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Lipid-modified cell-penetrating peptide-based self-assembly micelles for co-delivery of narciclasine and siULK1 in hepatocellular carcinoma therapy
No full textHepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and one therapeutic approach is to target both the AMPK and autophagy pathways in order to synergistically promote programmed cell death. Here, a series of amphiphilic, lipid-modified cell-penetrating peptides were synthesized and allowed to self-assemble into micelles loaded with the AMPK activator narciclasine (Narc) and short interfering RNA targeting the unc-51-like kinase 1 (siULK1). The size of these micelles, their efficiency of transfection into cells, and their ability to release drug or siRNA cargo in vitro were pH-sensitive, such that drug release was facilitated in the acidic microenvironment of the tumor. Transfecting the micelles into HCC cells significantly inhibited protective autophagy within tumor cells, and delivering the micelles into mice carrying HCC xenografts induced apoptosis, slowed tumor growth, and inhibited autophagy. Our results indicate that co-delivering Narc and siULK1 in biocompatible micelles can safely inhibit tumor growth and protective autophagy, justifying further studies into this promising therapeutic approach against HCC. Statement of Significance We have focused on the targeted therapy of HCC via synergistically inhibiting the autophagy and inducing apoptosis. The lipid-modified cell-penetrating peptide can not only aggregate into micelles to load natural product narciclasine and ULK1 siRNA simultaneously, but also facilitate uptake and endosome escape with a pH-sensitive manner in HepG2 cells. HepG2 cell treated with siULK1-M-Narc has increased apoptotic levels and declined autophagy via the targeted regulation of AMPK-ULK1 signaling axis. The in vivo studies have confirmed that siULK1-M-Narc efficiently reduce the growth of tumor on HCC xenograft models with good safety. Thus, we suppose the lipid-modified cell-penetrating peptide has good application prospects in the targeted combinational therapy of HCC. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved
Plant diversity enhances productivity and soil carbon storage
No full textDespite evidence from experimental grasslands that plant diversity increases biomass production and soil organic carbon (SOC) storage, it remains unclear whether this is true in natural ecosystems, especially under climatic variations and human disturbances. Based on field observations from 6,098 forest, shrubland, and grassland sites across China and predictions from an integrative model combining multiple theories, we systematically examined the direct effects of climate, soils, and human impacts on SOC storage versus the indirect effects mediated by species richness (SR), aboveground net primary productivity (ANPP), and belowground biomass (BB). We found that favorable climates (high temperature and precipitation) had a consistent negative effect on SOC storage in forests and shrublands, but not in grasslands. Climate favorability, particularly high precipitation, was associated with both higher SR and higher BB, which had consistent positive effects on SOC storage, thus offsetting the direct negative effect of favorable climate on SOC. The indirect effects of climate on SOC storage depended on the relationships of SR with ANPP and BB, which were consistently positive in all biome types. In addition, human disturbance and soil pH had both direct and indirect effects on SOC storage, with the indirect effects mediated by changes in SR, ANPP, and BB. High soil pH had a consistently negative effect on SOC storage. Our findings have important implications for improving global carbon cycling models and ecosystem management: Maintaining high levels of diversity can enhance soil carbon sequestration and help sustain the benefits of plant diversity and productivity
Evaluation of tofu as a potential tissue engineering scaffold
No full textTofu not only is a delicious vegetarian food, but also shows potential biomedical applications for its high protein content and typical porous scaffold structure. Herein, two kinds of porous soybean scaffolds were developed, the first based on the traditional tofu manufacturing processes, the second modified via covalent crosslinking. The morphology, physicochemical properties and biocompatibility in vitro and in vivo were systematically investigated. A similar porous micromorphology was observed in both the tofu scaffolds and crosslinked soybean protein scaffolds. Both scaffolds exhibited good cell proliferation and cellular adherence. No obvious inflammatory response was observed after subcutaneous implantation tests for either material. These results demonstrated that the tofu scaffolds or soybean protein scaffolds fabricated by tofu processing have potential as new food-source biomaterials in tissue engineering applications
Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells
No full textPhospholipids are asymmetrically distributed across mammalian plasma membrane with phosphatidylserine (PS) and phosphatidylethanolamine concentrated in the cytoplasmic leaflet of the membrane bilayer. This asymmetric distribution is dependent on a group of P4-ATPases named PS flippases. The proper transport and function of PS flippases require a beta-subunit transmembrane protein 30 A (TMEM30A). Disruption of PS flippases led to several human diseases. However, the roles of TMEM30A in the central nervous system remain elusive. To investigate the role of Tmem30a in the cerebellum, we developed a Tmem30a Purkinje cell (PC)-specific knockout (KO) mouse model. The Tmem30a KO mice displayed early-onset ataxia and progressive PC death. Deficiency in Tmem30a led to an increased expression of Glial fibrillary acidic protein and astrogliosis in regions with PC loss. Elevated C/EBP homologous protein and BiP expression levels indicated the presence of endoplasmic reticulum stress in the PCs prior to visible cell loss. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis suggested that apoptotic cell death occurred in the cerebellum. Our data demonstrate that loss of Tmem30a in PCs results in protein folding and transport defects, a substantial decrease in dendritic spine density, increased astrogliosis and PC death. Taken together, our data demonstrate an essential role of Tmem30a in the cerebellum PCs
