Inhibitors of Cyclophilin A: Current and Anticipated Pharmaceutical Agents for Inflammatory Diseases and Cancers.

Cyclophilin A, a widely prevalent cellular protein, exhibits peptidyl-prolyl cis-trans isomerase activity. This protein is predominantly located in the cytosol; additionally, it can be secreted by the cells in response to inflammatory stimuli. Cyclophilin A has been identified to be a key player in many of the biological events and is therefore involved in several diseases, including vascular and inflammatory diseases, immune disorders, aging, and cancers. It represents an attractive target for therapeutic intervention with small molecule inhibitors such as cyclosporin A. Recently, a number of novel inhibitors of cyclophilin A have emerged. However, it remains elusive whether and how many cyclophilin A inhibitors function in the inflammatory diseases and cancers. In this review, we discuss current available data about cyclophilin A inhibitors, including cyclosporin A and its derivatives, quinoxaline derivatives, and peptide analogues, and outline the most recent advances in clinical trials of these agents. Inhibitors of cyclophilin A are poised to enhance our comprehension of the molecular mechanisms that underpin inflammatory diseases and cancers associated with cyclophilin A. This advancement will aid in the development of innovative pharmaceutical treatments in the future.

Vibrio vulnificus necrotizing fasciitis with sepsis presenting with pain in the lower legs in winter: a case report.

BACKGROUND: Vibrio vulnificus infections develop rapidly and are associated with a high mortality rate. The rates of diagnosis and treatment are directly associated with mortality. CASE PRESENTATION: We describe an unusual case of a 61-year-old male patient with chronic liver disease and diabetes who presented with a chief complaint of pain in both lower legs due to V. vulnificus infection in winter. Within 12 h of arrival, typical skin lesions appeared, and the patient rapidly developed primary sepsis. Despite prompt appropriate antibiotic and surgical treatment, the patient died 16 days after admission. CONCLUSION: Our case findings suggest that V. vulnificus infection should be suspected in patients with an unclear infection status experiencing pain of unknown origin in the lower legs, particularly in patients with liver disease or diabetes, immunocompromised status, and alcoholism.

An enzymatic reaction mediated glucose sensor activated by MnO2 nanosheets acting as an oxidant and catalyst.

A self-regulated smart system would be highly desirable for analyte detection, in which a specific environment for detection could be self-modulated and the required reagents could also be in situ generated without further addition. Here, we have designed an intelligent glucose detection system composed of glucose, glucose oxidase (GOx), MnO2 and 3,3',5,5'-tetramethylbenzidine (TMB), based on the enzymatic oxidation of glucose and dual roles of synthesized MnO2 nanosheets acting as both an oxidant and catalyst. Upon the addition of glucose/GOx, the MnO2 nanosheets partially decompose due to H2O2in situ generated via glucose oxidation. Following the addition of TMB, a typical color reaction occurs under slightly acidic conditions, thereby enabling the colorimetric determination of glucose. For this system, the specific conditions and the required reagents for glucose detection can be self-modulated and self-generated via the enzymatic oxidation of glucose to gluconic acid and H2O2, performing smart self-regulated functions. This is an outstanding advantage of our designed glucose sensing system. Moreover, the present sensing system responds to glucose quickly and sensitively with a detection limit of 100 nM, and is stable and specific toward glucose detection.

Quenching cooperative transitions by destroying Yb3+-clusters.

In our previous study, we have reported the cooperative luminescence of Yb3+-trimers and cooperatively sensitized Gd3+ luminescence by Yb3+-tetramers in a doped CaF2 host. In this study, we experimentally observed an unusual luminescent phenomenon of Gd3+ in CaF2:Yb3+/Gd3+. Upon excitation with a 980 nm laser, the upconversion luminescence of Gd3+ first increases and then decreases in the Gd3+ concentration range of 0-0.9 mol%; this is different from the monotonic increase of Gd3+ luminescence observed in the downconversion spectra via the direct excitation of Gd3+. This special luminescent behavior was indicated to be related to the energy transfer from the Yb3+-tetramers to Gd3+ and the destruction of Yb3+-clusters. Herein, we proposed a new luminescence quenching mechanism, Yb3+-cluster destructive quenching, which was verified by fluorescence dynamic analysis and an optically inactive rare-earth ion-doping experiment.

