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1.
Biomark Res ; 11(1): 74, 2023 Aug 08.
Article in English | MEDLINE | ID: mdl-37553583

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal prognosis, and despite significant advances in our understanding of its genetic drivers, like KRAS, TP53, CDKN2A, and SMAD4, effective therapies remain limited. Here, we identified a new therapeutic target GRIN2D and then explored its functions and mechanisms in PDAC progression. METHODS: We performed a genome-wide RNAi screen in a PDAC xenograft model and identified GRIN2D, which encodes the GluN2D subunit of N-methyl-D-aspartate receptors (NMDARs), as a potential oncogene. Western blot, immunohistochemistry, and analysis on Gene Expression Omnibus were used for detecting the expression of GRIN2D in PDAC. Cellular experiments were conducted for exploring the functions of GRIN2D in vitro while subcutaneous and orthotopic injections were used in in vivo study. To clarify the mechanism, we used RNA sequencing and cellular experiments to identify the related signaling pathway. Cellular assays, RT-qPCR, and western blot helped identify the impacts of the NMDAR antagonist memantine. RESULTS: We demonstrated that GRIN2D was highly expressed in PDAC cells, and further promoted oncogenic functions. Mechanistically, transcriptome profiling identified GRIN2D-regulated genes in PDAC cells. We found that GRIN2D promoted PDAC progression by activating the p38 MAPK signaling pathway and transcription factor CREB, which in turn promoted the expression of HMGA2 and IL20RB. The upregulated GRIN2D could effectively promote tumor growth and liver metastasis in PDAC. We also investigated the therapeutic potential of NMDAR antagonism in PDAC and found that memantine reduced the expression of GRIN2D and inhibited PDAC progression. CONCLUSION: Our results suggested that NMDA receptor GRIN2D plays important oncogenic roles in PDAC and represents a novel therapeutic target.

2.
Int J Biochem Cell Biol ; 156: 106364, 2023 03.
Article in English | MEDLINE | ID: mdl-36639095

ABSTRACT

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.


Subject(s)
MicroRNAs , Neoplasms , Humans , RNA/genetics , RNA/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , Neoplasms/genetics , Neoplasms/therapy , MicroRNAs/genetics , RNA, Messenger/genetics , RNA, Small Interfering
3.
Mol Ther ; 30(4): 1597-1609, 2022 04 06.
Article in English | MEDLINE | ID: mdl-35121112

ABSTRACT

Long non-coding RNA HOX Transcript Antisense RNA (HOTAIR) is overexpressed in multiple cancers with diverse genetic profiles. Importantly, since HOTAIR heavily contributes to cancer progression by promoting tumor growth and metastasis, HOTAIR becomes a potential target for cancer therapy. However, the underlying mechanism leading to HOTAIR deregulation is largely unexplored. Here, we performed a pan-cancer analysis using more than 4,200 samples and found that intragenic exon CpG island (Ex-CGI) was hypermethylated and was positively correlated to HOTAIR expression. Also, we revealed that Ex-CGI methylation promotes HOTAIR expression through enhancing the transcription elongation process. Furthermore, we linked up the aberrant intragenic tri-methylation on H3 at lysine 4 (H3K4me3) and Ex-CGI DNA methylation in promoting transcription elongation of HOTAIR. Targeting the oncogenic CDK7-CDK9-H3K4me3 axis downregulated HOTAIR expression and inhibited cell growth in many cancers. To our knowledge, this is the first time that a positive feedback loop that involved CDK9-mediated phosphorylation of RNA Polymerase II Serine 2 (RNA PolII Ser2), H3K4me3, and intragenic DNA methylation, which induced robust transcriptional elongation and heavily contributed to the upregulation of oncogenic lncRNA in cancer has been demonstrated. Targeting the oncogenic CDK7-CDK9-H3K4me3 axis could be a novel therapy in many cancers through inhibiting the HOTAIR expression.


