Common CO2-based polycarbonates are known to be highly hydrophobic, and this “inert” property makes them difficult for the covalent immobilization of bioactive molecules. A practical method for ...modifying polymers is to introduce various functional groups that permit decoration of polymer chains with bioactive substances. In this report, CO2-based poly(2-vinyloxirane carbonate) (PVIC) with more than 99% carbonate linkages is isolated from the CO2/2-vinyloxirane alternating copolymerization catalyzed by the bifunctional catalyst (1R,2R)-SalenCo(III)(DNP)2 (1) (DNP = 2,4-dinitrophenolate) bearing a quaternary ammonium salt on the ligand framework. It was also observed that the presence of propylene oxide significantly activates 2-vinyloxirane for incorporation into the polymer chain as well as inhibits the formation of cyclic carbonate in the terpolymerization process. DSC studies demonstrate that the glass transition temperature (T g) decreases with the increase in the content of vinyl groups in the polycarbonate. By way of thiol–ene coupling, showing mainly “click” characteristics and nearly quantitative yields, amphiphilic polycarbonates (PVIC-OH and PVIC-COOH) with multiple hydroxy or carboxy functionalities have been prepared, providing suitable reactivities for further modifications (ring-opening of l-aspartic acid anhydride hydrochloride salt and deprotonation by aqueous ammonium hydroxide (NH4OH(aq))) to successfully isolate the water-soluble CO2-based polycarbonate PVIC-COONH4, and the PVIC-OH-Asp polymer which shows particles dispersed in water with an average hydrodynamic diameter D n = 32.2 ± 8.8 nm. It is presumed that this emerging class of amphiphilic/water-soluble polycarbonates could embody a powerful platform for bioconjugation and drug conjugation. In contrast to lower T gs of PVIC, (PVIC-co-PC), PVIC-OH, and PVIC-COOH, the polycarbonates PVIC-OH-Asp and PVIC-COONH4 show higher T gs as a consequence of their intrinsic ionic property (ammonium salts).
Abstract Chloroquine (CQ) and hydroxychloroquine (HCQ), two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ ...on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro . The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24) in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24) compared to immortalized uroepithelial cells (SV-Huc-1) or other reference cancer cell lines (PC3 and MCF-7). We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose) polymerase (PARP), caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer.
To investigate synergistic effect between geometric and electronic structures on directing CO2RR selectivity, water phase synthetic protocol and surface architecture engineering strategy are ...developed to construct monodispersed Bi‐doped Cu‐based nanocatalysts. The strongly correlated catalytic directionality and Bi3+ dopant can be rationalized by the regulation of *COOH/*CO adsorption capacities through the appropriate doping of Bi3+ electronic modulator, resulting in volcano relationship between FECO/TOFCO and surface EVBM values. Spectroscopic study reveals that the dual‐site binding mode (Cu─μ─C(═O)O─Bi3+) enabled by Cu1Bi3+2 motif in single‐phase Cu150Bi1 nanocatalyst drives CO2‐to‐CO conversion. In contrast, the study of dynamic Bi speciation and phase transformation in dual‐phase Cu50Bi1 nanocatalyst unveils that the Bi0‐Bi0 contribution emerges at the expense of BOC phase, suggesting metallic Bi0 phase acting as H˙ formation center switches CO2RR selectivity toward CO2‐to‐HCOO− conversion via *OCHO and *OCHOK intermediates. This work provides significant insight into how geometric architecture cooperates with electronic effect and catalytic motif/phase to guide the selectivity of electrocatalytic CO2 reduction through the distinct surface‐bound intermediates and presents molecular‐level understanding of catalytic mechanism for CO/HCOO− formation.
This work provides significant insight into how geometric architecture (single‐phase vs dual‐phase) cooperates with electronic effect (surface d‐band center modulation by Bi3+ dopant) and catalytic motif/phase (Cu1Bi3+2 vs Bi0) to guide the selectivity of CO2 electro‐reduction through the distinct surface‐bound intermediates (CO2˙ˉ vs H˙) for CO/HCOO− formation.
