ABSTRACT
Sorbin and SH3 domain-containing 2 (SORBS2) is an RNA-binding protein and has been implicated in the development of some cancers. However, its role in bladder cancer (BC) is yet to be established. The expression of SORBS2 in BC tissues was determined from the Gene Expression Omnibus and Gene Expression Profiling Interactive Analysis databases and collected paired tumor/normal samples. The effects of SORBS2 on BC cells were detected by CCK-8, colony formation, Transwell, dual-luciferase, RNA immunoprecipitation, chromatin immunoprecipitation, and DNA pull-down assays. In vivo, BC cell growth and metastasis were studied by a xenograft subcutaneous model and a tail-vein metastasis model. The results showed that SORBS2 expression was significantly decreased in BC tissues and cells. SORBS2 overexpression inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro and tumor growth and metastasis in vivo, while silencing SORBS2 produced the opposite effect. Mechanistically, we found that SORBS2 enhanced the stability of tissue factor pathway inhibitor (TFPI) mRNA via direct binding to its 3' UTR. Restoration of TFPI expression reversed SORBS2 knockdown-induced malignant phenotypes of BC cells. In addition, SORBS2 expression was negatively regulated by the transcription factor specificity protein 1 (SP1). Conversely, SORBS2 can be transcriptionally regulated by SP1 and inhibit BC cell growth and metastasis via stabilization of TFPI mRNA, indicating SORBS2 may be a promising therapeutic target for BC.
Subject(s)
Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , RNA-Binding Proteins , Sp1 Transcription Factor , Urinary Bladder Neoplasms , Animals , Female , Humans , Male , Mice , Cell Line, Tumor , Epithelial-Mesenchymal Transition/genetics , Mice, Inbred BALB C , Mice, Nude , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Xenograft Model Antitumor Assays , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/metabolism , Lipoproteins/genetics , Lipoproteins/metabolismABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Galactose/chemistry , Photochemotherapy , Photosensitizing Agents/pharmacology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Drug Resistance, Bacterial , Glycosylation , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/toxicity , Pseudomonas aeruginosa/physiology , Pseudomonas aeruginosa/ultrastructure , Solubility , WaterABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Boron Compounds/pharmacology , Galactose/chemistry , Photochemotherapy , Photosensitizing Agents/pharmacology , A549 Cells , Cations , Cell Membrane/drug effects , Cells, Cultured , Humans , Reactive Oxygen Species/metabolism , Solubility , Water/chemistryABSTRACT
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.
Subject(s)
Abdomen/surgery , Cystectomy/methods , Laparoscopy/methods , Neoplasm Recurrence, Local/pathology , Perioperative Care , Robotic Surgical Procedures/methods , Urinary Bladder Neoplasms/pathology , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/surgery , Prognosis , Retrospective Studies , Urinary Bladder Neoplasms/surgeryABSTRACT
One of the most abundant protein-protein interaction domains in the human proteome is the WD40 repeat (WDR) domain. A Gene Expression Omnibus dataset revealed 37 differentially expressed WDR domain genes in bladder cancer (BC). WD repeat domain 54 (WDR54), an upregulated WDR domain gene, was selected for further investigation. Sixty pairs of frozen BC tumor and non-malignant bladder tissues and 83 paraffin-embedded BC tissue specimens were obtained. Loss-/gain-of-function experiments were carried out using BC and xenograft tumor models. WDR54 was overexpressed in BC cells, and its high expression was linked to tumor stage and lymph node metastases in patients. WDR54 contributed to the tumorigenesis and metastasis of BC and impaired its chemosensitivity. WDR54 prevented the degradation and ubiquitination of the mediator of ErbB2-driven cell motility 1 (MEMO1). WDR54 also promoted the interaction between MEMO1 and insulin receptor substrate 1 (IRS1) and activated the IRS1/AKT/ß-catenin pathway in BC cells. Particularly, WDR54 depended on MEMO1 to exert its biological functions. Our study demonstrated the relevance of WDR54 in BC and provides insight into the molecular mechanism underlying BC.
Subject(s)
Intracellular Signaling Peptides and Proteins , Urinary Bladder Neoplasms , Humans , Carcinogenesis/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , WD40 RepeatsABSTRACT
The Myodural Bridge (MDB) is a physiological structure that is highly conserved in mammals and many of other tetrapods. It connects the suboccipital muscles to the cervical spinal dura mater (SDM) and transmits the tensile forces generated by the suboccipital muscles to the SDM. Consequently, the MDB has broader physiological potentials than just fixing the SDM. It has been proposed that MDB significantly contributes to the dynamics of cerebrospinal fluid (CSF) movements. Animal models of suboccipital muscle atrophy and hyperplasia were established utilizing local injection of BTX-A and ACE-031. In contrast, animal models with surgical severance of suboccipital muscles, and without any surgical operation were set as two types of negative control groups. CSF secretion and reabsorption rates were then measured for subsequent analysis. Our findings demonstrated a significant increase in CSF secretion rate in rats with the hyperplasia model, while there was a significant decrease in rats with the atrophy and severance groups. We observed an increase in CSF reabsorption rate in both the atrophy and hyperplasia groups, but no significant change was observed in the severance group. Additionally, our immunohistochemistry results revealed no significant change in the protein level of six selected choroid plexus-CSF-related proteins among all these groups. Therefore, it was indicated that alteration of MDB-transmitted tensile force resulted in changes of CSF secretion and reabsorption rates, suggesting the potential role that MDB may play during CSF circulation. This provides a unique research insight into CSF dynamics.
Subject(s)
Dura Mater , Neck Muscles , Animals , Rats , Hyperplasia , Dura Mater/physiology , Neck Muscles/physiology , Movement , Mammals , Atrophy , Cerebrospinal FluidABSTRACT
Bladder cancer (BC) is the most common type of malignant tumor in the genitourinary system. Through the microarray analysis of clinical samples, long noncoding RNA HAND2-AS1 expression was found to be downregulated in BC tissues. However, the function of HAND2-AS1 on BC and underlying mechanism are unclear. In this study, the correlations of HAND2-AS1 with clinicopathological parameters in BC patients were determined. The gain- and loss-of-function experiments were conducted to examine the role of HAND2-AS1 in malignant behaviors of BC cells in vitro and in vivo. Then, we paid attention to miR-17-5p/KLF9 axis to illustrate the molecular mechanism. Results showed that HAND2-AS1 was downregulated in BC tissues, and its overexpression significantly inhibited cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Knockdown of HAND2-AS1 caused an opposite effect on BC cell malignancies. Furthermore, miR-17-5p was shown to be a direct target of HAND2-AS1, and it reversed the inhibitory effect of HAND2-AS1 on BC malignancies. Also, as a downstream factor of miR-17-5p, KLF9 silencing was demonstrated to mediate the role of miR-17-5p inhibitor in BC cell proliferation and invasion. Thus, it suggests that HAND2-AS1 acts as a suppressor in BC development through miR-17-5p/KLF9 axis.
Subject(s)
Urinary Bladder NeoplasmsABSTRACT
PURPOSE: Bladder cancer is a kind of common malignant cancer in the urinary system. The expression of EDARADD (ectodysplasin-A receptor-associated death domain) in bladder cancer is higher than the normal samples. However, its role in bladder cancer remains unknown. In the present study, we analyzed the expression of EDARADD in 81 bladder cancer samples by immunohistochemistry as well as its correlation with clinical characteristics. In addition, the role of EDARADD was also explored through loss of function. MATERIALS AND METHODS: Cell proliferation assay and MTT assay were conducted to assess the proliferation of bladder cancer cells and transwell assay and wound healing assay were conducted to assess the migration of bladder cancer cells. On the other hand, the levels of epithelial-mesenchymal transition (EMT) associated proteins and the key molecules in the MAPK signaling pathway were detected by western blot. In vivo experiments were also conducted to determine the effect of EDARADD silencing on the metastasis of bladder cancer cells and the MAPK signaling pathway. RESULTS: EDARADD was highly expressed in bladder cancer samples, especially in high-grade bladder cancer samples. The high EDARADD level indicated a poor survival. Interestingly, EDARADD silencing suppressed the proliferation, migration and EMT of bladder cancer cells. Furthermore, the MAPK signaling pathway was repressed by EDARADD silencing. Additionally, silencing EDARADD also inhibited the metastasis of bladder cancer and the MAPK signaling pathway in vivo. It is indicated that silencing EDARADD may suppress the proliferation and metastasis of bladder cancer cells through the MAPK signaling pathway. CONCLUSION: These results indicate that EDARADD may become a probable target for the treatment of bladder cancer.
Subject(s)
Urinary Bladder Neoplasms , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Edar-Associated Death Domain Protein/metabolism , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
Checkpoint inhibitors, such as antibodies blocking the PD-1/PD-L1 pathway, are among the most promising immunotherapies to treat metastatic cancers, but their response rate remains low. In addition, the usage of monoclonal antibodies as checkpoint inhibitors is associated with a series of drawbacks. Herein, an all synthetic nanoparticle with PD-L1 blockade capability is developed for cancer photothermal-immunotherapy. The polymeric nanoparticle integrates photothermal treatment, antitumor vaccination, and PD-1/PD-L1 blockade in a single system to augment the antitumor efficacy. In a CT26 bilateral tumor model, intravenously injected nanoparticles accumulate in tumor sites and mediate strong photothermal effects, eradicate the NIR treated primary tumors and elicit strong antitumor immunity by inducing immunogenic cell death (ICD). Growth of the untreated distant tumors is also suppressed due to the synergies of systemic antitumor immune activation and PD-L1 blockade. Our strategy offers a simple but promising approach for the treatment of metastatic cancer.
Subject(s)
Nanoparticles , Neoplasms , Antibodies, Monoclonal , B7-H1 Antigen , Cell Line, Tumor , Humans , Immunotherapy , Neoplasms/therapyABSTRACT
Intracellular bacteria-mediated antibiotic tolerance, which acts as a "Trojan horse," plays a critical and underappreciated role in chronic and recurrent infections. Failure of conventional antibiotic therapy is often encountered because infected cells prevent drug permeation or the drug concentration is too low at the site of resident bacteria. New paradigms are therefore urgently needed for intracellular anti-infective therapy. Here, a novel therapeutic was developed for targeted delivery of antibiotics into bacteria-infected macrophages to improve drug accumulation in intracellular niches and bactericidal activity of antibiotics against intracellular pathogens. This hierarchical nanoplatform includes a glycocalyx-mimicking shell that enables rapid uptake by macrophages. Subsequently, the targeting moieties are activated in response to the bacteria, and the release of entrapped antibiotics is triggered by bacteria and bacteria-secreted enzymes. The self-immolative drug delivery nanoplatform eliminates intracellular pathogenic bacteria residing in macrophages more efficiently compared to drugs alone. The in vivo dynamically monitored nanosystem also efficiently inhibited the growth of intracellular Staphylococcus aureus in infected muscles of mice with negligible systemic toxicity. The novel dual-targeting design of an all-in-one therapeutic platform can be used as an alternative strategy to reanimate antibiotic therapy against multifarious intracellular bacterial infections.
Subject(s)
Parasitic Diseases , Staphylococcal Infections , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Delivery Systems , Mice , Parasitic Diseases/drug therapy , Staphylococcal Infections/drug therapy , Staphylococcus aureusABSTRACT
The efficacious delivery of antimicrobial drugs to intractable oral biofilms remains a challenge due to inadequate biofilm penetration and lack of pathogen targeting. Herein, we have developed a microenvironment-activated poly(ethylene glycol) (PEG)-sheddable nanoplatform to mediate targeted delivery of drugs into oral biofilms for the efficient prevention of dental caries. The PEGylated nanoplatform with enhanced biofilm penetration is capable of deshielding the PEG layer under slightly acidic conditions in a PEG chain length-dependent manner to re-expose the bacteria-targeting ligands, thereby facilitating targeted codelivery of ciprofloxacin (CIP) and IR780 to the bacteria after accumulation within biofilms. The nanoplatform tends to induce bacterial agglomeration and suffers from degradation in the acidic oral biofilm microenvironment, triggering rapid drug release on demand around bacterial cells. The self-modulating nanoplatform under near-infrared (NIR) irradiation accordingly displays greatly augmented potency in oral biofilm penetration and disruption compared with drugs alone. Topical oral treatment with nanoplatforms involving synergetic pharmacological and photothermal/photodynamic trinary therapy results in robust biofilm dispersion and efficacious suppression of severe tooth decay in rats. This versatile nanoplatform can promote local accumulation and specific drug transport into biofilms and represents a new paradigm for targeted drug delivery for the management of oral biofilm-associated infections.
ABSTRACT
During mammalian evolution, the Myodural Bridges (MDB) have been shown to be highly conserved anatomical structures. However, the putative physiological function of these structures remains unclear. The MDB functionally connects the suboccipital musculature to the cervical spinal dura mater, while passing through the posterior atlanto-occipital and atlanto-axial interspaces. MDB transmits the tensile forces generated by the suboccipital muscles to the cervical dura mater. Moreover, head movements have been shown to be an important contributor to human CSF circulation. In the present study, a 16-week administration of a Myostatin-specific inhibitor, ACE-031, was injected into the suboccipital musculature of rats to establish an experimental animal model of hyperplasia of the suboccipital musculature. Using an optic fiber pressure measurement instrument, the present authors observed a significant increase in intracranial pressure (ICP) while utilizing the hyperplasia model. In contrast, surgically severing the MDB connections resulted in a significant decrease in intracranial pressure. Thus, these results indicated that muscular activation of the MDB may affect CSF circulation, suggesting a potential functional role of the MDB, and providing a new research perspective on CSF dynamics.
Subject(s)
Intracranial Pressure , Neck Muscles , Animals , Dura Mater/physiology , Humans , Hyperplasia , Mammals , Neck , RatsABSTRACT
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.
Subject(s)
Colorectal Neoplasms/genetics , DNA Copy Number Variations/genetics , DNA, Mitochondrial/genetics , Sequence Deletion/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , China/epidemiology , DNA, Neoplasm/genetics , Female , Humans , Incidence , Male , Middle Aged , Molecular Sequence DataABSTRACT
Obstinate infections caused by drug-resistant bacteria severely threaten human health. And the emergence of multidrug-resistant bacteria increases the morbidity and mortality of patients, thus necessitating the development of innovative or alternative therapeutics. Here, a light-activated nanotherapeutic with broad-spectrum bacterial recognition is established as an antibiotic-free therapeutic agent against pathogens. The nanotherapeutic with external phenylboronic acid-based glycopolymers increases the stability and biocompatibility and shows the ability of bacterial recognition. Once irradiated with near-infrared light, this nanotherapeutic with high photothermal conversion efficiency disrupts the cytoplasmic membrane, thus killing bacterial cells. Importantly, it also eliminates the biofilms formed by both drug-resistant Gram-negative bacteria (Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus) effectively. Thus, this antibiotic-free nanotherapeutic with hypotoxicity offers a promising approach to fight increasingly serious antimicrobial resistance.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Drug Resistance, Multiple, Bacterial/genetics , Gram-Positive Bacteria/pathogenicity , Methicillin-Resistant Staphylococcus aureus/drug effects , Nanotechnology/methods , Anti-Bacterial Agents/pharmacology , HumansABSTRACT
Exogenous reactive oxygen species (ROS) generation is a promising antibacterial strategy. The short diffusion distance coupled with the transient existence of ROS restrict their precise release at inflammation sites, so it is imperative to regulate the reactive sites of ROS donors. In this work, we developed a glycomimetic-decorated fluorescent nanobiocide to mediate the release of ROS generated from CuInS/ZnS quantum dots. The introduction of glycomimetics innovatively improved the biocompatibility of the hydrophobic quantum dots, allowing pathogenic bacteria to be targeted. The functionalized CuInS/ZnS quantum dots allowed simultaneous fluorescent reporting and sterilization under 660 nm illumination. Moreover, the nanobiocide can serve as a cell-binding glue causing bacterial aggregation, disrupting bacterial adhesion to host cells and inhibiting biofilm formation. Collectively, this work indicated the far-reaching future of ROS-generating biomimetic design for multifunctional nanobiocides to combat bacterial infections.
Subject(s)
Anti-Bacterial Agents/chemistry , Fluorescent Dyes/chemistry , Infections/drug therapy , Quantum Dots/chemistry , 3T3 Cells , Adhesives/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Biofilms , Copper/chemistry , Erythrocytes , Humans , Indium/chemistry , Mice , Optical Imaging , Pseudomonas aeruginosa/drug effects , Sterilization , Sulfides/chemistry , Surface Properties , Zinc Compounds/chemistryABSTRACT
Hypoxia, a common characteristic of bacterial infections, is known to be closely associated with the emergence of multidrug-resistant bacteria, which hastens the need to develop advanced microbicides and antibacterial techniques. Photodynamic therapy is a promising strategy to reduce bacterial antibiotic resistance and employs photosensitizers, excitation light sources, and sufficient oxygen to generate toxic reactive oxygen species (ROS). The inherent limitation of PDT is that the generation of ROS is restricted by the hypoxic microenvironment in infection sites. Here, an oxygen self-supplying nanotherapeutic is developed to enhance antibacterial activity against multidrug-resistant bacteria on the basis of fluorinated boron dipyrromethene (BODIPY)-based glycomimetics. The nanotherapeutic not only could capture the bacteria efficiently but also was able to act as an oxygen carrier to relieve the hypoxic microenvironment of bacterial infections, thus achieving enhanced PDT efficacy. In a Pseudomonas aeruginosa infection of a rat cornea, typical administration of the nanotherapeutic decreased the infiltrate and showed a faster healing capacity in comparison with BODIPY-based glycomimetics. Self-supplying oxygen nanotherapeutics that relieve the hypoxic microenvironment and interfere with bacterial colonization have been shown to be a promising candidate for the management of drug-resistant microbial keratitis.