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1.
Plast Reconstr Surg ; 145(3): 552e-562e, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32097313

RESUMO

BACKGROUND: Several studies have verified that bone morphogenetic proteins (BMPs) may be involved in the development of craniosynostosis; little attention has been focused on the role of BMP9 in cranial suture biology. The authors investigated the role of BMP9 in suture progenitor cells. METHODS: The authors isolated and cultured prematurely fused and internal control patent suture progenitor cells from patients with nonsyndromic craniosynostosis. Overexpression of BMP9 was mediated by adenoviral vectors. Osteoblast and osteoclast differentiation-related markers were evaluated by staining techniques and touchdown quantitative polymerase chain reaction analysis. In vivo analysis of BMP9-induced suture progenitor cell osteogenesis was performed in an ectopic bone formation model. RESULTS: The authors demonstrated that the prematurely fused sutures have a higher endogenous expression of the osteogenic differentiation-related genes than patent sutures, whereas the same pattern of gene expression exists between fused and patent suture progenitor cells. Importantly, both patent and fused suture progenitor cells undergo osteogenic differentiation and express multiple lineage regulators and NELL-1 on BMP9 stimulation, whereas fused suture progenitor cells have a higher basal osteogenic potential than patent suture progenitor cells. BMP9 regulates the expression of osteoclast differentiation-related genes in suture progenitor cells. Forced BMP9 expression enhances the mineralization and maturity of ectopic bone formation of suture progenitor cells implanted in vivo. CONCLUSIONS: The authors' findings suggest that fused suture progenitor cells have elevated osteogenic potential. BMP9 could regulate the expression of multiple osteoblast and osteoclast differentiation-related genes, and NELL-1, in both suture progenitor cells, indicating that BMP9 may play a role in craniosynostosis.

2.
J Am Chem Soc ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32079390

RESUMO

When hydrolyzable cations such as aluminum interact with solid-water interfaces, macroscopic interfacial properties (e.g., surface charge and potential) and interfacial phenomena (e.g., particle adhesion) become tightly linked with the microscopic details of ion adsorption and speciation. We use in situ atomic force microscopy to directly image individual aluminum ions at a mica-water interface and show how adsorbate populations change with pH and aluminum activity. Complementary streaming potential measurements then allow us to build a triple layer model (TLM) that links surface potentials to adsorbate populations, via equilibrium binding constants. Our model predicts that hydrolyzed species dominate the mica-water interface, even when unhydrolyzed species dominate the solution. Ab initio molecular dynamics (AIMD) simulations confirm that aluminum hydrolysis is strongly promoted at the interface. The TLM indicates that hydrolyzed adsorbates are responsible for surface-potential inversions, and we find strong correlations between hydrolyzed adsorbates and particle-adhesion forces, suggesting that these species mediate adhesion by chemical bridging.

3.
Infect Drug Resist ; 13: 577-585, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110068

RESUMO

Purpose: Little is known about the epidemiology and carbapenem-resistance determinants of carbapenem-resistant K. aerogenes (CRKA) isolated from a single medical center. The present study was initiated to characterize the molecular epidemiology and the carbapenem-resistance mechanisms of CRKA isolated during 2012-2018 from a teaching hospital in southwest China, and to investigate the risk factors and clinical outcomes of CRKA infections as well. Methods: Pulsed-field gel electrophoresis (PFGE) was employed for epidemiological analysis. PCR amplification and DNA sequencing were used to examine the antibiotic-resistance determinants. Plasmids were extracted and characterized by PCR-based replicon typing and conjugation assays. In order to further investigate the risk factors and clinical outcomes of CRKA infections, a retrospective case-control study was also performed. Results: PFGE analysis showed 32 different PFGE patterns among the 36 non-duplicated CRKA strains collected. Most of the isolates harbored multi-drug resistance (MDR) genes, including 2 (5.6%) carrying bla NDM-1, 1 (2.8%) harboring bla KPC-2, 13 (36.1%) carrying ESBL genes, 23 (63.9%) carrying ampC genes, 34 (94.4%) carrying quinolone resistance determinants (QRD) genes and 9 (25%) carrying aminoglycoside resistance determinants (ARD) genes. The outer membrane porins, OmpE35 and OmpE36, were, respectively, lost in 4 and 2 isolates. The efflux pump inhibition experiments were positive in 25 (69.4%) of the CRKA strains. Multivariate analysis indicated that hypo-albuminaemia, invasive procedures, and carbapenem exposure were independent risk factors for acquiring CRKA infections. Conclusion: No clonality relationship was identified among most of the 36 CRKA isolates. The over-expression of ESBLs and AmpC coupled with the efflux pumps contributed to carbapenem resistance in K. aerogenes. Additionally, this is the first report of CRKA isolate co-harboring bla NDM-1, bla CTX-M-15, bla EBC, bla ACC, acc (6')-Ib, armA, qnrD and loss of OmpE36 in China. Hypo-albuminaemia, invasive procedures and carbapenem exposure were associated with acquisition of CRKA infections.

