Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.Subject terms: Liver cancer, Mitophagy, Apoptosis     

Autonomous-Strengthening Adhesive Provides Hydrolysis-Resistance and Enhanced Mechanical Properties in Wet Conditions

The low-viscosity adhesive that is used to bond composite restorative materials to the tooth is readily damaged by acids, enzymes, and oral fluids. Bacteria infiltrate the resulting gaps at the composite/tooth interface, demineralize the tooth, and further erode the adhesive. This paper presents the preparation and characterization of a low-crosslink-density hydrophilic adhesive that capitalizes on sol-gel reactions and free-radical polymerization to resist hydrolysis and provide enhanced mechanical properties in wet environments. Polymerization behavior, water sorption, and leachates were investigated. Dynamic mechanical analyses (DMA) were conducted using water-saturated adhesives to mimic load transfer in wet conditions. Data from all tests were analyzed using appropriate statistical tests (α = 0.05). The degree of conversion was comparable for experimental and control adhesives at 88.3 and 84.3%, respectively. HEMA leachate was significantly lower for the experimental (2.9 wt%) compared to control (7.2 wt%). After 3 days of aqueous aging, the storage and rubbery moduli and the glass transition temperature of the experimental adhesive (57.5MPa, 12.8MPa, and 38.7 °C, respectively) were significantly higher than control (7.4MPa, 4.3 MPa, and 25.9 °C, respectively). The results indicated that the autonomic sol-gel reaction continues in the wet environment, leading to intrinsic reinforcement of the polymer network, improved hydrolytic stability, and enhanced mechanical properties.     

Atmospheric CO_2 capture and photofixation to near-unity CO by Ti~(3+)-V_o-Ti~(3+) sites confined in TiO_2 ultrathin layers

To realize efficient atmospheric CO_2 chemisorption and activation,abundant Ti~(3+) sites and oxygen vacancies in TiO_2 ultrathin layers were designed.Positron annihilation lifetime spectroscopy and theoretical calculations first unveil each oxygen vacancy is associated with the formation of two Ti~(3+) sites,giving a Ti~(3+)-V_o-Ti~(3+)configuration.The Ti~(3+)-V_o-Ti~(3+) sites could bond with CO_2 molecules to form a stable configuration,which converted the endoergic chemisorption step to an exoergic process,verified by in-situ Fourier-transform infrared spectra and theoretical calculations.Also,the adjacent Ti~(3+) sites not only favor CO_2 activation into COOH*via forming a stable Ti~(3+)–C–O–Ti~(3+) configuration,but also facilitate the rate-limiting COOH~* scission to CO~* by reducing the energy barrier from 0.75 to 0.45 e V.Thus,the Ti~(3+)-V_o-TiO_2 ultrathinlayers could directly capture and photofix atmospheric CO_2 into near-unity CO,with the corresponding CO_2-to-CO conversion ratio of ca. 20.2%.     

Protective Effects of Ferulic Acid on Metabolic Syndrome: A Comprehensive Review

Metabolic syndrome (MetS) is a complex disease in which protein, fat, carbohydrates and other substances are metabolized in a disorderly way. Ferulic acid (FA) is a phenolic acid found in many vegetables, fruits, cereals and Chinese herbs that has a strong effect on ameliorating MetS. However, no review has summarized the mechanisms of FA in treating MetS. This review collected articles related to the effects of FA on ameliorating the common symptoms of MetS, such as diabetes, hyperlipidemia, hypertension and obesity, from different sources involving Web of Science, PubMed and Google Scholar, etc. This review summarizes the potential mechanisms of FA in improving various metabolic disorders according to the collected articles. FA ameliorates diabetes via the inhibition of the expressions of PEPCK, G6Pase and GP, the upregulation of the expressions of GK and GS, and the activation of the PI3K/Akt/GLUT4 signaling pathway. The decrease of blood pressure is related to the endothelial function of the aortas and RAAS. The improvement of the lipid spectrum is mediated via the suppression of the HMG-Co A reductase, by promoting the ACSL1 expression and by the regulation of the factors associated with lipid metabolism. Furthermore, FA inhibits obesity by upregulating the MEK/ERK pathway, the MAPK pathway and the AMPK signaling pathway and by inhibiting SREBP-1 expression. This review can be helpful for the development of FA as an appreciable agent for MetS treatment.     

