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

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-1ß, 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.

Macrophage ICAM-1 functions as a regulator of phagocytosis in LPS induced endotoxemia.

OBJECTIVE: Intracellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein belonging to the immunoglobulin superfamily, plays a critical role in mediating cell-cell interaction and outside-in cell signaling during the immune response. ICAM-1 is expressed on the cell surface of several cell types including endothelial cells, epithelial cells, leucocytes, fibroblasts, and neutrophils. Despite ICAM-1 has been detected on macrophage, little is known about the function and mechanism of macrophage ICAM-1. METHODS: To investigate the role of lipopolysaccharide (LPS) in ICAM-1 regulation, both the protein and cell surface expression of ICAM-1 were measured. The phagocytosis of macrophage was evaluated by flow cytometry and Confocal microscopy. Small interfering RNA and neutralizing antibody of ICAM-1 were used to assess the effect of ICAM-1 on macrophage phagocytosis. TLR4 gene knockout mouse and cytoplasmic and mitochondrial ROS scavenger were used for the regulation of ICAM-1 expression. ROS was determined using flow cytometry. RESULTS: In this study, we reported that macrophage can be stimulated to increase both the protein and cell surface expression of ICAM-1 by LPS. Macrophage ICAM-1 expression was correlated with enhanced macrophage phagocytosis. We found that using ICAM-1 neutralizing antibody or ICAM-1 silencing to attenuate the function or expression of ICAM-1 could decrease LPS-induced macrophage phagocytosis. Furthermore, we found that knocking out of TLR4 led to inhibited cytoplasmic and mitochondrial ROS production, which in turn, attenuated ICAM-1 expression at both the protein and cell surface levels. CONCLUSION: This study demonstrates that the mechanism of ICAM-1-mediated macrophage phagocytosis is depending on TLR4-mediated ROS production and provides significant light on macrophage ICAM-1 in endotoxemia.

Effects of stellate ganglion block on early brain injury in patients with subarachnoid hemorrhage: a randomised control trial.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a common neurosurgical emergency, and early brain injury (EBI) plays an important role in acute brain injury of SAH. Our objective is to investigate the effect of stellate ganglion block (SGB) on the clinical prognosis of patients with SAH (registration number ChiCTR2000030910). METHODS: A randomized controlled trial was conducted with 102 participants. Patients with SAH were assigned to the SGB or nSGB group. Patients in the SGB group received SGB four times (once every other day starting on the day of the surgery). In contrast, patients in the nSGB group only received standard care. Data were collected on the day before surgery (T0) and on the 1st (T1), 3rd (T2) and 7th day (T3) after surgery. The primary outcomes included EBI markers (including IL-1ß, IL-6, TNF-α, ET-1, NPY, NSE and S100ß), the mean cerebral blood flow velocity of the middle cerebral artery (Vm-MCA) and the basilar artery (Vm-BA). All cases were followed up for 6 months after surgery. RESULTS: The levels of the EBI markers in both groups were higher at T1-T3 than at T0 (P<0.05), and the Vm-MCA and Vm-BA were also increased at the same times. However, the levels of the EBI markers were lower in the SGB group than in the nSGB group (P<0.05), and the increases of Vm-MCA and Vm-BA were also lower (P<0.05). The prognosis score and neurological deficit were better in the SGB group than in the nSGB group (P<0.05). CONCLUSIONS: SGB can improve the prognosis of SAH patients by inhibiting the inflammatory response during EBI and by reducing endothelial dysfunction and relieving CVS. TRIAL REGISTRATION: Clinical trial number: ChiCTR2000030910 ; Registry URL: Chinese Clinical Trial Registry; Principal investigator's name: Ying Nie; Date of Trial registration: March, 2020 (retrospectively registered).

Propofol inhibits parthanatos via ROS-ER-calcium-mitochondria signal pathway in vivo and vitro.

Parthanatos is a new form of programmed cell death. It has been recognized to be critical in cerebral ischemia-reperfusion injury, and reactive oxygen species (ROS) can induce parthanatos. Recent studies found that propofol, a widely used intravenous anesthetic agent, has an inhibitory effect on ROS and has neuroprotective in many neurological diseases. However, the functional roles and mechanisms of propofol in parthanatos remain unclear. Here, we discovered that the ROS-ER-calcium-mitochondria signal pathway mediated parthanatos and the significance of propofol in parthanatos. Next, we found that ROS overproduction would cause endoplasmic reticulum (ER) calcium release, leading to mitochondria depolarization with the loss of mitochondrial membrane potential. Mitochondria depolarization caused mitochondria to release more ROS, which, in turn, contributed to parthanatos. Also, we found that propofol inhibited parthanatos through impeding ROS overproduction, calcium release from ER, and mitochondrial depolarization in parthanatos. Importantly, our results indicated that propofol protected cerebral ischemia-reperfusion via parthanatos suppression, amelioration of mitochondria, and ER swelling. Our findings provide new insights into the mechanisms of how ER and mitochondria contribute to parthanatos. Furthermore, our studies elucidated that propofol has a vital role in parthanatos prevention in vivo and in vitro, and propofol can be a promising therapeutic approach for nerve injury patients.

Mig6 reduces inflammatory mediators production by regulating the activation of EGFR in LPS-induced endotoxemia.

Epithelial growth factor receptor (EGFR), a tyrosine kinase receptor, plays a critical role in lipopolysaccharide (LPS)-induced endotoxemia. Meanwhile, EGFR signaling is regulated by multiple feedback regulators, including mitogen-inducible gene 6 protein (Mig6). However, as an EGFR regulator, the role of Mig6 in endotoxemia is still remained unknown. Here, we reported for the first time that LPS treatment increased the expression of Mig6 and this effect could be inhibited by EGFR inhibitor, PD168393 or erlotinib. Furthermore, knocking down of Mig6 expression led to increased EGFR activation and inflammatory mediators (TNF-α, il-1ß) production in response to LPS treatment. On the other hand, the increased EGFR activation and TNF-α or il-1ß production in LPS treatment could be inhibited by Mig6 overexpression. Besides, in LPS-induced endotoxemia, ERK1/2 and p-38 activation required Mig6. All these results indicated that Mig6 regulates the production of inflammatory mediators (TNF-α, il-1ß) through inhibiting the over activation of EGFR, which in turn inhibit MAPKs signaling (ERK1/2, p-38). These finding suggested that Mig6 may be a novel potential target for controlling the over inflammatory response in endotoxemia.