4.
ACS Appl Mater Interfaces ; 12(5): 6082-6089, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31939651

RESUMO

Advances in smart and wearable devices are driving innovations in multifunctional flexible materials at a tremendous pace. Here, drawing support from the unique flexible fluorophlogopite mica platform, we present a promising all-inorganic bendable Mn-modified 0.65(0.94Na0.5Bi0.5TiO3-0.06BaTiO3)-0.35SrTiO3 (NBBST) film with dual use in electrocaloric (EC) refrigeration and energy storage via a cost-effective transfer-free process. An appreciable room-temperature EC effect with adiabatic temperature change of 12 K and isothermal entropy of 18 J K-1 kg-1 was realized in the NBBST film, which benefits from the large change in dipolar ordering near depolarization temperature. Also, the film exhibits a broad operating temperature span over 25 °C because of its relaxor feature. Most importantly, the film can maintain a high EC performance either under bending deformation at 5 mm radius or after undergoing 104 bending-unbending cycles. Meanwhile, the flexible NBBST film possesses good energy storage property with a recoverable energy density of 56 J cm-3 and an efficiency of 66%. This is the first example of a lead-free all-inorganic multifunctional film capacitor toward the flexible EC refrigeration and energy storage devices. This work shows bright prospects in the emerging flexible e-market.

5.
Aging (Albany NY) ; 11(24): 12476-12496, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31825894

RESUMO

Understanding the bone and musculoskeletal system is essential to maintain the health and quality of life of our aging society. Mesenchymal stem cells (MSCs) can undergo self-renewal and differentiate into multiple tissue types including bone. We demonstrated that BMP9 is the most potent osteogenic factors although molecular mechanism underlying BMP9 action is not fully understood. Long noncoding RNAs (lncRNAs) play important regulatory roles in many physiological and/or pathologic processes. Here, we investigated the role of lncRNA Rmst in BMP9-induced osteogenic differentiation of MSCs. We found that Rmst was induced by BMP9 through Smad signaling in MSCs. Rmst knockdown diminished BMP9-induced osteogenic, chondrogenic and adipogenic differentiation in vitro, and attenuated BMP9-induced ectopic bone formation. Silencing Rmst decreased the expression of Notch receptors and ligands. Bioinformatic analysis predicted Rmst could directly bind to eight Notch-targeting miRNAs, six of which were downregulated by BMP9. Silencing Rmst restored the expression of four microRNAs (miRNAs). Furthermore, an activating Notch mutant NICD1 effectively rescued the decreased ALP activity caused by Rmst silencing. Collectively, our results strongly suggest that the Rmst-miRNA-Notch regulatory axis may play an important role in mediating BMP9-induced osteogenic differentiation of MSCs.

6.
Plast Reconstr Surg ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31860505

RESUMO

BACKGROUND: Several studies have verified that BMPs may be involved in the development of craniosynostosis; little attention has been focused on the role of BMP9 in cranial suture biology. BMP9 is the most osteogenic BMP and promotes the osteoblastic differentiation of mesenchymal stem cells. We investigated the role of BMP9 in suture progenitor cells (SuPs). METHODS: We isolated and cultured prematurely fused (FSuPs) and internal control patent (PSuPs) suture progenitor cells from patients with nonsyndromic craniosynostosis. Overexpression of BMP9 was mediated by adenoviral vectors. Osteoblast and osteoclast differentiation-related markers were evaluated by staining techniques and TqPCR analysis. In vivo analysis of BMP9-induced SuPs osteogenesis was performed in an ectopic bone formation model. RESULTS: We demonstrated that the prematurely fused sutures have a higher endogenous expression of the osteogenic differentiation-related genes than patent sutures, while the same pattern of gene expression exists between FSuPs and PSuPs. Importantly, both PSuPs and FSuPs undergo osteogenic differentiation and express multiple lineage regulators and NELL-1 upon BMP9 stimulation, while FSuPs have a higher basal osteogenic potential than PSuPs. BMP9 regulates the expression of osteoclast differentiation-related genes in SuPs. Forced BMP9 expression enhances the mineralization and maturity of ectopic bone formation of SuPs implanted in vivo. CONCLUSIONS: Our findings suggest that FSuPs have an elevated osteogenic potential. BMP9 could regulate the expression of multiple osteoblast and osteoclast differentiation-related genes, as well as NELL1 in both SuPs, indicating that BMP9 may play a role in craniosynostosis.

