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Background: Circular RNAs (circRNAs) play important roles in many biological processes. However, the detailed mechanism underlying the critical roles of circRNAs in cancer remains largely unexplored. We aim to explore the molecular mechanisms of circRTN4 with critical roles in pancreatic ductal adenocarcinoma (PDAC). Methods: CircRTN4 expression level was examined in PDAC primary tumors. The oncogenic roles of circRTN4 in PDAC tumor growth and metastasis were studied in mouse tumor models. Bioinformatics analysis, luciferase assay and miRNA pulldown assay were performed to study the novel circRTN4-miRNA-lncRNA pathway. To identify circRTN4-interacting proteins, we performed circRNA-pulldown and mass spectrometry in PDAC cells. Protein stability assay and 3-Dimensional structure modeling were performed to reveal the role of circRTN4 in stabilizing RAB11FIP1. Results: CircRTN4 was significantly upregulated in primary tumors from PDAC patients. In vitro and in vivo functional studies revealed that circRTN4 promoted PDAC tumor growth and liver metastasis. Mechanistically, circRTN4 interacted with tumor suppressor miR-497-5p in PDAC cells. CircRTN4 knockdown upregulated miR-497-5p to inhibit the oncogenic lncRNA HOTTIP expression. Furthermore, we identified critical circRTN4-intercting proteins by circRNA-pulldown in PDAC cells. CircRTN4 interacted with important epithelial-mesenchymal transition (EMT)- driver RAB11FIP1 to block its ubiquitination site. We found that circRTN4 knockdown promoted the degradation of RAB11FIP1 by increasing its ubiquitination. Also, circRTN4 knockdown inhibited the expression of RAB11FIP1-regulating EMT-markers Slug, Snai1, Twist, Zeb1 and N-cadherin in PDAC. Conclusion: The upregulated circRTN4 promotes tumor growth and liver metastasis in PDAC through the novel circRTN4-miR-497-5p-HOTTIP pathway. Also, circRTN4 stabilizes RAB11FIP1 to contribute EMT. [ABSTRACT FROM AUTHOR]

HOXA transcript at the distal tip (HOTTIP), a long noncoding RNA, is upregulated in pancreatic ductal adenocarcinoma (PDAC), but the HOTTIP–mediated oncogenic pathway is not fully understood. We identified canonical HOTTIP–HOXA13 targets, CYP26B1, CLIC5, CHI3L1 and UCP2—responsible for cell growth and cell invasion. Genome–wide analysis revealed that 38% of HOTTIP–regulated genes contain H3K4me3 and HOTTIP enrichment at their promoters, without HOXA13 binding. HOTTIP complexes with WDR5–MLL1 to trans –activate oncogenic proteins CYB5R2, SULT1A1, KIF26A, SLC1A4, and TSC22D1 by directly inducing H3K4me3 at their promoters. The WDR5, MLL1, and H3K4me3 levels at their promoters and their expression levels are sensitive to HOTTIP expression. These results indicate the importance of the noncanonical trans –acting HOTTIP–WDR5–MLL1 pathway in the HOTTIP regulatory mechanism by promoting oncogenic protein expression. Furthermore, HOTTIP is regulated by miR–497 in PDAC cells, but HOTTIP is negatively correlated with miR–497 levels in PDAC tissues. In conclusion, HOTTIP is upregulated in PDAC due to the loss of the inhibitory miR–497; HOTTIP promotes PDAC progression through the canonical HOTTIP–HOXA13 axis. A novel noncanonical trans –acting HOTTIP–WDR5–MLL1–H3K4me3 pathway is also delineated. • HOTTIP promotes PDAC cell growth and invasion. • CYB5R2, CYP26B1, CLIC5, CHI3L1, SULT1A1 and UCP2 promotes PDAC progression. • HOTTIP-HOXA13 pathway regulates CYP26B1, CLIC5, CHI3L1 and UCP2 expression. • Non-canonical HOTTIP-WDR5-MLL1 axis transactivates oncogenic proteins by H3K4me3. • miR-497 inhibits HOTTIP expression in PDAC. [ABSTRACT FROM AUTHOR]

