USP7 upregulated by TGF-ß1 promotes ferroptosis via inhibiting LATS1-YAP axis in sepsis-induced acute lung injury.

Our work aimed to investigate the interactive roles of transforming growth factor ß1 (TGF-ß1), ubiquitin-specific-processing protease 7 (USP7), and Yes-associated protein (YAP) in ferroptosis during sepsis-secondary acute lung injury (ALI). Our study demonstrated that ferroptosis was aggravated by TGF-ß1 in both cellular and animal models of acute lung injury. Additionally, YAP upregulated glutathione peroxidase 4 (GPX4) and SLC7A11 by regulating the binding of TEAD4 to GPX4/SLC7A11 promoters. Furthermore, large tumor suppressor kinase 1 (LATS1) knockdown resulted in YAP expression stimulation, while USP7 downregulated YAP via deubiquitinating and stabilizing LATS1/2. YAP overexpression or USP7/LATS1 silencing reduced ferroptosis process, which regulated YAP through a feedback loop. However, TGF-ß1 annulled the repression of ferroptosis by YAP overexpression or LATS1/USP7 knockdown. By elucidating the molecular interactions between TGF-ß1, USP7, LATS1/2, and YAP, we identified a new regulatory axis of ferroptosis in sepsis-secondary ALI. Our study sheds light on the pathophysiology of ferroptosis and proposes a potential therapeutic approach for sepsis-induced ALI.

Synthesis of Ottonia anisum Extract Mediated ZnO NPs and Their Local Anesthetic, Analgesic and HCl­induced Acute Lung Injury Activities.

In this study, we outlined the green synthesis of Zinc oxide nanoparticles (ZnO NPs) using the plant-mediated method. Employing the nitrate derivative of Zinc and the extract from the native medicinal plant, Ottonia anisum, the nanoparticles were effectively produced. After obtaining a yellow-colored paste, it was meticulously dried, gathered, and set aside for subsequent examination. The UV-visible spectrometry analysis indicated an absorption peak at 320 nm, which is indicative of ZnO NPs. Characterization techniques, such as XRD and HR-TEM, confirmed the existence of agglomerated ZnO NPs with an average diameter of 40 nm. Through EDS analysis, distinct energy signals for both Zinc and Oxygen were observed, confirming their composition. Furthermore, FT-IR spectroscopy highlighted an absorption peak for Zn-O bonding in the range of 400 to 600 cm -1 . Further, we employed three distinct pain models in mice to evaluate the influence of ZnO NPs on the nociceptive threshold. Our findings revealed that, when orally administered, ZnO NPs at concentrations ranging from 5-20 mg/kg exerted a dose-dependent analgesic effect in both the hot-plate and the acetic acid-induced writhing tests. Moreover, when ZnO NPs were administered at doses between 2.5-10 mg/kg, there was a notable reduction in pain responses during both the initial and subsequent phases of the formalin test, but no change in PGE 2 production within the mice's hind paw was found. On the other hand, acute lung injury studies revealed that the administration of ZnO NPs orally 90 minutes prior to HCl instillation decreased the neutrophil infiltration into the lungs in a doseresponsive manner. This reduction in pulmonary inflammation was paralleled by a significant decrease in lung edema, as evidenced by the reduced total protein content in the BALF. Additionally, the ZnO NPs appeared to recalibrate the lung's redox equilibrium following HCl exposure, which was determined through measurements of ROS, malondialdehyde, glutathione, and catalase activity. All these results further indicated the potential of biofabricated ZnO NPs for future applications in analgesics and acute lung injury treatments.

HOXA5-induced lncRNA DNM3OS promotes human embryo lung fibroblast fibrosis via recruiting EZH2 to epigenetically suppress TSC2 expression.

