A novel lncRNA PLK4 up‐regulated by talazoparib represses hepatocellular carcinoma progression by promoting YAP‐mediated cell senescence

A growing number of studies recognize that long non‐coding RNAs (lncRNAs) are essential to mediate multiple tumorigenic processes, including hepatic tumorigenesis. However, the pathological mechanism of lncRNA‐regulated liver cancer cell growth remains poorly understood. In this study, we identified a novel function lncRNA, named polo‐like kinase 4 associated lncRNA (lncRNA PLK4, GenBank Accession No. RP11‐50D9.3), whose expression was dramatically down‐regulated in hepatocellular carcinoma (HCC) tissues and cells. Interestingly, talazoparib, a novel and highly potent poly‐ADP‐ribose polymerase 1/2 (PARP1/2) inhibitor, could increase lncRNA PLK4 expression in HepG2 cells. Importantly, we showed that talazoparib‐induced lncRNA PLK4 could function as a tumour suppressor gene by Yes‐associated protein (YAP) inactivation and induction of cellular senescence to inhibit liver cancer cell viability and growth. In summary, our findings reveal the molecular mechanism of talazoparib‐induced anti‐tumor effect, and suggest a potential clinical use of talazoparib‐targeted lncRNA PLK4/YAP‐dependent cellular senescence for the treatment of HCC.     

ATPR triggers acute myeloid leukaemia cells differentiation and cycle arrest via the RARα/LDHB/ERK‐glycolysis signalling axis

Acute myeloid leukaemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. 4‐Amino‐2‐trifluoromethyl‐phenyl retinate (ATPR), a novel all‐trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show superior anticancer effect compared with ATRA on various cancers. However, its potential effect on AML remains largely unknown. Lactate dehydrogenase B (LDHB) is the key glycolytic enzyme that catalyses the interconversion between pyruvate and lactate. Currently, little is known about the role of LDHB in AML. In this study, we found that ATPR showed antileukaemic effects with RARα dependent in AML cells. LDHB was aberrantly overexpressed in human AML peripheral blood mononuclear cell (PBMC) and AML cell lines. A lentiviral vector expressing LDHB‐targeting shRNA was constructed to generate a stable AML cells with low expression of LDHB. The effect of LDHB knockdown on differentiation and cycle arrest of AML cells was assessed in vitro and vivo, including involvement of Raf/MEK/ERK signalling. Finally, these data suggested that ATPR showed antileukaemic effects by RARα/LDHB/ ERK‐glycolysis signalling axis. Further studies should focus on the underlying leukaemia‐promoting mechanisms and investigate LDHB as a therapeutic target.     

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Long non‐coding RNAs (LncRNAs) and DNA methylation are important epigenetic mark play a key role in liver fibrosis. Currently, how DNA methylation and LncRNAs control the hepatic stellate cell (HSC) activation and fibrosis has not yet been fully characterized. Here, we explored the role of antisense non‐coding RNA in the INK4 locus (ANRIL) and DNA methylation in HSC activation and fibrosis. The expression levels of DNA methyltransferases 3A (DNMT3A), ANRIL, α‐Smooth muscle actin (α‐SMA), Type I collagen (Col1A1), adenosine monophosphate‐activated protein kinase (AMPK) and p‐AMPK in rat and human liver fibrosis were detected by immunohistochemistry, qRT‐PCR and Western blotting. Liver tissue histomorphology was examined by haematoxylin and eosin (H&E), Sirius red and Masson staining. HSC was transfected with DNMT3A‐siRNA, over‐expressing ANRIL and down‐regulating ANRIL. Moreover, cell proliferation ability was examined by CCK‐8, MTT and cell cycle assay. Here, our study demonstrated that ANRIL was significantly decreased in activated HSC and liver fibrosis tissues, while Col1A1, α‐SMA and DNMT3A were significantly increased in activated HSC and liver fibrosis tissues. Further, we found that down‐regulating DNMT3A expression leads to inhibition of HSC activation. Reduction in DNMT3A elevated ANRIL expression in activated HSC. Furthermore, we performed the over expression ANRIL suppresses HSC activation and AMPK signalling pathways. In sum, our study found that epigenetic DNMT3A silencing of ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway. Targeting epigenetic modulators DNMT3A and ANRIL, and offer a novel approach for liver fibrosis therapy.     

