SS-31 Protects Liver from Ischemia-Reperfusion Injury via Modulating Macrophage Polarization

Ischemia-reperfusion injury (IRI) is a common complication in liver surgeries. It is a focus to discover effective treatments to reduce ischemia-reperfusion injury. Previous studies show that oxidative stress and inflammation response contribute to the liver damage during IRI. SS-31 is an innovated mitochondrial-targeted antioxidant peptide shown to scavenge reactive oxygen species and decrease oxidative stress, but the protective effects of SS-31 against hepatic IRI are not well understood. The aim of our study is to investigate whether SS-31 could protect the liver from damages induced by IRI and understand the protective mechanism. The results showed that SS-31 treatment can significantly attenuate liver injury during IRI, proved by HE staining, serum ALT/AST, and TUNEL staining which can assess the degree of liver damage. Meanwhile, we find that oxidative stress and inflammation were significantly suppressed after SS-31 administration. Furthermore, the mechanism revealed that SS-31 can directly decrease ROS production and regulate STAT1/STAT3 signaling in macrophages, thus inhibiting macrophage M1 polarization. The proinflammation cytokines are then significantly reduced, which suppress inflammation response in the liver. Taken together, our study discovered that SS-31 can regulate macrophage polarization through ROS scavenging and STAT1/STAT3 signaling to ameliorate liver injury; the protective effects against hepatic IRI suggest that SS-31 may be an appropriate treatment for liver IRI in the clinic

Additional file 1 of Insight into carbapenem resistance and virulence of Acinetobacter baumannii from a children’s medical centre in eastern China

Supplementary Material 1: Table S1 Genome sequence tabl

Dataset for: Identification of cancer-related potential biomarkers based on lncRNA-pseudogene-mRNA competitive networks

Accumulating evidences indicate that mRNAs and ncRNAs act as competitive endogenous RNAs and play a key role in tumorigenesis. However, the complex competitive relationship among genes remains unknown. In our study, the lncRNAs, pseudogenes and mRNAs that compete with the common miRNAs are defined as lncRNA-pseudogene-mRNA competitive triples. We find some candidate ceRNAs, modules and triples are related with cancers and can significantly divide patients into high-risk and low-risk groups, and thus they may serve as potential cancer biomarkers. In total, the work systematically analyzes the association between competitive triples and cancer, which will provide a reference for deep understanding of cancer progression

The Immune Adaptor ADAP Regulates Reciprocal TGF-β1-Integrin Crosstalk to Protect from Influenza Virus Infection

<div><p>Highly pathogenic avian influenza virus (HPAI, such as H5N1) infection causes severe cytokine storm and fatal respiratory immunopathogenesis in human and animal. Although TGF-β1 and the integrin CD103 in CD8⁺ T cells play protective roles in H5N1 virus infection, it is not fully understood which key signaling proteins control the TGF-β1-integrin crosstalk in CD8⁺ T cells to protect from H5N1 virus infection. This study showed that ADAP (Adhesion and Degranulation-promoting Adapter Protein) formed a complex with TRAF6 and TAK1 in CD8⁺ T cells, and activated SMAD3 to increase autocrine TGF-β1 production. Further, TGF-β1 induced CD103 expression via an ADAP-, TRAF6- and SMAD3-dependent manner. In response to influenza virus infection (i.e. H5N1 or H1N1), lung infiltrating ADAP^-/- CD8⁺ T cells significantly reduced the expression levels of TGF-β1, CD103 and VLA-1. ADAP^-/- mice as well as Rag1^-/- mice receiving ADAP^-/- T cells enhanced mortality with significant higher levels of inflammatory cytokines and chemokines in lungs. Together, we have demonstrated that ADAP regulates the positive feedback loop of TGF-β1 production and TGF-β1-induced CD103 expression in CD8⁺ T cells via the TβRI-TRAF6-TAK1-SMAD3 pathway and protects from influenza virus infection. It is critical to further explore whether the SNP polymorphisms located in human <i>ADAP</i> gene are associated with disease susceptibility in response to influenza virus infection.</p></div

Rag1^-/- mice receiving ADAP^-/- T cells reduces protection in response to H5N1 virus infection.

<p>Four days after Rag1^-/- mice were transferred with 4×10⁶ CD4⁺ and 2.5×10⁶ CD8⁺ T cells purified from wild type or ADAP^-/- splenocytes, the recipient mice were then infected with the H5N1 virus GX/12 (10⁶ EID₅₀) for the following analysis at day10 post infection (n = 5): bodyweight loss (A), HE staining of lungs (B), surface CD103 expression on the lung infiltrating CD8⁺ T cells (C), and the amount of viral NP (nucleoprotein) in lungs by IHC staining (D). Data are representative of two independent experiments.</p

Primers used for RT-PCR.

<p>Primers used for RT-PCR.</p

ADAP regulates TGF-β1 production in T cells via an autocrine manner.

<p>(A and B) Surface staining of LAP (TGF-β1) and the relative mRNA levels of TGF-β1 in CD8⁺ CTLs from wild type or ADAP^-/- OT1 Tg mice, which were generated with 10nM OVA_257-264-peptide stimulation for 3 days. Data are representative of three independent experiments. (C) Human C8166 T cells overexpressing GFP or ADAP were stimulated with 2ug/mL plate bound anti-CD3/CD28 antibodies, followed by surface staining of LAP (TGF-β1). Data are representative of two independent experiments. (D) Wild type or ADAP^-/- splenocytes were stimulated with 2ug/mL plate bound anti-CD3/CD28 antibodies, followed by surface staining of CD8 and LAP (TGF-β1). Data are representative of three independent experiments. (E) After stimulation with 5ng/mL TGF-β1 and 10nM OVA_257-264-peptide for 6hrs, Wild type or ADAP^-/- splenocytes were washed extensively and then incubated for further 18hr. Supernatants were collected to detect total TGF-β with ELISA. (F) In the presence or absence of the inhibitors SD208 and SB431542 (10uM respectively), the mRNA levels of TGF-β1 were examined in wild type or ADAP^-/- splenocytes after stimulated with 10nM OVA_257-264-peptide with or without 5ng/mL exogenous TGF-β1. Data are representative of three independent experiments.</p

ADAP deficiency reduces TGF-β1-induced CD103 expression in CD8+ T cells.

<p>Wild type and ADAP^-/- mice were infected with the H5N1 virus (n = 3). At day 10 post infection, surface CD103 expression levels on CD8⁺ T cells from BAL or MLNs (A, B) or the mRNA levels of CD103 or E-cadherin of lungs (C) were measured. Data are representative of two independent experiments. (D) The mRNA levels of CD103 were examined in 10nM OVA_257-264-stimulated CD8⁺ CTLs from wild type or ADAP^-/- OT1 Tg mice. Data are representative of two independent experiments. (E) Surface CD103 expression levels were examined from wild type or ADAP^-/- CD8⁺ T cells after treated with anti-CD3/CD28 (2ug/mL) and exogenous TGF-β1 (5ng/mL). Data are representative of two independent experiments. Data are representative of three independent experiments. (F) Surface levels of CD103 were examined from anti-CD3/CD28 and exogenous TGF-β1-stimulated wild type or ADAP^-/- CD8⁺ T cells, in the absence or presence of the TAK1 inhibitor (5Z-7-oxo; 2uM) or the TβRI inhibitor (SB431542; 10uM) respectively. Data are representative of two independent experiments. (G) Surface levels of CD103 were examined from wild type or TRAF6^+/- CD8⁺ T cells after stimulated with anti-CD3/28 antibody and exogenous TGF-β1. Data are representative of three independent experiments.</p