Circular RNAs (CircRNAs) regulate gene expression by functioning as microRNA sponges, regulating protein stability, and gilding proteins for gene transcription and translation. Also, limited circRNAs harbour protein-coding ability through cap-independent pathways. These molecular mechanisms of circRNAs contribute to their importance in several cellular processes. Particularly, the dysregulation of circRNAs also plays a critical role in disease development. Targeting disease-causing circRNAs by restoring their normal expression by gain-of-function or loss-of-function approach and regulating their molecular activities could be potential direction for the development of anti-cancer therapies. Furthermore, due to unique covalently closed circular structure, the superior stability of circRNAs also grants them as novel therapeutic tools replacing the therapeutic small interfering RNAs and messenger RNAs. Here, we will review the functional and molecular mechanisms of circRNAs in pathogenesis, the current methods for targeting the dysregulated circRNAs, and the potential of using synthetic circRNAs in disease treatment and prevention. • Endogenous circular RNAs have shown critical roles in cancer progression, metastasis, and drug resistance with significant conditional dysregulation. • Hence, either re-establishing the normal expression of circRNA levels or suppressing their functional interactions could serve as an enhanced approach for RNA-based therapies. • Due to their enhanced-structural stability, circRNAs posses high therapeutical use through sponging proteins and miRNAs, and for protein synthesis, improving the efficiency of mRNA-based therapies. [ABSTRACT FROM AUTHOR]

HOXA transcript at the distal tip (HOTTIP), a long noncoding RNA, is upregulated in pancreatic ductal adenocarcinoma (PDAC), but the HOTTIP-mediated oncogenic pathway is not fully understood. We identified canonical HOTTIP-HOXA13 targets, CYP26B1, CLIC5, CHI3L1 and UCP2-responsible for cell growth and cell invasion. Genome-wide analysis revealed that 38% of HOTTIP-regulated genes contain H3K4me3 and HOTTIP enrichment at their promoters, without HOXA13 binding. HOTTIP complexes with WDR5-MLL1 to trans-activate oncogenic proteins CYB5R2, SULT1A1, KIF26A, SLC1A4, and TSC22D1 by directly inducing H3K4me3 at their promoters. The WDR5, MLL1, and H3K4me3 levels at their promoters and their expression levels are sensitive to HOTTIP expression. These results indicate the importance of the noncanonical trans-acting HOTTIP-WDR5-MLL1 pathway in the HOTTIP regulatory mechanism by promoting oncogenic protein expression. Furthermore, HOTTIP is regulated by miR-497 in PDAC cells, but HOTTIP is negatively correlated with miR-497 levels in PDAC tissues. In conclusion, HOTTIP is upregulated in PDAC due to the loss of the inhibitory miR-497; HOTTIP promotes PDAC progression through the canonical HOTTIP-HOXA13 axis. A novel noncanonical trans-acting HOTTIP-WDR5-MLL1-H3K4me3 pathway is also delineated. [ABSTRACT FROM AUTHOR]

Berberine is a Chinese herbal medicine extracted from rhizoma coptidis that functions to improve insulin resistance, hyperlipidemia, hepatosteatosis and inflammation. Berberine can modify the activity of cell metabolism and signaling pathways by regulating expression of genes. However, the roles and effects of differential microRNA (miRNA) expression induced by berberine treatment are largely unexplored. It is believed that miRNAs expression modified by berberine contributes to its therapeutic effects to diseases such as hepatosteatosis and non-alcoholic fatty liver disease. By identifying novel miRNAs and their putative gene targets associated with abnormal hepatic lipid deposition, the underlying mechanism of these diseases could be established and effective therapies against the diseases could be developed. Here, we used the immortalized hepatocyte cell line MIHA as a model to study the effect of berberine on global miRNA expression profile of hepatocytes. Global miRNA expression levels were measured in berberine-treated MIHA cells by quantitative reverse transcription PCR miRNA panel, and the potential berberine regulated miRNAs were then validated in MIHA and HepG2 cells. MicroRNA-373 (MiR-373) was consistently upregulated in both cell lines upon berberine treatments. Gene expression microarray showed that berberine upregulated Early Growth Response 1 (EGR1) level which functioned to transactivate miR-373 expression. Subsequently, we showed that upregulation of miR-373 depleted its target gene AKT serine/threonine kinase 1 (AKT1) mRNA level, which led to the inhibition of AKT-mTOR-S6K signaling pathway in hepatocytes that was critical in the development of hepatosteatosis. Study of the therapeutic effect of manipulating miR-373 against abnormal lipid deposition in liver is warranted. [ABSTRACT FROM AUTHOR]

