While esters are frequently used as traditional electrophiles in substitution chemistry, their application in cross‐coupling chemistry is still in its infancy. This work demonstrates that methyl ...esters can be used as coupling electrophiles in Ni‐catalyzed Heck‐type reactions through the challenging cleavage of the C(acyl)−O bond under relatively mild reaction conditions at either 80 or 100 °C. With the σ‐NiII intermediate generated from the insertion of acyl NiII species into the tethered C=C bond, carbonyl‐retentive products were formed by domino Heck/Suzuki–Miyaura coupling and Heck/reduction pathways when organoboron and mild hydride nucleophiles are used.
Partner up: Methyl esters are shown to be viable cross‐coupling partners in intramolecular cyclization reactions with a tethered olefin. Both a boronic acid and mild hydride donors can be used in this nickel‐catalyzed reaction, providing differentially substituted indanone products.
Lanthanide-based upconversion nanomaterials have recently attracted considerable attention in both fundamental research and various frontier applications owing to their excellent photon upconversion ...performance and favourable physicochemical properties. In particular, the emergence of multi-layer core-shell (MLCS) nanostructures offers a versatile and powerful tool to realize well-defined matrix compositions and spatial distributions of the dopant on the nanometer length scale. In contrast to the conventional nanomaterials and commonly investigated core-shell nanoparticles, the rational design of MLCS nanostructures allows us to deliberately introduce more functional properties into an upconversion system, thus providing unprecedented opportunities for the precise manipulation of energy transfer channels, the dynamic control of upconversion processes, the fine tuning of switchable emission colours and new functional integration at a single-particle level. In this review, we present a summary and discussion on the key aspects of the recent progress in lanthanide-based MLCS nanoparticles, including the manipulation of emission and lifetime, the switchable multicolour output and the lanthanide ionic interactions on the nanoscale. Benefitting from the multifunctional and versatile luminescence properties, the MLCS nanostructures exhibit great potential in diversities of frontier applications such as three-dimensional display, upconversion laser, optical memory, anti-counterfeiting, thermometry, bioimaging, and therapy. The outlook and challenges as well as perspectives for the research in MLCS nanostructure materials are also provided. This review would be greatly helpful in exploring new structural designs of lanthanide-based materials to further manipulate the upconversion phenomenon and expand their application boundaries.
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)
Highly reactive metastable intermixed composites (MICs) have attracted much attention in the past decades. The MIC family of materials mainly includes traditional metal‐based nanothermites, novel ...core–shell‐structured, 3D ordered macroporous‐structured, and ternary nanocomposites. By applying special fabrication approaches, highly reactive MICs with uniformly dispersed reactants, “layer‐by‐layer” or “core–shell” structures, can be prepared. Thus, the combustion performance can be greatly improved, and the ignition characteristics and safety can be precisely controlled by using a certain preparation strategy. Here, the preparation and characterization of the MICs that have been developed during the past few decades are summarized. Traditional preparation methods for MICs generally include physical mixing, high‐energy ball milling, sol–gel synthesis, and vapor deposition, while the novel methods include self‐assembly, electrophoretic deposition, and electrospinning. Various preparation procedures and the ignition and combustion performance of different MIC reactive systems are compared and discussed. In particular, the advantages of novel structured MICs in terms of safety and combustion efficiency are clarified, based on which suggestions regarding the possible future research directions are proposed.
Highly reactive metastable intermixed composites (MICs) prepared by different strategies show various characteristics and properties. By applying special fabrication approaches, highly reactive MICs with uniformly dispersed reactants, assembled in either layer‐by‐layer or core–shell structure, can be prepared. Thus, the improved and desired performances can be achieved by using a certain preparation strategy.
The precise accumulation and extended retention of nanomedicines in the tumor tissue has been highly desired for cancer therapy. Here a novel supramolecular‐peptide derived nanodrug (SPN) that can be ...transformed to microfibers in response to intracellular polyamine in cancer cells for significantly enhanced tumor specific accumulation and retention is developed. The supramolecular‐peptide is constructed via the non‐covalent interactions between cucurbit7uril (CB7) and Phe on Phe‐Phe‐Val‐Leu‐Lys‐camptothecin conjugates (FFVLK‐CPT, PC). The resultant amphiphilic supramolecular complex subsequently self‐assembles into nanoparticles with a hydrodynamic diameter of 164.2 ± 3.7 nm. Upon internalization into spermine‐overexpressed cancer cells, the CB7‐Phe host–guest pairs can be competitively dissociated by spermine and can release free PC, which immediately form β‐sheet structures and subsequently reorganize into microfibers, leading to dramatically improved accumulation, retention, and sustained release of CPT in tumor cells for highly effective cancer therapy. Accordingly, this SPN exhibit rather low toxicity against non‐cancerous cells due to the morphological stability and fast exocytosis of the nanodrugs in those cells without abundant spermine. This study reports the first supramolecular peptide capable of polyamine‐responsive “nanoparticle‐to‐microfiber” transformation for specific tumor therapy with minimal side effects. This work also offers novel insights to the design and development of stimuli‐responsive nanomaterials as precision medicine.
