scholarly journals Chiral Resolution of a New Agent against Memory Impairment Connected to Neurodegenerative Diseases

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 15
Author(s):  
Cavalloro ◽  
Rui ◽  
Rossino ◽  
Rossi ◽  
Rapetti ◽  
...  
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Memory Impairment ◽  
Memory Loss ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Chiral Resolution ◽  
Low Levels

Nowadays, the incidence of neurodegenerative diseases is increasing, and these disorders will become one of the main challenges for medicine and public health in future years. Particularly, memory loss characterizes many neurodegenerative pathologies, and it is often related to low levels of cyclic adenosine monophosphate (cAMP). [...]

scholarly journals Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 935 ◽  
Author(s):  
Valeria Cavalloro ◽  
Katia Russo ◽  
Francesca Vasile ◽  
Luca Pignataro ◽  
Archimede Torretta ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Catalytic Domain ◽  
Memory Loss ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Chiral Resolution ◽  
Regulatory Domains ◽  
Downstream Effectors ◽  
Configuration Assignment ◽  
Ic50 Values

Alzheimer’s disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains.

scholarly journals High specificity antibodies and detection methods for quantifying phosphorylated tau from clinical samples

2021 ◽  
Author(s):  
Monika Arbaciauskaite ◽  
Yu Lei ◽  
Yong Ku Cho
Keyword(s):  
Neurodegenerative Diseases ◽  
Memory Loss ◽  
High Sensitivity ◽  
High Specificity ◽  
Detection Methods ◽  
Clinical Samples ◽  
Phosphorylated Tau ◽  
Comprehensive Survey ◽  
Low Levels ◽  
Development Engineering

Abstract The ability to measure total and phosphorylated tau levels in clinical samples is transforming the detection of Alzheimer’s disease (AD) and other neurodegenerative diseases. In particular, recent reports indicate that accurate detection of low levels of phosphorylated tau (p-tau) in plasma provides a reliable biomarker of AD long before sensing memory loss. Therefore, the diagnosis and monitoring of neurodegenerative diseases progression using blood samples is becoming a reality. These major advances were achieved by using antibodies specific to p-tau as well as sophisticated high sensitivity immunoassay platforms. This review focuses on these enabling advances in high-specificity antibody development, engineering, and novel signal detection methods. We will draw insights from structural studies on p-tau antibodies, engineering efforts to improve their binding properties, and efforts to validate their specificity. A comprehensive survey of high-sensitivity p-tau immunoassay platforms along with sensitivity limits will be provided. We conclude that although robust approaches for detecting certain p-tau species have been established, systematic efforts to validate antibodies for assay development is still needed for the recognition of biomarkers for AD and other neurodegenerative diseases.

scholarly journals Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimers Disease

2021 ◽  
Author(s):  
Yeon Ha Ju ◽  
Mridula Bhalla ◽  
Seung Jae Hyeon ◽  
Ju Eun Oh ◽  
Seonguk Yoo ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Gene Silencing ◽  
Memory Impairment ◽  
Therapeutic Strategy ◽  
Urea Cycle ◽  
Memory Loss ◽  
Alzheimers Disease ◽  
Urea Metabolism ◽  
Amyloid Aβ ◽  
By Products

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and significant progressive memory loss. In AD, astrocytes are known to take up and clear Aβ plaques. However, how Aβ induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas Aβ-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene-silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic by-products ammonia, H2O2, and GABA to recover from reactive astrogliosis and memory impairment in AD model. Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial Aβ detoxification and detrimental memory impairment in AD. We propose ODC1-inhibition as a promising therapeutic strategy for AD to facilitate removal of toxic molecules and prevent memory loss.

scholarly journals Role Of Triclosan (TCS)-Containing Hand Washes In Hormonal Imbalance And Impotency

2021 ◽  
Author(s):  
Abah Moses Owoicho ◽  
Mustapha Bakare ◽  
Deborah Oganya Ogenyi ◽  
Ogu Stephen ◽  
Ujah Moses Okwori
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
The Body ◽  
Hormone Levels ◽  
Hormonal Imbalance ◽  
Hypothermic Effect ◽  
The Central Nervous System ◽  
Low Levels ◽  
Trade Names

Research shows that, triclosan disrupts the biosynthesis of testosterone. when tested on isolated testicular leydig cells with various dosages, it was found out that triclosan dose-dependently decreases testosterone, and the mechanism is as follows: triclosan decreases the activity of adenylyl cyclase enzyme, resulting in the drop of cAMP (cyclic adenosine monophosphate). Another research shows that, triclosan completely hammered thyroid hormones, lowered luteinizing hormone levels, follicle stimulating hormone levels, and cholesterol synthesis. Concerns over triclosan interfering with the body‘s thyroid hor-mone metabolism led to a study that found that triclosan had a marked hypothermic effect, lowering the body temperature, and overall causing a ―nonspecific depressant effect on the central nervous system. Another study associated exposure to low levels (0.03 mi-crog/L) of triclosan with disrupted thyroid hormone. Due to the close resemblance of triclosan to certain estrogens, a more recent paper in Environment International shows that triclosan inhibits estrogen sulfotransferase in sheep placenta,an enzyme which helps metabolize the hormone and transport it to the developing fetus. The suspicion is that triclosan would be dangerous in pregnancy if enough of it gets through to the placenta to affect the enzyme. Conclusively, it is recommended that hands should be washed with detergent and warm water, or with bleach and complement with alcohol-containing hand sanitizers rather than using triclosan containing hand washes; also when selecting prod-ucts such as hand washes, antiseptic soaps, facial cleansers, toothpaste, deodorants, al-ways watch out for Triclosan trade names/chemical names on the ingredient list such as trichlorocarbonalide, irgasan®, Irgacare® and Microban®, triclosan is used as a built-in antimicrobial for product protection.

