ABSTRACT
OBJECTIVE: The present study aimed to investigate the effect and molecular mechanism of the PKM2 small molecule agonist TEPP-46 on the development of methionine choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH) in mice. MATERIALS AND METHODS: In this study, C57BL/6 mice were fed an MCD diet for 15 days to establish a NASH model. The protein expression levels of pyruvate kinase M2 (PKM2), PKM1, hypoxia-inducible factor-1α (HIF-1α) and NLRP3 in liver Kupffer cells (KCs) were measured by Western blotting. Immunofluorescence analysis was used to analyze the nuclear translocation of PKM2 in KCs, and the levels of IL-1ß and TNF-α in mouse serum and the cell polarization indexes were determined. The MCD diet-fed mice were injected with 30 mg/kg of TEPP-46 intraperitoneally every 5 days. After 15 days, the liver tissue and peripheral blood were collected for analysis. RESULTS: We found the NASH model was successfully established after the mice were fed an MCD diet for 15 days. MCD feeding promoted the expression of the PKM2 monomer/dimer and inhibited the expression of the PKM2 tetramer in KCs. Immunofluorescence analysis further confirmed that MCD feeding inhibited the nuclear translocation of PKM2. Besides, MCD feeding promoted the expression of HIF-1α and NLRP3 in KCs, promoted M1 KCs polarization and inhibited M2 KCs polarization. Intraperitoneal injection 30 mg/kg of TEPP-46 significantly inhibited the development of MCD diet-induced NASH, alleviated the pathological changes in the liver, improved liver function, promoted the expression of the PKM2 tetramer in KCs, and inhibited the expression of HIF-1α and NLRP3. CONCLUSIONS: This study demonstrated that TEPP-46, a small molecule agonist of PKM2, may inhibit the nuclear translocation of PKM2 and the activation of KCs by promoting the expression of PKM2 tetramers in KCs, thus inhibiting the development of MCD diet-induced NASH in mice.
Subject(s)
Non-alcoholic Fatty Liver Disease/drug therapy , Pyridazines/therapeutic use , Pyrroles/therapeutic use , Pyruvate Kinase/metabolism , Animals , Choline , Cytokines/blood , Cytokines/genetics , Diet , Inflammasomes/genetics , Inflammasomes/metabolism , Kupffer Cells/drug effects , Kupffer Cells/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Methionine , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Pyridazines/pharmacology , Pyrroles/pharmacologyABSTRACT
Splenic artery steal syndrome (SASS) has gained attention as a complication involving the hepatic artery and can cause ischemia in a grafted liver. This article presents 3 patients with SASS, including their diagnosis and treatment. Contrast-enhanced ultrasonography and angiography are useful in diagnosing SASS, and splenic artery trunk embolization is an effective treatment. The purpose of this article is to reinforce the understanding of the development and progression of SASS.
Subject(s)
Embolization, Therapeutic , Hepatic Artery , Liver Transplantation/adverse effects , Postoperative Complications , Splenic Artery , Splenic Diseases , Vascular Diseases , Angiography , Contrast Media , Female , Humans , Ischemia/etiology , Liver/blood supply , Male , Middle Aged , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Postoperative Complications/therapy , Spleen/blood supply , Splenic Diseases/diagnosis , Splenic Diseases/etiology , Splenic Diseases/therapy , Transplants/blood supply , Treatment Outcome , Vascular Diseases/diagnosis , Vascular Diseases/etiology , Vascular Diseases/therapyABSTRACT
The protein composition of sputum most faithfully reflects the state of the lungs. The aim of this study was to determine whether relative qualitative and quantitative differences in protein expression of sputum could be related to active pulmonary tuberculosis. Sputum samples were collected from 65 patients with active pulmonary tuberculosis and 38 healthy controls. Comprehensive proteomic approaches were used to profile the proteome changes of host sputum in response to Mycobacterium tuberculosis infection using two-dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry. Mascot software was used to identify proteins from protein databases. Enzyme-linked immunosorbent assay was used to confirm the proteomic results. A total of 62 differentially expressed proteins were identified, among which, 15 proteins were up-regulated and 47 proteins were down-regulated in the tuberculosis sputum compared with the controls. Bacterial protein UqhC was the most increased protein, whereas serum albumin was the most decreased protein in the tuberculosis sputum compared with the controls. The enzyme-linked immunosorbent assay analysis was consistent with proteomic data. Bioinformatics analysis suggested that multiple host cell pathways were involved in the tuberculosis infection processes, including acute phase response, signal transduction, cytoskeleton structure, immune response and so on. In all, for the first time, our results revealed that a number of proteins were differentially expressed during active pulmonary tuberculosis infection. These data will provide valuable clues for further investigation of tuberculosis pathogenesis and biomarkers for detection of active pulmonary tuberculosis infection.