(S)-3,4-Dihydroxybutyric acid ((S)-3,4-DHBA), an endogenous straight chain fatty acid, is a normal human urinary metabolite and can be obtained as a valuable chiral biomass for synthesizing ...statin-class drugs. Hence, its epoxide derivatives should serve as promising monomers for producing biocompatible polymers via alternating copolymerization with carbon dioxide. In this report, we demonstrate the production of poly(tert-butyl 3,4-dihydroxybutanoate carbonate) from racemic-tert-butyl 3,4-epoxybutanoate (rac- t Bu 3,4-EB) and CO2 using bifunctional cobalt(III) salen catalysts. The copolymer exhibited greater than 99% carbonate linkages, 100% head-to-tail regioselectivity, and a glass-transition temperature (T g) of 37 °C. By way of comparison, the similarly derived polycarbonate from the sterically less congested monomer, methyl 3,4-epoxybutanoate, displayed 91.8% head-to-tail content and a lower T g of 18 °C. The tert-butyl protecting group of the pendant carboxylate group was removed using trifluoroacetic acid to afford poly(3,4-dihydroxybutyric acid carbonate). Depolymerization of poly(tert-butyl 3,4-dihydroxybutanoate carbonate) in the presence of strong base results in a stepwise unzipping of the polymer chain to yield the corresponding cyclic carbonate. Furthermore, the full degradation of the acetyl-capped poly(potassium 3,4-dihydroxybutyrate carbonate) resulted in formation of the biomasses, β-hydroxy-γ-butyrolacetone and 3,4-dihydroxybutyrate, in water (pH = 8) at 37 °C. In addition, water-soluble platinum–polymer conjugates were synthesized with platinum loading of 21.3–29.5%, suggesting poly(3,4-dihydroxybutyric acid carbonate) and related derivatives may serve as platinum drug delivery carriers.
A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer‐associated immunosuppression in BC ...remains undetermined. In this study, we observed a negative correlation between the autophagy‐related markers LC3‐II and programmed death ligand‐1 (PD‐L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf‐A1) increased PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signal‐transduction pathway. Moreover, the treatment of BC cells with CQ and Baf‐A1 inhibited hsa‐microRNA‐34a (miR‐34a) expression and miR‐34a overexpression in BC cells prevented the autophagy blockade–induced PD‐L1 expression; a negative correlation between miR‐34a and PD‐L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR‐34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer‐associated immunosuppression through PD‐L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD‐L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.
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Our model illustrates the pharmacological inhibition of autophagy could induce PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signaling transduction pathway and miR‐34a downregulation, revealing the effect of genetic and epigenetic regulation of autophagy on PD‐L1. In consequence, BC cells expressing PD‐L1 suppress NK cell cytotoxic activity.
Bismuth quadruple therapy is recommended as a first-line treatment for Helicobacter pylori infection in the United States but hybrid therapy is an alternative option. Reverse hybrid therapy (proton ...pump inhibitor plus amoxicillin for 14 days, and clarithromycin plus metronidazole for the initial 7 days) is a simplified hybrid treatment. We aimed to assess the efficacies of reverse hybrid therapy vs bismuth quadruple therapy as first-line treatments for patients with H pylori infection in a randomized trial.
In a prospective study, patients with H pylori infection were randomly assigned to groups that received either reverse hybrid therapy (n = 176) or a bismuth quadruple therapy (pantoprazole, bismuth, tetracycline, and metronidazole for 14 days; n = 176). Patients were examined the end of therapy for adverse events. The study was performed from August 2015 through February 2017. The primary outcome was cure of H pylori infection, determined based on a negative result from the urea breath test, or negative results from histologic analysis, the urease test, and bacterial culture analyses.
H pylori infection was eradicated from 96.6% of patients who received reverse hybrid therapy and 96.0% who received bismuth quadruple therapy-this difference was not significant in the intention-to-treat analysis (95% CI, 8.0% ∼ 2.2%; P = .281). There were no significant differences between therapies eradication of clarithromycin-resistant strains (88.2% with reverse hybrid therapy vs 92.3% with bismuth quadruple therapy) or metronidazole-resistant strains (100% vs 96.9%). However, reverse hybrid therapy was associated with fewer adverse events (18.7% of patients) than bismuth quadruple therapy (47.7%) (P < .001).
In a randomized trial, we found 14-day reverse hybrid therapy to not be inferior to bismuth quadruple therapy as a first-line treatment for H pylori infection. Reverse hybrid therapy was associated with fewer adverse events. ClincialTrials.gov no: NCT02547038.