Brightness calibrates particle size in single particle fluorescence imaging.

This Letter provides a novel approach to quantify the particle sizes of highly bright semiconductor polymer dots (Pdots) for single-particle imaging and photobleaching studies. A quadratic dependence of single-particle brightness on particle size was determined by single-particle fluorescence imaging and intensity statistics. In terms of the same imaging conditions, the particle diameter can be quantified by comparing the individual brightness intensity with associated calibration curve. Based on this sizing method, photobleaching trajectories and overall photon counts emitted by single particles were analyzed. It is found that photobleaching rate constants of different sized Pdots are not strongly dependent on particle diameter except the sparsely occurring fluorescence blinking in certain dim particles and the rapid photobleaching component in some bright particles. The overall photon counts increase with increasing particle diameter. However, those larger than 30 nm deviate away from the increasing tendency. These results reveal the significance of selecting appropriate Pdots (≤30 nm) for single-particle imaging and tracking applications.

Luminescent CePO4:Tb colloids for H2O2 and glucose sensing.

Hydrogen peroxide (H2O2) is an essential molecule in intracellular signaling transduction and normal cell functions. It is critical to be able to detect H2O2 quantitatively in cellular processes for getting useful physiological information. Herein, we developed a novel fluorescent probe for H2O2 sensing, CePO4:Tb colloidal solution. Upon addition of H2O2, the luminescence of the colloidal CePO4:Tb solution responds linearly in a wide H2O2 concentration range of 0-200 µM, allowing for quantitative detection of H2O2. The H2O2 sensing by this method exhibits a rapid response within several minutes, a detection limit of 1.03 µM H2O2, and a relative standard deviation lower than 3.1%. This sensing material for H2O2 is also suitable for the detection of glucose since H2O2 is generated via the catalytic oxidation of glucose by oxidase enzymes. In addition to a wide linear response, a low detection limit and a high reproducibility, our present method for glucose sensing shows a highly specific response to glucose in a mixed carbohydrate solution due to the specificity of glucose oxidase to glucose. This lanthanide-based fluorescent sensing material might have potential for detecting H2O2 and glucose in biological applications.

Improved ultraviolet upconversion emissions of Ho3+ in hexagonal NaYF4 microcrystals under 980 nm excitation.

Under 980 nm excitation, enhanced ultraviolet (UV) upconversion (UC) emissions at 242.4 nm, 276.1 nm, 289.7 nm, 296.4 nm, 303.6 nm, 357.7 nm and 387.8 nm of Ho3+ ions were observed in beta-NaYF4:20%Yb3+, 1.5%Ho3+ microcrystals (MC) which were synthesized through a hydrothermal method. The results indicated that these UV emissions came from five- and four-photon UC processes. Dynamical analysis on Ho3+ excited states suggests that, for excited Ho3+ ions, the higher the energy level is, the shorter the lifetime is.

Near-infrared photocatalysis of ß-NaYF4:Yb3+,Tm3+@ZnO composites.

A novel near-infrared (NIR)-responsive photocatalyst, ß-NaYF4:Yb(3+),Tm(3+)@ZnO composites, was prepared by a two-step high temperature thermolysis method. In the NIR-responsive photocatalysis, ß-NaYF4:Yb,Tm served as a NIR-to-UV upconverter and provided "UV light" or "necessary energy" to the ZnO catalyst. The energy transfer in the composites and the mixtures of ß-NaYF4:Yb,Tm and ZnO was studied by using steady-state and dynamic fluorescence spectroscopy. The NIR photocatalytic activities were investigated by the decomposition of Rhodamine B. It was found that the energy transfer processes dominated the overall photocatalytic activities, and the generation of hydroxyl radicals was the origin of organic pollutant decomposition under NIR irradiation.

Improved 800 nm emission of Tm³âº sensitized by Yb³âº and Ho³âº in ß-NaYF4 nanocrystals under 980 nm excitation.

