Emerging evidence suggests that epithelial‐mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is ...crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor‐related miRNAs were significantly decreased. Among these miRNAs, miR‐125b expression was most strongly suppressed. We also found down‐regulation of miR‐125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR‐125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR‐125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR‐125b attenuated EMT‐associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR‐125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR‐125b suppressed EMT and EMT‐associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR‐125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR‐125b for liver cancer. Conclusion: miR‐125b exerts inhibitory effects on EMT and EMT‐associated traits in HCC by SMAD2 and 4. Ectopic expression of miR‐125b provides a promising strategy to treat HCC. (Hepatology 2015;62:801–815)
The hierarchical aggregation of molecular nanostructures from multiple components is a grand synthetic challenge, which requires highly selective linkage control. We demonstrate how two orthogonal ...linkage groups, that is, organotin and lanthanide cations, can be used to drive the aggregation of a giant molecular metal oxide superstructure. The title compound {(Sn(CH3)2)2O4{CeW5O18 TeW4O16CeSn(CH3)24TeW8O314}2}46− (1 a) features dimensions of ca. 2.2×2.3×3.4 nm3 and a molecular weight of ca. 25 kDa. Structural analysis shows the hierarchical aggregation from several independent subunits. Initial biomedical tests show that 1 features an inhibitory effect on the proliferation of HeLa cells based on an apoptosis pathway. In vivo experiments in mice reveal the antiproliferative activity of 1 and open new paths for further development of this new compound class.
Hierarchical assembly of a giant heterometallic polyoxotungstate supercluster with a molecular weight of ca. 25 kDa is reported. Geometrically unrestricted cerium(III) and geometrically restricted dimethyl tin cation linkers are used to gain access to a giant molecular species featuring three different polyoxometalate building units. The compound demonstrates in vitro and in vivo antiproliferative activity against HeLa cervical cancer cell lines.
Wild relatives of crops are an important source of genetic diversity for agriculture, but their gene repertoire remains largely unexplored. We report the establishment and analysis of a pan-genome of ...Glycine soja, the wild relative of cultivated soybean Glycine max, by sequencing and de novo assembly of seven phylogenetically and geographically representative accessions. Intergenomic comparisons identified lineage-specific genes and genes with copy number variation or large-effect mutations, some of which show evidence of positive selection and may contribute to variation of agronomic traits such as biotic resistance, seed composition, flowering and maturity time, organ size and final biomass. Approximately 80% of the pan-genome was present in all seven accessions (core), whereas the rest was dispensable and exhibited greater variation than the core genome, perhaps reflecting a role in adaptation to diverse environments. This work will facilitate the harnessing of untapped genetic diversity from wild soybean for enhancement of elite cultivars.
Smart regulation of substance permeability through porous membranes is highly desirable for membrane applications. Inspired by the stomatal closure feature of plant leaves at relatively high ...temperature, here we report a nano-gating membrane with a negative temperature-response coefficient that is capable of tunable water gating and precise small molecule separation. The membrane is composed of poly(N-isopropylacrylamide) covalently bound to graphene oxide via free-radical polymerization. By virtue of the temperature tunable lamellar spaces of the graphene oxide nanosheets, the water permeance of the membrane could be reversibly regulated with a high gating ratio. Moreover, the space tunability endows the membrane with the capability of gradually separating multiple molecules of different sizes. This nano-gating membrane expands the scope of temperature-responsive membranes and has great potential applications in smart gating systems and molecular separation.
The monogamy relation of quantum states has limited the shareability properties of quantum resources in multiparty quantum systems. It plays a vital role in information distribution and ...transformation over many sites in quantum communications. Here, we focus on the monogamy relations of quantum correlations in the context of three-flavor neutrino oscillations, related to the squared entanglement of formation, the squared of quantum discord and its geometric variant. The monogamy relations in terms of the squared entanglement of formation work for the electron and muon antineutrino oscillations, suggesting that the bipartite entanglement measured by squared entanglement of formation of the three-flavor neutrino system set a limitation to the sum of pairwise squared entanglement of formation. Furthermore, we found that the squared quantum discord is also monogamous in three-flavor neutrino system. As a comparison, we test the monogamy of the quantum discord in neutrino oscillations with the result that the quantum discord is not monogamous. In addition, it is found that the bipartite geometric quantum discord of three-flavor systems is equal to the sum of the pairwise geometric quantum discord, i.e., the monogamy relation for geometric quantum discord is saturated for three-flavor neutrino system. These monogamy relations of quantum correlations provide a way for studying the distribution of quantum resources in neutrino oscillations, which is of significance to explore the further applications of neutrino oscillations in quantum communications.