The first polyamine‐responsive, morphology‐transformable supramolecular peptide‐drug conjugates based nanodrug is constructed via self‐assembly of an amphiphillic cucurbit7uril‐peptide complex. This nanodrug can dissociate upon competition of overexpressed polyamine and re‐assemble into microfibers in situ inside tumor cells, leading to improved, selective drug accumulation and retention inside cancer cells for safe and effective cancer therapy.
Background and Purpose
In chronic kidney disease (CKD), patients inevitably reach end‐stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite ...disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1‐hydroxypyrene in mediating renal fibrosis.
Experimental Approach
We analysed 5406 urine and serum samples from patients with Stage 1–5 CKD using metabolomics, and 1‐hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine‐induced rats.
Key Results
We identified correlations between the urine and serum levels of 1‐hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1‐hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up‐regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up‐regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up‐regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK‐2 cells treated with 1‐hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1‐hydroxypyrene‐induced HK‐2 cells and mice.
Conclusion and Implications
Metabolite 1‐hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.
Positive cooperativity achieved through activating weak non‐covalent interactions is common in biological assemblies but is rarely observed in synthetic complexes. Two new molecular tubes have been ...synthesized and the syn isomer binds DABCO‐based organic cations with high orientational selectivity. Surprisingly, the ternary complex with two hosts and one guest shows a high cooperativity factor (α=580), which is the highest reported for synthetic systems without involving ion‐pairing interactions. The X‐ray single‐crystal structure revealed that the strong positive cooperativity likely originates from eight C−H⋅⋅⋅O hydrogen bonds between the two head‐to‐head‐arranged syn tube molecules. These relatively weak hydrogen bonds were not observed in the free hosts and only emerged in the complex. Furthermore, this complex was used as a basic motif to construct a robust 2+2 cyclic assembly, thus demonstrating its potential in molecular self‐assembly.
A high level of complexity: Strong positive allosteric cooperativity in a ternary complex involving two molecular tubes was revealed to be caused by the formation of relatively weak C−H⋅⋅⋅O hydrogen bonds. This robust binding motif was further applied to the construction of a large 2+2 cyclic complex.
Understanding the mechanism of nanosilver-dependent antibacterial activity against microorganisms helps optimize the design and usage of the related nanomaterials. In this study, we prepared four ...kinds of 10 nm-sized silver nanoparticles (AgNPs) with dictated surface chemistry by capping different ligands, including citrate, mercaptopropionic acid, mercaptohexanoic acid, and mercaptopropionic sulfonic acid. Their surface-dependent chemistry and antibacterial activities were investigated. Owing to the weak bond to surface Ag, short carbon chain, and low silver ion attraction, citrate-coated AgNPs caused the highest silver ion release and the strongest antibacterial activity against
, when compared to the other tested AgNPs. The study on the underlying antibacterial mechanisms indicated that cellular membrane uptake of Ag, NAD
/NADH ratio increase, and intracellular reactive oxygen species (ROS) generation were significantly induced in both AgNP and silver ion exposure groups. The released silver ions from AgNPs inside cells through a Trojan-horse-type mechanism were suggested to interact with respiratory chain proteins on the membrane, interrupt intracellular O
reduction, and induce ROS production. The further oxidative damages of lipid peroxidation and membrane breakdown caused the lethal effect on
. Altogether, this study demonstrated that AgNPs exerted antibacterial activity through the release of silver ions and the subsequent induction of intracellular ROS generation by interacting with the cell membrane. The findings are helpful in guiding the controllable synthesis through the regulation of surface coating for medical care purpose.
• During male gametogenesis in Arabidopsis, the haploid microspore undergoes an asymmetric division to produce a vegetative and a generative cell, the latter of which continues to divide ...symmetrically to form two sperms. This simple system couples cell cycle with cell fate specification.
• Here we addressed the role of DNA replication in male gametogenesis using a mutant bicellular pollen 1 (bice1), which produces bicellular, rather than tricellular, pollen grains as in the wild-type plant at anthesis.
• The mutation prolonged DNA synthesis of the generative cell, which resulted in c. 40% of pollen grains arrested at the two-nucleate stage. The extended S phase did not impact the cell fate of the generative cell as shown by cell-specific markers. BICE1 encodes a plant homolog of human D123 protein that is required for G1 progression, but the underlying mechanism is unknown.
• Here we showed that BICE1 interacts with MCM4 and MCM7 of the pre-replication complex. Consistently, double mutations in BICE1 and MCM4, or MCM7, also led to bicellular pollen and condensed chromosomes. These suggest that BICE1 plays a role in modulating DNA replication via interaction with MCM4 and MCM7.
PDF