scholarly journals Isolation of Adenosine and Cordysinin B from Anredera cordifolia that Stimulates CRE-Mediated Transcription in PC12 Cells

2021 ◽  
Vol 8 (01) ◽  
pp. e19-e24
Author(s):  
Yasushi Ohizumi ◽  
Michi Kawada ◽  
Maki Kamada ◽  
Akira Nakajima ◽  
Koji Kajima ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Memory Impairment ◽  
High Performance ◽  
Neurodegenerative Disorder ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Response Element ◽  
Water Layers ◽  
Adenosine A1 ◽  
Cyclic Amp Response Element

AbstractAlzheimer’s disease is a typical neurodegenerative disorder, and its prevention or treatment poses great concern in advanced countries. In our survey of numerous natural resources with neurotrophic activities, we found that Anredera cordifolia improved memory impairment and increased cyclic adenosine monophosphate (AMP) response element-mediated transcription, an important step in signal transduction for memory formation. The extracts of this food were dissolved in methanol and then partitioned with three organic solvents and water, separating into n-hexane, ethyl acetate, n-butanol, and water layers. The n-butanol layer with the strongest activity on cyclic AMP-response element-dependent transcription was fractionated using silica gel column chromatography and then the activity was monitored using preparative high-performance liquid chromatography to give adenosine and cordysinin B, respectively. Both compounds showed a concentration-dependent increase in cyclic AMP-response element-mediated transcription activity. These results suggest that both adenosine and cordysinin B may participate in improving the action of A. cordifolia on memory impairment, and these actions, at least in part, result from the activation of adenosine A1, A2A, and A2B receptors.

Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation

2011 ◽  
Vol 105 (03) ◽  
pp. 487-495 ◽  
Author(s):  
Hideo Yoshida ◽  
Yosuke Okamura ◽  
Naohide Watanabe ◽  
Yasuo Ikeda ◽  
Makoto Handa
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Block Shear ◽  
Platelet Receptor ◽  
Platelet Thrombus ◽  
Low Levels ◽  
Pde3 Inhibitor

SummaryPhosphodiesterase (PDE)3 inhibitors exert potent antiplatelet effects through maintaining elevated intracellular cyclic adenosine monophosphate levels, but do not prolong bleeding time. To resolve this discrepancy, we hypothesised that PDE3 inhibitors effectively suppress shear-induced platelet thrombus formation initiated by the interaction of the platelet receptor GPIb/V/IX with its ligand, von Willebrand factor (VWF), since arterial thrombosis is more dependent on shear stress as compared with haemostatic plug formation. To test the hypothesis, we compared the in vitro effects of K-134 (a PDE3 inhibitor), tirofiban (a GPIIb/IIIa inhibitor) and acetylsalicylic acid (ASA) on ristocetin-induced platelet aggregation and platelet thrombus formation on VWF or collagen surfaces under flow conditions. K-134 inhibited GPIIb/IIIa-dependent platelet aggregation to the same extent as tirofiban and more potently than ASA. Likewise, K-134 and tirofiban effectively inhibited stable platelet thrombus formation (platelet firm adhesion and subsequent aggregation) on the VWF or collagen surface under high shear, but ASA only inhibited aggregation. Notably, inhibition by K-134 became evident only when a low concentration of PGE1 was present. These inhibitors did not block shear-induced initial platelet contact with VWF via GPIb/V/IX. In contrast, under low shear, the inhibitory effects of K-134 on platelet aggregation on the collagen surface were lower than tirofiban or ASA. The observed shear-dependent suppression of platelet thrombus formation by PDE3 inhibitor in the presence of low levels of adenylate cyclase stimulator may contribute to high therapeutic benefit with low risk of bleeding.

Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires

2019 ◽  
Author(s):  
Bella Grigorenko ◽  
Igor Polyakov ◽  
Alexander Nemukhin
Keyword(s):  
Adenylyl Cyclase ◽  
Bond Cleavage ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Md Simulations ◽  
Coordination Shell ◽  
Energy Profile ◽  
One Step ◽  
Type V

<p>We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. Several stable six-fold coordination shells of Mg<sub>A</sub><sup>2+ </sup>are observed in MD simulations of ES complexes. In the lowest energy ES conformation, the coordination shell of Mg<sub>A</sub><sup>2+ </sup>does not include the O<sub>δ1</sub> atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized which includes proton transfer from the ribose O<sup>3'</sup>H<sup>3' </sup>group in ATP to Asp440 via a shuttling water molecule and P<sup>A</sup>-O<sup>3A</sup> bond cleavage and O<sup>3'</sup>-P<sup>A</sup> bond formation. The energy profile of this route is consistent with the observed reaction kinetics. In a higher energy ES conformation, Mg<sub>A</sub><sup>2+</sup> is bound to the O<sub>δ1</sub>(Asp440) atom as suggested in the relevant crystal structure of the protein with a substrate analog. The computed energy profile initiated by this ES is characterized by higher energy expenses to complete the reaction. Consistently with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O<sup>3'</sup>H<sup>3' </sup>group via shuttling water molecules. </p>

Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

2019 ◽  
Vol 18 (1) ◽  
pp. 34-38
Author(s):  
Chen Lei ◽  
Pan Xiang ◽  
Shen Yonggang ◽  
Song Kai ◽  
Zhong Xingguo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guinea Pig ◽  
Smooth Muscles ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

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