7.
Infect Drug Resist ; 12: 3017-3027, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576152

RESUMO

Purpose: This observational study aimed to identify the independent risk factors for both the acquisition and mortality of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) bacteremia and further assess the in vitro antimicrobial activities of ceftazidime-avibactam (CAZ/AVI) and aztreonam-avibactam (ATM/AVI) against recent CRE bacteremic isolates. Patients and methods: This observational study was conducted to reveal the risk factors and mortality rate for CP-CRE bacteremia between 2012 and 2018 and also evaluate the in vitro antimicrobial activities of CAZ/AVI and ATM/AVI against recent CRE bacteremic isolates from 2016 to 2018. Results: A total of 81 non-repetitive isolates were collected from 2012 to 2018, with 67.90% (55/81) being CP-CRE. Old age (P = 0.01), transfusion [odds ratio (OR): 17.19; 95% CI: 3.15-93.72; P = 0.001], longer ICU stay (P = 0.02), cancer (OR: 15.91; 95% CI: 3.56-71.37; P < 0.001), and previous carbapenem exposure (OR: 27.86; 95% CI: 5.03-154.19; P = 0.001) were identified as independent risk factors for the acquisition of CP-CRE bacteremia compared with the ESBL bacteremia. The in vitro antimicrobial activities of CAZ/AVI and ATM/AVI against the CRE bacteremic isolates from 2016 to 2018 showed a respective susceptibility rate of 70.68% (41/58) and 100.00% (58/58). Conclusion: The findings indicated that both CP-CRE/non-CP-CRE stratification and CRE resistance mechanism determination were necessary for better guiding the clinical management of CRE bacteremia: ATM/AVI probably works with both non-CP-CRE and CP-CRE bacteremia, even the most notorious double-carbapenemase producer with porin loss/deficiency, whereas CAZ/AVI works with most of the non-CP-CRE and KPC-producers in the region.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31639543

RESUMO

OBJECTIVES: Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are major public health threats, and the most important mechanism of resistance to carbapenems in CRE is the production of cabarpenemases. Early identification of carbapenemase-producing Enterobacteriaceae (CPE) leads to improved clinical outcomes. This systematic review was to assess the accuracy and applicability of the modified Hodge's test (MHT), carbapenemase Nordmann-Poirel test (Carba NP), modified carbapenem inactivation method (mCIM) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) for CPE detection. METHODS: The meta-analysis included pooled sensitivity, specificity, diagnostic odds ratio, summary receiver operating characteristic curve, and area under the curve. RESULTS: 67 studies were included for the analysis. The pooled sensitivities of MHT, Carba NP, mCIM and MALDI-TOF MS were 92% (95% CI: 87%-95%), 97% (95% CI: 94%-98%), 99% (95% CI: 99%-100%), and 99% (95% CI: 96%-100%), respectively; the pooled specificities were 93% (95% CI: 86%-97%), 100% (95% CI: 99%-100%), 99% (95% CI: 96%-100%), and 99% (95% CI: 96%-100%), respectively; the pooled diagnostic odds ratios were 98.156 (95% CI: 48.175-199.995), 1277.710 (95%CI: 751.391-2172.692), 3597.352 (95% CI: 1287.575-10000), and 1781.360 (95% CI: 651.827-4868.228), respectively; the pooled AUC values of the SROC were 0.97, 1, 1, and 1, respectively. CONCLUSIONS: Carba NP, mCIM and MALDI-TOF MS all demonstrated high accuracies in CPE detection, while MHT was not recommended due to some clear drawbacks. We recommended the selection of carbapenemase detection tests in the order of mCIM, Carba NP and MALDI-TOF MS according to their simplicities, costs and the equipments and skills involved.

