts was accompanied by an increase of the luminescence intensity after 2 - 3 hours after decapitation. Neoblast mitosis was described by two maximums of luminescence over 5.1 hours and 8.3 hours after decapitation. For the first time we demonstrated the opportunity of registering the physiological state of pluripotent stem cells at the level of the organism <em>in vivo</em>.</p>

scholarly journals Monitoring metabolism of synthetic cannabinoid 4F-MDMB-BINACA via high-resolution mass spectrometry assessed in cultured hepatoma cell line, fungus, liver microsomes and confirmed using urine samples

2020 ◽  
Author(s):  
Huey Sze Leong ◽  
Shimpei Watanabe ◽  
Unnikrishnan Kuzhiumparambil ◽  
Ching Yee Fong ◽  
Hooi Yan Moy ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Ester Hydrolysis ◽  
Butanoic Acid ◽  
C Elegans ◽  
Resolution Mass

Abstract Purpose A tert-leucinate derivative synthetic cannabinoid, methyl (2S)-2-([1-(4-fluorobutyl)-1H-indazole-3-carbonyl]amino)-3,3-dimethylbutanoate (4F-MDMB-BINACA, 4F-MDMB-BUTINACA or 4F-ADB) is known to adversely impact health. This study aimed to evaluate the suitability of three different modes of monitoring metabolism: HepG2 liver cells, fungus Cunninghamella elegans (C. elegans) and pooled human liver microsomes (HLM) for comparison with human in-vivo metabolism in identifying suitable urinary marker(s) for 4F-MDMB-BINACA intake. Methods Tentative structure elucidation of in-vitro metabolites was performed on HepG2, C. elegans and HLM using liquid chromatography–tandem mass spectrometry and high-resolution mass spectrometry analysis. In-vivo metabolites obtained from twenty authentic human urine samples were analysed using liquid chromatography–Orbitrap mass spectrometry. Results Incubation with HepG2, C. elegans and HLM yielded nine, twenty-three and seventeen metabolites of 4F-MDMB-BINACA, respectively, formed via ester hydrolysis, hydroxylation, carboxylation, dehydrogenation, oxidative defluorination, carbonylation or reaction combinations. Phase II metabolites of glucosidation and sulfation were also exclusively identified using C. elegans model. Eight in-vivo metabolites tentatively identified were mainly products of ester hydrolysis with or without additional dehydrogenation, N-dealkylation, monohydroxylation and oxidative defluorination with further oxidation to butanoic acid. Metabolites with intact terminal methyl ester moiety, i.e., oxidative defluorination with further oxidation to butanoic acid, were also tentatively identified. Conclusions The in-vitro models presented proved useful in the exhaustive metabolism studies. Despite limitations, HepG2 identified the major 4F-MDMB-BINACA ester hydrolysis metabolite, and C. elegans demonstrated the capacity to produce a wide variety of metabolites. Both C. elegans and HLM produced all the in-vivo metabolites. Ester hydrolysis and ester hydrolysis plus dehydrogenation 4F-MDMB-BINACA metabolites were recommended as urinary markers for 4F-MDMB-BINACA intake.

scholarly journals Untargeted Metabolic Profiling of 4-Fluoro-Furanylfentanyl and Isobutyrylfentanyl in Mouse Hepatocytes and Urine by Means of LC-HRMS

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 97
Author(s):  
Camilla Montesano ◽  
Flaminia Vincenti ◽  
Federico Fanti ◽  
Matteo Marti ◽  
Sabrine Bilel ◽  
...  
Keyword(s):  
Metabolic Profiling ◽  
High Resolution Mass Spectrometry ◽  
Intraperitoneal Administration ◽  
New Psychoactive Substances ◽  
Metabolic Pattern ◽  
Mouse Hepatocytes ◽  
First Time

The diffusion of new psychoactive substances (NPS) is highly dynamic and the available substances change over time, resulting in forensic laboratories becoming highly engaged in NPS control. In order to manage NPS diffusion, efficient and innovative legal responses have been provided by several nations. Metabolic profiling is also part of the analytical fight against NPS, since it allows to identify the biomarkers of drug intake which are needed for the development of suitable analytical methods in biological samples. We have recently reported the characterization of two new analogs of fentanyl, i.e., 4-fluoro-furanylfentanyl (4F-FUF) and isobutyrylfentanyl (iBF), which were found for the first time in Italy in 2019; 4F-FUF was identified for the first time in Europe and was notified to the European Early Warning System. The goal of this study was the characterization of the main metabolites of both drugs by in vitro and in vivo experiments. To this end, incubation with mouse hepatocytes and intraperitoneal administration to mice were carried out. Samples were analyzed by means of liquid chromatography-high resolution mass spectrometry (LC–HRMS), followed by untargeted data evaluation using Compound Discoverer software with a specific workflow, designed for the identification of the whole metabolic pattern, including unexpected metabolites. Twenty metabolites were putatively annotated for 4F-FUF, with the dihydrodiol derivative appearing as the most abundant, whereas 22 metabolites were found for iBF, which was mainly excreted as nor-isobutyrylfentanyl. N-dealkylation of 4F-FUF dihydrodiol and oxidation to carbonyl metabolites for iBF were also major biotransformations. Despite some differences, in general there was a good agreement between in vitro and in vivo samples.

Sign in / Sign up

Export Citation Format

Share Document