Biology subjects

Saleh, M. A.

Publications and source records attributed to Saleh, M. A..

3 recordsLinked to original sources

bioRxiv2024

GSK-3alpha-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia

Dysregulated autophagy/mitophagy is one of the major causes of cardiac injury in ischemic conditions. Glycogen synthase kinase-3alpha (GSK-3) has been shown to play a crucial role in the pathophysiology of cardiac diseases. However, the precise role of GSK-3 in cardiac mitophagy remains unknown. Herein, we investigated the role of GSK-3 in cardiac mitophagy by employing AC16 human cardiomyocytes under the condition of acute hypoxia. We observed that the gain-of-GSK-3 function profoundly induced mitophagy in the AC16 cardiomyocytes post-hypoxia. Moreover, GSK-3 overexpression led to increased ROS generation and mitochondrial dysfunction in cardiomyocytes, accompanied by enhanced mitophagy displayed by increased mt-mKeima intensity under hypoxia. Mechanistically, we identified that GSK-3 promotes mitophagy through upregulation of BNIP3, caused by GSK-3-mediated increase in expression of HIF-1 and FOXO3a in cardiomyocytes post-hypoxia. Moreover, GSK-3 displayed a physical interaction with BNIP3 and, inhibited PINK1 and Parkin recruitment to mitochondria was observed specifically under hypoxia. Taken together, we identified a novel mechanism of mitophagy in human cardiomyocytes. GSK-3 promotes mitochondrial dysfunction and regulates FOXO3a -mediated BNIP3 overexpression in cardiomyocytes to facilitate mitophagy following hypoxia. An interaction between GSK-3 and BNIP3 suggests a role of GSK-3 in BNIP3 recruitment to the mitochondrial membrane where it enhances mitophagy in stressed cardiomyocytes independent of the PINK1/Parkin.

cell biology↗

bioRxiv2024

Natural compound screening predicts novel GSK-3 isoform-specific inhibitors

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3 or GSK-3{beta} often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3 and GSK-3{beta}, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3 (IC50=2.26 {micro}M) vs. GSK-3{beta} (IC50=4.23 {micro}M) while Rosmarinic acid was found to be more potent against GSK-3{beta} (IC50=2.24 {micro}M) than GSK-3 (IC50=5.14 {micro}M). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3 and Rosmarinic for GSK-3{beta} isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers. HighlightsO_LICurrent GSK-3 inhibitors lack specificity and cause side effects. C_LIO_LIThis study identifies potential GSK-3 isoform-specific natural compounds. C_LIO_LIPsoralidin is likely a better inhibitor for GSK-3 while Rosmarinic for GSK-3{beta}. C_LIO_LIThese natural compounds may be promising future treatments. C_LI

biochemistry↗

bioRxiv2023

Does nonlinear blood-brain barrier transport matter for morphine dosing strategies?

Morphine blood-brain barrier (BBB) transport is governed by passive diffusion, active efflux and saturable active influx. These processes may be associated with nonlinear concentration-dependencies which impact plasma and brain extracellular fluid (brainECF) pharmacokinetics of morphine. In this study, we aim to evaluate the impact of nonlinear BBB transport on brainECF pharmacokinetics of morphine and its metabolites for different dosing strategies using a physiologically based pharmacokinetic simulation study. We extended the human physiologically based pharmacokinetic, LeiCNS-PK3.0, model with equations for nonlinear BBB transport of morphine. Simulations for brainECF pharmacokinetics were performed for various dosing strategies: intravenous (IV), oral immediate (IR) and extended release (ER) with dose range of 0.25-150mg and dosing frequencies of 1-6 times daily. The impact of nonlinear BBB transport on morphine CNS pharmacokinetics was evaluated by quantifying (i) the relative brainECF to plasma exposure (AUCu,brainECF/AUCu,Plasma) and (ii) the impact on the peak-to-trough ratio (PTR) of concentration-time profiles in brainECF and plasma. We found that the relative morphine exposure and PTRs are dose dependent for the evaluated dose range. The highest relative morphine exposure value of 1.4 was found for once daily 0.25mg ER and lowest of 0.1 for 6-daily 150mg IV dosing. At lower doses the PTRs were smaller and increased with increasing dose and stabilized at higher doses independent of dosing frequency. Relative peak concentrations of morphine in relation to its metabolites changed with increasing dose. We conclude that nonlinearity of morphine BBB transport affect the relative brainECF exposure and the fluctuation of morphine and its metabolites. HighlightsNonlinear transport affects relative morphine exposure in brainECF. Nonlinear transport affects PK fluctuations of morphine in brainECF. Nonlinear transport affects brainECF PK relationship of morphine and its metabolites. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

pharmacology and toxicology↗