A fully integrated new paradigm for lithium&amp;rsquo;s mode of action &amp;ndash; lithium utilizes latent cellular fail-safe mechanisms

Woerkom, A. E. van

doi:10.2147/ndt.s123612

Cited by 3 publications

(3 citation statements)

References 157 publications

(299 reference statements)

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“…Alterations in BDNF expression or function may result from BDNF gene mutations, which may affect brain and neuronal health. It may be important to consider vitamin C interacts with phosphatases and kinases in the context of compensatory mechanisms or moderating effects of BDNF -related mutations (van Woerkom and Treatment 2017 ). Quercetin targets 33.3% of oxidoreductase, 20% of kinase, and oxidoreductase.…”

Section: Discussionmentioning

confidence: 99%

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis

Sakhawat,

Khan,

Rehman

et al. 2023

AMB Expr

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Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of − 5.5, − 6.1, − 4.5, and − 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein–ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.

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Section: Discussionmentioning

confidence: 99%

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis

Sakhawat,

Khan,

Rehman

et al. 2023

AMB Expr

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“…These include the multiple sub-mechanisms that are known to enhance the activity of the inositol phosphates and other related sugar phosphates. It is believed that these two components can help maintain the cell's energy levels by regulating the interaction between different cellular functions [112].…”

Section: Discussionmentioning

confidence: 99%

Lithium Biological Action Mechanisms after Ischemic Stroke

Munteanu

Rotariu

Turnea

et al. 2022

Life

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Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems—which influence numerous cellular and molecular processes through not entirely explained mechanisms of action—generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the “mirror” method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5–1.5 mEq/l. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.

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“…Regarding the use of LiCl, it should be pointed out this drug has a dual manner of inhibiting GSK-3, by a direct inhibition with a high IC 50 but also by an indirect manner via an increase in the Ser-phosphorylated GSK-3 forms. Lithium salts compete with Mg 2+ ; hence, they inhibit other enzymes that are Mg 2+ -dependent, including some phosphatases [ 155 , 156 ]. It might be that the LiCl effects on Ser-phosphorylated GSK-3 forms are somehow related to phosphatase inhibition.…”

Section: Gsk-3 Signaling In MMmentioning

confidence: 99%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders.

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A fully integrated new paradigm for lithium’s mode of action – lithium utilizes latent cellular fail-safe mechanisms

Cited by 3 publications

References 157 publications

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis

Lithium Biological Action Mechanisms after Ischemic Stroke

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

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