Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents

Saudi Pharmaceutical Journal, Journal Year: 2024, Volume and Issue: 32(5), P. 102025 - 102025

Published: March 12, 2024

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series sulfonamide derivatives based pyrazole or pyridine moieties 3a, b, 7–9, 11–13, 15a, 16 were synthesized from amine sulfonyl chloride derivatives. The structures elucidated via spectroscopy (1H 13C NMR). biologically assessed vitro for their anti-diabetic (α-amylase α-glucosidase inhibition) anti-Alzheimer's (acetylcholinesterase activities. results revealed that compound 15a is powerful enzyme inhibitor α-amylase α-glucosidase. Also, 15b demonstrated activity against acetylcholinesterase enzyme. structure–activity relationship study was accomplished. Furthermore, complementary silico molecular properties, drug-likeness, ADMET prediction, surface properties two more fulfilled computed. These studies recommend candidates modifications before vivo assays.

Language: Английский

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Evidence that Alzheimer’s Disease Is a Disease of Competitive Synaptic Plasticity Gone Awry

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 99(2), P. 447 - 470

Published: April 23, 2024

Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized lines supporting this hypothesis highlighted similarities between Aβ anti-microbial peptides mediating cell/synapse competition. In cell competition, deploy multitude mechanisms ensure both self-protection competitor elimination. Here review recent studies showing similar are at play Aβ-mediated synapse competition perturbations these underpin Alzheimer’s disease (AD). Specifically, discuss ApoE, two crucial players AD, co-operate regulation Glial ApoE promotes by increasing production trophic monomeric inhibiting its assembly into toxic oligomers. Conversely, oligomers, once assembled, promote elimination synapses via direct activity amplification “eat-me” signals promoting weak synapses. further summarize neuronal may be part gene regulatory network normally plasticity, explaining selective vulnerability expressing neurons AD brains. Lastly, sleep key Aβ-orchestrated which not only induced but also required for underlining link AD. Together, results strongly argue gone awry, novel perspective research.

Language: Английский

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Alzheimer’s Disease: Models and Molecular Mechanisms Informing Disease and Treatments

Bioengineering, Journal Year: 2024, Volume and Issue: 11(1), P. 45 - 45

Published: Jan. 1, 2024

Alzheimer’s Disease (AD) is a complex neurodegenerative disease resulting in progressive loss of memory, language and motor abilities caused by cortical hippocampal degeneration. This review captures the landscape understanding AD pathology, diagnostics, current therapies. Two major mechanisms direct pathology: (1) accumulation amyloid β (Aβ) plaque (2) tau-derived neurofibrillary tangles (NFT). The most common variants Aβ pathway APP, PSEN1, PSEN2 are largely responsible for early-onset (EOAD), while MAPT, APOE, TREM2 ABCA7 have modifying effect on late-onset (LOAD). More recent studies implicate chaperone proteins degrading AD. Several tests, such as cognitive function, brain imaging, cerebral spinal fluid (CSF) blood used diagnosis. Additionally, several biomarkers seem to unique specific combination expression could potentially be improved, less invasive diagnostics. In addition genetic perturbations, environmental influences, altered gut microbiome signatures, affect Effective treatments been challenging develop. Currently, there FDA approved drugs (cholinesterase inhibitors, Aß-targeting antibodies an NMDA antagonist) that mitigate rate decline symptoms distress.

Language: Английский

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Fourteen years of cellular deconvolution: methodology, applications, technical evaluation and outstanding challenges

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(9), P. 4761 - 4783

Published: April 15, 2024

Abstract Single-cell RNA sequencing (scRNA-Seq) is a recent technology that allows for the measurement of expression all genes in each individual cell contained sample. Information at single-cell level has been shown to be extremely useful many areas. However, performing experiments expensive. Although cellular deconvolution cannot provide same comprehensive information as experiments, it can extract cell-type from bulk data, and therefore researchers conduct studies resolution existing datasets. For these reasons, great effort made develop such methods deconvolution. The large number available, requirement coding skills, inadequate documentation, lack performance assessment make difficult life scientists choose suitable method their experiment. This paper aims fill this gap by providing review 53 regarding methodology, applications, performance, outstanding challenges. More importantly, article presents benchmarking using 283 types 30 tissues 63 individuals. We also an R package named DeconBenchmark readers execute benchmark reviewed (https://github.com/tinnlab/DeconBenchmark).

Language: Английский

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Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 20, 2024

Abstract To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing 24 disease and control brains focused on vascular astrocyte clusters as main cell types of gliovascular-unit. The majority the transcriptional were pericytes. Of targets predicted to interact with astrocytic ligands, SMAD3 , upregulated pericytes, has highest number ligands including VEGFA downregulated astrocytes. We validated these findings external datasets comprising 4,730 pericyte 150,664 nuclei. Blood levels are associated disease-related neuroimaging outcomes. determined inverse relationships between pericytic human iPSC zebrafish models. Here, detect vast transcriptome at gliovascular-unit, prioritize perturbed -astrocytic interactions, validate cross-species models provide a mechanism disintegrity disease.

Language: Английский

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