Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice.

Reactive oxygen species (ROS) can induce oxidative injury and are generally regarded as toxic byproducts, although they are increasingly recognized for their signaling functions. Increased ROS often accompanies liver regeneration (LR) after liver injuries, however, their role in LR and the underlying mechanism remains unclear. Here, by employing a mouse LR model of partial hepatectomy (PHx), we found that PHx induced rapid increases of mitochondrial hydrogen peroxide (H2O2) and intracellular H2O2 at an early stage, using a mitochondria-specific probe. Scavenging mitochondrial H2O2 in mice with liver-specific overexpression of mitochondria-targeted catalase (mCAT) decreased intracellular H2O2 and compromised LR, while NADPH oxidases (NOXs) inhibition did not affect intracellular H2O2 or LR, indicating that mitochondria-derived H2O2 played an essential role in LR after PHx. Furthermore, pharmacological activation of FoxO3a impaired the H2O2-triggered LR, while liver-specific knockdown of FoxO3a by CRISPR-Cas9 technology almost abolished the inhibition of LR by overexpression of mCAT, demonstrating that FoxO3a signaling pathway mediated mitochondria-derived H2O2 triggered LR after PHx. Our findings uncover the beneficial roles of mitochondrial H2O2 and the redox-regulated underlying mechanisms during LR, which shed light on potential therapeutic interventions for LR-related liver injury. Importantly, these findings also indicate that improper antioxidative intervention might impair LR and delay the recovery of LR-related diseases in clinics.

Liquid-Phase Epitaxial Growth of Azapyrene-Based Chiral Metal-Organic Framework Thin Films for Circularly Polarized Luminescence.

Development of chiral metal-organic frameworks (MOFs) for circularly polarized luminescence (CPL) is a challenging but important task. In this work, we report a first example of azapyrene-based chiral MOF thin films [Zn2Cam2DAP]n grown on functionalized substrates (named SURchirMOF-4) for CPL property. By using a liquid-phase epitaxial layer-by-layer method, the resulted SURchirMOF-4 was constructed from chiral camphoric acid and 2,7-diazapyrene ligand, which has high orientation and homogeneity. The circular dichroism, CPL, and enantioselective adsorption results show that SURchirMOF-4 has strong chirality and CPL property as well as good enantioselective adsorption toward enantiomers of methyl-lactate. The synthesis of azapyrene-based chiral MOF thin films not only represents an ideal model for studying the enantioselective adsorption, but also will be a valuable approach for development of the chiral thin film exhibiting CPL property.

[Effect of extract of ginkgo biloba leaves on the precondition of liver graft in rat liver transplantation].

OBJECTIVE: To explore the effect of extract of ginkgo biloba leaves on the precondition of liver graft in rat liver transplantation. METHODS: Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation (OLT), and were randomly divided into extract of ginkgo biloba leaves group (Egb), NS control group (NS), and sham operation group (SO) according to whether the extract of ginkgo biloba leaves was injected by the venous (40 mg/kg) 1 h before the liver grafts harvesting. The rats were killed at 2 h, 6 h, and 24 h after the ischemia/reperfusion. The serum concentrations of ALT and AST were determined and the liver tissue were sampled to observe the expression of TNF-alpha and IL-1. RESULTS: After the ischemia/reperfusion the serum concentration of ALT and AST and expressions of TNF-alpha and IL-1 in the hepatic tissue in the NS group significantly increased (p<0.01), and the hepatocytic morphologic change was obvious compared with the SO group. The treatment of ginkgo biloba extract significantly decreased the serum concentration of ALT and AST and the expressions of TNF-alpha and IL-1 in the hepatic tissue in EGb group compared with the NS group (p<0.01), and relieved the hepatocyte swelling and necrosis. CONCLUSION: Ginkgo bilobA extract may decrease the release of TNF-alpha and IL-1 by inhibiting activation of kuffer cells and regulate the cell factors to protect the live.

Peroxisome proliferator-activated receptor-γ agonist inhibits collagen synthesis in human keloid fibroblasts by suppression of early growth response-1 expression through upregulation of miR-543 expression.