Subject(s)
Cyclin-Dependent Kinase 9 , Histones , Neoplasms , RNA Polymerase III , RNA, Long Noncoding , Cell Line, Tumor , Cyclin-Dependent Kinase 9/metabolism , DNA Methylation , Feedback, Physiological/physiology , Gene Expression Regulation, Neoplastic , Histones/metabolism , Humans , Neoplasms/genetics , Neoplasms/metabolism , RNA Polymerase III/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism
4.
Mol Cancer ; 21(1): 10, 2022 01 04.
Article in English | MEDLINE | ID: mdl-34983537

ABSTRACT

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.


Subject(s)
Epithelial-Mesenchymal Transition , MicroRNAs/genetics , Nogo Proteins/genetics , Pancreatic Neoplasms/etiology , Pancreatic Neoplasms/metabolism , RNA, Circular , RNA, Long Noncoding/genetics , Adult , Aged , Animals , Biomarkers, Tumor , Cell Line, Tumor , Disease Models, Animal , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Middle Aged , Neoplasm Grading , Neoplasm Staging , Pancreatic Neoplasms/pathology , RNA Interference
5.
Polymers (Basel) ; 13(14)2021 Jul 06.
Article in English | MEDLINE | ID: mdl-34300986

ABSTRACT

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.

6.
Cell Mol Gastroenterol Hepatol ; 10(4): 811-828, 2020.
Article in English | MEDLINE | ID: mdl-32615164

ABSTRACT

BACKGROUND & AIMS: Gemcitabine resistance is rapidly acquired by pancreatic ductal adenocarcinoma (PDAC) patients. Novel approaches that predict the gemcitabine response of patients and enhance gemcitabine chemosensitivity are important to improve patient survival. We aimed to identify genes as novel biomarkers to predict the gemcitabine response and the therapeutic targets to attenuate chemoresistance in PDAC cells. METHODS: Genome-wide RNA interference screening was conducted to identify genes that regulated gemcitabine chemoresistance. A cell proliferation assay and a tumor formation assay were conducted to study the role of lethal giant larvae homolog 1 (LLGL1) in gemcitabine chemoresistance. Levels of LLGL1 and its regulating targets were measured by immunohistochemical staining in tumor tissues obtained from patients who received gemcitabine as a single therapeutic agent. A gene-expression microarray was conducted to identify the targets regulated by LLGL1. RESULTS: Silencing of LLGL1 markedly reduced the gemcitabine chemosensitivity in PDAC cells. Patients had significantly shorter survival (6 months) if they bore tumors expressing low LLGL1 level than tumors with high LLGL1 level (20 months) (hazard ratio, 0.1567; 95% CI, 0.05966-0.4117). Loss of LLGL1 promoted cytokine receptor oncostatin M receptor (OSMR) expression in PDAC cells that led to gemcitabine resistance, while knockdown of OSMR effectively rescued the chemoresistance phenotype. The LLGL1-OSMR regulatory pathway showed great clinical importance because low LLGL1 and high OSMR expressions were observed frequently in PDAC tissues. Silencing of LLGL1 induced phosphorylation of extracellular signal-regulated kinase 2 and specificity protein 1 (Sp1), promoted Sp1 (pThr453) binding at the OSMR promoter, and enhanced OSMR transcription. CONCLUSIONS: LLGL1 possessed a tumor-suppressor role as an inhibitor of chemoresistance by regulating OSMR-extracellular signal-regulated kinase 2/Sp1 signaling. The data sets generated and analyzed during the current study are available in the Gene Expression Omnibus repository (ID: GSE64681).