9.
Cancer Gene Ther ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222181

RESUMO

MicroRNAs (miRNAs) are ~22 nucleotide noncoding RNAs that are involved in virtually all aspects of cellular process as their deregulations are associated with many pathological conditions. Mature miRNAs (mMIRs) are generated through a series of tightly-regulated nuclear and cytoplasmic processing events of the transcribed primary, precursor and mMIRs. Effective manipulations of miRNA expression enable us to gain insights into miRNA functions and to explore potential therapeutic applications. Currently, overexpression of miRNAs is achieved by using chemically-synthesized miRNA mimics, or shRNA-like stem-loop vectors to express primary or precursor miRNAs, which are limited by low transfection efficacy or rate-limiting miRNA processing. To overcome rate-limiting miRNA processing, we developed a novel strategy to express mMIRs which are driven by converging U6/H1 dual promoters. As a proof-of-concept study, we constructed mMIR expression vectors for hsa-miR-223 and hsa-Let-7a-1, and demonstrated that the expressed mMIRs effectively silenced target gene expression, specifically suppressed miRNA reporter activity, and significantly affected cell proliferation, similar to respective primary and precursor miRNAs. Furthermore, these mMIR expression vectors can be easily converted into retroviral and adenoviral vectors. Collectively, our simplified mMIR expression system should be a valuable tool to study miRNA functions and/or to deliver miRNA-based therapeutics.

10.
Mater Sci Eng C Mater Biol Appl ; 100: 514-522, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948088

RESUMO

Acute wounds are worldwide problems affecting millions of people and causing heavy economic burden to national healthcare systems. Herein, we describe novel wound dressing materials relying on core/shell electrospun mats incorporated with flurbiprofen and vancomycin for achieving programmable release of anti-inflammatory and anti-bacterial agents. The shell matrix of nanofibers consisted of polyethylene oxide while the core matrix was made from a blend of silk and collagen. Several optimal mat architectures were engineered with distinct configurations, of which release profiles displayed an exponential trend, which indicates a first-order process following Fickian diffusion behavior. The flurbiprofen release lasted from 2 to 6 days, which was much faster compared to the one of vancomycin prolonged up to about 20 days. Mechanical data indicated tensile modulus, tensile strength, elongation before break of core/shell electrospun mats became enhanced or comparable to those for human skin after methanol vapor treatment. Desirable release kinetics and mechanical characteristics achieved by novel core/shell electrospun mats were attributable to induced enrichment of ß-sheet phase in silk via methanol vapor treatment as well as water annealing process with time and judicious selections for matrix materials and mat configurations. The design principles considered in this study successfully addressed a range of inflammation and infection requirements in wound healing, potentially guiding construction of other biomedical coatings and devices.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Flurbiprofeno/farmacologia , Cinética , Metanol/química , Nanofibras/química , Estresse Mecânico , Vancomicina/farmacologia
11.
ACS Appl Mater Interfaces ; 11(13): 12647-12655, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30874425

RESUMO

A recent hot-spot topic for flexible and wearable devices involves high-performance nonvolatile ferroelectric memories operating under compressive or tensile mechanical deformations. This work presents the direct fabrication of a flexible (Mn,Ti)-codoped multiferroic BiFeO3 film capacitor with Pt bottom and Au top electrodes on mica substrate. The fabricated polycrystalline Bi(Fe0.93Mn0.05Ti0.02)O3 film on mica exhibits superior ferroelectric switching behavior with robust saturated polarization ( Ps ∼ 93 µC/cm2) and remanent polarization ( Pr ∼ 66 µC/cm2) and excellent frequency stability (1-50 kHz) and temperature resistance (25-200 °C), as well as reliable long-lifetime operation. More saliently, it can be safely bent to a small radius of curvature, as low as 2 mm, or go through repeated compressive/tensile mechanical flexing for 103 bending times at 4 mm radius without any obvious deterioration in polarization, retention time at 105 s, or fatigue resistance after 109 switching cycles. These findings demonstrate a novel route to designing flexible BiFeO3-based ferroelectric memories for information storage and data processing, with promising applications in next-generation smart electronics.