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Eye Infections, Bacterial/drug therapy , Hypoxia/drug therapy , Keratitis/drug therapy , Nanoparticles/therapeutic use , Oxygen/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/radiation effects , Biofilms/drug effects , Boron Compounds/chemistry , Boron Compounds/radiation effects , Boron Compounds/therapeutic use , Cornea/metabolism , Cornea/microbiology , Cornea/pathology , Drug Resistance, Multiple, Bacterial/drug effects , Eye Infections, Bacterial/metabolism , Eye Infections, Bacterial/pathology , Hypoxia/metabolism , Hypoxia/pathology , Keratitis/metabolism , Keratitis/pathology , Light , Mice , NIH 3T3 Cells , Nanoparticles/chemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Photosensitizing Agents/therapeutic use , Polymethacrylic Acids/chemistry , Pseudomonas Infections/drug therapy , Pseudomonas Infections/metabolism , Pseudomonas Infections/pathology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , RatsABSTRACT
Chronic infections caused by Pseudomonas aeruginosa pose severe threats to human health. Traditional antibiotic therapy has lost its total supremacy in this battle. Here, nanoplatforms activated by the clinical microenvironment are developed to treat P. aeruginosa infection on the basis of dynamic borate ester bonds. In this design, the nanoplatforms expose targeted groups for bacterial capture after activation by an acidic infection microenvironment, resulting in directional transport delivery of the payload to bacteria. Subsequently, the production of hyperpyrexia and reactive oxygen species enhances antibacterial efficacy without systemic toxicity. Such a formulation with a diameter less than 200 nm can eliminate biofilm up to 75%, downregulate the level of cytokines, and finally promote lung repair. Collectively, the biomimetic design with phototherapy killing capability has the potential to be an alternative strategy against chronic infections caused by P. aeruginosa.
Subject(s)
Anti-Bacterial Agents/chemistry , Indocyanine Green/chemistry , Nanocapsules/chemistry , Photosensitizing Agents/chemistry , Polymers/chemistry , Pseudomonas Infections/drug therapy , Pseudomonas Infections/radiotherapy , A549 Cells , Animals , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Drug Compounding , Drug Liberation , Drug Synergism , Humans , Indocyanine Green/pharmacology , Infrared Rays , Male , Methacrylates/chemistry , Mice, Inbred BALB C , Photochemotherapy , Photosensitizing Agents/pharmacology , Polyethylene Glycols/chemistry , Pseudomonas aeruginosa/drug effectsABSTRACT
Insulin injection causes great pain to the patient, and nasal mucosal administration of insulin is a novel route for the treatment of diabetes. This strategy could protect insulin from either extensive first-pass metabolism or enzyme degradation in the gastrointestinal tract. With the dynamic boronate esters reversibly formed by phenylboronic acid and diols on nasal mucosal epithelial cell surfaces, we herein developed phenylboronic-acid-functionalized dextran nanoplatforms to enhance the permeability of cargos and boost penetration. The nanoplatforms with excellent loading capacity exhibited significant endocytosis compared with naked insulin. The mechanism of endocytosis was involved in clathrin- and lipid raft/caveolae-dependent endocytic pathways. The in vivo nasal delivery of insulin suggested that these nanoplatforms did not trigger nasal epithelial inflammation and greatly decreased blood sugar levels and improved insulin bioavailability. Collectively, this proof-of-concept study demonstrates a novel carrier of phenylboronic-acid-decorated polymer for insulin delivery and provides a promising approach for the development of a diabetes therapeutic strategy.
ABSTRACT
The Gram-negative opportunistic pathogen Pseudomonas aeruginosa is endowed with intrinsic resistance to antibiotics. It is essential to explore alternative techniques to supplement the arsenal of methods to kill drug-resistant bacteria. Herein, we established an "on-demand" nanoplatform based on acid-degradable scaffolds by conjugating glycomimetic-based galactose ligands to target a key lectin on P. aeruginosa and guanidine moieties. This nanoplatform could capture bacteria through ligand-receptor interactions and electrostatic interactions, and subsequently reactive oxygen species produced by entrapped photodynamic agent Ce6 under light irradiation eliminated drug-resistant P. aeruginosa and its biofilm. Approximately 95% of the planktonic bacteria were killed and more than 70% of the biofilm was disrupted under light irradiation. This strategy of copolymer modification could improve the biocompatibility and therapeutic efficiency levels of antibacterial therapeutics through the targeting of function. Hence, utilizing this smart nanoplatform may be of significance in developing new strategies to solve the growing problem of bacterial resistance.
Subject(s)
Pharmaceutical Preparations , Photochemotherapy , Anti-Bacterial Agents/pharmacology , Biofilms , Pseudomonas aeruginosaABSTRACT
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.