Subject(s)
Carcinoma, Pancreatic Ductal/drug therapy , Cytoskeletal Proteins/genetics , Deoxycytidine/analogs & derivatives , Drug Resistance, Neoplasm , Pancreatic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/genetics , Cell Line, Tumor , Deoxycytidine/therapeutic use , Extracellular Signal-Regulated MAP Kinases/genetics , Female , Humans , Male , Middle Aged , Oncostatin M Receptor beta Subunit/genetics , Pancreatic Neoplasms/genetics , Sp1 Transcription Factor/genetics , Transcriptome , Young Adult , Gemcitabine , Pancreatic Neoplasms
7.
Cancer Res ; 80(11): 2138-2149, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32217695

ABSTRACT

The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared with nontumor human pancreatic ductal epithelial cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63% of primary tumors (53 of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell-cycle progression and apoptosis. circFOXK2 contained multiple miRNA binding sites, functioning as a sponge for miR-942, which in turn promoted expression of ANK1, GDNF, and PAX6. A novel and highly specific circRNA-pulldown followed by mass spectrometry analysis identified 94 circFOXK2-interacting proteins, which were involved in cell adhesion, mRNA splicing, and structural molecule activity. Of these, circFOKX2 interactions with YBX1 and hnRNPK enhanced expression of oncogenes NUF2 and PDXK. Knockdown of circFOXK2 reduced binding of YBX1 and hnRNPK to NUF2 and PDXK, in turn decreasing their expression. Collectively, our findings demonstrate that circFOXK2 in complex with YBX1 and hnRNPK promotes expression of oncogenic proteins that contribute to PDAC progression. SIGNIFICANCE: This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal/metabolism , Forkhead Transcription Factors/genetics , MicroRNAs/metabolism , Pancreatic Neoplasms/metabolism , RNA, Circular/metabolism , RNA-Binding Proteins/metabolism , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Growth Processes/physiology , Cell Line, Tumor , HEK293 Cells , Heterografts , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Neoplasm Metastasis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , RNA, Circular/genetics , RNA-Binding Proteins/genetics
8.
Cancer Lett ; 477: 1-9, 2020 05 01.
Article in English | MEDLINE | ID: mdl-32120024

ABSTRACT

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.


Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Pancreatic Neoplasms/genetics , RNA, Long Noncoding/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Proliferation , Gene Expression Regulation, Neoplastic , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , MicroRNAs/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Pancreatic Neoplasms/pathology , Transcriptional Activation , Up-Regulation , Pancreatic Neoplasms
9.
RSC Adv ; 10(14): 8087-8092, 2020 Feb 24.
Article in English | MEDLINE | ID: mdl-35497850

ABSTRACT

A colorimetric assay is developed for detection of lncRNA HOTTIP by one-step reverse transcription-loop-mediated isothermal amplification (RT-LAMP) coupled with positively-charged gold nanoparticles ((+)AuNP) for diagnosis of pancreatic cancer. This assay allows simple, rapid, and sensitive quantification of lncRNA down to 50 copies.

10.
World J Clin Cases ; 7(2): 171-190, 2019 Jan 26.
Article in English | MEDLINE | ID: mdl-30705894

ABSTRACT

BACKGROUND: Exosomes are microvesicles, measuring 30-100 nm in diameter. They are widely distributed in body fluids, including blood, bile, urine and saliva. Cancer-derived exosomes carry a wide variety of DNA, RNA, proteins and lipids, and may serve as novel biomarkers in cancer. AIM: To summarize the performance of exosomal biomarkers in cancer diagnosis and prognosis. METHODS: Relevant publications in the literature were identified by search of the "PubMed" database up to September 11, 2018. The quality of the included studies was assessed by QUADAS-2 and REMARK. For assessment of diagnostic biomarkers, 47 biomarkers and 2240 patients from 30 studies were included. RESULTS: Our results suggested that these exosomal biomarkers had excellent diagnostic ability in various types of cancer, with good sensitivity and specificity. For assessment of prognostic markers, 50 biomarkers and 4797 patients from 42 studies were included. We observed that exosomal biomarkers had prognostic values in overall survival, disease-free survival and recurrence-free survival. CONCLUSION: Exosomes can function as potential biomarkers in cancer diagnosis and prognosis.