12.
ACS Appl Mater Interfaces ; 11(9): 8749-8762, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30734555

RESUMO

Effective bone tissue engineering can restore bone and skeletal functions that are impaired by traumas and/or certain medical conditions. Bone is a complex tissue and functions through orchestrated interactions between cells, biomechanical forces, and biofactors. To identify ideal scaffold materials for effective mesenchymal stem cell (MSC)-based bone tissue regeneration, here we develop and characterize a composite nanoparticle hydrogel by combining carboxymethyl chitosan (CMCh) and amorphous calcium phosphate (ACP) (designated as CMCh-ACP hydrogel). We demonstrate that the CMCh-ACP hydrogel is readily prepared by incorporating glucono δ-lactone (GDL) into an aqueous dispersion or rehydrating the acidic freeze-dried nanoparticles in a pH-triggered controlled-assembly fashion. The CMCh-ACP hydrogel exhibits excellent biocompatibility and effectively supports MSC proliferation and cell adhesion. Moreover, while augmenting BMP9-induced osteogenic differentiation, the CMCh-ACP hydrogel itself is osteoinductive and induces the expression of osteoblastic regulators and bone markers in MSCs in vitro. The CMCh-ACP scaffold markedly enhances the efficiency and maturity of BMP9-induced bone formation in vivo, while suppressing bone resorption occurred in long-term ectopic osteogenesis. Thus, these results suggest that the pH-responsive self-assembled CMCh-ACP injectable and bioprintable hydrogel may be further exploited as a novel scaffold for osteoprogenitor-cell-based bone tissue regeneration.


Assuntos
Bioimpressão , Hidrogéis/química , Engenharia Tecidual , Tecidos Suporte/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Regeneração Óssea , Osso e Ossos/fisiologia , Fosfatos de Cálcio/química , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quitosana/análogos & derivados , Quitosana/química , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Humanos , Hidrogéis/síntese química , Concentração de Íons de Hidrogênio , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Nanopartículas/química , Osteogênese/efeitos dos fármacos
13.
Mol Med Rep ; 19(3): 1926-1934, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628682

RESUMO

Gastric cancer (GC) is the fourth most frequently occurring cancer and the second most common cause of cancer­associated mortality worldwide. An increasing number of studies have reported that microRNAs (miRNAs/miRs) contribute to the regulation of GC development and progression. Therefore, investigation of the miRNAs involved in the development of GC may result in identification of an effective therapeutic target for patients with this malignancy. miR­18b has been reported to be aberrantly expressed in several types of human cancer. However, the expression pattern, biological role and specific functional mechanism of miR­18b in GC remains to be elucidated. In the present study, reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis revealed that miR­18b was significantly upregulated in GC tissues and cell lines compared with normal gastric tissues and the human gastric epithelial immortalized cell line GES­1, respectively. High miR­18b expression was significantly associated with lymph node metastasis, invasive depth and the Tumor Node Metastasis stage of patients with GC. Additionally, functional assays indicated that the inhibition of miR­18b attenuated cell proliferation and invasion in GC. Furthermore, Kruppel­like factor (KLF)­6 was identified as a direct target gene of miR­18b in GC, from the results of bioinformatics analysis, a luciferase reporter assay, RT­qPCR and western blot analysis. An inverse association was observed between miR­18b and KLF6 mRNA levels in GC tissues. KLF6 knockdown partially abrogated the effects of miR­18b inhibition on GC cell proliferation and invasion. Therefore, miR­18b/KLF6 targeted therapy may provide a promising treatment for patients with GC.


Assuntos
Fator 6 Semelhante a Kruppel/metabolismo , MicroRNAs/metabolismo , Oncogenes , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Idoso , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 6 Semelhante a Kruppel/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Regulação para Cima/genética
14.
Lab Invest ; 99(1): 58-71, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353129

RESUMO

Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into multiple lineages including osteoblastic lineage. Osteogenic differentiation of MSCs is a cascade that recapitulates most, if not all, of the molecular events occurring during embryonic skeletal development, which is regulated by numerous signaling pathways including bone morphogenetic proteins (BMPs). Through a comprehensive analysis of the osteogenic activity, we previously demonstrated that BMP9 is the most potent BMP for inducing bone formation from MSCs both in vitro and in vivo. However, as one of the least studied BMPs, the essential mediators of BMP9-induced osteogenic signaling remain elusive. Here we show that BMP9-induced osteogenic signaling in MSCs requires intact Notch signaling. While the expression of Notch receptors and ligands are readily detectable in MSCs, Notch inhibitor and dominant-negative Notch1 effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic bone formation in vivo. Genetic disruption of Notch pathway severely impairs BMP9-induced osteogenic differentiation and ectopic bone formation from MSCs. Furthermore, while BMP9-induced expression of early-responsive genes is not affected by defective Notch signaling, BMP9 upregulates the expression of Notch receptors and ligands at the intermediate stage of osteogenic differentiation. Taken together, these results demonstrate that Notch signaling may play an essential role in coordinating BMP9-induced osteogenic differentiation of MSCs.