Catalyst-free synthesis of 2,3-dihydrobenzofurans through [4+1] cycloaddition of ortho-hydroxyphenylsubstituted para-quinone methides and sulfur ylides
No full textAn efficient [4+1] cycloaddition of ortho-hydroxyphenylsubstituted para-quinone methides, and sulfur ylides was achieved under the catalyst-free condition. With this developed protocol, a series of trans-2,3-dihydrobenzofurans were obtained in excellent yields (up to 99%) with high diastereoselectivities (>20:1 dr). The usefulness of the protocol was also demonstrated by the versatile conversions of the 2,3-dihydrobenzofurans into other functionalized benzofurans. (C) 2017 Elsevier Ltd. All rights reserved
TaAAP6-3B, a regulator of grain protein content selected during wheat improvement
No full textBackground: The content of grain protein (GPC) in cereals is an important part of total protein in human food. Exploring and utilizing new GPC genes is one of the most effective approaches for wheat quality breeding. Results: Three homoeologues of TaAAP6(-3A, 3B, 3D) were cloned by homology cloning from OsAAP6. Temporal and spatial expression analysis showed that TaAAP6homoeologues were preferentially expressed in developing grains, and TaAAP6-3B may play a major role in regulating GPC in wheat. Association analysis indicated thatTaAAP6-3B-I is significantly correlated with higher GPC than that of TaAAP6-3B-II for 115 wheat lines in all five environments. TaAAP6-3B-I, the favored allele of TaAAP6-3B, was preferentially expressed in preliminary developing grain stage. Two functional markers were developed to discriminate 197F(2)populations and the result showed that TaAAP6-3B-I (high-protein content) was completely dominant. Two cis-regulatory elements appear to be associated with high GPC were found in the 5'UTR of TaAAP6-3B-I. The change of the TaAAP6-3B locus types indicated that the gene was subjected to selection pressures during long process of artificial selection. Conclusions: TaAAP6-3B is a regulator of GPC and its favored allele TaAAP6-3BI exhibits an obvious potential application in wheat high-GPC breeding
Tomato UV-B receptor SlUVR8 mediates plant acclimation to UV-B radiation and enhances fruit chloroplast development via regulating SlGLK2
No full textPlants utilize energy from sunlight to perform photosynthesis in chloroplast, an organelle that could be damaged by solar UV radiation. The ultraviolet-B (UV-B) photoreceptor UVR8 is required for UV-B perception and signal transduction. However, little is known about how UVR8 influence chloroplast development under UV-B radiation. Here, we characterized tomato UVR8 gene (SlUVR8) and our results indicated that SlUVR8 facilitate plant acclimation to UV-B stress by orchestrating expression of the UVB-responsive genes (HY5 and CHS) and accumulating UV-absorptive compounds. In addition, we also discovered that SlUVR8 promotes fruit chloroplast development through enhancing accumulation of transcription factor GOLDEN2-LIKE2 (SlGLK2) which determines chloroplast and chlorophyll levels. Furthermore, UV-B radiation could increase expression of SlGLK2 and its target genes in fruits and leaves. SlUVR8 is required for UVB-induced SlGLK2 expression. Together, our work not only identified the conserved functions of SlUVR8 gene in response to UV-B stress, but also uncovered a novel role that SlUVR8 could boost chloroplast development by accumulating SlGLK2 proteins
Phosphorous fertilization alleviates drought effects on Alnus cremastogyne by regulating its antioxidant and osmotic potential
No full textAlnus cremastogyne, a broad-leaved tree endemic to south-western China, has both commercial and restoration importance. However, little is known of its morphological, physiological and biochemical responses to drought and phosphorous (P) application. A randomized experimental design was used to investigate how drought affected A. cremastogyne seedlings, and the role that P applications play in these responses. Drought had significant negative effects on A. cremastogyne growth and metabolism, as revealed by reduced biomass (leaf, shoot and root), leaf area, stem diameter, plant height, photosynthetic rate, leaf relative water content, and photosynthetic pigments, and a weakened antioxidative defence mechanism and high lipid peroxidation level. However, the reduced leaf area and enhanced osmolyte (proline and soluble sugars) accumulation suggests drought avoidance and tolerance strategies in this tree. Applying P significantly improved the leaf relative water content and photosynthetic rate of drought-stressed seedlings, which may reflect increased anti-oxidative enzyme (superoxide dismutase, catalase and peroxidase) activities, osmolyte accumulation, soluble proteins, and decreased lipid peroxidation levels. However, P had only a slight or negligible effect on the well-watered plants. A. cremastogyne is sensitive to drought stress, but P facilitates and improves its metabolism primarily via biochemical and physiological rather than morphological adjustments, regardless of water availability
Evolution of microbial biosensor based on functional RNA through fluorescence-activated cell sorting
No full textWhole-cell microbial biosensors are emerging as tools for rapid, economic and on-site detection. Anew approach to construct microbial biosensor with functional RNA for sensing of specific molecules is described here. The sensor is based on Spinach, an RNA mimic of GFP, and transcribed in living bacteria to detect intended molecules through fluorescent signals. Based on high-throughput cell cytometry, microbes with high selectivity and sensitivity could be screened out and evolved. Three microbial biosensors obtained through this method can efficiently detect tobramycin in different biosamples, providing a simple and economic solution for both qualitative and quantitative detection of antibiotics in the complex environments. This new strategy for the construction of whole-cell microbial biosensor and in vivo evolution protocol is especially suitable for any exogenous targets able to enter into bacteria and does not cause bacterial death in a short time, not just intracellular substances. (c) 2017 Elsevier B.V. All rights reserved