The incidence and mortality rate of colorectal cancer (CRC) have been significantly increasing. However, mechanisms involved in CRC progression are still unclear. LncRNA ZFAS1 has been verified as oncogenic molecular in a series of tumors, including CRC. However, the underlying mechanism of ZFAS1 in CRC carcinogenesis remains unclear. In the present study, our data showed that ZFAS1 expression was significantly upregulated in CRC tissues and cell lines. Correlation analysis showed that high ZFAS1 expression was significantly associated with Helicobacter pylori infection, lymph nodes metastasis, advanced TNM stage and poor overall survival of CRC patients. Loss-of-function experiments revealed that ZFAS1 inhibition could markedly suppress CRC cells proliferation and invasion both in vitro and in vivo. Bioinformatics analysis and luciferase reporter assay revealed that ZFAS1 directly interacted with miR-484. Rescue experiments showed that miR-484 inhibitor reversed the tumor suppressing roles of ZFAS1 knockdown on CRC cells. Therefore, our study suggested that ZFAS1 could act as an oncogene in CRC tumorigenesis, and discovered the functional regulatory pathway of ZFAS1 sponging miR-484.
Amphibians are a natural source of abundant antimicrobial peptides and thus have been widely investigated for isolation of such biomolecules. Many new antimicrobial peptide families have been discovered from amphibians. In this study, a novel antimicrobial peptide named Limnonectes fujianensis Brevinvin (LFB) has been identified in the skin secretion from the Fujian large headed frog, Limnonectes fujianensis. The cDNA sequence was cloned from a skin secretion library and the predicted mature peptide was identified through MS/MS fragmentation sequencing of reverse phase HPLC fractions on the same sample. LFB was predicted to be an amphipathic, hydrophobic, alpha helical, and beta turn peptide that inserts into a lipid bilayer in order to kill the cells. In antimicrobial assays, a synthetic replicate of this novel antimicrobial peptide demonstrated significant activity against the Gram-positive bacterium Staphylococcus aureus, the Gram-negative bacterium Escherichia coli and the yeast, Candida albicans. This novel peptide was highly potent (MIC 4.88 uM) against Gram-negative bacterium, and also has the ability to inhibit the growth of human cancer cell lines with IC50 values ranging from 18.9 μM down to 2.0 μM. These findings help to enrich our understanding of Brevinin-like peptides. Moreover, the data presented here validate frog secretion as a source of potential novel antimicrobial peptides, that also exhibit anti-tumor properties, that could be useful for the treatment of cancer.
A simple and feasible pH meter–based immunoassay is reported for detection of C-reactive protein (CRP) using glucose oxidase (GOD)–conjugated dendrimer loaded with platinum nanozyme. Initially, platinum nanozymes were loaded into the dendrimers through an in situ synthetic method. Then, GOD and monoclonal anti-CRP antibody with a high molar ratio were covalently conjugated onto carboxylated dendrimers via typical carbodiimide coupling. The immunoreaction was carried out with a competitive mode in a CRP-coated microplate. Along with formation of immunocomplex, the added glucose was oxidized into gluconic acid and hydrogen peroxide by GOD, and the latter was further decomposed by platinum nanozyme, thus accelerating chemical reaction in the positive direction. The produced gluconic acid changed the pH of detection solution, which was determined using a handheld pH meter. Under optimum conditions, the pH meter–based immunoassay gave a good signal toward target CRP from 0.01 to 100 ng mL−1. The limit of detection was 5.9 pg mL−1. An intermediate precision ≤ 11.2% was acquired with batch-to-batch identification. No nonspecific adsorption was observed during a series of procedures to detect target CRP, and the cross-reaction against other biomarkers was very low. Importantly, our system gave well-matched results for analysis of human serum samples relative to a referenced ELISA kit.Graphical abstract
Matrix metalloproteinases (MMPs) activatable imaging probe has been explored for tumor detection. However, activation of the probe is mainly done in the extracellular space without intracellular uptake of the probe for more sensitivity. Although cell-penetrating peptides (CPPs) have been demonstrated to enable intracellular delivery of the imaging probe, they nevertheless encounter off-target delivery of the cargos to normal tissues. Herein, we have developed a dual MMP-2-activatable and tumor cell-permeable magnetic nanoprobe to simultaneously achieve selective and intracellular tumor imaging. This novel imaging probe was constructed by self-assembling a hexahistidine-tagged (His-tagged) fluorescent fusion protein chimera and nickel ferrite nanoparticles via a chelation mechanism. The His-tagged fluorescent protein chimera consisted of a red fluorescent protein mCherry that acted as the fluorophore, the low-molecular-weight protamine peptide as the CPP, and the MMP-2 cleavage sequence fused with the hexahistidine tag, whereas the nickel ferrite nanoparticles functioned as the His-tagged protein binder and also the fluorescent quencher. Both in vitro and in vivo results revealed that this imaging probe would not only remain nonpermeable to normal tissues, thereby offsetting the nonselective cellular uptake, but was also suppressed of fluorescent signals during magnetic tumor-targeting in the circulation, primarily because of the masking of the CPP activity and quenching of the fluorophore by the associated NiFeO nanoparticles. However, these properties were recovered or "turned on" by the action of tumor-associated MMP-2 stimuli, leading to cell penetration of the nanoprobes as well as fluorescence restoration and visualization within the tumor cells. In this regard, the presented tumor-activatable and cell-permeable system deems to be an appealing platform to achieve selective tumor imaging and intracellular protein delivery. Its impact is therefore significant, far-reaching, and wide-spread.