Background: Chlorhexidine (CHX) is a widely used antimicrobial agent in dentistry. Herein, we report the synthesis of a novel mesoporous silica nanoparticle-encapsulated pure CHX (Nano-CHX), and its mechanical profile and antimicrobial properties against oral biofilms. Methodology/Principal Findings: The release of CHX from the Nano-CHX was characterized by UV/visible absorption spectroscopy. The antimicrobial properties of Nano-CHX were evaluated in both planktonic and biofilm modes of representative oral pathogenic bacteria. The Nano-CHX demonstrated potent antibacterial effects on planktonic bacteria and mono-species biofilms at the concentrations of 50–200 µg/mL against Streptococcus mutans, Streptococcus sobrinus, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans and Enterococccus faecalis. Moreover, Nano-CHX effectively suppressed multi-species biofilms such as S. mutans, F. nucleatum, A. actinomycetemcomitans and Porphyromonas gingivalis up to 72 h. Conclusions/Significance: This pioneering study demonstrates the potent antibacterial effects of the Nano-CHX on oral biofilms, and it may be developed as a novel and promising anti-biofilm agent for clinical use. [ABSTRACT FROM AUTHOR]

Highlights: [•] HepG2 transfection efficacies are studied with MRI, fluorescence and luminescence. [•] Sensing in receptor-mediated endocytosis depends on functional groups of composites. [•] Magnetofection enhances uptake efficacy with at most two orders of magnitude. [•] Cell viabilities of HepG2 and MDCK vary from 70 to 90% with different composites. [Copyright &y& Elsevier]

Type III-B first generation [3]rotaxane and second generation [4]rotaxane dendrimers have been synthesized via (1) a modified copper-catalyzed alkyne–azide cycloaddition (CuAAC), (2) Glaser–Hay's acetylenic oxidative homo-coupling, and (3) amide formation. The dendron does not reveal obvious cytotoxicities in L929 fibroblast cells. The rotaxane dendrimers can capture ammonia and are switchable both in solution and on surfaces. [ABSTRACT FROM AUTHOR]

Novel type III-B dendrimers are synthesized via a modified copper-catalyzed alkyne-azide cycloaddition, a Glaser-Hay′s acetylenic oxidative homocoupling, and an amide formation. [ABSTRACT FROM AUTHOR]

A magnetic personality: Magnetofection and gene delivery have been investigated in HepG2 cells using ternary organic–inorganic hybrid nanocomposites that contain deferoxamine ‐ coated iron oxide nanoparticles (NPs), circular plasmid DNA, and branched polyethylenimine (PEI). It was found that the cellular uptake efficacies depend on the ratio of components in PEI/DNA/NP, as assessed by Prussian staining, magnetic resonance imaging, and luciferase expression in the presence and absence of a magnet during transfection. [ABSTRACT FROM AUTHOR]

Several ternary composites that are based on branched polyethyleneimine (bPEI 25 kDa, polydispersity 2.5, 0.1 or 0.2 ng), citrate-coated ultrasmall superparamagnetic iron oxide nanoparticles (citrate-NPs, 8–10 nm, 0.1, 1.0, or 2.5 µg), and reporter circular plasmid DNA pEGFP-C1 or pRL-CMV (pDNA 0.5 µg) were studied for optimization of the best composite for transfection into glioblastoma U87MG or U138MG cells. The efficiency in terms of citrate-NP and plasmid DNA gene delivery with the ternary composites could be altered by tuning the bPEI/citrate-NP ratios in the polymer composites, which were characterized by Prussian blue staining, in vitro magnetic resonance imaging as well as green fluorescence protein and luciferase expression. Among the composites prepared, 0.2 ng bPEI/0.5 μg pDNA/1.0 µg citrate-NP ternary composite possessed the best cellular uptake efficiency. Composite comprising 0.1 ng bPEI/0.5 μg pDNA/0.1 μg citrate-NP gave the optimal efficiency for the cellular uptake of the two plasmid DNAs to the nucleus. The best working bPEI concentration range should not exceed 0.2 ng/well to achieve a relatively low cytotoxicity. [ABSTRACT FROM AUTHOR]