Monitoring the Levels of Cellular NF-κB Activation States

Meier-Soelch, Johanna; Mayr-Buro, Christin; Juli, J. Unternaehrer; Leib, Lisa; Linne, Uwe; Dreute, Jan; Papantonis, Argyris; Schmitz, M. Lienhard

doi:10.3390/cancers13215351

Cited by 26 publications

(13 citation statements)

References 123 publications

(153 reference statements)

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“…The reason is that direct activity assays of these types are rather difficult to perform in vivo or in tissue homogenates. Nevertheless, there is ample information that the 65kD subunit of NF-κB functions as a potent transcriptional activator and a target for v-Rel-mediated repression [ 75 ], and therefore, if this subunit is lower, it is likely that the NF-κB system’s activity is also likely suppressed. Likewise, although the quantification of phosphorylated ERKs and ERK1/2 ratios is more common than the quantification of ERK1/ERK2 ratios, a direct relationship between the ratio of phosphorylated ERKs and the quantitative expression ratio of ERKs has been previously shown [ 76 ]; therefore, the ratio measured here may well give some indication regarding the activity of this pathway.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

Martins

Santos

Rodrigues

et al. 2022

Cells

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Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the clinical introduction of several novel, ultrapotent PARP inhibitors, the concept of PARP inhibitor repurposing has re-emerged. Here, we evaluated the effect of 5 clinical-stage PARP inhibitors in oxidatively stressed cultured human epithelial cells and monocytes in vitro and demonstrated that all inhibitors (1–30 µM) provide a comparable degree of cytoprotection. Subsequent in vivo studies using a murine model of ALI compared the efficacy of olaparib and rucaparib. Both inhibitors (1–10 mg/kg) provided beneficial effects against lung extravasation and pro-inflammatory mediator production—both in pre- and post-treatment paradigms. The underlying mechanisms include protection against cell dysfunction/necrosis, inhibition of NF-kB and caspase 3 activation, suppression of the NLRP3 inflammasome, and the modulation of pro-inflammatory mediators. Importantly, the efficacy of PARP inhibitors was demonstrated without any potentiation of DNA damage, at least as assessed by the TUNEL method. These results support the concept that clinically approved PARP inhibitors may be repurposable for the experimental therapy of ALI.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

Martins

Santos

Rodrigues

et al. 2022

Cells

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“…Activation of the NF-κB signaling pathway promotes the expression of its downstream inflammation-related genes ( 33 , 34 ). It has been reported that NF-κB pathway activation induces the production of NLRP3, which in turn triggers the recruitment of the bridging protein ASC and caspase-1 to form a macromolecular complex in which caspase-1 is activated.…”

Section: Discussionunclassified

Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis

Ma¹,

Xing²,

Pei³

et al. 2022

Ann Transl Med

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Background: Ischemia-reperfusion injury (IRI) severely limits the efficacy and donor source of liver transplantation, and the crucial step in alleviating it is to control inflammation. Itaconic acid is a metabolite produced by intrinsic immune cells (especially macrophages) in the inflammatory state and can promote inflammation subsidence. However, its role in liver ischemia-reperfusion is insufficiently clarified.Methods: A mouse liver ischemia-reperfusion model was constructed, and blood and liver tissue samples were collected by sequential euthanasia of mice at pre-set time points. Liver function and inflammatory factor concentrations were measured, and HE staining was conducted. In the hypoxia-reoxygenation model, proteins were collected at pre-set time points, and the expression of NF-κB pathway-associated protein and its downstream inflammation-associated protein NLRP3 and caspase-1 were detected by Western blot, immunohistochemistry, and immunofluorescence. The level of P-P65 in the nucleus was detected by immunofluorescence.Results: In the liver ischemia-reperfusion model, liver function and inflammatory factors were dynamically varied with reperfusion time in mice, and itaconic acid significantly modified liver function and inflammatory status during this process. NF-κB pathway activity was dynamically varied during hypoxia-reoxygenation, and itaconic acid significantly inhibited the activity of the pathway and significantly suppressed the expression of its downstream inflammation-related proteins.Conclusions: Itaconic acid inhibits NF-κB pathway activation and reduces the accumulation of P-P65 in the nucleus. In turn, this reduces NLRP3 and caspase-1 expression of downstream inflammation-related proteins, promotes inflammation regression, and attenuates liver IRI.

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“…However, some studies in vivo showed that the increased NF-κB activity in macrophages resulted in reduced tumor burden and persistent macrophage M1 polarization [ 165 ]. There are five members of the NF-κB family of transcription factors: p65 (RELA), p50 (NFKB1), p52 (NFKB2), c-REL, and RELB [ 166 ]. These members can couple to form different homo- or heterodimers, which have opposing effects on macrophage polarization, depending on the source of macrophage populations and the way that macrophages are activated [ 167 ].…”

Section: Hypoxia-driven Crosstalk Between Tumor Cells and Tamsmentioning

confidence: 99%

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

et al. 2022

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Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.

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Monitoring the Levels of Cellular NF-κB Activation States

Cited by 26 publications

References 123 publications

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

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