[Intervention effect of Chuanxiong-Chishao herb pair on circRNA/lncRNA expression profile in a myocardial infarction-atherosclerosis model].

This study aimed to explore the intervention effect of Chuanxiong-Chishao herb pair(CX-CS) on a myocardial infarction-atherosclerosis(MI-AS) mouse model and investigate its effect on the expression profile of circular RNAs(circRNAs)/long non-coding RNAs(lncRNAs) in ischemic myocardium and aorta. Sixty male ApoE~(-/-) mice were randomly assigned to a model group, high-, medium-, and low-dose CX-CS groups(7.8, 3.9, and 1.95 g·kg~(-1)), and a positive drug group(metoprolol 26 mg·kg~(-1) and simvastatin 5.2 mg·kg~(-1)), with 12 mice in each group. Male C57BL/6J mice were assigned to the sham group. The mice in the model group and the groups with drug intervention were fed on a high-fat diet for 10 weeks, followed by anterior descending coronary artery ligation. After that, the mice were fed on a high-fat diet for another two weeks to induce the MI-AS model. The mice in the sham group received normal feed, followed by sham surgery without coronary artery ligation. Mice in the groups with drug intervention received CX-CS or positive drug by gavage for four weeks from the 9th week of high-fat feeding, and those in the model group and the sham group received an equal volume of normal saline. Whole transcriptome sequencing was performed on the heart and aorta tissues of the medium-dose CX-CS group, the model group, and the sham group after administration. The results showed that the medium-and high-dose CX-CS groups showed improved cardiac function and reduced myocardial fibrosis area, and the medium-dose CX-CS group showed significantly reduced plaque area. CX-CS treatment could reverse the expression of circRNA＿07227 and circRNA＿11464 in the aorta of AS model and circRNA expression(such as circRNA＿11505) in the heart of the MI model. Differentially expressed circRNAs between the CX-CS-treated mice and the model mice were mainly enriched in lipid synthesis, lipid metabolism, lipid transport, inflammation, and angiogenesis in the aorta, and in angiogenesis, blood pressure regulation, and other processes in the heart. CX-CS treatment could reverse the expression of lncRNAs such as ENSMUST00000162209 in the aorta of the AS model and TCONS＿00002123 in the heart of the MI model. Differentially expressed lncRNAs between the CX-CS-treated mice and model mice were mainly enriched in lipid metabolism, angiogenesis, autophagy, apoptosis, and iron death in the aorta, and in angiogenesis, autophagy, and iron death in the heart. In summary, CX-CS can regulate the expression of a variety of circRNAs and lncRNAs, and its intervention mechanism in coronary heart disease may be related to the regulation of angiogenesis and inflammation in ischemic myocardium, as well as lipid metabolism, lipid transport, inflammation, angiogenesis in AS aorta.

[Effect and mechanism of Huangqi Shengmai Decoction in treatment of joint rat model of fatigue and myocardial injury].

This study aims to investigate the effects and the underlying mechanism of Huangqi Shengmai Decoction(HQSMD) in the treatment of fatigue and myocardial injury in a joint rat model. Wistar rats were assigned into 4 groups: sham, model, diltiazem hydrochloride(positive control), and HQSMD. The joint model of fatigue and myocardial injury was established by 14-day exhausted swimming followed by high ligation of the left anterior descending coronary artery. The rats in the sham group underwent a sham operation without coronary artery ligation or swimming. Since the fourth day after the ligation, swimming was continued in the model group and the drug-treated groups for the following 4 weeks. Meanwhile, the rats in the positive control group and the HQSMD group were respectively administrated intragastrically with diltiazem hydrochloride(20 mg·kg~(-1)·d~(-1)) and HQSMD(0.95 g·kg~(-1)·d~(-1)) for 4 weeks, while the shams and the models were given the same volume of normal saline. The left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), grip strength, and myocardial pathophysiological changes were measured to evaluate the anti-fatigue and cardioprotective effects of HQSMD. The protein levels of PTEN-induced putative kinase 1(PINK1) and parkin in the myocardium were measured by Western blot to preliminarily elucidate the mechanism of HQSMD in ameliorating myocardial injury by suppressing mitochondrial autophagy. Compared with the shams, the models showed weakened heart function(LVEF and LVFS, P<0.01), decreased grasping ability(P<0.05), elevated blood urea nitrogen(BUN) and aldosterone(ALD) levels(P<0.01), aggravated myocardial fibrosis and connective tissue hyperplasia(P<0.01), and up-regulated protein levels of PINK1(P<0.01) and parkin(P<0.05). Four-week treatment with HQSMD increased the LVEF and LVFS levels(P<0.01), enhanced the grip strength(P<0.01), reduced the serum levels of BUN(P<0.01) and ALD(P<0.05), alleviated the pathological injury and fibrosis in the myocardium(P<0.01), and down-regulated the protein levels of PINK1(P<0.01) and parkin(P<0.05) in heart tissue. The results demonstrate that HQSMD may alleviate myocardial fibrosis and protect myocardium by suppressing the excessive mitochondrial auto-phagic activity and reducing the excessively elevated ALD level, thereby ameliorating fatigue and myocardial injury.