Assuntos
Fatores de Diferenciação de Crescimento/fisiologia , Células-Tronco Mesenquimais/fisiologia , Osteogênese , Receptores Notch/metabolismo , Diferenciação Celular , Células HEK293 , Humanos , Transdução de Sinais , Regulação para Cima
15.
Sci Rep ; 8(1): 17914, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559409

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignancies with <5% five-year survival rate due to late diagnosis, limited treatment options and chemoresistance. There is thus an urgent unmet clinical need to develop effective anticancer drugs to treat pancreatic cancer. Here, we study the potential of repurposing monensin as an anticancer drug for chemo-resistant pancreatic cancer. Using the two commonly-used chemo-resistant pancreatic cancer cell lines PANC-1 and MiaPaCa-2, we show that monensin suppresses cell proliferation and migration, and cell cycle progression, while solicits apoptosis in pancreatic cancer lines at a low micromole range. Moreover, monensin functions synergistically with gemcitabine or EGFR inhibitor erlotinib in suppressing cell growth and inducing cell death of pancreatic cancer cells. Mechanistically, monensin suppresses numerous cancer-associated pathways, such as E2F/DP1, STAT1/2, NFkB, AP-1, Elk-1/SRF, and represses EGFR expression in pancreatic cancer lines. Furthermore, the in vivo study shows that monensin blunts PDAC xenograft tumor growth by suppressing cell proliferation via targeting EGFR pathway. Therefore, our findings demonstrate that monensin can be repurposed as an effective anti-pancreatic cancer drug even though more investigations are needed to validate its safety and anticancer efficacy in pre-clinical and clinical models.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Monensin/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Mol Ther Nucleic Acids ; 13: 556-567, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30414569

RESUMO

MicroRNAs (miRNAs) are an evolutionarily conserved class of small regulatory noncoding RNAs, binding to complementary target mRNAs and resulting in mRNA translational inhibition or degradation, and they play an important role in regulating many aspects of physiologic and pathologic processes in mammalian cells. Thus, efficient manipulations of miRNA functions may be exploited as promising therapeutics for human diseases. Two commonly used strategies to inhibit miRNA functions include direct transfection of chemically synthesized miRNA inhibitors and delivery of a gene vector that instructs intracellular transcription of miRNA inhibitors. While most miRNA inhibitors are based on antisense molecules to bind and sequester miRNAs from their natural targets, it is challenging to achieve effective and stable miRNA inhibition. Here we develop a user-friendly system to express circular inhibitors of miRNA (CimiRs) by exploiting the noncanonical head-to-tail backsplicing mechanism for generating endogenous circular RNA sponges. In our proof-of-principle experiments, we demonstrate that the circular forms of the hsa-miR223-binding site of human ß-arrestin1 (ARRB1) 3' UTR sponge RNA (BUTR), the bulged anti-miR223 (cirBulg223) and bulged anti-miR21 (cirBulg21), exhibit more potent suppression of miRNA functions than their linear counterparts. Therefore, the engineered CimiR expression system should be a valuable tool to target miRNAs for basic and translational research.

