Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward

Ruiz, Sara Arciniegas; Eldar-Finkelman, Hagit

doi:10.3389/fnmol.2021.792364

Cited by 61 publications

(35 citation statements)

References 376 publications

(467 reference statements)

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“…Furthermore, in our study, we propose the use of reprogramming with BIO for adoptive cell therapies. Given the multisystemic effects that GSK3-targeting drugs could have in vivo ( 78 ), it will be necessary to explore the use of other GSK3 inhibitors with proven clinical safety and tolerability ( 78 , 79 ) that could be injected systemically to reprogram CD8 + T cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

Perdomo‐Celis¹,

Passaes²,

Monceaux³

et al. 2022

Journal of Clinical Investigation

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Virus-specific CD8 + T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8 + T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8 + T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1 + less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8 + T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

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Section: Discussionmentioning

confidence: 99%

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

Perdomo‐Celis¹,

Passaes²,

Monceaux³

et al. 2022

Journal of Clinical Investigation

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“…Further analysis showed that the main phytochemicals that target these molecules are butyl-β- D -fructopyranoside (13 targets), oxyhylladiketone (13 targets), oxyphyllol B (12 targets), yakuchinone B (12 targets), 5-HYD (11 targets), tectochrysin and β- D -glucopyranoside (11 targets), and 1-methyl butyl (11 targets) ( Figure 8B ). GSK3β (encoded by GSK3B) has been demonstrated to be important in neuronal death ( Arciniegas and Eldar-Finkelman, 2021 ). Molecular docking results showed that 5-HYD, rhamnetin, β- D -glucopyranoside, 2-hydroxy-5-methoxyphenyl, rhamnocitrin, and (S)-1-phenylethyl β- D -glucopyranoside had strong binding affinities for GSK3β ( Figure 8C ).…”

Section: Resultsmentioning

confidence: 99%

Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia

Zeng

Liu

Wang

et al. 2022

Front. Aging Neurosci.

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The dried and ripe fruits of Alpinia oxyphylla and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer’s disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski’s rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-β-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.

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“…GSK-3β plays a key role in axon regeneration. Inactivation of GSK-3β promotes axonal growth and neurological recovery in the central nervous system ( Arciniegas Ruiz and Eldar-Finkelman, 2021 ; Rodriguez-Jimenez et al, 2021 ). MiR-22-3p derived from adipose-tissue MSC exosomes can alleviate cerebral ischemia injury by inhibiting the BMP2/BMF axis mediated by kdm6b.…”

Section: Exosomes and Mesenchymal Stem Cellsmentioning

confidence: 99%

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

et al. 2022

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Ischemic stroke is defined as an infarction in the brain, caused by impaired cerebral blood supply, leading to local brain tissue ischemia, hypoxic necrosis, and corresponding neurological deficits. At present, revascularization strategies in patients with acute ischemic stroke include intravenous thrombolysis and mechanical endovascular treatment. However, due to the short treatment time window (<4.5 h) and method restrictions, clinical research is focused on new methods to treat ischemic stroke. Exosomes are nano-sized biovesicles produced in the endosomal compartment of most eukaryotic cells, containing DNA, complex RNA, and protein (30–150 nm). They are released into surrounding extracellular fluid upon fusion between multivesicular bodies and the plasma membrane. Exosomes have the characteristics of low immunogenicity, good innate stability, high transmission efficiency, and the ability to cross the blood–brain barrier, making them potential therapeutic modalities for the treatment of ischemic stroke. The seed sequence of miRNA secreted by exosomes is base-paired with complementary mRNA to improve the microenvironment of ischemic tissue, thereby regulating downstream signal transduction activities. With exosome research still in the theoretical and experimental stages, this review aims to shed light on the potential of exosomes derived from mesenchymal stem cells in the treatment of ischemic stroke.

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Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward

Cited by 61 publications

References 376 publications

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

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