Truncated TEAD-binding protein of TAZ inhibits glioma survival through the induction of apoptosis and repression of epithelial-mesenchymal transition.

Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, promotes tumor progression by serving as a transcriptional coactivator with TEAD. Here, we introduced a new construct which can express the TEAD-binding domain of TAZ protein (TAZBD), and determined its antitumor effect in malignant glioma both in vitro and in vivo. We first observed that TAZ was upregulated in glioma tissues and related to malignant clinicopathologic characteristic, indicating the crucial role of TAZ during glioma progression. In U87 and U251 cells, TAZBD expression increased the proportion of apoptotic cells, and suppressed the colony formation and tumorigenicity. Further, TAZBD also decreased cell metastasis through the repression of epithelial-mesenchymal transition. The mechanistic study showed that TAZBD suppression of glioma cells was predominantly through blocking the TAZ-TEAD complex formation by competing with endogenous TAZ. Thus, the gene therapy of malignant glioma through blocking TAZ-TEAD complex by TAZBD may provide a new way for the targeted therapy of glioma.

Decorated bacteria-cellulose ultrasonic metasurface.

Cellulose, as a component of green plants, becomes attractive for fabricating biocompatible flexible functional devices but is plagued by hydrophilic properties, which make it easily break down in water by poor mechanical stability. Here we report a class of SiO2-nanoparticle-decorated bacteria-cellulose meta-skin with superior stability in water, excellent machining property, ultrathin thickness, and active bacteria-repairing capacity. We further develop functional ultrasonic metasurfaces based on meta-skin paper-cutting that can generate intricate patterns of ~10 µm precision. Benefited from the perfect ultrasound insulation of surface Cassie-Baxter states, we utilize meta-skin paper-cutting to design and fabricate ultrathin (~20 µm) and super-light (<20 mg) chip-scale devices, such as nonlocal holographic meta-lens and the 3D imaging meta-lens, realizing complicated acoustic holograms and high-resolution 3D ultrasound imaging in far fields. The decorated bacteria-cellulose ultrasonic metasurface opens the way for exploiting flexible and biologically degradable metamaterial devices with functionality customization and key applications in advanced biomedical engineering technologies.

Blockage of glioma cell survival by truncated TEAD-binding domain of YAP.

BACKGROUND: Gliomas are highly aggressive and lack of efficient targeted therapy. YAP, as a Hippo pathway downstream effector, plays a key role in promoting tumor development through the interaction with transcription factor TEAD on the NH3-terminal proline-rich domain. Therefore, targeting TEAD-interacting domain of YAP may provide a novel approach for the treatment of gliomas. MATERIALS AND METHODS: We generated a truncated YAP protein which includes the TEAD-binding domain (YAPBD), and supposed YAPBD can interact with endogenous TEAD but lost the function to activate YAP target gene expressions. The association of YAP expression with the malignant characters of glioma tissues were determined by immunohistochemistry. TEAD-binding capacity of YAPBD was determined by co-immunoprecipitation. The cell proliferation and migration were determined by MTT assay, xenograft assay, wound healing assay and transwell assay, respectively. YAP target genes were detected by Western blot. RESULTS: YAP was highly expressed in glioma tissues and associated with tumor malignancy. YAPBD could block the TEAD-YAP complex formation by competing with YAP binding to TEAD. YAPBD could inhibit glioma cell growth both in vitro and in vivo, through the induction of cell cycle arrest and apoptosis. The cell cycle-related gene cyclin D1 and c-myc, and anti-apoptotic gene Bcl-2, Bcl-xL and survivin were inhibited after YAPBD overexpression. Furthermore, YAPBD also decreased cell migration and invasion, and repressed epithelial-mesenchymal transition. CONCLUSION: YAPBD can block glioma cell survival and repress YAP-dependent gene expressions, indicating gene therapy which targets TEAD-YAP complex would be a potential and significant novel approach for human malignant gliomas.

Super-resolution acoustic image montage via a biaxial metamaterial lens.

Ever since the Victorian era, montage, the process of pictorial composition made by juxtaposing or superimposing photographs, has been a very popular post-editing imaging technique. Despite showing a strong power in demonstrating complex wave field effects, this technique has neither been fully explored in acoustic imaging nor been realized in real-time systems with the capability beyond diffraction limits. On the other hand, the recent prospect of metamaterials has shown their great potentials in super-resolution acoustic imaging. However, the miracle jigsaw of more advanced functional modulation of acoustic wave fields at deep subwavelength scale still remains elusive. Here we report the experimental implementation of super-resolution acoustic image montage through a judiciously designed biaxial metamaterial lens. Based on the non-diffraction birefringence in the biaxial metamaterials, we realized various montage functionalities such as duplication, composition, and decomposition of sound images with distinctive deep subwavelength features. Our work represents an important step in developing versatile functional acoustic metamaterial devices for imaging purposes, as it provides on-demand editing of sound field patterns beyond diffraction limits.

Probability-Density-Based Deep Learning Paradigm for the Fuzzy Design of Functional Metastructures.