A keloid is a benign skin tumor formed by an overgrowth of granulation tissue in affected patients. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists were reported to be able to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanism of PPAR-γ agonist troglitazone treatment for fibroblasts obtained from keloid patients. The data revealed that troglitazone treatment of keloid fibroblasts (KFs) downregulated the expression of early growth response-1 (Egr1) and collagen-1 (Col1). Level of Egr1 were closely associated with KF-induced fibrosis. The miRNA profiling data revealed that miR-543 was transcriptionally activated after troglitazone treatment. Bioinformatic analysis and experimental data showed that miR-543 was able to target Egr1. ELISA data confirmed that Col1 protein in the supernatant were modulated by the feedback regulatory axis of PPAR-γ agonist-induced miR-543 to inhibit Egr1 expression, whereas PPAR-γ antagonist treatment abolished such effect on Col1 suppression in KFs. This study demonstrated that the PPAR-γ agonist-mediated miR-543 and Egr1 signaling plays an important role in the suppression of collagen synthesis in KFs. Future in vivo studies are needed to confirm these in vitro data.

Peroxisome proliferator-activated receptor-γ agonist troglitazone suppresses transforming growth factor-ß1 signalling through miR-92b upregulation-inhibited Axl expression in human keloid fibroblasts in vitro.

Keloid, a skin benign tumor, is characterized by overgrowth of fibroblasts and the excessive deposition of extracellular matrix in wounded skin. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist was recently evaluated to inhibit fibrosis. This study explored the underlying mechanisms. Fibroblasts isolated from 25 keloid patients (KFs) and fibroblasts isolated from healthy controls (NSFBs) were also subjected to treatment with PPAR-γ agonist troglitazone and antagonist GW9662 or for transfection with miR-92 mimics or inhibitor, Axl siRNA, and miR-92b or Axl promoter constructs, as well as being subjected to qRT-PCR, ELISA, Western blot, protein array, luciferase, and ChIP assays. The data demonstrated that TGF-ß1 and Axl proteins were significantly elevated in samples from keloid patients, while troglitazone treatment significantly reduced levels of TGF-ß1 and Axl mRNA and proteins in KFs. Moreover, knockdown of Axl expression reduced expression of TGF-ß1 and its pathway genes (such as α-SMA and Snail). PPAR-γ regulation of Axl expression was through transcriptional activation of miR-92b. miR-92b expression downregulated Axl expression at both mRNA and protein levels, whereas GW9662 completely reversed the inhibitory effects of miR-92b mimics on Axl expression. Gene ontology analysis of miR-92b targeting genes showed that TGF-ß and Axl were both potential targets of miR-92b, as confirmed by luciferase assay. These findings demonstrated that PPAR-γ-induced miR-92b expression inhibited Axl expression and in turn reduced expression of TGF-ß1 and the downstream genes in KFs, suggesting that targeting of this novel gene pathway may be useful for therapeutic control of fibrosis or keloid.

Knockdown of lncRNA-ATB suppresses autocrine secretion of TGF-ß2 by targeting ZNF217 via miR-200c in keloid fibroblasts.

Abnormally high activation of transforming growth factor-ß (TGF-ß) signaling has been demonstrated to be involved in the initiation and progression of keloids. However, the functional role of long non-coding RNA (lncRNA)-activated by TGF-ß (lncRNA-ATB) in keloids has not been documented. Here we investigated the role of lncRNA-ATB in the autocrine secretion of TGF-ß in keloid fibroblasts (KFs) and explored the underlying molecular mechanism. Using immunohistochemistry and quantitative RT-PCR analysis, we showed that lncRNA-ATB and ZNF217, a transcriptional activator of TGF-ß, were overexpressed and miR-200c, which targets ZNF217, was under-expressed in keloid tissue and keloid fibroblasts. Through gain- and loss-of-function studies, we demonstrated that knockdown of lncRNA-ATB decreased autocrine secretion of TGF-ß2 and ZNF217 expression but upregulated expression of miR-200c in KFs. Stable downregulation of ZNF217 expression decreased the autocrine secretion of TGF-ß2. miR-200c was endogenously associated with lncRNA-ATB, and inhibition of miR-200c overcame the decrease in ZNF217 expression in KFs. Taken together, these findings indicate that lncRNA-ATB governs the autocrine secretion of TGF-ß2 in KFs, at least in part, by downregulating the expression level of ZNF217 via miR-200c, suggesting a signaling axis consisting of lncRNA-ATB/miR-200c/ZNF217/TGF-ß2. These findings may provide potential biomarkers and targets for novel diagnostic and therapeutic approaches for keloids.