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1.
Cancer Med ; 9(2): 724-736, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31769229

RESUMO

LncRNAs have been shown to play essential roles in bladder cancer (BC) progress. Our microarrays of clinical samples firstly screened that lncRNA muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) was poorly expressed in BC tissues. However, its biological function in BC remains not well understood. Here we examined the clinical correlations with MBNL1-AS1 in BC patients. Then, 5673 and T24 cell lines were employed to investigate the role of MBNL1-AS1 in the proliferation and apoptosis of BC cells in vitro and in vivo. Furthermore, miR-135a-5p (miR-135a)/PHLPP2/FOXO1 axis was focused to explore its regulatory mechanism in BC. The results showed that MBNL1-AS1 was significantly downregulated in bladder tumor tissues, and associated with BC progression. In vitro, MBNL1-AS1 knockdown increased the number of viable cells and bromodeoxyuridine-positive cells, accelerated cell cycle, and dysregulated proliferative regulators (Ki67, p21, p27, and Cyclin D1) in BC cells. The apoptotic cells and the cleavages of caspase-3/9 were reduced in MBNL1-AS1-silenced BC cells. Overexpression of MBNL1-AS1 had opposite effects on BC cell proliferation and apoptosis. Moreover miR-135a was demonstrated to interact with MBNL1-AS1, and inhibiting miR-135a reversed the effects of shMBNL1-AS1 on BC cells. The downstream effectors (PHLPP2 and FOXO1) were positively regulated by MBNL1-AS1, but negatively regulated by miR-135a. Similar results were also observed in xenograft tumors. In conclusion, this study firstly suggests that MBNL1-AS1 acts as a tumor suppressor of BC by targeting miR-135a/PHLPP2/FOXO1 axis, providing a novel insight for BC diagnosis and treatment.

2.
ACS Appl Mater Interfaces ; 11(43): 39648-39661, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31591880

RESUMO

Pseudomonas aeruginosa can cause a multitude of inflammations in humans. Due to its ability to form biofilm, the bacteria show durable resistance to drugs. Herein, we developed a heteromultivalent ligand-decorated nanotherapeutic inspired by living system for inhibition of antibiotic-resistant bacterial pneumonia. The nanotherapeutic with a heteromultivalent glycomimetic shell can specifically recognize P. aeruginosa to inhibit its biofilm formation and protect native cells from bacterial infection; the rate of biofilm inhibition was up to 85%. The nanotherapeutic with a bioresponsive hydrophobic core can protonate and control drug release in the microenvironment of bacterial infections. By utilizing these properties, the nanotherapeutics can effectively penetrate the internal structure of biofilms to release the drug, dispersing the biofilm by over 80% under laser irradiation. In vivo bioinspired nanotherapeutics have the potential to efficiently inhibit antibiotic-resistant P. aeruginosa-induced pneumonia. Collectively, we expect biomimicking systems to be the next generation of prevention and treatment as integrated antibacterial agents against P. aeruginosa.

3.
Adv Mater ; 31(7): e1806024, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30589118

RESUMO

The chronic infections by pathogenic Pseudomonas aeruginosa (P. aeruginosa) remain to be properly addressed. In particular, for drug-resistant strains, limited medication is available. An in vivo pneumonia model induced by a clinically isolated aminoglycoside resistant strain of P. aeruginosa is developed. Tobramycin clinically treating P. aeruginosa infections is found to be ineffective to inhibit or eliminate this drug-resistant strain. Here, a newly developed non-antibiotics based nanoformulation plus near-infrared (NIR) photothermal treatment shows a remarkable antibacterial efficacy in treating this drug-resistant pneumonia. The novel formulation contains 50-100 nm long nanorods decorated with two types of glycomimetic polymers to specifically block bacterial LecA and LecB lectins, respectively, which are essential for bacterial biofilm development. Such a 3D display of heteromultivalent glycomimetics on a large scale is inspired by the natural strengthening mechanism for the carbohydrate-lectin interaction that occurs when bacteria initially infects the host. This novel formulation shows the most efficient bacteria inhabitation and killing against P. aeruginosa infection, through lectin blocking and the near-infrared-light-induced photothermal effect of gold nanorods, respectively. Collectively, the novel biomimetic design combined with the photothermal killing capability is expected to be an alternative treatment strategy against the ever-threatening drug-resistant infectious diseases when known antibiotics have failed.


