scholarly journals Discovery of 1-Pyrimidinyl-2-Aryl-4,6-Dihydropyrrolo [3,4-d]Imidazole-5(1H)-Carboxamide as a Novel JNK Inhibitor

2020 ◽  
Vol 21 (5) ◽  
pp. 1698
Author(s):  
Miyoung Jang ◽  
Youri Oh ◽  
Hyunwook Cho ◽  
Songyi Yang ◽  
Hyungwoo Moon ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuronal Apoptosis ◽  
High Selectivity ◽  
Selective Inhibitors ◽  
Ic50 Value ◽  
Novel Scaffold

We designed and synthesized 1-pyrimidinyl-2-aryl-4, 6-dihydropyrrolo [3,4-d] imidazole-5(1H)-carboxamide derivatives as selective inhibitors of c-Jun-N-terminal Kinase 3 (JNK3), a target for the treatment of neurodegenerative diseases. Based on the compounds found in previous studies, a novel scaffold was designed to improve pharmacokinetic characters and activity, and compound 18a, (R)-1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-4,6-dihydro pyrrolo [3,4-d]imidazole-5(1H)-carboxamide, showed the highest IC50 value of 2.69 nM. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases, having mild activity against JNK2, RIPK3, and GSK3β, which also known to involve in neuronal apoptosis.

Selective inhibitors of phosphodiesterases: therapeutic promise for neurodegenerative disorders

MedChemComm ◽  
2015 ◽  
Vol 6 (12) ◽  
pp. 2063-2080 ◽  
Author(s):  
Tarana Umar ◽  
Nasimul Hoda
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Selective Inhibitors ◽  
Pde Inhibitors

PDE inhibitors: significant contributors to the treatment of neurodegenerative diseases.

scholarly journals Identification of Novel PI3Kδ Selective Inhibitors by SVM-Based Multistage Virtual Screening and Molecular Dynamics Simulations

2019 ◽  
Vol 20 (23) ◽  
pp. 6000 ◽  
Author(s):  
Jing-wei Liang ◽  
Shan Wang ◽  
Ming-yang Wang ◽  
Shi-long Li ◽  
Wan-qiu Li ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Screening Method ◽  
Support Vector ◽  
Selective Inhibitors ◽  
Ligand Interaction ◽  
Lipid Kinase ◽  
Isoform Selectivity ◽  
Phosphoinositide 3 Kinase ◽  
Dynamics Simulations ◽  
Novel Scaffold

Phosphoinositide 3 kinase delta (PI3Kδ) is a lipid kinase that has been implicated in a variety of immune mediated disorders. The research on isoform selectivity was crucial for reducing side effects. In the current study, an optimized hierarchical multistage virtual screening method was utilized for screening the PI3Kδ selective inhibitors. The method sequentially applied a support vector machine (SVM), a protein ligand interaction fingerprint (PLIF) pharmacophore, and a molecular docking approach. The evaluation of the validation set showed a high hit rate and a high enrichment factor of 75.1% and 301.66, respectively. This multistage virtual screening method was then utilized to screen the NCI database. From the final hit list, Compound 10 has great potential as the PI3Kδ inhibitor with micromolar inhibition in the PI3Kδ kinase activity assay. This compound also shows selectivity against PI3Kδ kinase. The method combining SVM, pharmacophore, and docking was capable of screening out the compounds with potential PI3Kδ selective inhibitors. Moreover, structural modification of Compound 10 will contribute to investigating the novel scaffold and designing novel PI3Kδ inhibitors.

scholarly journals Transducing oxidative stress to death signals in neurons

2015 ◽  
Vol 211 (4) ◽  
pp. 741-743 ◽  
Author(s):  
Xu Cao ◽  
Yanshan Fang
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Neurodegenerative Diseases ◽  
Neuronal Apoptosis ◽  
Axonal Degeneration ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cell Biol ◽  
Death Signals

Accumulation of reactive oxygen species (ROS) has been associated with aging and neurodegenerative diseases. Nevertheless, how elevated ROS levels cause neurodegeneration is unclear. In this issue, Wakatsuki et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201506102) delineate how oxidative stress is transduced into death signals, leading to neuronal apoptosis and axonal degeneration.

scholarly journals 4-Amino-pyrrolopyridine-5-carboxamide: A Novel Scaffold for JAK1-Selective Inhibitors

2014 ◽  
Vol 62 (3) ◽  
pp. 217-220
Author(s):  
Heerim Shin ◽  
Mi Kyoung Kim ◽  
Youhoon Chong
Keyword(s):  
Selective Inhibitors ◽  
Novel Scaffold

scholarly journals Oxidation Stress-Mediated MAPK Signaling Pathway Activation Induces Neuronal Loss in the CA1 and CA3 Regions of the Hippocampus of Mice Following Chronic Cold Exposure

2019 ◽  
Vol 9 (10) ◽  
pp. 273 ◽  
Author(s):  
Bin Xu ◽  
Li-Min Lang ◽  
Shuai Lian ◽  
Jing-Ru Guo ◽  
Jian-Fa Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cold Stress ◽  
Signaling Pathway ◽  
Cold Exposure ◽  
Neuronal Apoptosis ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Tunel Staining ◽  
Oxidation Stress ◽  
Pathway Activation

