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     

Cold Sintering of Li6.4La3Zr1.4Ta0.6O12/PEO Composite Solid Electrolytes

Ceramic/polymer composite solid electrolytes integrate the high ionic conductivity of in ceramics and the flexibility of organic polymers. In practice, ceramic/polymer composite solid electrolytes are generally made into thin films rather than sintered into bulk due to processing temperature limitations. In this work, Li_6.4La₃Zr_1.4Ta_0.6O₁₂ (LLZTO)/polyethylene-oxide (PEO) electrolyte containing bis(trifluoromethanesulfonyl)imide (LiTFSI) as the lithium salt was successfully fabricated into bulk pellets via the cold sintering process (CSP). Using CSP, above 80% dense composite electrolyte pellets were obtained, and a high Li-ion conductivity of 2.4 × 10⁻⁴ S cm^–1 was achieved at room temperature. This work focuses on the conductivity contributions and microstructural development within the CSP process of composite solid electrolytes. Cold sintering provides an approach for bridging the gap in processing temperatures of ceramics and polymers, thereby enabling high-performance composites for electrochemical systems.     

Protective Effect of Flavonoids from Mulberry Leaf on AAPH-Induced Oxidative Damage in Sheep Erythrocytes

To evaluate the antioxidant activity of flavonoids extracted from Chinese herb mulberry leaves (ML), flavonoids from mulberry leaves (FML) were extracted and purified by using ultrasonic-assisted enzymatic extraction and D101 macroporous resin. Using LC-MS/MS-Liquid Chromatography with tandem mass spectrometry analysis, hesperidin, rutoside, hyperoside, cyanidin-3-o-glucoside, myricitrin, cyanidin, and quercetin were identified, and NMR and UV were consistent with the verification of IR flavonoid characteristics. The antioxidant activity of FML has also been evaluated as well as the protective effect on 2,2 0-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced oxidative stress. The results showed that FML exhibited powerful antioxidant activity. Moreover, FML showed dose-dependent protection against AAPH-induced sheep erythrocytes’ oxidative hemolysis. In the enzymatic antioxidant system, pretreatment with high FML maintained the balance of SOD, CAT, and GSH-Px; in the non-enzymatic antioxidant system, the content of MDA can be effectively reduced after FML treatment. This study provides a research basis for the development of natural products from mulberry leaves.     

Electro-optic crosslinkable chromophores with ultrahigh electro-optic coefficients and long-term stability

The development of organic electro-optic materials with ultrahigh electro-optic coefficients and high long-term alignment stability is the most challenging topic in this field. Next-generation crosslinkable nonlinear optical chromophore molecular glasses were developed to address this problem. A highly stable EO system including crosslinkable binary chromophores QLD1 and QLD2 or crosslinkable single chromophore QLD3 and multichromophore QLD4 with large hyperpolarizability was synthesized using tetrahydroquinoline as the donor. When the temperature continues to rise after poling, the chromophores modified with anthracene and acrylate can undergo Diels–Alder crosslinking reaction to fix the oriented chromophores through chemical bonds. After crosslinking, the QLD1/QLD2 and QLD2/QLD4 films achieved very high maximum r₃₃ values of 327 and 373 pm V⁻¹, respectively, which are the highest values reported for crosslinkable chromophore systems. After Diels–Alder cycloaddition, the glass transition temperature of the EO film increased by ∼90 °C to 185 °C, which is higher than for any other pure chromophore films. After being annealed at 85 °C, 99.63% of the initial r₃₃ value could be maintained for over 500 h. The ultrahigh electro-optic activity and high long-term alignment stability of these materials showed new breakthroughs in organic EO materials for practical device explorations.

Ultrahigh electro-optic activity and high long-term alignment stability were achieved with crosslinkable binary chromophores QLD1 and QLD2 or crosslinkable single chromophore QLD3 and multichromophore QLD4 with large hyperpolarizability using tetrahydroquinoline as the donor.     

Flavonoids from Lycium barbarum Leaves Exhibit Anti-Aging Effects through the Redox-Modulation

Lycium barbarum leaves are a kind of vegetable, and modern nutrition studies have found that they have an anti-aging function. Our study aims to investigate the anti-aging effects of Lycium barbarum leaf flavonoid (LBLF) extracts and its underlying molecular mechanism. LBLFs were purified using D101 and polyamide resin, characterized by ultraperformance liquid chromatography coupled with mass spectrometry, and administered to hydrogen peroxide (H₂O₂)-treated human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans. Appropriate enrichment conditions were optimized through dynamic adsorption and desorption experiments, the content of flavonoids reached 909.84 mg/g, rutin and kaempferol being the main ones. LBLFs attenuated H₂O₂-induced HUVEC apoptosis, decreased reactive oxygen species and malondialdehyde production levels, increased superoxide dismutase, glutathione peroxidase and catalase activities. Furthermore, pre-treatment with LBLF increased mRNA expression of erythropoietin (EPO) and heme oxygenase-1 (HO-1) via the mitogen-activated protein kinase (MAPK) signaling pathway in HUVECs. Compared with 100 µM rutin monomer, LBLF prolonged the lifespan of Caenorhabditis elegans, enhanced their mobility in middle life stages and upregulated expression of sod-2, gcs-1 and skn-1 genes, which indicated that the anti-aging effects of LBLF were due to its redox-modulation.     