In vitro and in vivo bioimaging, Yb/Tm doped fluoride nanocrystals (NCs) as nanoprobes have attracted much attention due to their near infrared (NIR) upconversion (UC) emission at 800 nm under NIR 980 nm excitation. Our paper presents a simple and general method which can further improve the intensity of NIR 800 nm emission of Tm³âº through adding Ho³âº as the second sensitizer of Tm³âº in Yb/Tm doped NaYF4 nanorods. The intensity of the NIR 800 nm emission is demonstrated to increase by up to 3 times along with the adding of Ho³âº. Experimental data illustrates that the sensitizations of Tm³âº by both Yb³âº and Ho³âº provide a more efficient energy transfer (ET) route for intense 800 nm emission than that by Yb³âº alone.

High Color-Purity Red, Green, and Blue-Emissive Core-Shell Upconversion Nanoparticles Using Ternary Near-Infrared Quadrature Excitations.

Development of multicolor-emitting upconversion nanoparticles (UCNPs) is of significant importance for applications in optical encoding, anti-counterfeiting, display, and bioimaging. However, realizing the orthogonal three-primary color (TPC) upconversion luminescence in a single nanoparticle remains a huge challenge. Herein, we have rationally designed core-multishell-structured NaYF4 UCNPs through regulating the dopant concentration, composition of luminescent layers, and shell position and thickness, which are capable of emitting red, green, and blue luminescence with high color purity in response to ternary near-infrared quadrature excitations (1560/808/980 nm). Moreover, their high color purity is well retained with varying excitation power densities. This orthogonal TPC emissions property of such UCNPs endows them with great promise in the field of security. As a proof-of-concept, we have demonstrated the feasibility of combining such UCNPs with MnO2 nanosheets for information encryption and decryption. This work not only offers a new way to achieve TPC upconversion luminescence at a single nanoparticle level but also broadens the scope of application for security protection.

Fluorescent sensing of colloidal CePO4:Tb nanorods for rapid, ultrasensitive and selective detection of vitamin C.

Vitamin C is an essential biological molecule for living organisms. The detection of vitamin C is always required due to its wide use in chemical, biological and pharmaceutical engineering. Here, we established a novel sensing system for rapid, ultrasensitive and highly selective detection of vitamin C based on a 'turn-on' fluorescent method. The turn-on fluorescent sensing system was built up of a colloidal CePO(4):Tb nanocrystalline solution with its fluorescence quenched by KMnO(4). The addition of vitamin C leads to a linear increase of fluorescence. The sensing principle of nanocrystalline CePO(4):Tb is based on a redox reaction via simply modulating the surface chemistry of nanocrystals. Our present sensing system for vitamin C exhibits a rapid response rate of less than 2 min, and highly selective and ultrasensitive detection with a detection limit of 108 nM, which is two orders of magnitude lower than that acquired by previously reported methods. The repeated reversibility of fluorescence quenching/recovery with time revealed a high reproducibility and long-term stability of our sensing materials. Furthermore, our developed sensing material overcomes the disadvantages such as complex surface modification/immobilization and serious biotoxicity compared to quantum-dot-based fluorescent sensing systems.

An efficient and biocompatible fluorescence resonance energy transfer system based on lanthanide-doped nanoparticles.

This work demonstrates an efficient and bio-friendly fluorescence resonance energy transfer (FRET) system based on lanthanide-doped inorganic nanoparticles. A facile aqueous route was used to synthesize the CePO(4):Tb nanorods with homogeneous colloidal dispersion, which emits a bright green light with a high quantum yield (∼0.36) and a long fluorescence lifetime (∼3.50 ms) upon UV excitation. Upon treatment of CePO(4):Tb with aqueous Rhodamine B (RhB), an efficient FRET occurs from the Tb(3+) to the RhB molecules, giving rise to well resolved and ratiometric emissions of donors and acceptors, respectively, with an energy transfer efficiency of up to 0.85. When incubated with HeLa cells at 37 °C, the CePO(4):Tb treated with RhB shows bright intracellular luminescence, indicating that it can be successfully internalized inside the cells and the FRET remains in the living cells. Moreover, the cytotoxic measurements demonstrate good biocompatibility and low cytotoxicity of our present FRET system. The advantages presented above including high quantum yield of donors, high energy transfer efficiency, ratiometric fluorescent emission and good biocompatibility, indicate the high potential of the CePO(4):Tb/RhB FRET system for monitoring biological events.

Nanocrystalline CePO(4):Tb as a novel oxygen sensing material on the basis of its redox responsive reversible luminescence.