Diabetic wound is one of the most intractable chronic wounds that is prone to bacterial infection. Hypoxia is an important feature in its microenvironment. However, it is challenging for ...antimicrobial therapy to directly apply the existing hypoxia-responsive drug delivery systems due to the active targeting deficiency and the biofilm obstacle. Herein, we customizes a hypoxia-responsive carrier, lactose-modified azocalix4arene (LacAC4A) with the ability to actively target and inhibit biofilm. By loading ciprofloxacin (Cip), the resultant supramolecular nanoformulation Cip@LacAC4A demonstrates enhanced antibacterial efficacy resulting from both the increased drug accumulation and the controlled release at the site of infection. When applied on diabetic wounds together with multidrug-resistant Pseudomonas aeruginosa infection in vivo, Cip@LacAC4A induces definitely less inflammatory infiltration than free Cip, which translates into high wound healing performance. Importantly, such design principle provides a direction for developing antimicrobial drug delivery systems.
The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches ...including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. ...Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
Precisely regulating water and molecule permeation through membranes is of crucial significance in broad domains such as water filtration and smart reactors. Comparing with routine stiff membranes, ...stimuli‐response polymers endow porous membranes with various gating properties, but most of these membranes have only one‐way gating performance, that is, either positive or negative. Here poly(N‐isopropylacrylamide) (PNIPAM) grafted graphene oxide (GO) membranes with reversible positive/negative gating regularity are constructed by simply tuning the molecule grafting density. The water and small molecule permeance of the membranes can be regulated by adjusting environment temperature. Based on this tunable thermoresponsive gating regularity, a bidirectional fluidic controlling system is designed by integrating a positive membrane and a negative membrane, which can be employed as a self‐adaptive gating reactor. This strategy provides an insight into constructing smart gating membranes with extraordinary properties, showing promising applications in micro/nanofluidic valves and temperature sensitive biochemical reactors.
Thermoresponsive graphene membranes with reversible positive/negative gating regularity are fabricated by simply tuning poly(N‐isopropylacrylamide) (PNIPAM) grafting density on graphene oxide (GO). This strategy breaks the restriction of a traditional gating membrane with monotype gating regularity and can be used to construct a self‐adaptive fluidic system to intelligently control fluid transportation.
Combination chemotherapy refers to the use of multiple drugs to treat cancer. In this therapy, the optimal ratio of the drugs is essential to achieve drug synergism and the desired therapeutic ...effects. However, most delivery strategies are unable to precisely control the ratio of the drugs during the drug loading and delivery processes, resulting in inefficient synergy and unpredictable efficacy. Herein, a macrocyclic‐amphiphile‐based self‐assembled nanoparticle (MASN) that achieves precise loading and ratiometric delivery of therapeutic combinations is presented. By integrating multiple macrocyclic cavities within a single nanoparticle, the MASN can load multiple drug molecules via the host–guest interaction, and the ratio of the drugs loaded can be predicted with their initial concentrations and characteristic binding affinity. Moreover, MASNs are readily degraded under a hypoxic microenvironment, allowing spontaneous release of the drugs upon reaching tumor tissues. With precise drug loading and controlled release mechanisms, MASNs achieve ratiometric delivery of multiple commercial drugs to tumors, thereby achieving optimal anti‐tumor effects. Since the optimal drug ratio of a therapeutic combination can be quickly determined in vitro, MASNs can translate this optimal ratio to the therapeutic benefits in vivo, providing a potential platform for the rapid development of effective combination cancer therapies involving multiple drugs.
A macrocyclic‐amphiphile‐based self‐assembled nanoparticle (MASN) with the capability of precise loading and ratiometric delivery of different drugs is developed for effective combination chemotherapy. The MASN can quickly convert the optimal drug ratio of a therapeutic combination identified in vitro into therapeutic benefits in vivo, providing a potential platform for the rapid development of effective combinations of cancer therapies.
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