Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi, Qingya; Pei, Fen; Perlmutter, David H.; Liu, Bing; Bahar, İvet

doi:10.1101/2020.03.25.007344

Cited by 6 publications

(1 citation statement)

References 118 publications

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“…Furthermore, the glibenclamide group showed significant increase in H score of Beclin-1 when compared to the IRI group. To support this finding, Shi et al [25] reported that glibenclamide could modulate autophagy and suppress tubular cell apoptosis through downregulation of Beclin-1 gene transcription. Furthermore, the combined group obviously showed significant increase of H score of Beclin-1 when compared with the other groups, which may be attributed to the potent stimulatory effect of autophagy activity of both carvedilol and glibenclamide.…”

Section: Discussionmentioning

confidence: 92%

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

Elfakhrany

Abo-Elsoud²,

Kareem³

et al. 2022

Open Access Maced J Med Sci

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BACKGROUND: Reactive oxygen species and cytokines are the main players in the development of renal ischemia-reperfusion (I/R) injury. AIM: The current study aimed to evaluate the effects of carvedilol and/or glibenclamide and the interaction between autophagy and oxidative stress. METHODS: 50 male rats were divided into five groups: Control, IR injury (IRI), carvedilol pretreated, glibenclamide pretreated, and combined carvedilol and glibenclamide pretreated. Measurements of renal blood flow (RBF), creatinine clearance, serum blood urea nitrogen (BUN), histopathological, and immunohistochemical evaluation of autophagy marker Becl-1 in the rat kidney were performed. Beclin-1and light chain 3 (LC3) Mrna expression was detected by real time polymerase chain reaction. RESULTS: IRI was associated with significant increases in BUN, tumor necrosis factor-alpha, nuclear factor κB, and histo (H) score value of Becl-1. However, there was a significant decrease in RBF, creatinine clearance, and glutathione peroxidase compared to the control group. There was significant increase in Beclin-1 and LC3 mRNA gene expression in carvedilol, glibenclamide, and combined treatment groups as compared to IRI and control groups. Combination of carvedilol and glibenclamide significantly restored IRI changes when compared with the other pretreated groups. CONCLUSION: This study suggests that carvedilol and glibenclamide are promising reno-protective drugs to reduce renal injury induced by I/R through their antioxidant and autophagy stimulation.

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Section: Discussionmentioning

confidence: 92%

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

Elfakhrany

Abo-Elsoud²,

Kareem³

et al. 2022

Open Access Maced J Med Sci

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Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy ofMycobacterium tuberculosisandSalmonella entericainfections

Heemskerk

Korbee

Esselink

et al. 2021

Preprint

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The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis (TB) treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

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RNA Sequencing in Hypoxia-Adapted T98G Glioblastoma Cells Provides Supportive Evidence for IRE1 as a Potential Therapeutic Target

White

Liu

Hákonarson

et al. 2023

Genes

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Glioblastoma (GBM) is an aggressive brain cancer with a median survival time of 14.6 months after diagnosis. GBM cells have altered metabolism and exhibit the Warburg effect, preferentially producing lactate under aerobic conditions. After standard-of-care treatment for GBM, there is an almost 100% recurrence rate. Hypoxia-adapted, treatment-resistant GBM stem-like cells are thought to drive this high recurrence rate. We used human T98G GBM cells as a model to identify differential gene expression induced by hypoxia and to search for potential therapeutic targets of hypoxia adapted GBM cells. RNA sequencing (RNAseq) and bioinformatics were used to identify differentially expressed genes (DEGs) and cellular pathways affected by hypoxia. We also examined expression of lactate dehydrogenase (LDH) genes using qRT-PCR and zymography as LDH dysregulation is a feature of many cancers. We found 2630 DEGs significantly altered by hypoxia (p < 0.05), 1241 upregulated in hypoxia and 1389 upregulated in normoxia. Hypoxia DEGs were highest in pathways related to glycolysis, hypoxia response, cell adhesion and notably the endoplasmic reticulum, including the inositol-requiring enzyme 1 (IRE1)-mediated unfolded protein response (UPR). These results, paired with numerous published preclinical data, provide additional evidence that inhibition of the IRE1-mediated UPR may have therapeutic potential in treating GBM. We propose a possible drug repurposing strategy to simultaneously target IRE1 and the spleen tyrosine kinase (SYK) in patients with GBM.

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Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Cited by 6 publications

References 118 publications

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy ofMycobacterium tuberculosisandSalmonella entericainfections

RNA Sequencing in Hypoxia-Adapted T98G Glioblastoma Cells Provides Supportive Evidence for IRE1 as a Potential Therapeutic Target

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