A Novel Aptamer-Imprinted Polymer-Based Electrochemical Biosensor for the Detection of Lead in Aquatic Products

Lead contamination in aquatic products is one of the main hazard factors. The aptasensor is a promising detection method for lead ion (Pb(II)) because of its selectivity, but it is easily affected by pH. The combination of ion-imprinted polymers(IIP) with aptamers may improve their stability in different pH conditions. This paper developed a novel electrochemical biosensor for Pb(II) detection by using aptamer-imprinted polymer as a recognition element. The glassy carbon electrode was modified with gold nanoparticles and aptamers. After the aptamer was induced by Pb(II) to form a G-quadruplex conformation, a chitosan-graphene oxide was electrodeposited and cross-linked with glutaraldehyde to form an imprint layer, improving the stability of the biosensor. Under the optimal experimental conditions, the current signal change (∆I) showed a linear correlation of the content of Pb(II) in the range of 0.1–2.0 μg/mL with a detection limit of 0.0796 μg/mL (S/N = 3). The biosensor also exhibited high selectivity for the determination of Pb(II) in the presence of other interfering metal ion. At the same time, the stability of the imprinted layer made the sensor applicable to the detection environment with a pH of 6.4–8.0. Moreover, the sensor was successfully applied to the detection of Pb(II) in mantis shrimp.     

An unusual autocatalysis with an air-stable Pd complex to promote enantioselective synthesis of Si-stereogenic enynes

Given the powerful potential of chiral-at-silicon chemistry, enantioselective synthesis of Si-stereogenic centers has attracted substantial research interest in recent years. However, the catalytic asymmetric synthesis of Si-stereogenic organosilicon compounds remains an appealing venture and is a challenging subject because of the difficulty in achieving high reactivity and stereoselectivity for “silicon-center” transformations. Herein, we disclose a highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes, which enables the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields and excellent ees (up to >99%) by desymmetrization. The unusual stereoselectivity in this reaction is achieved by precisely controlling the steric hindrance and electronic effect of the newly developed chiral ligands, resulting in a wide range of chiral silanes and a Si-containing polymer bearing a Si-stereogenic center which is otherwise difficult to access. The key to the high enantioselectivity relies on catalyst aggregation-induced non-covalent interaction, which exerts a remarkably positive influence on the Si–H bond activation and enhancement of enantioselectivity, in which the palladium/P-ligand complex was proved to be air-stable and moisture-insensitive in this reaction.

A highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes was established for the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields with excellent ees.     

Thermodynamic Resolution of Pharmaceutical Precursor Modafinil Acid on the Basis of Chiral-at-Metal Strategy

Main observation and conclusion Chiral-at-metal strategy was developed to resolve the essential sulfoxide pharmaceutical intermediates R-modafinil acid and its ...     

单相氟磷灰石微晶玻璃晶相特征和生物相容性研究

采用熔融-淬火-烧结法制备氟磷灰石微晶玻璃,研究其析晶机制和体外生物相容性.采用X射线衍射(XRD)和场发射扫描电镜(FE-SEM)分析了不同烧结温度下样品的晶相组成和微观结构,利用能量色散X射线光谱仪(EDS)分析了化学成分.结果表明,氟磷灰石是烧结微晶玻璃中的唯一晶相,其晶体可以在较宽的温度范围内析出.显微组织结构致密,显微硬度为644～709 Hv0.1.氟磷灰石晶体在FE-SEM中有针状和多边形两种形态,多边形是短棒状晶体的横断面.低温下,以固相烧结为主,氟磷灰石析晶以表面析晶为主,晶体生长为针形;高温下玻璃液较多,在保温和冷却凝固过程中析出短棒状晶.在37℃温度下将样品在模拟体液中浸泡14 d,SEM/EDS和FT-IR检测结果表明,样品表面包含磷酸根和羟基的吸收带,形成了羟基磷灰石层,可作为骨或牙齿修复材料.     

Effect of Plane Deformation on Superconducting and structural Properties of YBa2Cu3–yFeyO7–x Ceramics

Russian Physics Journal -     

Amorphous Manganese–Cobalt Nanosheets as Efficient Catalysts for Hydrogen Evolution Reaction (HER)

Catalysis Surveys from Asia - A facile and efficient electrocatalyst for hydrogen evolution reaction (HER) to produce hydrogen is very important for future energy. In this paper, amorphous...