Background: Idiopathic pulmonary fibrosis (IPF) is an unrepairable disease that results in lung dysfunction and decreased quality of life. Prevention of pulmonary fibrosis is challenging, while its pathogenesis remains largely unknown. Herein, we investigated the effect and mechanism of long non-coding RNA (lncRNA) DNM3OS/Antisense RNA in the pathogenesis of pulmonary fibrosis. Methods: EdU (5-ethynyl-2'-deoxyuridine) and wound healing assays were employed to evaluate the role of DNM3OS on cell proliferation and migration. Western blot detected the proteins expressions of alpha-smooth muscle actin (α-SMA), vimentin, and fibronectin. The interactions among genes were evaluated by RNA pull-down, luciferase reporter, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and chromatin Isolation by RNA purification (ChIRP) assays. Results: DNM3OS was upregulated by transforming growth factor beta 1 (TGF-ß1) in a dose- and time-dependent manner. DNM3OS knockdown repressed the growth and migration of lung fibroblast, and fibrotic gene expression (CoL1α1, CoL3α1, α-SMA, vimentin, and fibronectin), while suppression of TSC2 accelerated the above process. DNM3OS recruited EZH2 to the promoter region of TSC2, increased the occupancy of EZH2 and H3K27me3, and thereby suppressed the expression of TSC2. HOXA5 promoted the transcription of DNM3OS. Conclusions: HOXA5-induced DNM3OS promoted the proliferation, migration, and expression of fibrosis-related genes in human embryo lung fibroblast via recruiting EZH2 to epigenetically suppress the expression of TSC2.

Black titanium dioxide@manganese dioxide for glutathione-responsive MR imaging and enhanced photothermal therapy.

Multifunctional nanoprobes with tumor microenvironment response are playing important roles in highly efficient theranostics of cancers. Herein, a kind of theranostic nanoprobe was synthesized by coating manganese dioxide (MnO2) on the surface of black commercial P25 titanium dioxide (b-P25). The resultant nanoprobe (b-P25@MnO2) possessed glutathione (GSH)-responsive magnetic resonance (MR) imaging and enhanced photothermal therapy (PTT). In tumor microenvironments, the excessive GSH was consumed by reacting with MnO2 to generate Mn2+ for GSH-responsive MR imaging, in which the longitudinal relaxation rate of b-P25@MnO2 was up to 30.44 mM-1 s-1, showing excellent cellular and intratumoral MR imaging. Moreover, the prepared b-P25@MnO2 exhibited stable and strong photothermal conversion capability with a high photothermal conversion efficiency of 30.67%, by which the 4T1 tumors disappeared completely, indicating safe and highly efficient PTT performance. The current work developed GSH-responsive b-P25@MnO2 nanoprobes, demonstrated for MR imaging and enhanced PTT in cancers.

In vivo multiparametric magnetic resonance imaging study for differentiating the severity of hepatic warm ischemia-reperfusion injury in a rabbit model.

OBJECTIVES: To assess the value of multiparametric magnetic resonance imaging including intravoxel incoherent motion (IVIM), diffusion tensor imaging (DTI) and blood oxygen level dependent (BOLD) MRI in differentiating the severity of hepatic warm ischemia-reperfusion injury (WIRI) in a rabbit model. METHODS: Fifty rabbits were randomly divided into a sham-operation group and four test groups (n = 10 for each group) according to different hepatic warm ischemia times. IVIM, DTI and BOLD MRI were performed on a 3 T MR scanner with 11 b values (0 to 800 s/mm2), 2 b values (0 and 500 s/mm2) on 12 diffusion directions, multiple-echo gradient echo (GRE) sequences (TR/TE, 75/2.57-24.25 ms), respectively. IVIM, DTI and BOLD MRI parameters, hepatic biochemical and histopathological parameters were compared. Pearson and Spearman correlation methods were performed to assess the correlation between these MRI parameters and laboratory parameters. Furthermore, receiver operating characteristic (ROC) curves were compiled to determine diagnostic efficacies. RESULTS: True diffusion (Dslow), pseudodiffusion (Dfast), perfusion fraction (PF), mean diffusivity (MD) significantly decreased, while R2* significantly increased with prolonged warm ischemia times, and significant differences were found in all of biochemical and histopathological parameters (all P < 0.05). Dslow, PF, and R2* correlated significantly with all of biochemical and histopathological parameters (all |r| = 0.381-0.746, all P < 0.05). ROC analysis showed that the area under the ROC curve (AUC) of IVIM across hepatic WIRI groups was the largest among IVIM, DTI and BOLD. CONCLUSIONS: Multiparametric MRI may be helpful with characterization of early changes and determination of severity of hepatic WIRI in a rabbit model.