DNAzyme‐based gene therapy holds immense prospects for effectively treating severe diseases, yet is constrained with inefficient delivery and unconditional activation. Herein, we designed a ...bioinspired self‐catabolic DNA nanocapsule for sustaining tumor‐specific cascade activation of therapeutic DNAzyme. The exquisite DNAzyme was temporarily masked by the self‐excising DNAzyme in the hierarchical rolling circle replication (RCR) nanostructures, thus stayed in an inactive state in physiological fluids. Through the multivalent tumor‐anchoring aptamer strands, the RCR nanocapsule was specifically accumulated in cancer cells and was sequentially activated for motivating the ultimate DNAzyme‐mediated gene silencing via the intelligent stimuli‐responsive cascade DNAzyme activation. By virtue of the programmable RCR assembly strategy, our compact DNAzyme nanoplatform shows great promise for developing versatile smart gene therapeutics and personalized nanomedicines.
An exquisite cascade DNAzyme‐sustained gene silencing platform was assembled to program the “mask‐cleave‐release” of therapeutic DNAzyme from the intelligent DNAzyme nanosponge, where the upstream self‐catabolic DNAzyme mediated the specific and accurate activation of downstream therapeutic DNAzyme for guaranteeing the efficient gene silencing with improved bioavailability.
The role of exosomes in human cancers has been identified, while the effect of cancer-associated fibroblasts (CAFs)-derived exosomes (CAF-exos) transmitting microRNAs (miRNAs) on colorectal cancer ...(CRC) remains largely unknown. We aim to explore the impact of CAF-derived exosomal miR-135b-5p on CRC progression by targeting thioredoxin-interacting protein (TXNIP).
CRC tissues were collected to obtain CAF-exos, which were used to co-culture with LoVo and HT29 cells. The effect of miR-135b-5p and TXNIP on the in vivo growth, in vitro proliferation, apoptosis, migration, invasion and angiogenesis of CRC cells. miR-135b-5p and TXNIP expression in exosomes and CRC cells were detected and their targeting relationship was confirmed.
MiR-135b-5p was upregulated whereas TXNIP was downregulated in CRC tissues and cells. The CAF-exos and CAF-exos upregulating miR-135b-5p promoted in vivo growth, in vitro proliferation, migration and invasion, and suppressed apoptosis of CRC cells, and also promoted the HUVEC angiogenesis. TXNIP was confirmed as a target of miR-135b-5p and overexpression of TXNIP could weaken the pro-CRC effect of exosomal miR-135b-5p, CONCLUSION: CAF-exos upregulate miR-135b-5p to promote CRC cell growth and angiogenesis by inhibiting TXNIP.
A fluorescent molecular probe, a 1,1′-bi-2-naphthol (BINOL)-based bis(naphthylimine) compound (R)-4, is designed to exhibit very different fluorescent responses at two emission wavelengths toward a ...variety of chiral functional amines including diamines, amino alcohols, and amino acids. At one emission wavelength (λ1), it shows high sensitivity toward the substrates, and at another wavelength (λ2), it shows high enantioselectivity. This is the first rational design of such a dual responsive fluorescent sensor which can be used to simultaneously determine both the concentration and the enantiomeric composition of functional chiral amines by one fluorescent measurement. This strategy is potentially generally applicable for the construction of sensors for rapid assay of structurally diverse chiral substrates. When (R)-4 is treated with various chiral functional amines in the presence of Zn(OAc)2, its 2-naphthylamine units are displaced off to show large fluorescent enhancement at λ1 = 427 nm (I 1) due to the restored emission of 2-naphthylamine. The combination of the remaining chiral binaphthyl unit with the chiral substrates leads to highly enantioselective fluorescent enhancement at λ2 > 500 nm (I 2). Since I 1 is only concentration dependent but independent of the chiral configuration, it allows the determination of the substrate concentration. The highly enantioselective I 2 allows the determination of the enantiomeric composition. Thus, using one fluorescent probe with one fluorescent measurement, both the concentration and the enantiomeric composition are determined. The dual responsive mechanism of (R)-4 is studied by using various spectroscopic methods including fluorescence, UV–vis, NMR, and mass analyses.
The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes pyroptosis and inflammatory cytokine release to control pathogen infection, but how pathogens evade this immune response remains ...largely unexplored. Here we identify the known protein phosphatase PtpB from
as a phospholipid phosphatase inhibiting the host inflammasome-pyroptosis pathway. Mechanistically, PtpB dephosphorylated phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, thus disrupting the membrane localization of the cleaved GSDMD to inhibit cytokine release and pyroptosis of macrophages. Notably, this phosphatase activity requires PtpB binding to ubiquitin. Disrupting phospholipid phosphatase activity or the ubiquitin-interacting motif of PtpB enhanced host GSDMD-dependent immune responses and reduced intracellular pathogen survival. Thus, pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition.
Gut microbiota and dietary fiber are critical for protecting body from obesity, diabetes and cancer. Butyrate, produced in the gut by bacterial fermentation of dietary fibers, is demonstrated to be ...protective against the development of colorectal cancer as a histone deacetylase (HDAC) inhibitor. We report that high-fiber diet and butyrate significantly inhibited the growth lymphoma tumors. Butyrate induced apoptosis of lymphoma tumor cells and significantly up-regulated histone 3 acetylation (H3ac) level and target genes such as Fas, P21, P27. Our results unravel an instrumental role of fiber diet and their metabolites on lymphoma tumor and demonstrate an intervention potential on the prevention and therapy of lymphoma.
Two enantioselective fluorescent sensors, namely, the 1,1′-binaphthol (BINOL)-amino alcohol (S)-1 and the H8BINOL-amino alcohol (R)-2, have been prepared as a pseudoenantiomeric pair. These two ...compounds have the opposite chiral configuration at both the axially chiral biaryl centers and the amino alcohol units. In methylene chloride solution, (R)-mandelic acid greatly enhances the emission of (S)-1 at λ1 = 374 nm and (S)-mandelic acid greatly enhances the emission of (R)-2 at λ2 = 330 nm. A 1:1 mixture of (S)-1 and (R)-2 was used to interact with mandelic acid at a variety of concentrations with various enantiomeric compositions. It was found that both the concentration of mandelic acid and its enantiomeric composition can be directly determined by measuring the sum and difference of the fluorescence intensities at λ1 and λ2.
Silent information regulator 1 (SIRT1) exerts neuroprotection in many neurodegenerative diseases. However, it is not clear if SIRT1 has protective effects after intracerebral hemorrhage (ICH)-induced ...brain injury in rats. Thus, our goal was to examine the influence of SIRT1 on ICH injuries and any underlying mechanisms of this influence. Brain injury was induced by autologous arterial blood (60 μL) injection into rat brains, and data show that activation of SIRT1 with SRT1720 (5 mg/kg) restored nuclear SIRT1, deacetylation of PGC-1α, and mitochondrial biogenesis and decreased mortality, behavioral deficits, and brain water content without significant changes in phosphorylated AMP-activated protein kinase (pAMPK) induced by ICH. Activation of SIRT1 with SRT1720 also restored mitochondrial electron transport chain proteins and decreased apoptotic proteins in ICH; however, these changes were reversed after ICH. In contrast, treatment with PGC-1α siRNA yielded opposite effects. To explore the protective effects of SIRT1 after ICH, siRNAs were used to knockdown SIRT1. Treatment with SIRT1 siRNA increased mortality, behavioral deficits, brain water content, mitochondrial dysfunction, and neurocyte apoptosis after ICH. Thus, activation of SIRT1 promotes recovery of mitochondrial protein and function by increasing mitochondrial biogenesis and reduces apoptosis after ICH via the PGC-1α mitochondrial pathway. These data may suggest a new therapeutic approach for ICH injuries.
The addition of Zn 2+ dramatically enhanced the enantioselective fluorescent responses of 3,3′-diformyl-1,1′-bi-2-naphthol toward chiral functional amines in methanol. One enantiomer of the chiral ...substrates, including diamines, amino alcohols and amino acids, was found to turn on the emission of this molecular probe at λ > 500 nm much more than the other enantiomer. This emission signal is greatly red-shifted from most of the other BINOL-based enantioselective fluorescent sensors whose fluorescent signals are generally at 400 ± 50 nm. Thus, a new window is opened for the use of BINOLs to observe chiral recognition events. The fluorescent responses of the new probe in the presence of Zn 2+ toward a chiral diamine have also allowed a visual discrimination of these two enantiomers because of their different emitting color and intensity. The mass spectroscopic analyses for the reaction of the probe plus Zn 2+ with the two enantiomers of a chiral diamine have revealed that the chirality match and mismatch between the probe and the substrate have produced different reaction products, generating very different fluorescent responses.
General language model BERT pre-trained on cross-domain text corpus, BookCorpus and Wikipedia, achieves excellent performance on a couple of natural language processing tasks through the way of ...fine-tuning in the downstream tasks. But it still lacks of task-specific knowledge and domain-related knowledge for further improving the performance of BERT model and more detailed fine-tuning strategy analyses are necessary. To address these problem, a BERT-based text classification model BERT4TC is proposed via constructing auxiliary sentence to turn the classification task into a binary sentence-pair one, aiming to address the limited training data problem and task-awareness problem. The architecture and implementation details of BERT4TC are also presented, as well as a post-training approach for addressing the domain challenge of BERT. Finally, extensive experiments are conducted on seven public widely-studied datasets for analyzing the fine-tuning strategies from the perspectives of learning rate, sequence length and hidden state vector selection. After that, BERT4TC models with different auxiliary sentences and post-training objectives are compared and analyzed in depth. The experiment results show that BERT4TC with suitable auxiliary sentence significantly outperforms both typical feature-based methods and fine-tuning methods, and achieves new state-of-the-art performance on multi-class classification datasets. For binary sentiment classification datasets, our BERT4TC post-trained with suitable domain-related corpus also achieves better results compared with original BERT model.
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