Ultrafine Co3Se4 Nanoparticles in Nitrogen‐Doped 3D Carbon Matrix for High‐Stable and Long‐Cycle‐Life Lithium Sulfur Batteries

Lithium–sulfur batteries are a promising high energy output solution for substitution of traditional lithium ion batteries. In recent times research in this field has stepped into the exploration of practical applications. However, their applications are impeded by cycling stability and short life‐span mainly due to the notorious polysulfide shuttle effect. In this work, a multifunctional sulfur host fabricated by grafting highly conductive Co₃Se₄ nanoparticles onto the surface of an N‐doped 3D carbon matrix to inhibit the polysulfide shuttle and improve the sulfur utilization is proposed. By regulating the carbon matrix and the Co₃Se₄ distribution, N‐CN‐750@Co₃Se₄‐0.1 m with abundant polar sites is experimentally and theoretically shown to be a good LiPSs absorbent and a sulfur conversion accelerator. The S/N‐CN‐750@Co₃Se₄‐0.1 m cathode shows excellent sulfur utilization, rate performance, and cyclic durability. A prolonged cycling test of the as‐fabricated S/N‐CN‐750@Co₃Se₄‐0.1 m cathode is carried out at 0.2 C for more than 5 months which delivers a high initial capacity of 1150.3 mAh g^?1 and retains 531.0 mAh g^?1 after 800 cycles with an ultralow capacity reduction of 0.067% per cycle, maintaining Coulombic efficiency of more than 99.3%. The reaction details are characterized and analyzed by ex situ measurements. This work highly emphasizes the potential capabilities of transition‐metal selenides in lithium–sulfur batteries.     

Nature of FeSe2/N‐C Anode for High Performance Potassium Ion Hybrid Capacitor

Potassium ion hybrid capacitors have great potential for large‐scale energy devices, because of the high power density and low cost. However, their practical applications are hindered by their low energy density, as well as electrolyte decomposition and collector corrosion at high potential in potassium bis(fluoro‐sulfonyl)imide‐based electrolyte. Therefore, anode materials with high capacity, a suitable voltage platform, and stability become a key factor. Here, N‐doping carbon‐coated FeSe₂ clusters are demonstrated as the anode material for a hybrid capacitor, delivering a reversible capacity of 295 mAh g^?1 at 100 mA g^?1 over 100 cycles and a high rate capability of 158 mAh g^?1 at 2000 mA g^?1 over 2000 cycles. Meanwhile, through density functional theory calculations, in situ X‐ray diffraction, and ex situ transmission electron microscopy, the evolution of FeSe₂ to Fe₃Se₄ for the electrochemical reaction mechanism is successfully revealed. The battery‐supercapacitor hybrid using commercial activated carbon as the cathode and FeSe₂/N‐C as the anode is obtained. It delivers a high energy density of 230 Wh kg^?1 and a power density of 920 W kg^?1 (the energy density and power density are calculated based on the total mass of active materials in the anode and cathode).     

Synthesis of Novel Aryloxyethylamine Derivatives and Evaluation of Their in Vitro and in Vivo Neuroprotective Activities

A series of aryloxyethylamine derivatives were designed, synthesized and evaluated for their biological activity. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, FT‐IR and HR‐ESI‐MS. The preliminary screening of neuroprotection of compounds in vitro was detected by MTT, and the anti‐ischemic activity in vivo was tested using bilateral common carotid artery occlusion in mice. Most of these compounds showed potential neuroprotective effects against the glutamate‐induced cell death in differentiated rat pheochromocytoma cells (PC12 cells), especially for (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone, (4‐bromophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone, (4‐chlorophenyl)(1‐{2‐[(naphthalen‐2‐yl)oxy]ethyl}piperidin‐4‐yl)methanone, (4‐chlorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone and {1‐[2‐(4‐bromophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone, which exhibited potent protection of PC12 cells at three doses (0.1, 1.0, 10 μM). Compounds (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, (4‐fluorophenyl){1‐[2‐(naphthalen‐2‐yloxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone and {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone possessed the significant prolongation of the survival time of mice subjected to acute cerebral ischemia and decreased the mortality rate at all five doses tested (200, 100, 50, 25, 12.5 mg/kg) and had significant neuroprotective activity. In addition, (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone and {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone possessed outstanding neuroprotection in vitro and in vivo. These compounds can be used as a promising neuroprotective agents for future development of new anti‐ischemic stroke agents. Basic structure–activity relationships are also presented.     

