Neutrophil extracellular traps activate lung fibroblast to induce polymyositis‐related interstitial lung diseases via TLR9‐miR‐7‐Smad2 pathway

Excessive neutrophil extracellular trap (NET) formation may contribute to polymyositis (PM)‐associated interstitial lung diseases (ILD), but the underlying mechanism is not fully revealed. In this study, we found that NET accelerated the progression of ILD and promoted pulmonary fibrosis (PF) in vivo. miR‐7 expression was down‐regulated in lung tissue of PM group than control group, and NETs further decreased miR‐7 expression. TLR9 and Smad2 were up‐regulated in lung tissue of PM group than control group, and NETs further increased TLR9 and Smad2 expressions. In vitro experiments showed that PMA‐treated NETs accelerated the proliferation of LF and their differentiation into myofibroblast (MF), whereas DNase I decreased the promotion effect of NETs. Neutrophil extracellular trap components myeloperoxidase (MPO) and histone 3 also promoted the proliferation and differentiation of LF. In addition, we demonstrated that TLR9 involved in the regulation of NETs on LF proliferation and differentiation, and confirmed the interaction between miR‐7 and Smad2 in LF. Finally, miR‐7‐Smad2 pathway was confirmed to be involved in the regulation of TLR9 on LF proliferation and differentiation. Therefore, NETs promote PM‐related ILD, and TLR9‐miR‐7‐Smad2 signalling pathway is involved in the proliferation of LFs and their differentiation into MFs.     

LncRNA TUG1 alleviates cardiac hypertrophy by targeting miR-34a/DKK1/Wnt-β-catenin signalling

The current study was designed to explore the role and underlying mechanism of lncRNA taurine up-regulated gene 1 (TUG1) in cardiac hypertrophy. Mice were treated by transverse aortic constriction (TAC) surgery to induce cardiac hypertrophy, and cardiomyocytes were treated by phenylephrine (PE) to induce hypertrophic phenotype. Haematoxylin-eosin (HE), wheat germ agglutinin (WGA) and immunofluorescence (IF) were used to examine morphological alterations. Real-time PCR, Western blots and IF staining were used to detect the expression of RNAs and proteins. Luciferase assay and RNA pull-down assay were used to verify the interaction. It is revealed that TUG1 was up-regulated in the hearts of mice treated by TAC surgery and in PE-induced cardiomyocytes. Functionally, overexpression of TUG1 alleviated cardiac hypertrophy both in vivo and in vitro. Mechanically, TUG1 sponged and sequestered miR-34a to increase the Dickkopf 1 (DKK1) level, which eventually inhibited the activation of Wnt/β-catenin signalling. In conclusion, the current study reported the protective role and regulatory mechanism of TUG1 in cardiac hypertrophy and suggested that TUG1 may serve as a novel molecular target for treating cardiac hypertrophy.     

Serum miR‐92a‐1 is a novel diagnostic biomarker for colorectal cancer

Colorectal cancer (CRC) is one of the most common cancers worldwide, with high mortality. Abnormally expressed microRNAs (miRNAs) are considered novel biomarkers in cancer diagnosis. The aim of this study was to investigate the diagnostic value of miR‐92a‐1 in patients with CRC. Serum samples were collected from 148 patients pathologically diagnosed with CRC and 68 gender‐ and age‐matched healthy volunteers. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to measure serum miR‐92a‐1 level. Relationship between miR‐92a‐1 and clinicopathological features of CRC cases was analysed via chi‐square test. Receiver operating characteristic (ROC) curve was plotted to estimate the diagnostic value of miR‐92a‐1 in CRC. Serum miR‐92a‐1 was significantly up‐regulated in CRC patients compared with healthy individuals (P < .001). Moreover, miR‐92a‐1 expression was correlated with TNM stage (P = .02), histological stage (P = .003), lymph node metastasis (P = .003) and distant metastasis (P < .001). ROC analysis showed that the area under the ROC curve (AUC) was 0.914, suggesting high diagnostic accuracy of miR‐92a‐1 in ROC. The optimal cut‐off value was 1.485, with a sensitivity of 81.8% and a specificity of 95.6%. MiR‐92a‐1 is increased in CRC patients and correlated with aggressive clinical characteristics. Serum miR‐92a‐1 may be a potential diagnostic biomarker for CRC.     