11.
Cancer Res ; 79(7): 1305-1317, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30718359

ABSTRACT

Long noncoding RNAs (lncRNA) play critical roles in the development of cancer, including hepatocellular carcinoma (HCC). However, the mechanisms underlying their deregulation remain largely unexplored. In this study, we report that two lncRNAs frequently downregulated in HCC function as tumor suppressors and are epigenetically silenced by histone methyltransferase EZH2. lncRNAs TCAM1P-004 and RP11-598D14.1 were inhibited by EZH-mediated trimethylation of H3K27me3 at their promoters. Downregulation of TCAM1P-004 and RP11-598D14.1 was frequently observed in HCC tumors compared with adjacent normal tissues. Both lncRNAs inhibited cell growth, cell survival, and transformation in HCC cells in vitro as well as tumor formation in vivo. Using RNA pull-down and mass spectrometry, we demonstrated that TCAM1P-004 bound IGF2BP1 and HIST1H1C, whereas RP11-598D14.1 bound IGF2BP1 and STAU1. These lncRNA-protein interactions were critical in regulating p53, MAPK, and HIF1α pathways that promoted cell proliferation in HCC. Overexpression of EZH2 was critical in repressing TCAM1P-004 and RP11-598D14.1, and EZH2-TCAM1P-004/RP11-598D14.1-regulated pathways were prevalent in human HCC. Aberrant suppression of TCAM1P-004 and RP11-598D14.1 led to loss of their tumor-suppressive effects by disrupting the interaction with IGF2BP1, HIST1H1C, and STAU1, which in turn promoted HCC development and progression. Collectively, these findings demonstrate the role of TCAMP1P-004 and RP11-598D14.1 in suppressing tumor growth and suggest that EZH2 may serve as a therapeutic target in HCC. SIGNIFICANCE: EZH2-mediated loss of lncRNAs TCAM1P-004 and RP11-598D14.1 hinders the formation of tumor suppressor lncRNA-protein complexes and subsequently promotes HCC growth.


Subject(s)
Carcinoma, Hepatocellular/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Epigenesis, Genetic , Gene Silencing , Genome, Human , Liver Neoplasms/genetics , RNA, Long Noncoding/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/physiology , Genes, Tumor Suppressor , Histones/physiology , Humans , Liver Neoplasms/pathology , Methylation , RNA-Binding Proteins/physiology
12.
Eur J Pharmacol ; 825: 107-118, 2018 Apr 15.
Article in English | MEDLINE | ID: mdl-29477657

ABSTRACT

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.


Subject(s)
Berberine/pharmacology , Fatty Liver/drug therapy , Fatty Liver/metabolism , Hepatocytes/drug effects , MicroRNAs/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6 Kinases/metabolism , Cell Line, Tumor , HEK293 Cells , Hep G2 Cells , Hepatocytes/metabolism , Humans , Liver/drug effects , Liver/metabolism , RNA, Messenger/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Up-Regulation/drug effects
13.
World J Gastroenterol ; 22(31): 7046-57, 2016 Aug 21.
Article in English | MEDLINE | ID: mdl-27610015

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC.


Subject(s)
Acinar Cells/pathology , Cellular Reprogramming , Pancreatic Neoplasms/pathology , Adaptor Proteins, Signal Transducing , Carcinoma, Pancreatic Ductal/pathology , Chemokines , Humans , Intercellular Signaling Peptides and Proteins/physiology , MAP Kinase Signaling System/physiology , Metaplasia , NFATC Transcription Factors/physiology , Pancreatic Neoplasms/therapy , SOX9 Transcription Factor/physiology , TRPP Cation Channels/physiology , Wnt Signaling Pathway
14.
Int J Nanomedicine ; 11: 2471-80, 2016.
Article in English | MEDLINE | ID: mdl-27330290

