Desmodin and isopongachromene as potential inhibitors of cyclin-dependent kinase 5: phytoconstituents targeting anticancer and neurological therapy DOI
Akhtar Atiya,

Shivani Batra,

Taj Mohammad

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: 41(16), P. 8042 - 8052

Published: Oct. 2, 2022

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine-threonine protein vital for neuronal cell cycle arrest and differentiation. It activates by binding with p35 p39 important the functioning of nervous system. A growing body evidence suggests that CDK5 contributes to onset progression neurodegeneration tumorigenesis represents itself as potential therapeutic target. Our research illustrates virtual screening phytochemicals from IMPPAT (Indian Medicinal Plants, Phytochemistry Therapeutics) library search inhibitors CDK5. Initially, compounds parent were filtered out via their physicochemical properties following Lipinski rule five. Then sequentially, molecular docking-based screening, PAINS filter, ADMET, PASS analysis, dynamics (MD) simulation done using various computational tools adversities can cause hindrances in identification Finally, two selected extensive showing significant ATP-binding pocket ultimately potent ATP-competitive we propose elucidated Desmodin Isopongachromene be used further drug discovery process act therapeutics medical industry treat certain complex diseases, including cancer neurodegeneration.Communicated Ramaswamy H. Sarma.

Language: Английский

Topological influence of immediate-early genes in brain genetic networks and their link to Alzheimer's disease DOI Creative Commons
Margarita Zachariou, Eleni M. Loizidou, George M. Spyrou

et al.

Computers in Biology and Medicine, Journal Year: 2025, Volume and Issue: 190, P. 110043 - 110043

Published: March 30, 2025

Language: Английский

Citations

0
Synthesis of 3‐hydroxy‐2‐naphthohydrazide‐based hydrazones and their implications in diabetic management via in vitro and in silico approaches DOI Open Access
Mussarat Tasleem, Saeed Ullah, Sobia Ahsan Halim

et al.

Archiv der Pharmazie, Journal Year: 2023, Volume and Issue: 357(2)

Published: Nov. 27, 2023

Abstract Diabetes mellitus (DM) has prevailed as a chronic health condition and become serious global issue due to its numerous consequences high prevalence. We have synthesized series of hydrazone derivatives tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, “α‐glucosidase.” Several approaches including fourier transform infrared, 1 H NMR, 13 C NMR were utilized confirm structures all derivatives. In vitro analysis compounds 3a – 3p displayed more effective inhibitory activities against α‐glucosidase with IC 50 in range 2.80–29.66 µM compared commercially available inhibitor, acarbose (IC = 873.34 ± 1.67 M). Compound 3h showed highest an value 2.80 0.03 µM, followed 3i 4.13 0.06 µM), 3f 5.18 0.10 3c 5.42 0.11 3g 6.17 0.15 3d 6.76 0.20 9.59 0.14 3n 10.01 0.42 µM). Kinetics most potent compound revealed concentration‐dependent form inhibition K i 4.76 0.0068 µM. Additionally, silico docking approach was applied predict binding patterns compounds, which indicates that hydrazide naphthalene‐ol groups play vital role residues (i.e., Glu277 Gln279) enzyme.

Language: Английский

Citations

8
Comparative metabolic profiling of mycelia, fermentation broth, spore powder and fruiting bodies of Ophiocordyceps gracilis by LC–MS/MS DOI
Yue Wang, Linhui Yang,

Lingling Tong

et al.

Phytochemical Analysis, Journal Year: 2023, Volume and Issue: 34(8), P. 984 - 996

Published: July 22, 2023

Abstract Introduction Ophiocordyceps gracilis , a type of edible and medicinal fungus, exhibits multiple health‐promoting effects. Due to the scarcity natural O. artificial cultures have been developed as its substitutes. However, lacking comprehension metabolite composition limits utilisation. Objective This research aimed evaluate nutritional value four by analysing their composition. In addition, metabolic pathways in mycelia fruiting bodies were analysed explore body formation mechanism at level. Method The mycelia, fermentation broth, spore powder cultivated this study. Their was compared using an untargeted metabolomics approach based on liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results Principal component analysis (PCA) orthogonal projections latent structures discriminant (OPLS‐DA) showed that noticeable differences A total 612 metabolites identified, among which 159 significant differences, these differential classified into 13 categories. most abundant with other cultures. each culture had own advantages significantly accumulates some active respectively. Pearson's correlation mutual relationship metabolites. seven closely related formation, such “Biosynthesis plant secondary metabolites”, “amino acids metabolism”, “tricarboxylic acid (TCA) cycle”. Conclusion study offered reference functional foods medicine.

Language: Английский

Citations

7
MARK4 promotes the malignant phenotype of gastric cancer through the MAPK/ERK signaling pathway DOI

Fubin Ma,

Jibin Yao,

Xingdong Niu

et al.

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 261, P. 155471 - 155471

Published: July 20, 2024

Language: Английский

Citations

1
Nanozyme-triggered polymerization amplification strategy for constructing highly sensitive surface plasmon resonance immunosensing DOI

Feng Shi,

Guiling Li,

Haibing Zhu

et al.

