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Extracellular vesicles (EVs) have emerged as important vectors of intercellular dialogue. High mobility group box protein 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, which is cytotoxic and leads to cell death and tissue injury. Whether EVs are involved in the release of HMGB1 in lipopolysaccharide (LPS)-induced acute liver injuries need more investigation. EVs were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The co-localization of HMGB1, RAGE (receptor for advanced glycation end-products), EEA1, Rab5, Rab7, Lamp1 and transferrin were detected by confocal microscopy. The interaction of HMGB1 and RAGE were investigated by co-immunoprecipitation. EVs were labeled with the PKH67 and used for uptake experiments. The pyroptotic cell death was determined by FLICA 660-YVAD-FMK. The expression of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasomes were analyzed by western-blot or immunohistochemistry. Serum HMGB1, ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase) and MPO (myeloperoxidase) were measured using a commercial kit. The extracellular vesicle HMGB1 was detected in the serums of sepsis patients. Macrophages were found to contribute to HMGB1 release through the EVs. HMGB1-RAGE interactions participated in the loading of HMGB1 into the EVs. These EVs shuttled HMGB1 to target cells by transferrin-mediated endocytosis leading to hepatocyte pyroptosis by the activation of NLRP3 inflammasomes. Moreover, a positive correlation was verified between the sepsis serum EVs-HMGB1 level and clinical liver damage. This finding provides insights for the development of novel diagnostic and therapeutic strategies for acute liver injuries.

Aberrant expression of miR-224 is usually found in cancer studies; however, the role of miR-224 has seldom been reported in bladder cancer (BC). We explored miR-224's function and the underlying mechanism in BC. It was found that miR-224 expression was significantly up-regulated in BC tissues and cell lines. Knockdown of miR-224 decreased BC cell growth and invasion both in vitro and in vivo. We identified the SUFU protein as a downstream target of miR-224 by using luciferase and western blot assays. We proposed that miR-224 promoted BC cell growth and invasion via sustaining the activity of Hedgehog pathway, which was negatively regulated by SUFU. Taken together, our study demonstrated that miR-224 may function as an onco-miR in BC and suggested that miR-224 may be a potential therapeutic target for BC patients.

Background: Liver injury is a common feature of heat stroke (HS). Exosomes, which are recognized as a novel cell-cell communication pathway that harbour functional cargo, may be involved in the pathogenesis underlying HS. However, little is known about the role of hepatocyte-derived exosomes in HS liver injury and their protein expression patterns under HS. Methods: In this study, isobaric tags for relative and absolute quantitation (iTRAQ) technology with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were applied to explore changes in the proteomic profiles of HS-hepatocyte exosomes. Findings: In total, 53 and 21 proteins were identified as up- and downregulated in the HS-exosomes. Based on bioinformatics analysis using gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) pathway database, we found that regulation of programmed cell death was the most significantly altered pathway. Next, a candidate protein (TRAIL, TNF-related apoptosis-inducing ligand) that played a central role in the target pathway was chosen for validation. Western blotting clearly demonstrated enrichment of TRAIL in the HS-exosomes. We also confirmed that serum exosomal TRAIL could be used as a clinical marker for disease severity assessment and prognostic prediction of HS liver injury. Interpretation: Taken together, this study presented the first comprehensive analysis of the HS-hepatocyte exosomal proteome, confirming the induction of HS liver injury by exosomes and revealing novel potential pathways and proteins awaiting further investigation for clinical application. Funding Statement: This work was supported by the National Natural Science Foundation of China (grant No. 81471839, No. 81671896 and No. 81873583). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All animal experiments were conducted in compliance with the criteria outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication 86-23, 1985 revision) and were approved by the Animal Care and Use Committee of the General Hospital of Guangzhou Military Command.

Aims: Angiotensin II (AngII), a vasoconstrictive peptide of the renin–angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1–7) [Ang-(1–7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1β axis in liver fibrosis. Results: In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1–7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-κB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1–7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects. Innovation and Conclusions: Mir-21 mediates AngII-activated NLRP3 inflammasome and resultant HSC activation via targeting Spry1 and Smad7. Ang-(1–7) protected against BDL or AngII infusion-induced hepatic fibrosis and inhibited mir-21 expression. Antioxid. Redox Signal. 27, 1–20.

To investigate the effect of losartan in regulating oxidative stress and the underlying mechanism in mice with ventilator-induced lung injury.Thirty-six male C57 mice were randomly divided into control group, losartan treatment group, mechanical ventilation model group, and ventilation plus losartan treatment group. After the corresponding treatments, the lung injuries in each group were examined and the expressions of caveolin-1 and NOX4 in the lung tissues were detected.The mean Smith score of lung injury was significantly higher in mechanical ventilation model group (3.3) than in the control group (0.4), and losartan treatment group (0.3); the mean score was significantly lowered in ventilation plus losartan treatment group (2.3) compared with that in the model group (P0.05). The expressions of caveolin-1 and NOX4 were significantly higher in the model group than in the control and losartan treatment groups (P0.05) but was obviously lowered after losartan treatment (P0.05). Co-expression of caveolin-1 and NOX4 in the lungs was observed in the model group, and was significantly decreased after losartan treatment.Losartan can alleviate ventilator-induced lung injury in mice and inhibit the expression of caveolin-1 and NOX4 and their interaction in the lungs.