17.
Sci Rep ; 8(1): 17247, 2018 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467352

RESUMO

This work is concerned with investigating the effect of substrate hydrophobicity and zeta potential on the dynamics and kinetics of the initial stages of bacterial adhesion. For this purpose, bacterial pathogens Staphylococcus aureus and Escherichia coli O157:H7 were inoculated on the substrates coated with thin thiol layers (i.e., 1-octanethiol, 1-decanethiol, 1-octadecanethiol, 16-mercaptohexadecanoic acid, and 2-aminoethanethiol hydrochloride) with varying hydrophobicity and surface potential. The time-resolved adhesion data revealed a transformation from an exponential dependence to a square root dependence on time upon changing the substrate from hydrophobic or hydrophilic with a negative zeta potential value to hydrophilic with a negative zeta potential for both pathogens. The dewetting of extracellular polymeric substances (EPS) produced by E. coli O157:H7 was more noticeable on hydrophobic substrates, compared to that of S. aureus, which is attributed to the more amphiphilic nature of staphylococcal EPS. The interplay between the timescale of EPS dewetting and the inverse of the adhesion rate constant modulated the distribution of E. coli O157:H7 within microcolonies and the resultant microcolonial morphology on hydrophobic substrates. Observed trends in the formation of bacterial monolayers rather than multilayers and microcolonies rather than isolated and evenly spaced bacterial cells could be explained by a colloidal model considering van der Waals and electrostatic double-layer interactions only after introducing the contribution of elastic energy due to adhesion-induced deformations at intercellular and substrate-cell interfaces. The gained knowledge is significant in the context of identifying surfaces with greater risk of bacterial contamination and guiding the development of novel surfaces and coatings with superior bacterial antifouling characteristics.


Assuntos
Escherichia coli O157/fisiologia , Matriz Extracelular de Substâncias Poliméricas/metabolismo , Staphylococcus aureus/fisiologia , Compostos de Sulfidrila/química , Aderência Bacteriana , Escherichia coli O157/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Cinética , Staphylococcus aureus/metabolismo , Propriedades de Superfície , Termodinâmica
18.
Genes Dis ; 5(2): 77-106, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30258937

RESUMO

As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/ß-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.

19.
Genes Dis ; 5(2): 137-149, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30258943

RESUMO

Glomerular podocytes are highly specialized epithelial cells and play an essential role in establishing the selective permeability of the glomerular filtration barrier of kidney. Maintaining the viability and structural integrity of podocytes is critical to the clinical management of glomerular diseases, which requires a thorough understanding of podocyte cell biology. As mature podocytes lose proliferative capacity, a conditionally SV40 mutant tsA58-immortalized mouse podocyte line (designated as tsPC) was established from the Immortomouse over 20 years ago. However, the utility of the tsPC cells is hampered by the practical inconvenience of culturing these cells. In this study, we establish a user-friendly and reversibly-immortalized mouse podocyte line (designated as imPOD), on the basis of the tsPC cells by stably expressing the wildtype SV40 T-antigen, which is flanked with FRT sites. We show the imPOD cells exhibit long-term high proliferative activity, which can be effectively reversed by FLP recombinase. The imPOD cells express most podocyte-related markers, including WT-1, Nephrin, Tubulin and Vinculin, but not differentiation marker Synaptopodin. The imPOD cells do not form tumor-like masses in vivo. We further demonstrate that TGFß1 induces a podocyte injury-like response in the FLP-reverted imPOD cells by suppressing the expression of slit diaphragm-associated proteins P-Cadherin and ZO-1 and upregulating the expression of mesenchymal markers, α-SMA, Vimentin and Nestin, as well as fibrogenic factors CTGF and Col1a1. Collectively, our results strongly demonstrate that the newly engineered imPOD cells should be a valuable tool to study podocyte biology both under normal and under pathological conditions.

20.
Genes Dis ; 5(2): 172-184, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30258947

RESUMO

Mesenchymal stem cells (MSCs) are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic, chondrogenic and adipogenic lineages. We previously identified BMP9 as one of the most potent BMPs that induce osteoblastic differentiation of MSCs although exact molecular mechanism through which BMP9 regulates osteogenic differentiation remains to be fully understood. Here, we seek to develop a recombinant adenovirus system to optimally silence mouse BMP9 and then characterize the important role of BMP9 in osteogenic differentiation of MSCs. Using two different siRNA bioinformatic prediction programs, we design five siRNAs targeting mouse BMP9 (or simB9), which are expressed under the control of the converging H1 and U6 promoters in recombinant adenovirus vectors. We demonstrate that two of the five siRNAs, simB9-4 and simB9-7, exhibit the highest efficiency on silencing exogenous mouse BMP9 in MSCs. Furthermore, simB9-4 and simB9-7 act synergistically in inhibiting BMP9-induced expression of osteogenic markers, matrix mineralization and ectopic bone formation from MSCs. Thus, our findings demonstrate the important role of BMP9 in osteogenic differentiation of MSCs. The characterized simB9 siRNAs may be used as an important tool to investigate the molecular mechanism behind BMP9 osteogenic signaling. Our results also indicate that recombinant adenovirus-mediated expression of siRNAs is efficient and sustained, and thus may be used as an effective delivery vehicle of siRNA therapeutics.

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