Hepatocyte-Conditional Knockout of Phosphatidylethanolamine Binding Protein 4 Aggravated LPS/D-GalN-Induced Acute Liver Injury via the TLR4/NF-κB Pathway.

Acute liver injury (ALI) is a disease that seriously threatens human health and life, and a dysregulated inflammation response is one of the main mechanisms of ALI induced by various factors. Phosphatidylethanolamine binding protein 4 (PEBP4) is a secreted protein with multiple biological functions. At present, studies on PEBP4 exist mainly in the field of tumors and rarely in inflammation. This study aimed to explore the potential roles and mechanisms of PEBP4 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALI. PEBP4 was downregulated after treatment with LPS/D-GalN in wild-type mice. PEBP4 hepatocyte-conditional knockout (CKO) aggravated liver damage and repressed liver functions, including hepatocellular edema, red blood cell infiltration, and increased aspartate aminotransferase (AST)/alanine aminotrans-ferase (ALT) activities. The inflammatory response was promoted through increased neutrophil infiltration, myeloperoxidase (MPO) activities, and cytokine secretions (interleukin-1ß, IL-1ß; tumor necrosis factor alpha, TNF-α; and cyclooxygenase-2, COX-2) in PEBP4 CKO mice. PEBP4 CKO also induced an apoptotic effect, including increasing the degree of apoptotic hepatocytes, the expressions and activities of caspases, and pro-apoptotic factor Bax while decreasing anti-apoptotic factor Bcl-2. Furthermore, the data demonstrated the levels of Toll-like receptor 4 (TLR4), phosphorylation-inhibitor of nuclear factor kappaB Alpha (p-IκB-α), and nuclear factor kappaB (NF-κB) p65 were upregulated, while the expressions of cytoplasmic IκB-α and NF-κB p65 were downregulated after PEBP4 CKO. More importantly, both the NF-κB inhibitor (Ammonium pyrrolidinedithiocarbamate, PDTC) and a small-molecule inhibitor of TLR4 (TAK-242) could inhibit TLR4/NF-κB signaling activation and reverse the effects of PEBP4 CKO. In summary, the data suggested that hepatocyte-conditional knockout of PEBP4 aggravated LPS/D-GalN-induced ALI, and the effect is partly mediated by activation of the TLR4/NF-κB signaling pathway.

The Roles And Signaling Pathways Of Phosphatidylethanolamine-Binding Protein 4 In Tumors.

Phosphatidylethanolamine-binding protein 4 (PEBP4) has been found to be highly expressed in many tumors and to be closely related to the proliferation, differentiation, and metastasis of tumors. PEBP4 has also been found to be involved in many cancer-activated signaling pathways and to cause therapeutic resistance. In this study, we first reviewed the morphological structure and expression of PEBP4, then discussed the roles of PEBP4 in individualized treatment of some cancers, and finally explored the possibilities of cultivating PEBP4 as a therapeutic target.We also identified the main signaling pathways in which PEBP4 affects different cancers. It is here concluded that over-expression of PEBP4 can enhance the proliferation and metastasis of the cancer cells and the resistance to radiotherapy/chemotherapy in cancers.

BML-111, a lipoxin receptor agonist, protects against acute injury via regulating the renin angiotensin-aldosterone system.

BACKGROUND: The renin angiotensin-aldosterone system (RAAS) and lipoxins (LXs) have similar roles in many processes. We previously reported that BML-111, a Lipoxin receptor agonist, inhibited chronic injury hepatic fibrosis by regulating RAAS, but whether LXs are involved in BML-111-mediated protection from acute injury is unclear still. METHODS: We established models of acute liver/lung injury and confirmed them with histopathology and myeloperoxidase (MPO) measurements. BML-111, a lipoxin receptor agonist, was applied to mimic the effects of LXs. The contents and activities of angiotensin converting enzyme(ACE) and angiotensinconverting enzyme 2 (ACE2) were measured through ELISA and activity assay kits respectively. Angiotensin II (AngII), angiotensin-(1-7) (Ang-1-7), AngII type 1 receptor (AT1R), and Mas receptor were quantified with ELISA and Western blot. RESULTS: Models of acute injury were established successfully and BML-111 protected LPS-induced acute lung injury and LPS/D-GalN-induced acute liver injury. BML-111 repressed the activity of ACE, but increased the activity of ACE2. BML-111 decreased the expression levels of ACE, AngII, and AT1R, meanwhile increased the levels of ACE2, Ang-(1-7), and Mas. Furthermore, BOC-2, an inhibitor of lipoxin receptor, reversed all the effects. CONCLUSION: BML-111 could protect against acute injury via regulation RAAS.

Lipoxin A4 attenuates LPS-induced acute lung injury via activation of the ACE2-Ang-(1-7)-Mas axis.

Previous studies have reported that lipoxin A4 (LXA4) and the angiotensin I-converting enzyme 2 (ACE2), angiotensin-(1-7) [Ang-(1-7)], and its receptor Mas [ACE2-Ang-(1-7)-Mas] axis play important protective roles in acute lung injury (ALI). However, there is still no direct evidence of LXA4-mediated protection via the ACE2-Ang-(1-7)-Mas axis during ALI. This work was performed using an LPS-induced ALI mouse model and the data indicated the following. First, the animal model was established successfully and LXA4 ameliorated LPS-induced ALI. Second, LXA4 could increase the concentration and activity of ACE2 and the levels of Ang-(1-7) and Mas markedly. Third, LXA4 decreased the levels of TNF-α, IL-1ß, and reactive oxygen species while increasing IL-10 levels. Fourth, LXA4 inhibited the activation of the NF-κB signal pathway and repressed the degradation of inhibitor of NF-κB, the phosphorylation of NF-κB, and the translocation of NF-κB. Finally, and more importantly, BOC-2 (LXA4 receptor inhibitor), MLN-4760 (ACE2 inhibitor), and A779 (Mas receptor antagonist) were found to reverse all of the effects of LXA4. Our data provide evidence that LXA4 protects the lung from ALI through regulation of the ACE2-Ang-(1-7)-Mas axis.