Toward a Reversible Mn4+/Mn2+ Redox Reaction and Dendrite‐Free Zn Anode in Near‐Neutral Aqueous Zn/MnO2 Batteries via Salt Anion Chemistry

Rechargeable aqueous Zn/MnO₂ batteries are very attractive large‐scale energy storage technologies, but still suffer from limited cycle life and low capacity. Here the novel adoption of a near‐neutral acetate‐based electrolyte (pH ≈ 6) is presented to promote the two‐electron Mn⁴⁺/Mn²⁺ redox reaction and simultaneously enable a stable Zn anode. The acetate anion triggers a highly reversible MnO₂/Mn²⁺ reaction, which ensures high capacity and avoids the issue of structural collapse of MnO₂. Meanwhile, the anode‐friendly electrolyte enables a dendrite‐free Zn anode with outstanding stability and high plating/stripping Coulombic efficiency (99.8%). Hence, a high capacity of 556 mA h g^?1, a lifetime of 4000 cycles without decay, and excellent rate capability up to 70 mA cm^?2 are demonstated in this new near‐neutral aqueous Zn/MnO₂ battery by simply manipulating the salt anion in the electrolyte. The acetate anion not only modifies the surface properties of MnO₂ cathode but also creates a highly compatible environment for the Zn anode. This work provides a new opportunity for developing high‐performance Zn/MnO₂ and other aqueous batteries based on the salt anion chemistry.     

阿加曲班抗凝对连续血液净化患儿凝血功能及单核细胞TLR2rMnX、TLR4rMnX表达水平的影响

目的:探讨阿加曲班抗凝治疗连续血液净化患儿的疗效及对凝血功能及单核细胞TLR2rMnX、TLR4rMnX表达水平的影响。方法:选取从2017年3月至2018年10月于我院儿童重症医学科接受连续血液净化治疗的患儿86例进行研究,将其按照随机抽签法分成研究组与对照组。对照组予以普通肝素抗凝治疗,研究组予以阿加曲班抗凝治疗。分别比较两组的28 d死亡率、治疗前后凝血功能血小板计数(PLT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)和单核细胞TLR2rMnX、TLR4rMnX表达水平、治疗过程中滤器与管路凝血程度、使用寿命以及穿刺部位出血情况的差异。结果:研究组28d死亡率(2.33%)比对照组(9.30%)低,但差异无统计学意义(x2=0.849,P=0.357)。治疗后研究组APTT(31.61±1.26)s、FIB水平(6.61±1.80)g/L较对照组的(27.92±1.44)s、(5.58±1.72)g/L明显更高(t=12.646、2.713,P=0.000、0.008)。研究组治疗过程中滤器与管路凝血程度0级人数占比(93.02%)相比对照组(76.74%)较高,而Ⅱ级人数占比(0.00%)相比对照组(9.30%)较低(x2=4.440、4.195,P=0.035,0.041)。研究组穿刺部位出血等级为0级人数占比(93.02%)高于对照组(74.42%),而Ⅱ级人数占比(0.00%)低于对照组(9.30%)(x2=5.460,4.195;P=0.019,0.041)。研究组管路、滤器使用寿命(18.73±7.74)h、(20.84±8.01)h相比对照组的(14.57±6.88)h、(16.20±7.15)h均较长(t=2.634、2.834,P=0.010,0.006)。治疗后研究组单核细胞TLR2rMnX、TLR4rMnX表达水平为(4.72±1.39)、(3.22±0.82),均低于对照组的(8.30±1.44)、(5.11±0.94)(t=11.729、9.936,P=0.000、0.000)。结论:阿加曲班抗凝应用于连续血液净化患儿中的疗效相比普通肝素抗凝更佳,且有利于改善凝血功能和单核细胞TLR2rMnX、TLR4rMnX表达水平,能够降低滤器或管路凝血发生风险,同时有效降低穿刺部位出血风险,增加管路、滤器使用寿命。