Chinese Chemical Letters, Journal Year: 2024, Volume and Issue: unknown, P. 110333 - 110333

Published: Aug. 1, 2024

Language: Английский

Citations

1
Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches DOI Creative Commons

Ghulam Md Ashraf,

Debarati DasGupta, Mohammad Zubair Alam

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(14), P. 4652 - 4652

Published: July 21, 2022

Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate microtubule-associated proteins (MAP's). MARK4 is known for major role in tau phosphorylation via phosphorylating Ser262 residue KXGS motif, which results detachment from microtubule. In lieu this vital pathology, a hallmark Alzheimer's disease (AD), druggable target treat AD and other neurodegenerative disorders (NDs). There growing evidence that NDs diabetes are connected with many pieces literature demonstrating high risk developing diabetic patients. Metformin (Mtf) has been drug use against type 2 mellitus (T2DM) long time; however, recent studies have established therapeutic effect diseases (NDs), namely AD, Parkinson's (PD) amnestic mild cognitive impairment. study, we explored inhibitory potential Mtf, employing silico vitro approaches. Molecular docking demonstrated Mtf binds significant -6.9 kcal/mol forming interactions binding pocket's critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into MARK4. ATPase assay presence shows it inhibits IC50 = 7.05 µM. The fluorescence constant 0.6 × 106 M-1. present study provides additional axis towards utilization as inhibitor targeting NDs.

Language: Английский

Citations

6
Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View? DOI Open Access

Kinga Czarnota-Łydka,

Katarzyna Kucwaj‐Brysz,

Patryk Pyka

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(15), P. 8768 - 8768

Published: Aug. 7, 2022

In view of the unsatisfactory treatment cognitive disorders, in particular Alzheimer’s disease (AD), aim this review was to perform a computer-aided analysis state art that will help search for innovative polypharmacology-based therapeutic approaches fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, hope effectively treating has been placed on serotonin 5-HT6 receptor (5-HT6R), due its proven, both agonists and antagonists, beneficial procognitive effects animal models; however, research into so far not successfully translated human patients. Recent lines evidence strongly emphasize role kinases, microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein I/II (ROCKI/II) cyclin-dependent 5 (CDK5) etiology AD, pointing potential their inhibitors only symptoms, but also causes disease. Thus, finding drug acts simultaneously 5-HT6R one those kinases provide breakthrough treatment. The pharmacophore- docking-based comprehensive literature performed herein serves answer question whether design these kind dual agents is possible, conclusions turned out be highly promising.

Language: Английский

Citations

6
Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease DOI Creative Commons
Mohd Adnan, Debarati DasGupta,

Saleha Anwar

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 19, 2023

Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation “neurofibrillary tangles,” a histopathological hallmark associated with onset AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) evolutionarily conserved Ser-Thr (S/T) that phosphorylates microtubule-associated proteins, thus playing critical role pathology. The uncontrolled neuronal migration attributed overexpressed MARK4, disruption microtubule dynamics. Inhibiting MARK4 attractive strategy therapeutics. Methods: Molecular docking was performed see interactions between galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were investigate stability conformational dynamics MARK4–GLT complex. We fluorescence binding isothermal titration calorimetry measure affinity GLT MARK4. Finally, enzyme inhibition assay activity presence absence GLT. Results: showed GLT, acetylcholinesterase inhibitor, binds active site cavity appreciable affinity. simulation for demonstrated Fluorescence suggested strong further show inhibits significantly (IC 50 = 5.87 µM). Conclusion: These results suggest potential inhibitor could be promising therapeutic target AD. GLT’s provides newer insights into mechanism action, which already used improve cognition patients.

Language: Английский

Citations

2
Immediate-Early Genes as Influencers in Genetic Networks and their Role in Alzheimer's Disease DOI Creative Commons
Margarita Zachariou, Eleni M. Loizidou, George M. Spyrou

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 29, 2024

Abstract/Summary Immediate-early genes (IEGs) are a class of activity-regulated (ARGs) that transiently and rapidly activated in the absence de novo protein synthesis response to neuronal activity. We explored role IEGs genetic networks pinpoint potential drug targets for Alzheimer’s disease (AD). Using combination network analysis genome-wide association study (GWAS) summary statistics we show (1) exert greater topological influence across different human mouse gene compared other ARGs, (2) ARGs sparsely involved diseases significantly more mutational constrained non-ARGs, (3) Many AD-linked variants regions, mainly MARK4 near FOSB, with an AD risk eQTL increases expression cortical areas, (4) holds influential place dense multi-omic high druggability score. Our work on IEGs’ is valuable contribution guiding interventions marked by dysregulation their downstream highlights as promising underexplored AD-target. Highlights topologically brain human. Activity-regulated Genes highly sparse gene-disease relevance. There several AD-associated FOSB . GWAS ARG’s target.

Language: Английский

Citations

0
Systemic Modulators: Potential Mechanism for the 5-HT System to Mediate Exercise Amelioration in Alzheimer's Disease DOI Creative Commons

Qingxu Wu,

Qiang He, Xianliang Zhang

et al.

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

As a neurodegenerative disease closely related to age-related changes, Alzheimer's (AD) is rapidly becoming one of the most resource-intensive and deadly diseases this century. systemic neurotransmitter system with widespread distribution throughout central peripheral nervous systems, 5-hydroxytryptamine (5-HT) not only plays an important role in antidepressant therapy but also shows potential value improving AD symptoms. The 5-HT may facilitate prevention treatment by impacting its pathological processes through various pathways, such as regulation Aβ deposition, hyperphosphorylation Tau, neuroinflammation, interactions cholinergic BDNF systems. In addition, regular exercise, non-pharmacological intervention, provides multi-level physical health benefits. Given high sensitivity paper reviews crucial mechanisms alleviating exercise. From perspective integrative biology we propose several crosstalk between systems mediated system. These serve bridge for offer novel ideas strategies future therapeutic approaches.

Language: Английский

Citations

0