A novel MT1-MMP activatable fluorogenic probe for tumor detection with enhanced specificity was developed via high-affinity and specific peptide conjugation.
It is difficult to develop highly selective substrate-based fluorescent nanoprobes for specific matrix metalloproteinases (MMPs) due to overlapping substrate specificities among the family of MMP enzymes. To resolve this issue, we have developed novel fluorescent nanoprobes that are highly selective for soluble MMP-2. Herein, MMP-2-responsive nanoprobes were prepared by immobilizing fluorescent fusion proteins on nickel ferrite nanoparticles via the His-tag nickel chelation mechanism. The fusion protein consisted of a fluorescent mCherry protein with a cell penetrating peptide (CPP) moiety. An MMP-2 cleavage site was also introduced within the fusion protein, which was directly linked to the nickel ferrite nanoparticles. The selectivity of nanoprobes was modulated by hiding the cleavage site of MMP-2 substrates deeply inside the system, which could result in strong steric hindrance between the nanoprobes and MMPs, especially for membrane-tethered MMPs such as MMP-14. A cell-based assay demonstrated that the nanoprobes could only be activated by tumor cells secreting soluble MMP-2, but not membrane-tethered MMP-14. To further evaluate the contribution of the steric hindrance effect on the nanoprobes, a truncated recombinant MMP-14 was employed to confer their cleavage activity as compared to native membrane-tethered MMP-14. Furthermore, a designed probe with a diminished steric hindrance effect was proved to be activated by membrane-tethered type MMP-14. The results indicated that the design of fluorescent nanoprobes employing the steric hindrance effect can greatly enhance the selectivity of MMP-responsive nanoprobes realizing the specific detection of soluble MMP-2 in a tumor microenvironment. We believe that highly selective MMP-2-responsive fluorescent nanoprobes have broad impacts on biomedical applications including molecular imaging and labeling for tumor detection.
ObjectiveMyeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells derived from bone marrow, which has a significant ability in inhibition of immune cell response. In this study, the role of miR-6991-3p in regulating function of MDSCs was investigated.MethodsMDSCs were isolated from different tissues of the control and hepatoma-bearing mice, and then expression of miR-6991-3p was detected with qPCR. Then, the miR-6991-3p mimic and inhibitor were respectively transfected into MDSCs, and behaviors of MDSCs were evaluated, including expansion, apoptosis, and production of inflammatory factors. Furthermore, we explored the underlying mechanism from which miR-6991-3p regulated MDSC functions.ResultsExpression miR-6991-3p was markedly decreased in the MDSCs derived from spleen and further decreased in the MDSCs derived from the tumor tissue. MiR-6991-3p mimic transfection suppressed expansion and promoted apoptosis of MDSCs, accompanied by a significant decrease in the production of IL-6 and GM-CSF that are identified as stimulators in MDSC expansion. In contrast, miR-6991-3p inhibitor transfection displayed the opposite effect. miR-6991-3p bound with and negatively regulated expression of LGALS9, a newly identified immune checkpoint gene and activator of STAT3, suppressing production of multiple factors that were customarily used to characterize the activation of MDSCs. MiR-6991-3p-accommodated MDSCs displayed less suppression on T cells, while miR-6991-3p inhibitor enhanced the suppression of MDSCs on T cells.ConclusionMiR-6991-3p is identified as a novel suppressor in the expansion and activation of myeloid-derived suppressor cells, which may be regarded as a promising target for modulating the function of MDSCs.
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