This work reports for the first time on a new finding of luminescent CePO(4):Tb nanocrystals providing a novel oxygen sensing material on the basis of the redox responsive reversible luminescence in an oxidizing/reducing atmosphere. The origin of the luminescence quenching/recovery of nanocrystalline CePO(4):Tb was clearly demonstrated, from the surface chemistry of nanocrystals and the fluorescence decay dynamics of Tb(III). Our present work represents a preliminary demonstration of the feasibility of using nanocrystalline CePO(4):Tb as a novel oxygen sensing material since it yields several advantages including surfactant-free synthesis, dual detection functioning, rapid response, high sensitivity and good reproducibility.

Retraction of "UBE2C, Directly Targeted by miR-548e-5p, Increases the Cellular Growth and Invasive Abilities of Cancer Cells Interacting with the EMT Marker Protein Zinc Finger E-box Binding Homeobox 1/2 in NSCLC".

[This retracts the article DOI: 10.7150/thno.32738.].

Corrigendum to "UBE2C Induces Cisplatin Resistance via ZEB1/2-Dependent Upregulation of ABCG2 and ERCC1 in NSCLC Cells".

[This corrects the article DOI: 10.1155/2019/8607859.].

Correction to: m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis.

An amendment to this paper has been published and can be accessed via the original article.

[Study on concentration quenching and energy transfer in Ln3+ (Ln = Tb, Tm, Eu) in Y2O3 nanocrystal powders].

Nano-powders Y2O3 with various particle sizes and different doping concentrations of Ln (Ln = Tb, Tm, Eu) were prepared by using a combustion technique. The bulky powders doped with concentrations corresponding to nano-powders were obtained by annealing the nano-powders at high temperature. The emission spectra, XRD spectra and TEM were used in the present study. The concentration quenching of luminescent centers and energy transfer between luminescent centers in Y2O3 : Ln nanocrystal powders were investigated. It was found that the behaviors of luminescence concentration quenching for 5D4 --> 7F5 : Tb3+ and 5D0 --> 7F2 : Eu3+ in nano-powders are similar to that in bulky powders. On the contrary, the quenching concentrations for 5D3 --> 7F5 : Tb3+ and 1D2 --> 3H4 : Tm3+ are distinctly higher than that in bulk powders. This owes to the size confinement effect: the interface of nanocrystal particles can stop a portion of the energy transfer, which happens in the bulk ones, between luminescent centers. The size confinement effect can bring different influences to the different types of energy transfer. For instance, it will restrain the energy transfer (governed by electric dipole-dipole interaction) between the ions in long distances, and will hardly affect the energy transfer (governed by exchange interaction) between the ions locating at near intervals.

A MnO2-[Ru(dpp)3]Cl2 system for colorimetric and fluorimetric dual-readout detection of H2O2.

Two-dimensional (2D) MnO2 nanosheets were synthesized by a template-free and one-step route, and the dye [Ru(dpp)3]Cl2 was linked onto the MnO2 nanosheet surface via electrostatic interaction. The formed MnO2-[Ru(dpp)3]Cl2 hybrid was used for a dual optical detection for H2O2, an important reactive oxygen species (ROS). Upon addition of H2O2, the reaction of MnO2 with H2O2 results in the dissolution of MnO2 nanosheets and simultaneous generation of O2. The fading of the solution and simultaneous fluorescence change of [Ru(dpp)3]Cl2, sensitive to O2, enables colorimetric and fluorimetric dual-mode detection of H2O2. The dual-output assay in a single probe provides a good sensitivity with a detection limit of 0.18 µM H2O2. The dual-signal strategy can efficiently overcome the shortcoming of the single detection mode, and improve the detection accuracy by an additional correction of output signals from each other. Moreover, the successful determination of H2O2 in the serum samples demonstrates the potential applicability of the MnO2-[Ru(dpp)3]Cl2 based probe in biosensing and bioanalysis.

UBE2C, Directly Targeted by miR-548e-5p, Increases the Cellular Growth and Invasive Abilities of Cancer Cells Interacting with the EMT Marker Protein Zinc Finger E-box Binding Homeobox 1/2 in NSCLC.