Chronic stress can damage homeostasis and induce various primary diseases. Although chronic cold stress is becoming an increasing problem for people who must work or live in extreme environments, risk-induced diseases in the central nervous system remain unstudied. Male C57BL/6 mice were exposed to an environment of 4 °C, 3 h per day for 1, 2, and 3 weeks and homeostasis in the hippocampus and neuronal apoptosis were evaluated by Western blotting, immunohistochemistry, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and immunofluorescence. The phenomena of oxidation stress, MAPK signaling pathway activation, anti-oxidation protein release, neuronal apoptosis increases, and neuronal proliferation inhibition were demonstrated in the CA1 and CA3 regions of mouse hippocampal tissues following cold exposure. We speculated that these phenomena were mediated by the MAPK pathway and were closely linked with oxidative stress in the hippocampus. This study provides novel concepts regarding neurodegenerative diseases, suggesting that chronic cold stress may be a critical factor to induce neurodegenerative diseases.

A fluorescent method based on magnetic nanoparticles for detection of CGG trinucleotide repeat genes

2019 ◽  
Vol 43 (3) ◽  
pp. 1322-1327 ◽  
Author(s):  
Ziqi Ren ◽  
Xiaoqian Zhu ◽  
Hehong Lv ◽  
Heng Liu ◽  
Hanping He ◽  
...  
Keyword(s):  
Magnetic Nanoparticles ◽  
Early Diagnosis ◽  
Neurodegenerative Diseases ◽  
Linear Correlation ◽  
High Selectivity ◽  
Trinucleotide Repeat ◽  
Fluorescent Sensor ◽  
Trinucleotide Repeats ◽  
Short Report ◽  
Fluorescent Method

A novel fluorescent sensor based on magnetic nanoparticles as the separator and short report DNA was designed and prepared for the detection of d(CGG)ntrinucleotide repeats. The method exhibited high selectivity and sensitivity, and excellent linear correlation from 100 pM to 150 nM, which is useful for the early diagnosis of neurodegenerative diseases.

scholarly journals Salivary Redox Biomarkers in Selected Neurodegenerative Diseases

2020 ◽  
Vol 9 (2) ◽  
pp. 497 ◽  
Author(s):  
Mateusz Maciejczyk ◽  
Anna Zalewska ◽  
Karolina Gerreth
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Neuronal Apoptosis ◽  
Medical Personnel ◽  
Brain Inflammation ◽  
Non Invasive ◽  
Diagnosis And Prognosis ◽  
The Central Nervous System ◽  
Saliva Collection ◽  
Cerebral Degeneration

Neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are disorders, which cause irreversible and progressive deterioration of the central nervous system. The pathophysiology of NDDs is still not fully explained; nevertheless, oxidative stress is considered as a critical mediator of cerebral degeneration, brain inflammation, as well as neuronal apoptosis. Therefore, it is not surprising that redox biomarkers are increasingly used in the diagnosis of neurodegenerative diseases. As saliva is a very easy to obtain bioliquid, it seems promising to use this biomaterial in the diagnosis of NDDs. Saliva collection is easy, cheap, stress-free, and non-infectious, and it does not require the help of a specialised medical personnel. Additionally, the concentrations of many salivary redox biomarkers correlate with their content in blood serum as well as the degree of disease progression, which makes them non-invasive indicators of NDDs. This paper reviews the latest knowledge concerning the use of salivary redox biomarkers in the diagnosis and prognosis of selected neurodegenerative diseases.

scholarly journals ANTIOXIDANT EFFECT OF FLAVONOIDS IN NEURODEGENERATIVE DISEASES

2017 ◽  
Vol 16 (2) ◽  
pp. 46-52
Author(s):  
Adriana E. Bulboaca ◽  
◽  
Sorana S. Bolboaca ◽  
Ioana C. Stanescu ◽  
Carmen A. Sfrangeu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Reactive Nitrogen Species ◽  
Neuronal Apoptosis ◽  
Antioxidant Effect ◽  
Pathophysiological Mechanism ◽  
Parkinson’S Diseases ◽  
Dietary Components ◽  
Antioxidant Mechanisms ◽  
Antioxidant Effects

The investigation of the mechanisms that leads to neuronal apoptosis is under investigation all over the world. The enhancement of oxidative stress in brain neurons is one of the most important pathophysiological mechanism associated with neurodegeneration. The antioxidant effect of flavonoids can be one important mechanism for modulation of neuronal apoptosis in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In addition to their influence on the cerebral blood flow, flavonoids interact with signalization cascades that lead to the inhibition of neuronal death by oxidative stress apoptosis and thus promote neuronal survival and synaptic plasticity. Acting on the intracellular antioxidant mechanisms the flavonoids can become a balance regulator for production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Addition of antioxidant effect of flavonoids to dietary components can constitute an adjuvant therapy for delaying the neurodegenerative processes. The aim of this paper was to review the antioxidant effects of flavonoids in Alzheimer’s and Parkinson’s diseases.

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