Formononetin,J1 and J2 have different effects on endothelial cells via EWSAT1‐TRAF6 and its downstream pathway

Formononetin is a natural isoflavone compound found mainly in Chinese herbal medicines such as astragalus and red clover. It is considered to be a typical phytooestrogen. In our previous experiments, it was found that formononetin has a two‐way regulatory effect on endothelial cells (ECs): low concentrations promote the proliferation of ECs and high concentrations have an inhibitory effect. To find a specific mechanism of action and provide a better clinical effect, we performed a structural transformation of formononetin and selected better medicinal properties for formononetin modifier J1 and J2 from a variety of modified constructs. The MTT assay measured the effects of drugs on human umbilical vein endothelial cell (HUVEC) activity. Scratch and transwell experiments validated the effects of the drugs on HUVEC migration and invasion. An in vivo assessment effect of the drugs on ovariectomized rats. Long‐chain non‐coding RNA for EWSAT1, which is abnormally highly expressed in HUVEC, was screened by gene chip, and the effect of the drug on its expression was detected by PCR after the drug was applied. The downstream factors and their pathways were analysed, and the changes in the protein levels after drug treatment were evaluated by Western blot. In conclusion, the mechanism of action of formononetin, J1 and J2 on ECs may be through EWSAT1‐TRAF6 and its downstream pathways.     

Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner

m6A modification is the most prevalent RNA modification in eukaryotes. As the critical N6-methyladenosine (m6A) methyltransferase, the roles of methyltransferase like 3 (METTL3) in colorectal cancer (CRC) are controversial. Here, we confirmed that METTL3, a critical m6A methyltransferase, could facilitate CRC progression in vitro and in vivo. Further, we found METTL3 promoted CRC cell proliferation by methylating the m6A site in 3′-untranslated region (UTR) of CCNE1 mRNA to stabilize it. Moreover, we found butyrate, a classical intestinal microbial metabolite, could down-regulate the expression of METTL3 and related cyclin E1 to inhibit CRC development. METTL3 promotes CRC proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner, representing a promising therapeutic strategy for the treatment of CRC.     

AT2R agonist NP‐6A4 mitigates aortic stiffness and proteolytic activity in mouse model of aneurysm

Clinical and experimental studies show that angiotensin II (AngII) promotes vascular pathology via activation of AngII type 1 receptors (AT1Rs). We recently reported that NP‐6A4, a selective peptide agonist for AngII type 2 receptor (AT2R), exerts protective effects on human vascular cells subjected to serum starvation or doxorubicin exposure. In this study, we investigated whether NP‐6A4–induced AT2R activation could mitigate AngII‐induced abdominal aortic aneurism (AAA) using AngII‐treated Apoe^?/? mice. Male Apoe^?/? mice were infused with AngII (1 µg/kg/min) by implanting osmotic pumps subcutaneously for 28 days. A subset of mice was pre‐treated subcutaneously with NP‐6A4 (2.5 mg/kg/day) or vehicle for 14 days prior to AngII, and treatments were continued for 28 days. NP‐6A4 significantly reduced aortic stiffness of the abdominal aorta induced by AngII as determined by ultrasound functional analyses and histochemical analyses. NP‐6A4 also increased nitric oxide bioavailability in aortic tissues and suppressed AngII‐induced increases in monocyte chemotactic protein‐1, osteopontin and proteolytic activity of the aorta. However, NP‐6A4 did not affect maximal intraluminal aortic diameter or AAA incidences significantly. These data suggest that the effects of AT2R agonist on vascular pathologies are selective, affecting the aortic stiffness and proteolytic activity without affecting the size of AAA.     

LncRNA H19 ameliorates myocardial infarction‐induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A

Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide, and novel therapeutic targets still need to be investigated to alleviate myocardial injury and the ensuing maladaptive cardiac remodelling. Accumulating studies have indicated that lncRNA H19 might exert a crucial regulatory effect on cardiovascular disease. In this study, we aimed to explore the biological function and molecular mechanism of H19 in MI. To investigate the biological functions of H19, miRNA‐22‐3p and KDM3A, gain‐ and loss‐of‐function experiments were performed. In addition, bioinformatics analysis, dual‐luciferase reporter assays, RNA immunoprecipitation (RIP) assays, RNA pull‐down assays, quantitative RT‐PCR and Western blot analyses as well as rescue experiments were conducted to reveal an underlying competitive endogenous RNA (ceRNA) mechanism. We found that H19 was significantly down‐regulated after MI. Functionally, enforced H19 expression dramatically reduced infarct size, improved cardiac performance and alleviated cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation. However, H19 knockdown resulted in the opposite effects. Bioinformatics analysis and dual‐luciferase assays revealed that, mechanistically, miR‐22‐3p was a direct target of H19, which was also confirmed by RIP and RNA pull‐down assays in primary cardiomyocytes. In addition, bioinformatics analysis and dual‐luciferase reporter assays also demonstrated that miRNA‐22‐3p directly targeted the KDM3A gene. Moreover, subsequent rescue experiments further verified that H19 regulated the expression of KDM3A to ameliorate MI‐induced myocardial injury in a miR‐22‐3p‐dependent manner. The present study revealed the critical role of the lncRNAH19/miR‐22‐3p/KDM3A pathway in MI. These findings suggest that H19 may act as a potential biomarker and therapeutic target for MI.     

