Development of high-efficiency superparamagnetic drug delivery system with MPI imaging capability.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.

Berberine Alleviates Ischemic Brain Injury by Enhancing Autophagic Flux via Facilitation of TFEB Nuclear Translocation.

Berberine has been demonstrated to alleviate cerebral ischemia/reperfusion injury, but its neuroprotective mechanism has yet to be understood. Studies have indicated that ischemic neuronal damage was frequently driven by autophagic/lysosomal dysfunction, which could be restored by boosting transcription factor EB (TFEB) nuclear translocation. Therefore, this study investigated the pharmacological effects of berberine on TFEB-regulated autophagic/lysosomal signaling in neurons after cerebral stroke. A rat model of ischemic stroke and a neuronal ischemia model in HT22 cells were prepared using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD), respectively. Berberine was pre-administered at a dose of 100[Formula: see text]mg/kg/d for three days in rats and 90[Formula: see text][Formula: see text]M in HT22 neurons for 12[Formula: see text]h. 24[Formula: see text]h after MCAO and 2[Formula: see text]h after OGD, the penumbral tissues and OGD neurons were obtained to detect nuclear and cytoplasmic TFEB, and the key proteins in the autophagic/lysosomal pathway were examined using western blot and immunofluorescence, respectively. Meanwhile, neuron survival, infarct volume, and neurological deficits were assessed to evaluate the therapeutic efficacy. The results showed that berberine prominently facilitated TFEB nuclear translocation, as indicated by increased nuclear expression in penumbral neurons as well as in OGD HT22 cells. Consequently, both autophagic activity and lysosomal capacity were simultaneously augmented to alleviate the ischemic injury. However, berberine-conferred neuroprotection could be greatly counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Meanwhile, autophagy inhibitor 3-Methyladenine (3-MA) also slightly neutralized the pharmacological effect of berberine on ameliorating autophagic/lysosomal dysfunction. Our study suggests that berberine-induced neuroprotection against ischemic stroke is elicited by enhancing autophagic flux via facilitation of TFEB nuclear translocation in neurons.

A Fast and Reversible Responsive Bionic Transmembrane Nanochannel for Dynamic Single-Cell Quantification of Glutathione.

Biological channels can rapidly and continuously modulate ion transport behaviors in response to external stimuli, which play essential roles in manipulating physiological and pathological processes in cells. Here, to mimic the biological channels, a bionic nanochannel is developed by synergizing a cationic silicon-substituted rhodamine (SiRh) with a glass nanopipette for transmembrane single-cell quantification. Taking the fast and reversible nucleophilic addition reaction between glutathione (GSH) and SiRh, the bionic nanochannel shows a fast and reversible response to GSH, with its inner-surface charges changing between positive and negative charges, leading to a distinct and reversible switch in ionic current rectification (ICR). With the bionic nanochannel, spatiotemporal-resolved operation is performed to quantify endogenous GSH in a single cell, allowing for monitoring of intracellular GSH fluctuation in tumor cells upon photodynamic therapy and ferroptosis. Our results demonstrate that it is a feasible tool for in situ quantification of the endogenous GSH in single cells, which may be adapted to addressing other endogenous biomolecules in single cells by usage of other stimuli-responsive probes.

Organic Molecular Probe Enabled Ionic Current Rectification toward Subcellular Detection of Glutathione with High Selectivity, Sensitivity, and Recyclability.

Single-cell interrogation with the solid-state nanoprobes enables understanding of the linkage between cellular behavior and heterogeneity. Herein, inspired by the charge property of the organic molecular probe (OMP), a generic ionic current rectification (ICR) single-cell methodology is established, exemplified by subcellular detection of glutathione (GSH) with high selectivity, sensitivity, and recyclability. The as-developed nanosensor can transduce the subcellular OMP-GSH interaction via a sensitive ionic response, which stems from the superior specificity of OMP and its essential charge property. In addition, the nanosensor exhibits good reversibility, since the subsequent tandem reaction after the recognition can well recover the sensing surface. Given the diverse structures and tailorable charge properties of OMP, this work underpins a new and general method of OMP-based ICR single-cell analysis.

Photocontrolled Nanopipette Biosensor for ATP Gradient Electroanalysis of Single Living Cells.

Emerging nanopipette tools have demonstrated substantial potential for advanced single-cell analysis, which plays vital roles from fundamental cellular biology to biomedical diagnostics. Highly recyclable nanopipettes with easy and quick regeneration are of special interest for precise and multiple measurements. However, existing recycle strategies are generally plagued by operational complexity and limited efficiency. Light, acting in a noncontact way, should be the ideal external stimulus to address this issue. Herein, we present the photocontrolled nanopipette capable of probing cellular adenosine triphosphate (ATP) gradient at single-cell level with good sensitivity, selectivity, and reversibility, which stems from the use of ATP-specific azobenzene (Azo)-incorporated DNA aptamer strands (AIDAS) and thereby the sensible transduction of variable nanopore size by the ionic currents passing through the aperture. Photoisomerized conformational change of the AIDAS by alternative UV/vis light stimulation ensures its noninvasive regeneration and repeated detection. Inducement and inhibition of the cellular ATP could also be probed by this nanosensor.

LINC00511/miRNA-143-3p Modulates Apoptosis and Malignant Phenotype of Bladder Carcinoma Cells via PCMT1.

Bladder cancer has easy recurrence characteristics, but its occurrence and development mechanism are still unclear. Non-coding RNA is a kind of RNA that exists widely and cannot be translated into proteins, which has played a key role in the regulation of biological functions of tumor cells. However, the regulation mechanism of non-coding RNA on bladder tumors is not fully understood. By microarray analysis and database analysis, we found that LINC00511 was significantly highly expressed in bladder cancer. The expressions of LINC00511, miR-143-3p, and PCMT in bladder cancer tissues and cells were detected by quantitative reverse transcription-polymerase chain reaction. The relationship between the expressions of miR-143-3p and PCMT1 and the clinicopathological parameters of the tumor was analyzed. The proliferation and invasion of bladder cancer cells were detected by MTT assay and Transwell assay. The expression levels of E-cadherin and vimentin in bladder cancer cells were detected by Western blot. Cell apoptosis was detected by flow cytometry. In vivo, TCCSUP or SW780 cells were inoculated into BALB/c nude mice to detect tumor volume and weight. Bioinformatics and dual luciferase reporter gene were used to analyze the relationship between LINC00511 and miR-143-3p and its downstream target gene PCMT1. The results showed that LINC00511 could target miR-143-3p/PCMT1 to regulate the proliferation, migration, and apoptosis of bladder cancer TCCSUP or SW780 cells and promote the occurrence and development of bladder cancer.

Twin Nanopipettes for Real-Time Electrochemical Monitoring of Cytoplasmic Microviscosity at a Single-Cell Level.

Cytoplasmic microviscosity (CPMV) plays essential roles in governing the diffusion-mediated cellular processes and has been recognized as a reliable indicator of the cellular response of many diseases and malfunctions. Current CPMV studies are exclusively established by probe-assisted optical methods, which nevertheless necessitate the complicated synthesis and delivery of optical probes into cells and thus the issues of biocompatibility and bio-orthogonality. Using twin nanopipettes integrated with a patch-clamp system, a practical electrochemical single-cell measurement is presented, which is capable of real-time and long-term CPMV detection without cell disruption. Specifically, upon the operation of the twin nanopipettes, the cellular CPMV status, which is correlated to cytoplasmic ionic mobility, could be sensibly transduced via the ionic current passing through the nanosystem. The average CPMV value of HeLa cells was detected as ca. 86 cP. Notably, the correlation between chemotherapy and CPMV alterations makes this approach possible for the real-time and long-term assessment of the evolution of external stimuli, as exemplified by the two natural products taxol and colchicine. Integrated with the patch-clamp setup, this study features the first use of twin nanopipettes for electrochemical CPMV monitoring of single living cells, and it is expected to inspire more interest in the exploitation of dual- and multiple nanopipettes for advanced single-cell analysis.

Wuhan's experience in fighting against COVID-19:How to prevent COVID-19 infection among health care workers / 中国感染控制杂志

In the context of the coronavirus disease 2019 (COVID-19)pandemic,thousands of health care wor- kers (HCWs)worldwide infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),some even have lost their lives.At the early stage of the epidemic,some Chinese HCWs were infected.Owing to limited knowledge of characteristics of SARS-CoV-2,more than 3,000 HCWs in Hubei Province contracted SARS-CoV-2 at the early stage of the outbreak.Due to overloaded work of HCWs in local hospitals,more than 42,000 HCWs (including HCWs from the military)were dispatched to Hubei Province from all over the country.At the peak of epidemic,one in 10 intensive care HCWs in China were working in Wuhan.During fighting against COVID-19 in China,although a certain number of HCWs were infected with SARS-CoV-2 at the early stages of the epidemic, effective prevention was achieved through timely adoption of prevention measures,including fast diagnosis,timely isolation of patients,strengthening of HCWs'safety,intensified training on basic protective knowledge and unified management of HCWs,there was no report about infection among the 42,632 members of the national medical teams sent to Hubei,and the number of COVID-19 cases among HCWs in local hospitals also significantly de- creased,thereby indicating that healthcare-associated infection (HAI)of COVID-19 among HCWs are fully pre- ventable.This paper explores how to prevent HCWs from contracting SARS-CoV-2 through effective measures during the epidemic in Wuhan,China.

Role of p-ERK1/2 in Benign Prostatic Hyperplasia during Hyperinsulinemia.

PURPOSE: Using a rat model of hyperinsulinemia, the present study investigated the role of p-ERK1/2 in benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Forty male Sprague-Dawley rats were randomly selected and assigned to four groups: high fat diet (HFD)+BPH (n=10), HFD (n=10), BPH (n=10), and control (n=10) groups. Hyperinsulinemia was induced by HFD feeding, while BPH was induced using testosterone propionate. Plasma glucose, plasma insulin and bodyweight were examined weekly. Immunohistochemistry (IHC) and western blot analysis were used to analyze the expression of ERK1/2 and p-ERK1/2 in rat prostates. RESULTS: Plasma glucose and plasma insulin levels were significantly greater in the HFD+BPH and HFD groups, when compared to the other two groups (P<0.05). Prostate weights were significantly greater in the HFD+BPH, HFD and BPH groups, than in the control group (P<0.05). IHC and western blot analysis revealed that p-ERK1/2 expression was greater in the HFD+BPH group than in the other three groups (P<0.05). CONCLUSION: Androgens plus a hyperinsulinemic condition induced by HFD can result in prostatic cell hyperplasia, and this mechanism may be correlated to the upregulation of p-ERK1/2. Further investigations of this possibility are required.

Boosting the biocatalytic precipitation with enzyme-loaded liposomes: Toward a general platform for amplified photoelectrochemical immunoassay.

Liposome-assisted photoelectrochemical (PEC) bioanalysis represents one of the latest frontiers in the arena of PEC bioanalysis. This work reports a general enzyme-amplified liposomal PEC bioanalysis protocol via the use of enzyme-loaded liposomes to boost the biocatalytic precipitation (BCP) effect. In the representative system, the horseradish peroxidase (HRP)-loaded liposome (HRPLL) and the Au nanoclusters (NCs)/Au nanoparticles (NPs)/TiO2 nanotubes (NTs) framework (AATF) were used as liposomal label and photoelectrode, respectively. In the detection, the sandwich immunocomplex reaction was accomplished in a 96-well plate to confine the HRPLL label, which was then lysed to release the HRP molecules to initiate the BCP process. Due to the amplified formation of HRP-induced BCP on the AATF scaffold, the photo-current response correlated closely with the immunorecognition process and the analyte could be detected very sensitively. This work features the first integration of enzyme-loaded liposomes and the BCP for sensitive PEC bioanalysis, which to our knowledge has not been reported. With the use of various other enzymes, this work could serve as a general basis for the PEC bioanalysis of numerous other target of interest.

In situ chemical redox and functionalization of graphene oxide: toward new cathodic photoelectrochemical bioanalysis.

This report outlines the first exploration of graphene oxide (GO) itself as a light harvesting material with an innovative in situ chemical redox and functionalization (CRF) strategy for versatile and high-throughput cathodic photoelectrochemical (PEC) bioanalysis.

Three-Dimensional TiO2@Cu2O@Nickel Foam Electrodes: Design, Characterization, and Validation of O2-Independent Photocathodic Enzymatic Bioanalysis.

This work reports the innovative design and application of a three-dimensional (3D) TiO2@Cu2O@nickel foam electrode synergized with enzyme catalysis toward the proof-of-concept study for oxygen-independent photocathodic enzymatic detection. Specifically, a 3D-nanostructured photoelectrode has great potential in the semiconductor-based photoelectrochemical (PEC) biological analysis. On the other hand, using various photocathodes, cathodic PEC bioanalysis, especially the photocathodic enzymatic detection, represents an attractive frontier in the field. Different from state-of-the-art photocathodic enzymatic studies that are oxygen-dependent, herein, we present the ingenious design, characterization, and implementation of 3D TiO2@Cu2O@nickel foam photocathodes for the first oxygen-independent example. In such a configuration, the Cu2O acted as the visible-light absorber, while the TiO2 shell would simultaneously function as a protective layer for Cu2O and as a desirable substrate for the immobilization of enzyme biomolecules. Especially, because of the proper band positions, the as-designed photocathode exhibited unique O2-independent PEC property. Exemplified by glucose oxidases, the as-developed sensor exhibited positive response to glucose with good performance. Because various oxidases could be integrated with the system, this protocol could serve as a universal O2-independent platform for many other targets. This work is also anticipated to catalyze more studies in the advanced 3D photoelectrodes toward innovative enzymatic applications.

Nanoporous Semiconductor Electrode Captures the Quantum Dots: Toward Ultrasensitive Signal-On Liposomal Photoelectrochemical Immunoassay.

Liposomal photoelectrochemical (PEC) bioanalysis has recently emerged and exhibited great potential in sensitive biomolecular detection. Exploration of the facile and efficient route for advanced liposomal PEC bioanalysis is highly appealing. In this work, we report the split-type liposomal PEC immunoassay system consisting of sandwich immunorecognition, CdS quantum dots (QDs)-loaded liposomes (QDLL), and the release and subsequent capture of the QDs by a separated TiO2 nanotubes (NTs) electrode. The system elegantly operated upon the protein binding and lysis treatment of CdS QDLL labels within the 96-well plate, and then the CdS QDs-enabled sensitization of TiO2 NTs electrode. Exemplified by cardiac markers troponin I (cTnI) as target, the proposed system achieved efficient activation of TiO2 NTs electrode and thus the signal generation toward the split-type PEC immunoassay. This work features the first use of QDs for liposomal PEC bioanalysis and is expected to inspire more interests in the design and implementation of numerous QDs-involved liposomal PEC bioanalysis.

Unique Redox Reaction between CuO Photocathode and Cysteine: Insight into the Mechanism for Cathodic Photoelectrochemical Bioanalysis.

Previously reported copper oxide-based cathodic photoelectrochemical bioanalysis of cysteine had attributed the decrease of the photocurrents to the binding of cysteine onto the CuO surface. However, our latest investigation found that the previous explanation was not correct. This Letter presents the in-depth study of such phenomena and a new insight into the underlying mechanism. Specifically, the unique redox reaction between the CuO photocathode and cysteine produced [Cys-Cu(I)] and cystine, and the insoluble complex blocked the partial contact between the photoelectrode and the dissolved O2-containing electrolyte and reduced the effective working area of the photocathode, leading to the decrease of photocurrent.

Additive antitumor effect of arsenic trioxide combined with intravesical bacillus Calmette-Guerin immunotherapy against bladder cancer through blockade of the IER3/Nrf2 pathway.

