Drug Repurposing: Escitalopram attenuates acute lung injury by inhibiting the SIK2/ HDAC4/ NF-κB signaling cascade

Wang, Tiantian; Zheng, Ruihe; Sun, Song Yung

doi:10.1016/j.bbrc.2022.02.015

Cited by 11 publications

(10 citation statements)

References 24 publications

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“…Nucleocytoplasmic shuttling of endogenous class IIa HDAC’s has been indicated in a variety of mammalian cells, including: cardiomyocytes ( Liu et al, 2020 ; Helmstadter et al, 2021 ), hepatocytes ( Mihaylova et al, 2011 ), macrophages ( Wang et al, 2022 ), endothelial cells ( Liu et al, 2017 ), and neurons ( Kassis et al, 2015 ). Depending on cell and tissue type, intracellular localization of HDAC4 and HDAC5 plays a role in the physiology of: long-term memory formation ( Wang et al, 2011 ; Schlumm et al, 2013 ; Main et al, 2021 ), angiogenesis ( Liu et al, 2017 ), glycogen storage ( Mihaylova et al, 2011 ), and cell proliferation ( Guan et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 4 and 5 translocation elicited by microsecond pulsed electric field exposure is mediated by kinase activity

Safaei

Thompson

2022

Front. Bioeng. Biotechnol.

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Electroporation-based technologies using microsecond pulsed electric field (µsPEF) exposures are established as laboratory and clinical tools that permeabilize cell membranes. We demonstrate a µsPEF bioeffect on nucleocytoplasmic import and export of enzymes that regulate genetic expression, histone deacetylases (HDAC) -4 and -5. Their μsPEF-induced nucleocytoplasmic transport depends on presence and absence of extracellular calcium ions (Ca2+) for both MCF7 and CHO-K1 cells. Exposure to 1, 10, 30 and 50 consecutive square wave pulses at 1 Hz and of 100 µs duration with 1.45 kV/cm magnitude leads to translocation of endogenous HDAC4 and HDAC5. We posit that by eliciting a rise in intracellular Ca2+ concentration, a signaling pathway involving kinases, such as Ca2+/CaM-dependent protein kinase II (CaMKII), is activated. This cascade causes nuclear export and import of HDAC4 and HDAC5. The potential of µsPEF exposures to control nucleocytoplasmic transport unlocks future opportunities in epigenetic modification.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase 4 and 5 translocation elicited by microsecond pulsed electric field exposure is mediated by kinase activity

Safaei

Thompson

2022

Front. Bioeng. Biotechnol.

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“…#ab692, dilution 1:500). Sections were rinsed with .1 M PBS and exposed to donkey secondary antibodies conjugated with Alexa Fluor 488 or 647 (Abcam, dilution 1:1,000) at room temperature for 2 h. After an additional rinse, cells were then counterstained with 4′, 6-diamidino-2-phenylindole (DAPI) for nuclear labelling ( Wang et al, 2022 ). Fluorescence images were captured with a confocal microscope.…”

Section: Methodsmentioning

confidence: 99%

Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway

Niu

Wei

et al. 2023

Front. Pharmacol.

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Introduction: Venlafaxine is one of the most commonly used anti-depressant and antineoplastic drug. Previous studies have predicted venlafaxine as an anti-cancer compound, but the therapeutic effects of venlafaxine in melanoma have not yet been demonstrated. Nur77 is an orphan nuclear receptor that highly expressed in melanoma cells and can interact with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic protein.Method: We examined the effects of venlafaxine in MV3 cells in vitro and MV3 xenograft tumor in nude mice. Western-blot, PCR, TUNEL assay and immunofluorescence were used to reveal the growth of melanoma cells.Results: Here, our data revealed that venlafaxine could reduce the growth, and induce apoptosis of melanoma cells through a Nur77-dependent way. Our results also showed that treatment with venlafaxine (20 mg/kg, i.p.) potently inhibited the growth of melanoma cells in nude mice. Mechanistically, venlafaxine activated JNK1/2 signaling, induced Nur77 expressions and mitochondrial localization, thereby promoting apoptosis of melanoma cells. Knockdown of Nur77 and JNK1/2, or inhibition of JNK1/2 signaling with its inhibitor SP600125 attenuated the anti-cancer effects of venlafaxine.Conclusion: In summary, our results suggested venlafaxine as a potential therapy for melanoma.

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“…In addition, the SIKs have also been found to regulate proinflammatory macrophage mediator production. HG-9-91-01 reduces the production of TNF-α and IL-6 in LPS-stimulated BMDMs ( 20 ), and escitalopram (traditionally a selective serotonin reuptake inhibitor) has been shown to inhibit SIK2 activity and block the LPS-driven production of TNF-α, IL-6, and IL-1β in Raw 264.7 macrophages ( 218 ). Furthermore, production of TNF-α, IL-6, and IL-12 was significantly lower in LPS-stimulated macrophages isolated from KI mice of all SIK isoforms ( 85 ), whereas the overexpression SIK1, 2, or 3 in ANA-1 macrophages reversed the inhibitory effect of HG-9-91-01 on LPS-induced expression of TNF-α and IL-12 ( 217 ).…”

Section: The Physiological Roles Of Salt-inducible Kinasesmentioning

confidence: 99%

“…This strongly suggests that all three SIK isoforms act to regulate the production of proinflammatory cytokines. However, the mechanism by which this occurs is currently unclear, as it has been reported that SIK controls the phosphorylation of HDAC4 to regulate NF-κB signaling ( 218 ), whereas CRTC3 has been suggested to mediate the proinflammatory impact of SIK OE ( 217 ). Therefore, future work is needed to fully understand the mechanism(s) by which the SIKs control proinflammatory mediator production.…”

Section: The Physiological Roles Of Salt-inducible Kinasesmentioning

confidence: 99%

The multiple roles of salt-inducible kinases in regulating physiology

Jagannath

Taylor

et al. 2023

Physiological Reviews

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Salt-Inducible kinases, which comprise a family of three homologous serine-threonine kinases were first described for their role in sodium sensing, but have since been shown to regulate multiple aspects of physiology. These kinases are activated or deactivated in response to extracellular signals that are cell surface receptor mediated, and go on to phosphorylate multiple targets including the transcription co-factors CRTC1-3 and the Class IIa histone deacetylases (HDACs). Thus, the SIK family conveys signals about the cellular environment to reprogram transcriptional and post-transcriptional processes in response. In this manner, SIKs have been shown to regulate metabolic responses to feeding/fasting, cell division and oncogenesis, inflammation, and immune responses and most recently, sleep and circadian rhythms. Sleep and circadian rhythms are master regulators of physiology and are exquisitely sensitive to regulation by environmental light, and physiological signals such as need for sleep. Salt-Inducible kinases have been shown to be central the molecular control of both these processes. Here we summarise the molecular mechanisms by which SIKs control these different domains of physiology and highlight where there is mechanistic overlap with sleep/circadian rhythm control.

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Drug Repurposing: Escitalopram attenuates acute lung injury by inhibiting the SIK2/ HDAC4/ NF-κB signaling cascade

Cited by 11 publications

References 24 publications

Histone deacetylase 4 and 5 translocation elicited by microsecond pulsed electric field exposure is mediated by kinase activity

Histone deacetylase 4 and 5 translocation elicited by microsecond pulsed electric field exposure is mediated by kinase activity

Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway

The multiple roles of salt-inducible kinases in regulating physiology

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