In quantum mechanics, a norm-squared wave function can be interpreted as the probability density that describes the likelihood of a particle to be measured in a given position or momentum. This statistical property is at the core of the fuzzy structure of microcosmos. Recently, hybrid neural structures raised intense attention, resulting in various intelligent systems with far-reaching influence. Here, we propose a probability-density-based deep learning paradigm for the fuzzy design of functional metastructures. In contrast to other inverse design methods, our probability-density-based neural network can efficiently evaluate and accurately capture all plausible metastructures in a high-dimensional parameter space. Local maxima in probability density distribution correspond to the most likely candidates to meet the desired performances. We verify this universally adaptive approach in but not limited to acoustics by designing multiple metastructures for each targeted transmission spectrum, with experiments unequivocally demonstrating the effectiveness and generalization of the inverse design.

Mirror-symmetry induced topological valley transport along programmable boundaries in a hexagonal sonic crystal.

Valley states, labeling the frequency extrema in momentum space, carry a new degree of freedom (valley pseudospin) for topological transport of sound in sonic crystals. Recently, the field of valley acoustics has become a hotspot due to its potentials in developing various topological-insulator-based devices. In most previous works, topological valley transport is implemented at the interfaces of two connected artificial crystals. With respect to the interface, the mirror symmetry of crystal structures supports either even-mode or odd-mode valley states. In this work, we propose a physical insight of transforming one hexagonal crystal into a virtual lattice by utilizing the mirror operation of rigid or soft boundaries, which greatly reduces the dimension of the acoustic structure and provides a possible way to implement the programmable routing of topological propagation. We investigate two cases that the rigid and soft boundaries are introduced either at the edge or inside a single hexagonal crystal. Our results clearly demonstrate the high-transmission valley transport along the folded boundaries, where reflection or scattering is prohibited at the sharp bending or corners due to topological protection. Three functional devices are exemplified, which are single-crystal-based topological delay-line filter, delay-line switcher and beam splitter. Our work reveals the inherent relation between the field symmetries of valley states and structural symmetries of sonic crystals. Programmable routing of topological sound transport through boundary engineering provides a platform for developing integrated and versatile topological-insulator-based devices.

Inhibition of eIF4F complex loading inhibits the survival of malignant glioma.

The eukaryotic initiation factor (eIF)4E­binding proteins (4E­BPs) regulate cap­dependent protein translation and control the assembly of the eIF4F complex. In the present study, a phosphorylation­deficient truncated 4E­BP2 (eIF4FD) was constructed into the eukaryotic expression vector pSecTag2, and the in vitro and in vivo effects on malignant glioma survival were determined through inhibiting eIF4F complex assembly. Cell cycle distribution analysis and TUNEL staining show that overexpression of eIF4FD suppressed cell proliferation and induced apoptosis in U251 cells. Western blotting showed that the cell cycle­related genes cyclin D1 and C­myc, and anti­apoptotic genes B­cell lymphoma 2 (Bcl­2), Bcl­extra large and survivin were reduced following the overexpression of eIF4FD. Furthermore, eIF4FD suppressed glioma vascularization via reductions in the expression of ß­catenin and vascular endothelial growth factor. In the orthotopic xenograft model, the stable expression of eIF4FD in U251 cells attenuated cell growth and increased the rate of apoptosis. Accordingly, pSecTag2­PTD­eIF4FD injection via the tail vein of mice also lead to cell growth inhibition and the induction of apoptosis. Therefore, the study showed that phosphorylation­deficient truncated 4E­BP2 efficiently inhibited eIF4E and prevented the formation of the eIF4F complex, which further contributed to the inhibition of cell proliferation and vascularization, and the induction of apoptosis. Therefore, the 4E­BP2­based phosphorylation­deficient truncation designed in the present study may represent a novel approach for the targeted therapy of human malignant glioma though inhibition of the translation initiation complex.

The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells.

Translation initiation factors (eIFs) are over-activated in many human cancers and may contribute to their progression. The small molecule 4EGI-1, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anti-cancer effects in human cancer cells. The goal of the present study was to evaluate the anti-cancer effects of 4EGI-1 in human glioma U251 cells. We found that 4EGI-1 impaired the assembly of the eIF4F complex, and inhibited proliferation of U251 cells via inducing apoptosis. 4EGI-1 treatment induced collapse of mitochondrial membrane potential (MMP) and production of intracellular reactive oxygen species (ROS), which were prevented by the ROS scavenger N-acetyl-cysteine (NAC). In addition, 4EGI-1 inhibited mitochondrial ATP synthesis via suppressing complex I activity, but had no effects on mitochondrial biogenesis. The results of fluorescence staining showed that 4EGI-1 indeed fragmented the mitochondrial network of U251 cells. We found a significant decrease in optic atrophy type 1 (Opa-1) and mitofusin 1 (Mfn-1) related to fusion proteins as well as an increase in fission protein dynamin-related protein 1 (Drp-1). Furthermore, the anti-cancer effects of 4GI-1 were partially nullified by knock down of Drp-1 using siRNA. These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy.