Identification of miR-6794-3p as a suppressor in pancreatic cancer metastasis.

Metastasis is a major cause of treatment failure in patients with pancreatic cancer, highlighting the urgent need for effective therapeutic strategies. Here, we focused on identifying novel miRNAs with key roles in metastasis of pancreatic cancer. Microarray analysis of miRNA expression in metastatic and non-metastatic pancreatic cancer samples revealed significantly lower expression of miR-6794-3p in the metastatic tumor group.

Ratiometric Fluorescence Sensing System for Lead Ions Based on Self-Assembly of Bioprobes Triggered by Specific Pb-Peptide Interactions.

Lead is one of the most toxic substances. However, there are few ratiometric fluorescent probes for sensing Pb in aqueous solution as well as living cells because specific ligands for Pb ions have not been well characterized. Considering the interactions between Pb and peptides, we developed ratiometric fluorescent probes for Pb based on the peptide receptor in two steps.

NQO1 regulates cell cycle progression at the G2/M phase.

Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is associated with tumor cell proliferation and growth in several human cancer types. However, the molecular mechanisms underlying the activity of NQO1 in cell cycle progression are currently unclear. Here, we report a novel function of NQO1 in modulation of the cell cycle regulator, cyclin-dependent kinase subunit-1 (CKS1), at the G2/M phase through effects on the stability of c‑Fos.

Tuning of Peptide Cytotoxicity with Cell Penetrating Motif Activatable by Matrix Metalloproteinase-2.

Although diverse cell penetrating motifs not only from naturally occurring proteins but also from synthetic peptides have been discovered and developed, the selectivity of cargo delivery connected to these motifs into the desired target cells is generally low. Here, we demonstrate the selective cytotoxicity tuning of an anticancer KLA peptide with a cell penetrating motif activatable by matrix metalloproteinase-2 (MMP2). The anionic masking sequence introduced at the end of the KLA peptide through an MMP2-cleavable linker is selectively cleaved by MMP2 and the cationic cell penetrating motif is activated.

Multi-Layer Nanofibrous PCL Scaffold-Based Colon Cancer Cell Cultures to Mimic Hypoxic Tumor Microenvironment for Bioassay.

Three-dimensional (3D) cancer cell culture systems have been developed to aid the study of molecular mechanisms in cancer development, identify therapeutic targets, and test drug candidates. In this study, we developed a strategy for mimicking the hypoxic tumor microenvironment in a 3D cancer cell culture system using multi-layer, nanofibrous poly(ε-caprolactone) (PCL) scaffold (pNFS)-based cancer cell cultures. We found that human colon cancer cells infiltrated pNFS within 3 days and could be cultured three-dimensionally within the NFS.

A strategy to prevent atherosclerosis via TNF receptor regulation.

Atherosclerosis is a chronic inflammatory disease of the arterial wall. It has been known that development of atherosclerosis is closely related to activation of tumor necrosis factor α (TNF-α). The objective of this study was to elucidate the effects of TNF-α blockade with brusatol on endothelial activation under pro-atherosclerotic conditions.

Fluorescent Detection of Methyl Mercury in Aqueous Solution and Live Cells Using Fluorescent Probe and Micelle Systems.

It is highly challenging to develop fast and sensitive fluorescent methods for monitoring organic mercury in purely aqueous solutions as well as live cells. Especially, selective fluorescent detection of methylmercury over inorganic mercury ions has not been reported. We developed a fast and sensitive fluorescent detection method for Hg ions as well as methylmercury using an amino acid-based fluorescent probe () and SDS micelles.

Fast and sensitive fluorescent detection of inorganic mercury species and methylmercury using a fluorescent probe based on the displacement reaction of arylboronic acid with the mercury species.

We present a reaction-based fluorescent probe (1) for Hg and CHHg, based on the displacement reaction of the arylboronic acid with the mercury species. 1 showed promising sensing properties for Hg and CHHg, such as high selectivity and sensitivity, turn-on response, fast response to Hg (<2 min) and CHHg (<5 min), low detection limits and operation in purely aqueous solutions.

Stimuli-Responsive Conformational Transformation of Peptides for Tunable Cytotoxicity.

The stimuli-responsive conformational transformation of peptides possessing a constrained form triggered by specific biological microenvironment would provide an effective strategy for the development of highly specific peptide therapeutics. Here, we developed a peptide containing a cytotoxic helical KLA sequence with therapeutic specificity through the use of stimuli-responsive conformational transformation. The KLA peptide is modified to form a cyclic structure to allow for constrained helicity that confers low cytotoxicity.

Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer.

5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays.

Hypoxia-induced microRNA-590-5p promotes colorectal cancer progression by modulating matrix metalloproteinase activity.

Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. MicroRNAs (miRNAs) are small non-coding RNA that have emerged as key players involved in cancer development and progression. Hypoxia alters a set of hypoxia-mediated miRNAs expression during tumor development and it may function as oncogenes or tumor-suppressors.

Mesoporous Silica Nanocarriers with Cyclic Peptide Gatekeeper: Specific Targeting of Aminopeptidase N and Triggered Drug Release by Stimuli-Responsive Conformational Transformation.

Utilizing stimuli-responsive conformational transformation of a cyclic peptide as a gatekeeper for mesoporous nanocarriers has several advantages such as facile introduction of targeting capabilities, low enzymatic degradation during blood circulation and enhanced specific binding to selected cells. In this report, a Asn-Gly-Arg (NGR)-containing dual-functional cyclic peptide gatekeeper on the surface of mesoporous nanocarrier is prepared not only for active targeting of the aminopeptidase N (APN) expressed on cancer cells but also stimuli-responsive intracellular drug release triggered by a glutathione (GSH)-induced conformational transformation of the peptide gatekeeper. The peptide gatekeeper on the surface of nanocarriers exhibits on-off gatekeeping by conformational transformation triggered by intracellular glutathione of the cancer cells.

Stimulus-Induced Conformational Transformation of a Cyclic Peptide for Selective Cell-Targeting On-Off Gatekeeper for Mesoporous Nanocarriers.

α β Integrin is upregulated on many cancer cells. We designed a dual functional cyclic peptide gatekeeper with a capability of stimuli-responsive conformational transformation which could serve as a selective cell-targeting on-off gatekeeper for mesoporous nanocarriers. The advantage of employing the motif of stimuli-induced conformational transformation of cyclic peptides is that they could be utilized not only as an on-off gatekeeper for the triggered release of cargo drugs but also as a targeting ligand of the carriers to desired cells with their respective binding receptors.

Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia.

HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~100 genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In the present study, we investigated the molecular mechanisms underlying brusatol-induced HIF-1α degradation and cell death in colorectal cancer under hypoxia (0.5% O).

Mesoporous nanocarriers with a stimulus-responsive cyclodextrin gatekeeper for targeting tumor hypoxia.

Tissue hypoxia developed in most malignant tumors makes a significant difference to normal tissues in the reduction potential and the activity of various bioreductive enzymes. Given the superior enzymatic activity of NAD(P)H:quinone oxidoreductase 1 (NQO1, a cytosolic reductase up-regulated in many human cancers) in hypoxia relative to that in normoxia, NQO1 has great potential for targeting hypoxic tumor cells. In the present report, the core concept of hypoxic NQO1-responsive mesoporous silica nanoparticles (MSNs) is based on the reasoning that the superior enzymatic activity of NQO1 within hypoxic cancer cells can be utilized as a key stimulus for the selective cleavage of an azobenzene stalk triggering the on-off gatekeeping for controlled release of guest drugs.

NQO1 inhibits proteasome-mediated degradation of HIF-1α.

Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers.

Docetaxel induced-JNK2/PHD1 signaling pathway increases degradation of HIF-1α and causes cancer cell death under hypoxia.

HIF-1 (hypoxia-inducible factor-1) regulates the expression of more than 70 genes involved in angiogenesis, tumor growth, metastasis, chemoresistance, and radioresistance. Thus, there is growing interest in using HIF-1 inhibitors as anticancer drugs. Docetaxel, a Food and Drug Administration-approved anticancer drug, is reported to enhance HIF-1α degradation.

Development of new peptide-based receptor of fluorescent probe with femtomolar affinity for Cu(+) and detection of Cu(+) in Golgi apparatus.

Developing fluorescent probes for monitoring intracellular Cu(+) is important for human health and disease, whereas a few types of their receptors showing a limited range of binding affinities for Cu(+) have been reported. In the present study, we first report a novel peptide receptor of a fluorescent probe for the detection of Cu(+). Dansyl-labeled tripeptide probe (Dns-LLC) formed a 1:1 complex with Cu(+) and showed a turn-on fluorescent response to Cu(+) in aqueous buffered solutions.

A mesoporous nanocontainer gated by a stimuli-responsive peptide for selective triggering of intracellular drug release.

Mesoporous silica nanocontainers (MSNs) with biologically responsive gatekeepers have great potential for effective delivery of cargo molecules to the desired sites. For that purpose, peptides could be effective candidates as gatekeepers because of their bioresponsiveness and targeting capability. Taking advantage of the zinc finger domain peptide (CXXC), we designed a biocompatible all-peptide gatekeeper (WCGKC) with on-off gatekeeping capability through stimulus-responsive conformational conversion and the steric bulkiness of the tryptophan unit.

Selective and Sensitive Detection of Heavy Metal Ions in 100% Aqueous Solution and Cells with a Fluorescence Chemosensor Based on Peptide Using Aggregation-Induced Emission.

A fluorescent peptidyl chemosensor for the detection of heavy metal ions in aqueous solution as well as in cells was synthesized on the basis of the peptide receptor for the metal ions using an aggregation-induced emission fluorophore. The peptidyl chemosensor (1) bearing tetraphenylethylene fluorophore showed an exclusively selective turn-on response to Hg(2+) among 16 metal ions in aqueous buffered solution containing NaCl. The peptidyl chemosensor complexed Hg(2+) ions and then aggregated in aqueous buffered solution, resulting in the significant enhancement (OFF-On) of emissions at around 470 nm.

Self-Assembled Dendron-Cyclodextrin Nanotubes with a Polyethylenimine Surface and Their Gene Delivery Capability.

Self-assembled dendron-cyclodextrin nanotubes (Den-CD-NTs) with selected surface functionalities can serve as templates for the formation of complexes with polymers, and the resulting nanotube-polymer complexes can be utilized as gene carriers. The negatively charged surfaces of Den-CD-NTs were covered with a positively charged polyethylenimine (PEI) layer using electrostatic interactions, and the resulting nanotube-PEI complex, having a positively charged surface exhibited intracellular uptake. Furthermore, the nanotube-PEI complex exhibited the capability for DNA complexation with reduced enzymatic degradation, and also showed higher transfection efficiency and lower cytotoxicity than PEI.

Implications of NQO1 in cancer therapy.

quinone oxidoreductase (NQO1), an obligatory two-electron reductase, is a ubiquitous cytosolic enzyme that catalyzes the reduction of quinone substrates. The NQO1- mediated two-electron reduction of quinones can be either chemoprotection/detoxification or a chemotherapeutic response, depending on the target quinones. When toxic quinones are reduced by NQO1, they are conjugated with glutathione or glucuronic acid and excreted from the cells.

NQO1-induced activation of AMPK contributes to cancer cell death by oxygen-glucose deprivation.

Oxygen and glucose deprivation (OGD) due to insufficient blood circulation can decrease cancer cell survival and proliferation in solid tumors. OGD increases the intracellular [AMP]/[ATP] ratio, thereby activating the AMPK. In this study, we have investigated the involvement of NQO1 in OGD-mediated AMPK activation and cancer cell death.