Sorafenib inhibits LPS-induced inflammation by regulating Lyn-MAPK-NF-kB/AP-1 pathway and TLR4 expression

Abstract

Sorafenib is an anti-tumor drug widely used in clinical treatment, which can inhibit tyrosine kinase receptor on cell surface and serine/threonine kinase in downstream Ras/MAPK cascade signaling pathway of cells. Tyrosine kinase phosphorylation plays an important role in inflammatory mechanism, such as TLR4 tyrosine phosphorylation, MAPK pathway protein activation, and activation of downstream NF-кB. However, the effects of sorafenib on LPS-induced inflammatory reaction and its specific mechanism have still remained unknown. We found that sorafenib inhibited the phosphorylation of tyrosine kinase Lyn induced by LPS, thereby reducing the phosphorylation level of p38 and JNK, inhibiting the activation of c-Jun and NF-κB, and then inhibiting the expression of inflammatory factors IL-6, IL-1β, and TNF-α. Furthermore, sorafenib also decreased the expression of TLR4 on the macrophage membrane to inhibit the expression of inflammatory factors latterly, which may be related to the inactivation of Lyn. These results provide a new perspective and direction for the clinical treatment of sepsis.

Pomegranate Peel Extract Sensitizes Hepatocellular Carcinoma Cells to Ionizing Radiation, Induces Apoptosis and Inhibits MAPK, JAK/STAT3, β-Catenin/NOTCH, and SOCS3 Signaling

“…Interestingly, complex connections exist between the NF-kB signal transduction pathway and many biochemical pathways. 24 …”

“…Interestingly, complex connections exist between the NF-kB signal transduction pathway and many biochemical pathways. 24 Janus kinase/signal transducer activator of transcription factor (JAK/STAT), as well as the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ ERK), Wnt/β-catenin are a number of molecular cellular pathways that are essential for the development, growth, and metastasis of HCC tumors. 25 Liver cancer, typically activates the MAPK/ERK signaling cascade.…”

Conditionalin vivodeletion of LYN kinase has little effect on aBRCA1loss-of-function-associated mammary tumour model

“…MEK and IKKα, which activates NFkB signalling, were shown to be downstream targets of LYN in an analysis of the kinomes of imatinib-sensitive and resistant leukaemia cells (Cooper et al, 2013). LYN is required for TLR2-mediated NFkB activation though PI3K signalling in HEK293 cells engineered to express TLR2 (Toubiana et al, 2015) while TLR4-mediated NFkB activation in macrophages as a response to LPS treatment is associated with LYN activation and subsequent activation of downstream MAP pathways (Li et al, 2022). Furthermore, Lyn -/- mast cells show less MAPK and IkB phosphorylation and less NFkB nuclear translocation after TLR4 triggering than wild type cells (Avila et al, 2012).…”

Targeting SARS-CoV-2 Main Protease (MPro) with Kinase Inhibitors: A Promising Approach for Discovering Antiviral and Anti-inflammatory Molecules against SARS-CoV-2

“…25−27 On the other hand, Sorafenib is a multiple kinase inhibitor, with action in the Raf/MEK/ERK signaling pathway; more recently, its antiinflammatory effects have also been proposed. 28,29 All inhibitors described above have the potential to be effective against the consequences of cytokine storm typically observed in SARS-CoV-2 infections. Although some of them have been tested in clinical trials for COVID-19 treatment due to their reported anti-inflammatory activities, none were evaluated as potential SARS-CoV-2 MPro inhibitors.…”

“…Clinical trials are evaluating the potential of kinases inhibitors in COVID-19 treatment. , The promising compounds in clinic to treat the inflammatory phase of COVID-19 are JAK-inhibitorsBaricitinib, Ruxolitinib, and Tofacitinib being well known for their anti-inflammatories activities. − MAPK are responsible for regulating inflammatory responses in mammalian cells, consisting of p38, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) . Compounds BIRB-796 (Doramapimod) and Skepinone-L are p38 MAPK inhibitors with potential to treat several types of cancer, as well as inflammatory chronic diseases. − On the other hand, Sorafenib is a multiple kinase inhibitor, with action in the Raf/MEK/ERK signaling pathway; more recently, its anti-inflammatory effects have also been proposed. , All inhibitors described above have the potential to be effective against the consequences of cytokine storm typically observed in SARS-CoV-2 infections. Although some of them have been tested in clinical trials for COVID-19 treatment due to their reported anti-inflammatory activities, none were evaluated as potential SARS-CoV-2 MPro inhibitors.…”