Protective Antioxidant Effects of Amentoflavone and Total Flavonoids from Hedyotis diffusa on H2O2‐Induced HL‐O2 Cells through ASK1/p38 MAPK Pathway

In this study, total flavonoids and total triterpenoid acid were extracted with ethyl acetate from Hedyotis diffusa Willd, and hepatoprotective activities of them and five compounds from total flavonoids against H₂O₂ induced hepatocyte damage on HL‐02 cells were determined. In particular, amentoflavone and total flavonoids had influence on the leakage of ALT, AST, LDH, the activities of SOD and the content of MDA. They effectively reduced the loss of MMP, the release of Cyt C, and then inhibited activation of caspase‐3/caspase‐9 cascade in hepatotoxic cells. The contents of ROS were significantly reduced to inhibit p38 in amentoflavone and flavonoids groups which decreased ASK1 and p‐p38 levels through increasing thioredoxin Trx1 and reductase TrxR1. These results suggesting that the antioxidant protection of amentoflavone and flavonoids might be reducing ROS to inhibit the H₂O₂‐induced upstream of pathway via increasing levels of Trx1 and TrxR1, which were pivotal in blocking the down streaming effectors of ASK1/p38 MAPK pathway and alleviating hepatotoxicity.     

High‐Efficiency CsPbI2Br Perovskite Solar Cells with Dopant‐Free Poly(3‐hexylthiophene) Hole Transporting Layers

CsPbI₂Br is emerging as a promising all‐inorganic material for perovskite solar cells (PSCs) due to its more stable lattice structure and moisture resistance compared to CsPbI₃, although its device performance is still much behind this counterpart. Herein, a preannealing process is developed and systematically investigated to achieve high‐quality CsPbI₂Br films by regulating the nucleation and crystallization of perovskite. The preannealing temperature and time are specifically optimized for a dopant‐free poly(3‐hexylthiophene) (P3HT)‐based device to target dopant‐induced drastic performance degradation for spiro‐OMeTAD‐based devices. The resulting P3HT‐based device exhibits comparable power conversion efficiency (PCE) to spiro‐OMeTAD‐based devices but much enhanced ambient stability with over 95% PCE after 1300 h. A diphenylamine derivative is introduced as a buffer layer to improve the energy‐level mismatch between CsPbI₂Br and P3HT. A record‐high PCE of 15.50% for dopant‐free P3HT‐based CsPbI₂Br PSCs is achieved by alleviating the open‐circuit voltage loss with the buffer layer. These results demonstrate that the preannealing processing together with a suitable buffer layer are applicable strategies for developing dopant‐free P3HT PSCs with high efficiency and stability.     

In Situ Conversion of Cu3P Nanowires to Mixed Ion/Electron‐Conducting Skeleton for Homogeneous Lithium Deposition

The introduction of 3D wettable current collectors is one of the practical strategies toward realizing high reversibility of lithium (Li) metal anodes, yet its effect is usually insufficient owing to single electron‐conductive skeleton. Here, homogeneous Li deposition behavior and enhanced Coulombic efficiency is reported for electrochemically lithiated Cu₃P nanowires, owing to the formation of a mixed ion/electron‐conducting skeleton (MIECS). In particular, by evaluating the Gibbs free energy change, the possible chemical reaction between Cu₃P and molten Li is used to construct a MIECS containing Li₃P and Cu–Li alloy phase. The successful conversion of Cu₃P nanowires to Li₃P and Cu–Li alloy nanocomposite not only greatly reduces the surface energy between molten Li and Cu₃P, but also induces uniform Li stripping/plating behavior via balanced ion/electron transport. Thus, the as‐obtained Li@MIECS composite anode displays superior cycling stability in both symmetric cells and full cells. This work provides a promising option for the preparation of high‐performance composite Li anodes containing MIECS by thermally pre‐storing Li.