Background: Recent evidence indicates that UBE2C participates in carcinogenesis by regulating the cell cycle, apoptosis, metastasis, and transcriptional processes. Additionally, miR-548e-5p dysregulation plays a vital role in tumor progression. However, the molecular mechanism via which UBE2C is directly targeted by miR-548-5p, resulting in increase in cellular growth and invasiveness of cancer cells, and its interactions with the epithelial-mesenchymal transition (EMT) marker protein ZEB1/2 in non-small cell lung cancer (NSCLC) is not understood. Methods: Expression of UBE2C and miR-548e-5p was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The protein level of UBE2C and ZEB1/2 was analyzed using western blotting and immunofluorescence staining. Cellular proliferation was detected using the cell counting kit 8 (CCK8) and 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell migration, invasion, and growth were analyzed using the wound healing and transwell assay. Promoter activity and transcription was analyzed using the luciferase reporter assay. Chromatin immunoprecipitation was used to detect binding of UBE2C to 5'UTR-ZEB1/2. Results: We observed that 4,5-ubiquitin-conjugating enzyme E2C (UBE2C) expression was higher in NSCLC tissue than in the adjacent normal tissue and was associated with increased cell proliferation and invasion. UBE2C enhanced NSCLC progression and metastasis by affecting the cell cycle and inhibiting apoptosis. We also observed that miR-548e-5p was significantly downregulated in lung cancer tissue specimens, which decreased the expression of its direct substrate, UBE2C. Moreover, miR-548e-5p overexpression and UBE2C under-expression significantly suppressed lung cancer cell proliferation, migration, and invasion. Luciferase reporter and chromatin immunoprecipitation assays indicated that miR-548e-5p directly binds to the 3'-UTR of UBE2C and decreases UBE2C mRNA expression. Furthermore, UBE2C knockdown downregulated the mesenchymal marker vimentin and upregulated the epithelial marker E-cadherin. Bioinformatics assays, coupled with western blotting and luciferase assays, revealed that UBE2C directly binds to the 5'-untranslated region (UTR) of the transcript of the E-cadherin repressor ZEB1/2 and promotes EMT in lung cancer cells. Conclusion: miR-548e-5p directly binds to the 3'-UTR of UBE2C and decreases UBE2C mRNA expression. UBE2C is an oncogene that promotes EMT in lung cancer cells by directly targeting the 5'-UTR of the transcript encoding the E-cadherin repressor ZEB1/2. miR-548e-5p, UBE2C, and ZEB1/2 constitute the miR-548e-5p-UBE2C-ZEB1/2 signal axis, which enhances cancer cell invasiveness by directly interacting with e EMT marker proteins. We believe that the miR-548e-5p-UBE2C-ZEB1/2 signal axis may be a suitable diagnostic marker and a potential target for lung cancer therapy.

UBE2C Induces Cisplatin Resistance via ZEB1/2-Dependent Upregulation of ABCG2 and ERCC1 in NSCLC Cells.

OBJECTIVES: Cisplatin (DDP) is one of the most commonly used chemotherapeutic drugs for several cancers, including non-small-cell lung cancer (NSCLC). However, resistance to DDP eventually develops, limiting its further application. New therapy targets are urgently needed to reverse DDP resistance. METHODS: The mRNA expression of UBE2C, ZEB1/2, ABCG2, and ERCC1 was analyzed by reverse transcription-polymerase chain reaction. The protein levels of these molecules were analyzed by Western blotting and immunofluorescent staining. Cell proliferation was detected by CCK8 and MTT assays. Cell migration and invasion were analyzed by wound healing assay and Transwell assays. Promoter activities and gene transcription were analyzed by luciferase reporter assay. RESULTS: In this study, we examined the effect of UBE2C and ZEB1/2 expression levels in DDP-resistant cells of NSCLC. We confirmed that aberrant expression of UBE2C and ZEB1/2 plays a critical role in repressing the DDP sensitivity to NSCLC cells. Additionally, knockdown of UBE2C significantly sensitized resistant cells to DDP by repressing the expression of ZEB1/2. Mechanistic investigations indicated that UBE2C transcriptionally regulated ZEB1/2 by accelerating promoter activity. This study revealed that ZEB1/2 promotes the epithelial mesenchymal transition and expression of ABCG2 and ERCC1 to participate in UBE2C-mediated NSCLC DDP-resistant cell progression, metastasis, and invasion. CONCLUSION: UBE2C may be a novel therapy target for NSCLC for sensitizing cells to the chemotherapeutic agent DDP.