Bladder cancer (BC) is the second most common urologic malignancy and the ninth most common malignancy worldwide. Surgical resection is the mainstay of treatment for patients with early-stage ...disease, whereas therapeutic options are limited for patients with advanced-stage or residual BC. Programmed cell death ligand-1 (PD-L1) is an important target for immunotherapy. It is known that PD-L1 is overexpressed in BC; a clinical trial involving PD-L1 immune checkpoint inhibitors in advanced BC is ongoing. In the present study, we used Western blot and quantitative real-time PCR (qPCR) to define the expression level of PD-L1 after cisplatin treatment in BC-derived cell lines. The signal activation was also evaluated by Western blot in BC-derived cell lines. We found that chemotherapeutic drug cisplatin can induce PD-L1 but not PD-L2 expression in BC-derived cell lines. Furthermore, the expression level of PD-L1 was increased in a dose- and time-dependent manner after cisplatin treatment. The cisplatin-induced PD-L1 expression is mainly mediated by ERK1/2 but not Akt/mTOR signal pathway. Moreover, we found that cisplatin activates transcription factor activator protein-1 (AP-1) to regulate PD-L1 expression. The chemotherapy drug such as cisplatin may trigger resistance of BC through PD-L1 up-regulation. The present study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic BC.
Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective ...proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells.
After miconazole treatment, the p62-KEAP1-NRF2 activation was analyzed by qPCR and Western blot. The nuclear translocation indicating NRF2 activation was further confirmed by immunofluorescence. Finally, the ROS production was detected by CM-H2DCFDA staining.
We demonstrate in this study that miconazole dramatically increases NRF2 activation in bladder cancer cells, in a dose- and time-dependent manner. Interestingly, levels of expression of p62, a noncanonical pathway that mediates NRF2 activation, appeared to increase in accordance with NRF2. We also investigated levels of the negative regulator kelch-like ECH-associated protein 1 (KEAP1), which is involved in NRF2 activation. As expected, a decrease in KEAP1 expression was found after miconazole exposure. Confirmation of NRF2 nuclear translocation was monitored by immunofluorescence. Miconazole-induced generation of reactive oxygen species (ROS) promoted NRF2 activation. Pretreatment of bladder cancer cells with ROS scavengers abolished NRF2 expression and nuclear translocation, indicating that miconazole activates the noncanonical p62-KEAP1-NRF2 pathway, which is regulated by ROS production.
Our study elucidates the mechanisms through which miconazole stimulates NRF2 which may contribute to cancer chemopreventive effects.
Bladder cancer (BC) is the second most common urological tumour in Western countries. Approximately, 80% of patients with BC will present with non-muscle invasive bladder cancer (NMIBC), whereas a ...quarter will have muscle invasive disease (MIBC) at the time of BC diagnosis. However, patients with NMIBC are at risk of BC recurrence or progression into MIBC, and an MIBC prognosis is determined by the presence of progression and metastasis. Matrix metalloproteinase 2 (MMP2), a type of matrix metalloproteinase (MMP), plays a major role in tumour invasion and is well-characterized in BC prognosis. In BC, the mechanisms regulating MMP2 expression, and, in turn, promote cancer invasion, have hardly been explored. Thrombospondin-4 (THBS4/TSP4) is a matricellular glycoprotein that regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion and extracellular matrix modelling. Based on the results of a meta-analysis in the Gene Expression Profiling Interactive Analysis 2 database, we observed that TSP4 expression levels were consistent with overall survival (OS) rate and BC progression, with the highest expression levels observed in the advanced stages of BC and associated with poor OS rate. In our pilot experiments, incubation with recombinant TSP4 promoted the migration and invasion in BC cells. Furthermore, MMP2 expression levels increased after recombinant TSP4 incubation. TSP4-induced-MMP2 expression and cell motility were regulated via the AKT signalling pathway. Our findings facilitate further investigation into TSP4 silencing-based therapeutic strategies for BC.
Search engine optimization (SEO) has been considered one of the most important techniques in internet marketing. This study establishes a decision model of search engine ranking for administrators to ...improve the performances of websites that satisfy users’ needs. To probe into the interrelationship and influential weights among criteria of SEO and evaluate the gaps of performance to achieve the aspiration level in real world, this research utilizes hybrid modified multiple criteria decision-making models, including decision-making trial and evaluation laboratory (DEMATEL), DEMATEL-based analytic network process (called DANP), and VlseKriterijumska Optimizacija I Kompromisno Resenje (VIKOR). The empirical findings discover that the criteria of SEO possessed a self-effect relationship based on DEMATEL technique. According to the influential network relation map (INRM), external website optimization is the top priority dimension that needs to be improved when implementing SEO. Among the six criteria for evaluation, meta tags is the most significant criterion influencing search engine ranking, followed by keywords and website design. The evaluation of search engine ranking reveals that the website with lowest gap would be the optimal example for administrators of websites to make high ranking website during the time that this study is executed.
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