ABSTRACT

We reported two forms (sphere and wire) of newly fabricated chlorhexidine (CHX)-loaded mesoporous silica nanoparticles (MSNs), and investigated their releasing capacities and anti-biofilm efficiencies. The interactions of the blank MSNs with planktonic oral microorganisms were assessed by field emission scanning electron microscopy. The anti-biofilm effects of the two forms of nanoparticle-encapsulated CHX were examined by 2,3-bis (2-methoxy- 4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide. The profiles of biofilm penetration were analyzed by fluorescent-labeled MSNs using confocal microscopy and ImageJ. The spherical MSNs with an average diameter of 265 nm exhibited a larger surface area and faster CHX-releasing rate than the MSN wires. The field emission scanning electron microscopy images showed that both shaped MSNs enabled to attach and further fuse with the surfaces of testing microbes. Meanwhile, the nanoparticle-encapsulated CHX could enhance the anti-biofilm efficiency with reference to its free form. Notably, the spherical nanoparticle-encapsulated CHX presented with a greater anti-biofilm capacity than the wire nanoparticle-encapsulated CHX, partly due to their difference in physical property. Furthermore, the relatively even distribution and homogeneous dispersion of spherical MSNs observed in confocal images may account for the enhanced penetration of spherical nanoparticle-encapsulated CHX into the microbial biofilms and resultant anti-biofilm effects. These findings reveal that the spherical nanoparticle-encapsulated CHX could preferably enhance its anti-biofilm efficiency through an effective releasing mode and close interactions with microbes.


Subject(s)
Biofilms/drug effects , Chlorhexidine/pharmacology , Drug Liberation , Microbial Interactions/drug effects , Nanoparticles/chemistry , Humans , Microscopy, Confocal , Nanoparticles/ultrastructure , Particle Size , Plankton/drug effects , Plankton/ultrastructure , Silicon Dioxide/chemistry , Spectrometry, Fluorescence , Temperature
15.
Nanomaterials (Basel) ; 6(4)2016 Apr 07.
Article in English | MEDLINE | ID: mdl-28335189

ABSTRACT

Scutellariabaicalensis (SB) is a traditional Chinese medicine for treating infectious and inflammatory diseases. Our recent study shows potent antibacterial effects of nanoparticle-encapsulated chlorhexidine (Nano-CHX). Herein, we explored the synergistic effects of the nanoparticle-encapsulated SB (Nano-SB) and Nano-CHX on oral bacterial biofilms. Loading efficiency of Nano-SB was determined by thermogravimetric analysis, and its releasing profile was assessed by high-performance liquid chromatographyusing baicalin (a flavonoid compound of SB) as the marker. The mucosal diffusion assay on Nano-SB was undertaken in a porcine model. The antibacterial effects of the mixed nanoparticles (Nano-MIX) of Nano-SB and Nano-CHX at 9:1 (w/w) ratio were analyzed in both planktonic and biofilm modes of representative oral bacteria. The Nano-MIX was effective on the mono-species biofilms of Streptococcus (S.) mutans, S. sobrinus, Fusobacterium (F.) nucleatum, and Aggregatibacter (A.) actinomycetemcomitans (MIC 50 µg/mL) at 24 h, and exhibited an enhanced effect against the multi-species biofilms such as S. mutans, F. nucleatum, A. actinomycetemcomitans, and Porphyromonas (P.) gingivalis (MIC 12.5 µg/mL) at 24 h that was supported by the findings of both scanning electron microscopy (SEM) and confocal scanning laser microscopy (CLSM). This study shows enhanced synergistic antibacterial effects of the Nano-MIX on common oral bacterial biofilms, which could be potentially developed as a novel antimicrobial agent for clinical oral/periodontal care.

16.
PLoS One ; 9(8): e103234, 2014.
Article in English | MEDLINE | ID: mdl-25170958

ABSTRACT

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.