Assuntos
Materiais Biomiméticos , Hipertermia Induzida/métodos , Fototerapia/métodos , Infecções por Pseudomonas/terapia , Pseudomonas aeruginosa , Células A549 , Abscesso/tratamento farmacológico , Abscesso/patologia , Adesinas Bacterianas/metabolismo , Animais , Biofilmes , Farmacorresistência Bacteriana , Escherichia coli , Compostos de Ouro , Humanos , Lactose/análogos & derivados , Lectinas/antagonistas & inibidores , Lectinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanotubos , Pneumonia Bacteriana/patologia , Pneumonia Bacteriana/terapia , Ácidos Polimetacrílicos , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/metabolismo
4.
Chem Commun (Camb) ; 54(90): 12754-12757, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30361728

RESUMO

An entirely new strategy is explored for directional transport delivery of antibiotics to bacteria utilizing a bacteria-activated nanoplatform. The nanoplatform can effectively prevent the premature leakage of the therapeutic payload, but release was triggered when the nanoplatforms adhere to bacteria, promising potential applications for the delivery of a wide-range of antimicrobials.


Assuntos
Antibacterianos/farmacologia , Bacillus amyloliquefaciens/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tamanho da Partícula , Propriedades de Superfície
5.
Nanoscale ; 10(39): 18520-18530, 2018 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-30211421

RESUMO

The chronic infection of humans by antibiotic-resistant bacteria and their related biofilm have, so far, not been properly addressed. In the present work, we developed a novel antibacterial nanoplatform showing the most efficient antibiotic-resistant bacteria inhibition and biofilm eradication. This particular formulation contains tobramycin-conjugated graphene oxide, for efficiently capturing bacteria through electrostatic interactions and eliminating bacteria as a "nano-knife", and copper sulphide nanoparticles for enhancing the photothermal and photodynamic properties. This novel formulation can selectively eliminate bacteria over NIH 3T3 cells, and the biofilm eradication capacity was up to 70%. Importantly, the nanoplatforms can inhibit bacterial growth and promote the repair of antibiotic-resistant bacteria-infected wounds on rats without non-specific damage to normal tissue. This work provides an effective, simple, and rapid method for the design and fabrication of near-infrared light-induced nanoplatforms that offer possibilities to treat biofilm-related infections.


Assuntos
Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Grafite , Nanoestruturas/química , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Tobramicina , Animais , Grafite/química , Grafite/farmacologia , Humanos , Camundongos , Células NIH 3T3 , Tobramicina/química , Tobramicina/farmacologia
6.
Bioconjug Chem ; 29(9): 3222-3230, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30152991

RESUMO

Due to the rapid development of bacterial resistance, there is an urgent need to explore new antibacterial agents to substitute for traditional antibiotic therapy. Photodynamic therapy has been identified as a promising bactericidal method to conquer antibiotic-resistant pathogens. To solve the problem of photosensitizer damage to normal tissues in vivo, we developed a boron-dipyrrolemethene (BODIPY)-based glycosylated photosensitizer for ablating Pseudomonas aeruginosa ( P. aeruginosa). This glycosylated photosensitizer exhibited good water solubility and generated 1O2 rapidly in an aqueous solution under light exposure. The photosensitizer did not cause detectable toxicity to human cells in the dark. Importantly, the photosensitizer was able to selectively attach to P. aeruginosa over normal cells, thus resulting in effective pathogen ablation by reactive oxygen species. Moreover, the photosensitizer inhibited over 90% of the biofilm formation produced by P. aeruginosa. The results indicate that the design of the macromolecular photosensitizer-induced bacterial death and inhibited biofilm formation provide a novel strategy for overcoming bacterial infection.


Assuntos
Antibacterianos/farmacologia , Galactose/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana , Glicosilação , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/toxicidade , Pseudomonas aeruginosa/fisiologia , Pseudomonas aeruginosa/ultraestrutura , Solubilidade , Água
7.
ACS Appl Mater Interfaces ; 10(17): 14426-14437, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29651836

RESUMO

Biofilm is closely related to chronic infections and is difficult to eradicate. Development of effective therapy strategies to control biofilm infection is still challenging. Aiming at biofilm architecture, we designed and prepared near-infrared-activated thermosensitive liposomes with photothermal and antibiotic synergistic therapy capacity to eliminate Pseudomonas aeruginosa biofilm. The liposomes with positive charge and small size aided to enter the biofilm microchannels and locally released antibiotics in infection site. The liposomes could remain stable at 37 °C and release about 80% antibiotics over 45 °C. The biofilm dispersion rate was up to 80%, which was a 7- to 8-fold rise compared to excess antibiotic alone, indicating that the localized antibiotic release and photothermal co-therapy improved the antimicrobial efficiency. In vivo drug-loaded liposomes in treating P. aeruginosa-induced abscess exhibited an outstanding therapeutic effect. Furthermore, photothermal treatment could stimulate the expression of bcl2-associated athanogene 3 to prevent normal tissue from thermal damage. The near-infrared-activated nanoparticle carriers had the tremendous therapeutic potential to dramatically enhance the efficacy of antibiotics through thermos-triggered drug release and photothermal therapy.


Assuntos
Biofilmes , Antibacterianos , Raios Infravermelhos , Lipossomos , Pseudomonas aeruginosa
8.
World J Surg Oncol ; 16(1): 10, 2018 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343302

RESUMO

BACKGROUND: Laparoscopic radical cystectomy (LRC) has been shown to have less estimated blood loss (EBL), transfusion rate, narcotic analgesic requirement, earlier return of bowel function, and shorter hospital stay. The aim of this study was to investigate the feasibility, peri-operative and oncologic outcomes of laparoscopic radical cystectomy (LRC) in patients with previous abdominal surgery (PAS). METHODS: We retrospectively reviewed 243 patients undergoing open radical cystectomy (ORC) or LRC with bilateral pelvic lymph node dissection and urinary diversion or cutaneous ureterostomy at a single center from January 2010 to December 2015. Demographic parameters, intra-operative variables, peri-operative records, pathologic outcomes, and complication rate were reviewed to assess the impact of PAS on peri-operative and oncologic outcomes. RESULTS: Patients in both ORC and LRC subgroups were homogeneous in terms of demography characteristics including age, gender, BMI, ASA score, and comorbidity. Estimated blood loss (EBL) was higher in patients with PAS undergoing ORC compared to those with no PAS (P = 0.008). However, there was no significant difference of EBL among patients undergoing LRC with or without PAS (P = 0.896). There was no statistical difference in peri-operative parameters and pathological outcomes. Patients with PAS undergoing ORC and ileal conduit had a higher vascular injury rate (P = 0.017). Comparing patients with PAS performed by LRC and ORC, the number of patients with the vascular injury was higher in ORC groups regardless of the type of diversion (ileal conduit, P = 0.001, cutaneous ureterostomy, P = 0.025). There is no significant difference in other complications. CONCLUSION: The presence of adhesions from PAS is not a contraindication to LRC. Patients with PAS may benefit from LRC with lower estimated blood loss, fewer transfusion rates, and vascular injuries. Furthermore, the overall oncologic outcomes and complication rate are similar between LRC and ORC patients with PAS.


Assuntos
Abdome/cirurgia , Cistectomia/métodos , Laparoscopia/métodos , Recidiva Local de Neoplasia/patologia , Assistência Perioperatória , Procedimentos Cirúrgicos Robóticos/métodos , Neoplasias da Bexiga Urinária/patologia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/cirurgia
9.
Biomacromolecules ; 19(1): 141-149, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29141147

RESUMO

A multitude of serious chronic infections are involved in bacterial biofilms that are difficult to eradicate. Here, a water-soluble galactose-functionalized cationic 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based photodynamic therapy agent was synthesized for selectively eliminating the bacterial biofilm. These conjugates can capture bacteria to form aggregations through electrostatic interaction and then generate a large number of reactive oxygen species (ROS) under visible light irradiation to kill the bacteria without the emergence of bacterial resistance. Simultaneously, this agent could effectively inhibit and eradicate both Gram-positive and Gram-negative bacterial biofilms. The in-depth analysis of the antimicrobial mechanism confirmed that the conjugates can quickly bind on the bacterial surface, irreversibly disrupt the bacterial membrane, and distinctly inhibit intracellular enzyme activity, ultimately leading to the bacterial death. Importantly, these conjugates are highly selective toward bacterial cells over mammalian cells as well as no cytotoxicity to A549 cells and no discernible hemolytic activity. Collectively, this water-soluble galactose-decorated cationic BODIPY-based photodynamic therapy agent design provides promising insights for the development of therapy for antibiotic-resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Compostos de Boro/farmacologia , Galactose/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Cátions , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Espécies Reativas de Oxigênio/metabolismo , Solubilidade , Água/química
10.
ACS Appl Mater Interfaces ; 9(36): 30470-30479, 2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28832120

RESUMO

The emergence of antibiotic-resistant bacterial strains has made conventional antibiotic therapies less efficient. The development of a novel nanoantibiotic approach for efficiently ablating such bacterial infections is becoming crucial. Herein, a collection of poly(5-(2-ethyl acrylate)-4-methylthiazole-g-butyl)/copper sulfide nanoclusters (PATA-C4@CuS) was synthesized for efficient capture and effective ablation of levofloxacin-resistant Gram-negative and Gram-positive bacteria upon tissue-penetrable near-infrared (NIR) laser irradiation. In this work, we took advantage of the excellent photothermal and photodynamic properties of copper sulfide nanoparticles (CuSNPs) upon NIR laser irradiation and thiazole derivative as a membrane-targeting cationic ligand toward bacteria. The conjugated nanoclusters could anchor the bacteria to trigger the bacterial aggregation quickly and efficiently kill them. These conjugated nanoclusters could significantly inhibit levofloxacin-resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Bacillus amyloliquefaciens at 5.5 µg/mL under NIR laser irradiation (980 nm, 1.5 W cm-2, 5 min), which suggested that the heat and reactive oxygen species (ROS) generated from the irradiated CuSNPs attached to bacteria were effective in eliminating and preventing the regrowth of the bacteria. Importantly, the conjugated nanoclusters could promote healing in bacteria-infected rat wounds without nonspecific damage to normal tissue. These findings highlight the promise of the highly versatile multifunctional nanoantibiotics in bacterial infection.


Assuntos
Farmacorresistência Bacteriana , Animais , Antibacterianos , Bactérias , Cobre , Nanoestruturas , Ratos , Sulfetos
11.
BMC Med Genet ; 12: 8, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21232124

RESUMO

BACKGROUND: qualitative and quantitative changes in human mitochondrial DNA (mtDNA) have been implicated in various cancer types. A 4,977 bp deletion in the major arch of the mitochondrial genome is one of the most common mutations associated with a variety of human diseases and aging. METHODS: we conducted a comprehensive study on clinical features and mtDNA of 104 colorectal cancer patients in the Wenzhou area of China. In particular, using a quantitative real time PCR method, we analyzed the 4,977 bp deletion and mtDNA content in tumor tissues and paired non-tumor areas from these patients. RESULTS: we found that the 4,977 bp deletion was more likely to be present in patients of younger age (≤65 years, p = 0.027). In patients with the 4,977 bp deletion, the deletion level decreased as the cancer stage advanced (p = 0.031). Moreover, mtDNA copy number in tumor tissues of patients with this deletion increased, both compared with that in adjacent non-tumor tissues and with in tumors of patients without the deletion. Such mtDNA content increase correlated with the levels of the 4,977 bp deletion and with cancer stage (p < 0.001). CONCLUSIONS: our study indicates that the mtDNA 4,977 bp deletion may play a role in the early stage of colorectal cancer, and it is also implicated in alteration of mtDNA content in cancer cells.


Assuntos
Neoplasias Colorretais/genética , Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Deleção de Sequência/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , China/epidemiologia , DNA de Neoplasias/genética , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular
12.
Ann N Y Acad Sci ; 1201: 26-33, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20649535

RESUMO

Abnormal mitochondria have long been hypothesized to be involved in tumorigenesis. Mitochondrial DNA (mtDNA) mutations have been found in various cancer cells, yet their role in tumorigenesis remains largely unknown. Our long-term goal is to understand the role of mtDNA polymorphism and mtDNA mutations in tumorigenesis. We focused on the role of the mtDNA haplogroup; a 4,977 bp common mtDNA deletion; mtDNA mutations in the main control region of mtDNA or displacement loop; and mtDNA heteroplasmy in cancer occurrence and cancer development. Our results indicate that qualitative and quantitative changes in mtDNA play an important role in cancer development.


Assuntos
DNA Mitocondrial/genética , Neoplasias/genética , Trifosfato de Adenosina/metabolismo , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Haplótipos , Humanos , Modelos Genéticos , Mutação , Neoplasias/patologia , Fosforilação Oxidativa , Oxigênio/química , Polimorfismo Genético
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