Methylation-mediated miR-214 regulates proliferation and drug sensitivity of renal cell carcinoma cells through targeting LIVIN

LIVIN, a member of the inhibitor of apoptosis proteins (IAPs), is reported playing important roles in the development and progression of multiple human cancers. However, its underlined mechanisms in human renal cell carcinoma (RCC) are still needed to be clarified. In the present study, we reported that inhibition of miR-214 promoted the expression of LIVIN, then facilitated RCC cells growth and reduced the sensitivity of RCC cells to chemotherapeutic drugs. In constant, overexpression of miR-214 had contradictory effects. Further investigation showed that miR-214 was down-regulated in RCC because of abnormal methylation. In addition, DNA methyltransferase DNMT1, miR-214 and LIVIN are directly correlated in RCC patients. In conclusion, these results suggest that abnormal miR-214 methylation negatively regulates LIVIN, which may promote RCC cells growth and reduced the sensitivity of RCC cells to chemotherapeutic drugs.     

Absent in melanoma 2 enhances anti‐tumour effects of CAIX promotor controlled conditionally replicative adenovirus in renal cancer

Conditionally replicative adenoviruses (CRAds) were promising approach for solid tumour treatment, but its oncolytic efficiency and toxicity are still not satisfactory for further clinical application. Here, we developed the CAIX promotor (CAIX^promotor)‐controlled CRAd armed with a tumour suppressor absent in melanoma 2 (AIM2) to enhance its oncolytic potency. The CAIX^promotor‐AIM2 adenoviruses (Ad‐CAIX^promotor‐AIM2) could efficiently express E1A and AIM2 in renal cancer cells. Compared with Ad‐CAIX^promotor, Ad‐CAIX^promotor‐AIM2 significantly inhibited cell proliferation and enhanced cell apoptosis and cell killing, thus resulting in the oncolytic efficiency in 786‐O cells or OSRC‐2 cells. To explore the therapeutic effect, various Ads were intratumourally injected into OSRC‐2‐xenograft mice. The tumour growth was remarkably inhibited in Ad‐CAIX^promotor‐AIM2‐treated group as demonstrated by reduced tumour volume and weight with a low toxicity. The inflammasome inhibitor YVAD‐CMK resulted in the reduction of anti‐tumour activity by Ad‐CAIX^promotor‐AIM2 in vitro or in vivo, suggesting that inflammasome activation response was required for the enhanced therapeutic efficiency. Furthermore, lung metastasis of renal cancer mice was also suppressed by Ad‐CAIX^promotor‐AIM2 treatment accompanied by the decreased tumour fossil in lung tissues. These results indicated that the tumour‐specific Ad‐CAIX^promotor‐AIM2 could be applied for human renal cancer therapy. The therapeutic strategy of AIM2‐based CRAds could be a potential and promising approach for the therapy of primary solid or metastasis tumours.     

Circulating exosome‐derived bona fide long non‐coding RNAs predicting the occurrence and metastasis of hepatocellular carcinoma

Although the diagnosis and therapy approach developed, techniques for the early diagnosis of HCC remain insufficient which results in poor prognosis of patients. The traditional biomarker AFP, however, has been proved with low specificity. Circulating exosomal ncRNAs revealed different profiles reflecting the characteristics of tumour. In this study, we mainly focused on circulating exosomal ncRNAs which might be the fingerprint for HCC, especially for the diagnosis or metastasis prediction. A high throughput lncRNA microarray in exosomes extracted from cell‐free plasma was applied. The risk score analysis was employed to screen the potential exosome‐derived lncRNAs in two independent sets based on different clinical parameters in 200 paired HCC patients. After a multi‐stage validation, we finally revealed three lncRNAs, ENSG00000248932.1, ENST00000440688.1 and ENST00000457302.2, increased in HCC comparing with the both chronic hepatitis (CH) patients and cancer‐free controls. ROC curve revealed a higher sensitivity and specificity in predicting the occurrence of HCC from cancer‐free controls and CH patients with the area under curve (AUC) of 0.905 and 0.879 by combining AFP. The three lncRNA panel combined with AFP also indicted a fingerprint function in predicting the metastasis of HCC with the AUC of 0.870. In conclusion, ENSG00000248932.1, ENST00000440688.1 and ENST00000457302.2 might be the potential biomarker for the tumorigenesis prediction from CH patients or healthy controls and may also be applied for dynamic monitoring the metastasis of HCC.     

