Pharmacological preconditioning with the cellular stress inducer thapsigargin protects against experimental sepsis

Wei, Yaping; Meng, Mei; Tian, Zhenyu; Xie, Fubo; Yin, Qihui; Dai, Chaochao; Wang, Jingjing; Zhang, Qunye; Liu, Yu; Liu, Chang; Yan, Feng; Jiang, Fan; Guo, Xinfeng

doi:10.1016/j.phrs.2018.12.017

Cited by 10 publications

(7 citation statements)

References 56 publications

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“…While thapsigargin had no effect on IL-8, IL-6, CXCL2 and CCL20 in cell culture (Fig. S7), a single bolus of the compound was shown to efficiently reduce the translation of pro-inflammatory cytokines in preclinical models of sepsis (Wei et al, 2019). Thus, an additional benefit of thapsigargin treatment may arise from dampening overshooting tissue inflammation in COVID-19 patients.…”

Section: Discussionmentioning

confidence: 97%

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Shaban

Müller

Mayr-Buro

et al. 2020

Preprint

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Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.One Sentence Summary / Running titleSuppression of coronavirus replication through thapsigargin-regulated ER stress, ERQC / ERAD and metabolic pathways

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Section: Discussionmentioning

confidence: 97%

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Shaban

Müller

Mayr-Buro

et al. 2020

Preprint

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“…While thapsigargin had no effect on IL-8, IL-6, CXCL2, and CCL20 in cell culture (Supplementary Fig. 11 ), a single bolus of the compound was shown to efficiently reduce the translation of pro-inflammatory cytokines in preclinical models of sepsis 96 . Thus, an additional benefit of thapsigargin treatment may arise from dampening overshooting tissue inflammation in COVID-19 patients.…”

Section: Discussionmentioning

confidence: 99%

Multi-level inhibition of coronavirus replication by chemical ER stress

et al. 2021

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Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types including primary differentiated human bronchial epithelial cells, (partially) reverses the virus-induced translational shut-down, improves viability of infected cells and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide analyses revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including essential (HERPUD1) or novel (UBA6 and ZNF622) factors of ER quality control, and ER-associated protein degradation complexes. Additionally, thapsigargin blocks the CoV-induced selective autophagic flux involving p62/SQSTM1. The data show that thapsigargin hits several central mechanisms required for CoV replication, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.

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“…Thapsigargin ( 13) is an inhibitor of the sarco/endoplasmic reticulum (ER) calcium ATPase (SERCA) pump. The blockage of the SERCA pump results in malfunction of cellular calcium homeostasis and exerts a critical role in normal cell metabolism, leading to apoptosis [236,237]. Moreover, this sesquiterpene lactone causes apoptosis at all stages of the cell cycle.…”

Section: Thapsigarginmentioning

confidence: 99%

Section: Thapsigarginmentioning

confidence: 99%

“…Zhong et al[250] proposed that thapsigargin causes vomiting by triggering the phosphorylation of CaMKIIα (Ca 2+ /calmodulin kinase IIα) and ERK1/2 (extracellular signal-regulated protein kinase 1/2) cascade in the brainstem. Pharmacological preconditioning with the cell-stress inducer thapsigargin (0.3 mg/kg) protects against experimental sepsis in male KM (Kunming) mice[237].Thapsigargin (13) is widely used as an experimental tool for endoplasmic reticulum stress inhibition and the discovery of new active therapeutic derivatives[232,251]. A new thapsigargin (13) derivative named mipsagargin, (8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-γ-Gluγ-Glu-γ-GluGluOH (14) (Figure10), has been developed for anticancer therapy, notably for the treatment of prostate cancer.…”

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confidence: 99%

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Applications of Sesquiterpene Lactones: A Review of Some Potential Success Cases

et al. 2020

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Sesquiterpene lactones, a vast range of terpenoids isolated from Asteraceae species, exhibit a broad spectrum of biological effects and several of them are already commercially available, such as artemisinin. Here the most recent and impactful results of in vivo, preclinical and clinical studies involving a selection of ten sesquiterpene lactones (alantolactone, arglabin, costunolide, cynaropicrin, helenalin, inuviscolide, lactucin, parthenolide, thapsigargin and tomentosin) are presented and discussed, along with some of their derivatives. In the authors’ opinion, these compounds have been neglected compared to others, although they could be of great use in developing important new pharmaceutical products. The selected sesquiterpenes show promising anticancer and anti-inflammatory effects, acting on various targets. Moreover, they exhibit antifungal, anxiolytic, analgesic, and antitrypanosomal activities. Several studies discussed here clearly show the potential that some of them have in combination therapy, as sensitizing agents to facilitate and enhance the action of drugs in clinical use. The derivatives show greater pharmacological value since they have better pharmacokinetics, stability, potency, and/or selectivity. All these natural terpenoids and their derivatives exhibit properties that invite further research by the scientific community.

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Pharmacological preconditioning with the cellular stress inducer thapsigargin protects against experimental sepsis

Cited by 10 publications

References 56 publications

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Multi-level inhibition of coronavirus replication by chemical ER stress

Applications of Sesquiterpene Lactones: A Review of Some Potential Success Cases

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