Subject(s)
Anti-Infective Agents, Local/administration & dosage , Bacterial Physiological Phenomena/drug effects , Biofilms/drug effects , Chlorhexidine/administration & dosage , Drug Carriers/chemistry , Mouth/microbiology , Nanoparticles/chemistry , Aggregatibacter actinomycetemcomitans/drug effects , Aggregatibacter actinomycetemcomitans/physiology , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents, Local/pharmacology , Bacteria/drug effects , Bacterial Infections/drug therapy , Chlorhexidine/pharmacology , Dental Plaque/drug therapy , Dental Plaque/microbiology , Fusobacterium nucleatum/drug effects , Fusobacterium nucleatum/physiology , Humans , Nanoparticles/ultrastructure , Porphyromonas gingivalis/drug effects , Porphyromonas gingivalis/physiology , Streptococcus mutans/drug effects , Streptococcus mutans/physiology
17.
Chem Commun (Camb) ; 49(92): 10781-3, 2013 Nov 28.
Article in English | MEDLINE | ID: mdl-24081452

ABSTRACT

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.


Subject(s)
Dendrimers/chemical synthesis , Rotaxanes/chemical synthesis , Animals , Cell Line , Cell Survival , Cyclization , Dendrimers/chemistry , Fibroblasts/cytology , Mice , Molecular Structure , Rotaxanes/chemistry
18.
Methods ; 64(3): 315-21, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-23811300

ABSTRACT

This paper describes comparative studies and protocols in (1) self-assembling of ultrasmall superparamagnetic iron oxide nanoparticle (NP), circular plasmid DNA, and branched polyethylenimine (PEI) composites; (2) magnetofection; (3) gene delivery, (4) magnetic resonance imaging (MRI), and (5) cytotoxicity of the composites toward hepatocellular carcinoma HepG2 cells.


Subject(s)
Nanocomposites/chemistry , Staining and Labeling , Alginates/chemistry , Animals , Carcinoma, Hepatocellular , Cell Survival , Citrates/chemistry , DNA, Circular/chemistry , DNA, Circular/genetics , Dogs , Ferrosoferric Oxide/chemistry , Green Fluorescent Proteins/biosynthesis , Hep G2 Cells , Humans , Luciferases, Renilla/biosynthesis , Madin Darby Canine Kidney Cells , Magnetic Resonance Imaging , Plasmids/chemistry , Plasmids/genetics , Polyethyleneimine/chemistry , Transfection
20.
ACS Appl Mater Interfaces ; 5(5): 1566-74, 2013 Mar 13.
Article in English | MEDLINE | ID: mdl-23402574

ABSTRACT

Core@shell nanoparticles with superparamagnetic iron oxide core, mesoporous silica shell, and crown ether periphery were fabricated toward drug delivery and tumor cell imaging. By the concept of nanovalve based on supramolecular gatekeeper, stimuli-responsive drug delivery nanosystems Fe3O4@SiO2@meso-SiO2@crown ethers were synthesized by (i) modified solvothermal reaction; (ii) sol-gel reaction; and (iii) amide coupling reaction. The successful coupling of the dibenzo-crown ethers onto the mesoporous silica shell was confirmed by thermogravimetric analysis and Infrared spectroscopy. In this system, the "ON/OFF" switching of the gatekeeper supramolecules can be controlled by pH-sensitive intramolecular hydrogen bonding or electrostatic interaction (such as metal chelating). Biological evaluation of the nanoparticles renders them noncytotoxic and can be uptaken by L929 cells. In this work, the antitumor drug (doxorubicin) loading and release profiles which were studied by the UV/visible absorption spectroscopy. The mechanism involves the best-fit binding of crown ethers with cesium or sodium ions at different pH values with ultrasonic wave in phosphate buffered saline (PBS). Magnetic resonance imaging analysis of the particles reveals a high relaxivity, rendering them potentially useful theranostic agents.


Subject(s)
Antineoplastic Agents/chemistry , Delayed-Action Preparations/chemistry , Doxorubicin/chemistry , Drug Carriers/chemistry , Drug Delivery Systems/methods , Magnetite Nanoparticles/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Delayed-Action Preparations/pharmacology , Doxorubicin/pharmacology , Drug Compounding , Drug Delivery Systems/instrumentation , Ether/chemistry , Humans , Hydrogen-Ion Concentration , Particle Size , Silicon Dioxide/chemistry , Ultrasonics
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