MALT1 is a potential therapeutic target in glioblastoma and plays a crucial role in EGFR‐induced NF‐κB activation

Glioblastoma multiforme (GBM) is the most common malignant tumour in the adult brain and hard to treat. Nuclear factor κB (NF‐κB) signalling has a crucial role in the tumorigenesis of GBM. EGFR signalling is an important driver of NF‐κB activation in GBM; however, the correlation between EGFR and the NF‐κB pathway remains unclear. In this study, we investigated the role of mucosa‐associated lymphoma antigen 1 (MALT1) in glioma progression and evaluated the anti‐tumour activity and effectiveness of MI‐2, a MALT1 inhibitor in a pre‐clinical GBM model. We identified a paracaspase MALT1 that is involved in EGFR‐induced NF‐kB activation in GBM. MALT1 deficiency or inhibition significantly affected the proliferation, survival, migration and invasion of GBM cells both in vitro and in vivo. Moreover, MALT1 inhibition caused G1 cell cycle arrest by regulating multiple cell cycle–associated proteins. Mechanistically, MALTI inhibition blocks the degradation of IκBα and prevents the nuclear accumulation of the NF‐κB p65 subunit in GBM cells. This study found that MALT1, a key signal transduction cascade, can mediate EGFR‐induced NF‐kB activation in GBM and may be potentially used as a novel therapeutic target for GBM.     

Caesalpanins A–C,Three Dimeric Cassane Diterpenoids from the Seeds of Caesalpinia sappan L.

Three dimeric cassane diterpenoids, caesalpanins A–C, were isolated from the seeds of Caesalpinia sappan L., as well as three known compounds. Their structures were determined via analysis of 1D‐, 2D‐NMR, and HR‐ESI‐MS data. Caesalpanins A and B were the second and third compounds that presented a nitrogen‐containing cassane diterpenoid dimer linked through one ether bond between C‐19 and C‐20′. Caesalpanin B exhibited moderate cytotoxic activity against MCF‐7 cell lines with IC₅₀ value of 29.98 μm . Caesalpanins A and B had weak inhibitory effects against LPS‐induced nitric oxide (NO) production in RAW 264.7 macrophages at 50 μm with inhibitory rate of 36.01 % and 32.93 %, respectively.     

Membrane‐Free Zn/MnO2 Flow Battery for Large‐Scale Energy Storage

The traditional Zn/MnO₂ battery has attracted great interest due to its low cost, high safety, high output voltage, and environmental friendliness. However, it remains a big challenge to achieve long‐term stability, mainly owing to the poor reversibility of the cathode reaction. Different from previous studies where the cathode redox reaction of MnO₂/MnOOH is in solid state with limited reversibility, here a new aqueous rechargeable Zn/MnO₂ flow battery is constructed with dissolution–precipitation reactions in both cathodes (Mn²⁺/MnO₂) and anodes (Zn²⁺/Zn), which allow mixing of anolyte and catholyte into only one electrolyte and remove the requirement for an ion selective membrane for cost reduction. Impressively, this new battery exhibits a high discharge voltage of ≈1.78 V, good rate capability (10C discharge), and excellent cycling stability (1000 cycles without decay) at the areal capacity ranging from 0.5 to 2 mAh cm^‐2. More importantly, this battery can be readily enlarged to a bench scale flow cell of 1.2 Ah with good capacity retention of 89.7% at the 500th cycle, displaying great potential for large‐scale energy storage.     

Interface Engineering of Hierarchical Branched Mo‐Doped Ni3S2/NixPy Hollow Heterostructure Nanorods for Efficient Overall Water Splitting

Rational design and construction of bifunctional electrocatalysts with excellent activity and durability is imperative for water splitting. Herein, a novel top‐down strategy to realize a hierarchical branched Mo‐doped sulfide/phosphide heterostructure (Mo‐Ni₃S₂/Ni_xP_y hollow nanorods), by partially phosphating Mo‐Ni₃S₂/NF flower clusters, is proposed. Benefitting from the optimized electronic structure configuration, hierarchical branched hollow nanorod structure, and abundant heterogeneous interfaces, the as‐obtained multisite Mo‐Ni₃S₂/Ni_xP_y/NF electrode has remarkable stability and bifunctional electrocatalytic activity in the hydrogen evolution reaction (HER)/oxygen evolution reaction (OER) in 1 m KOH solutions. It possesses an extremely low overpotential of 238 mV at the current density of 50 mA cm^?2 for OER. Importantly, when assembled as anode and cathode simultaneously, it merely requires an ultralow cell voltage of 1.46 V to achieve the current density of 10 mA cm^?2, with excellent durability for over 72 h, outperforming most of the reported Ni‐based bifunctional materials. Density functional theory results further confirm that the doped heterostructure can synergistically optimize Gibbs free energies of H and O‐containing intermediates (OH*, O*, and OOH*) during HER and OER processes, thus accelerating the catalytic kinetics of electrochemical water splitting. This work demonstrates the importance of the rational combination of metal doping and interface engineering for advanced catalytic materials.