Prolonged lifespan of initial-anode-free lithium-metal battery by pre-lithiation in Li-rich Li2Ni0.5Mn1.5O4 spinel cathode

Anode-free lithium metal batteries (AF-LMBs) can deliver the maximum energy density. However, achieving AF-LMBs with a long lifespan remains challenging because of the poor reversibility of Li⁺ plating/stripping on the anode. Here, coupled with a fluorine-containing electrolyte, we introduce a cathode pre-lithiation strategy to extend the lifespan of AF-LMBs. The AF-LMB is constructed with Li-rich Li₂Ni_0.5Mn_1.5O₄ cathodes as a Li-ion extender; the Li₂Ni_0.5Mn_1.5O₄ can deliver a large amount of Li⁺ in the initial charging process to offset the continuous Li⁺ consumption, which benefits the cycling performance without sacrificing energy density. Moreover, the cathode pre-lithiation design has been practically and precisely regulated using engineering methods (Li-metal contact and pre-lithiation Li-biphenyl immersion). Benefiting from the highly reversible Li metal on the Cu anode and Li₂Ni_0.5Mn_1.5O₄ cathode, the further fabricated anode-free pouch cells achieve 350 W h kg⁻¹ energy density and 97% capacity retention after 50 cycles.

Benefiting from highly reversible structure evolution of pre-lithiated Li-rich Li₂Ni_0.5Mn_1.5O₄ cathode, the corresponding anode-free pouch cell delivers a considerable energy density of 350 W h kg⁻¹ and 97% capacity retention after 50 cycles.     

利用广义内积值迭代加权的空时协方差矩阵估计方法

精确估计协方差矩阵是空时自适应处理(STAP)的核心问题,基于最大似然的样本协方差矩阵估计方法仅适用于均匀检测环境。为了提高非均匀场景下协方差矩阵的估计精度,该文提出迭代加权的空时协方差矩阵估计方法。该方法依据广义内积值(GIP)与其统计均值的距离确定样本的加权系数,并通过建立广义内积直方图及迭代处理的方式进一步提高协方差矩阵的估计精度。仿真结果表明,该方法能够提高非均匀环境下协方差矩阵的估计性能。     

前视阵高速雷达空时处理方法研究

多普勒严重模糊,训练样本有限是高速平台雷达面临的重要问题,协方差矩阵估计误差以及目标约束误差将使处理器性能严重下降。针对上述问题,该文对前视阵杂波自由度进行了研究,分析表明杂波特征谱与孔径带宽积、时宽带宽积以及空时耦合特性有关。该文提出基于主瓣区域空时多波束的鲁棒空时处理方法,首先通过空时多波束降低杂波自由度,然后利用多普勒区间约束的方法,提高了处理器的性能和系统鲁棒性。仿真实验证明了该文方法的有效性,当样本中存在目标信号时,该文方法相比传统固定约束矢量的方法输出信杂噪比性能平均提高5 dB左右。     

电子束发散角的直接测量技术模拟研究

切伦科夫辐射是一种方向性极好的辐射,其辐射能量发射方向严格地与带电粒子的运动方向相关,辐射光携带了带电粒子的方向信息,利用这种特性可以进行电子束发散角及其分布的测量。在基于切伦科夫辐射原理的基础上,考虑电子与物质作用时的多重库仑散射、电离等效应,进行了电子束发散角测量的蒙特卡罗数值模拟程序的建模工作,并完成了理想电子束及具有发散角分布的电子束的测量技术模拟工作。大量模拟结果显示,这种测量方法是可行的,具有对电子束发散角分布进行直接测量的能力,并且其测量系统结构简单。     

非临界相位匹配RTP晶体1.6 μm光参量振荡器

采用非临界相位匹配切割,尺寸4 mm4 mm20 mm的磷酸钛氧铷（RTP）晶体作为非线性光学晶体,进行了半导体激光端面抽运Nd:YAG/RTP的内腔式光参量振荡获得人眼安全激光的实验研究。对比了不同声光调Q重复频率下的信号光输出特性。在10.5 W的抽运功率和15 kHz的重复频率下,获得了最高900 mW的1.62 m人眼安全激光输出,光光转换效率达8.6%。1.62 m信号光和对应的1.06 m基频光的脉冲宽度分别为4.6和8.2 ns。信号光中心波长在1618 nm,谱线宽度小于0.5 nm。