BACKGROUND: As an inorganic compound used to treat various cancers and other diseases, arsenic trioxide (As2O3) has been reported to induce cellular apoptosis in certain kinds of cancers including bladder cancer. The aim of the present study was to elucidate the crucial cooperative role of As2O3 and intravesical bacillus Calmette-Guerin (BCG) immunotherapy and its ability to protect against bladder cancer by targeting the IER3/Nrf2 pathway. METHOD: Initially, an orthotopic bladder cancer model was established in mice by means of intravesical instillation of the human bladder cancer cell line 5637. The expression of IL-6/IL-8 in dendritic cells (DCs) and the proportion of CD4+ cells and ratio of CD4+/CD8+ T cells were subsequently determined. RT-qPCR and Western blot assay methods were employed to determine the expressions of IER3, Nrf2, NQO1, IL-6 and IL-8. Finally, tumor cell apoptosis and the volume and weight of the in vivo tumors were evaluated in an attempt to determine the contributory role of As2O3 in combination with BCG immunotherapy in treating bladder cancer. RESULTS: The additive effect of As2O3 and BCG was demonstrated to promote the expressions of IL-6/IL-8 among DCs. Additionally, the proportion of CD4+ cells, ratio of CD4+/CD8+ T cells and rate of tumor cell apoptosis were all elevated, while decreased in vivo tumor volume and weight were detected. Of importance, we determined the role that ad-shNrf2 (adenoviral vectors expressing shRNA against Nrf2) played in inhibiting the effects of As2O3 on bladder cancer. CONCLUSION: Taken together, the key findings of the present study provide evidence defining the effect of As2O3 on inducing the inhibitory effect of BCG on the development of bladder cancer via the IER3/Nrf2 pathway, highlighting the potential of As2O3 as a treatment option for bladder cancer through its enhancement of intravesical BCG.

Ferroelectric Perovskite Oxide@TiO2 Nanorod Heterostructures: Preparation, Characterization, and Application as a Platform for Photoelectrochemical Bioanalysis.

This work reports the first synthesis and characterization of a ferroelectric perovskite oxide-based heterostructure as well as its application for photoelectrochemical (PEC) bioanalytical purposes. Specifically, exemplified by [KNbO3]1- x[BaNi1/2Nb1/2O3-δ] x (KBNNO), the ferroelectric perovskite oxides were prepared by solid-state synthesis, while the TiO2 nanorod (NR) arrays were obtained via a hydrothermal method. Using the technique of pulsed laser deposition (PLD), KBNNO were then deposited on TiO2 NRs to form KBNNO@TiO2 NR heterostructures. Various characterization techniques were applied to reveal compositional and structural information on the as-fabricated sample, and favorable alignment existed between the two components as displayed by the PEC test. In the detection of l-cysteine, the as-fabricated KBNNO@TiO2 NRs demonstrated good performance in terms of sensitivity and selectivity. This work revealed the potential of ferroelectric perovskite oxide and its heterostructures for innovative PEC bioanalytical applications, and we hope it will generate more interest in the development of various ferroelectrics-based heterostructures for advanced PEC bioanalysis.

Hierarchical CuInS2-based heterostructure: Application for photocathodic bioanalysis of sarcosine.

In this study, on the basis of hierarchical CuInS2-based heterostructure, a novel cathodic photoelectrochemical (PEC) enzymatic bioanalysis of the sarcosine detection was reported. Specifically, heterostructured CuInS2/NiO/ITO photocathode was prepared and sarcosine oxidases (SOx) were integrated for the construction of the enzymatic biosensor. In the bioanalysis, the O2-dependent suppression of the cathodic photocurrent can be observed due to the competition between the as-fabricated O2-sensitive photocathode and the SOx-catalytic event toward O2 reduction. Based on the sarcosine-controlled O2 concentration, a novel photocathodic enzymatic biosensor could be realized for the sensitive and specific sarcosine detection. This work manifested the great potential of CuInS2-based heterostructure as a novel platform for future PEC bioanalytical development and also a PEC method for sarcosine detection, which could be easily extended to numerous other enzymatic systems and to our knowledge has not been reported. This work is expected to stimulate more interest in the design and implementation of numerous CuInS2-based heterostructured photocathodic enzymatic sensing.

Improving rational use of antimicrobial agents by infection prevention and control / 中国感染控制杂志

Objective To evaluate the efficacy of infection prevention and control measures on the management of rational use of antimicrobial agents.Methods Patients who were admitted in a hospital from 2011 to 2015 were as the research object,a series of infection prevention and control intervention measure were taken,efficacy of intervention measures were evaluated.Results After the implementation of comprehensive intervention measures,compliance rate of hand hygiene increased year by year,from 38.17 ％ in 2011 to 87.16 ％ in 2015,difference was statistically significant (x2 =48.50,P＜0.05).Incidence of healthcare-associated infection dropped from 1.45％ to 1.06％,difference was statistically significant (x2 =42.50,P＜0.05);antimicrobial use density in 2011-2015 were 63.1,44.4,40.0,40.8,and 40.5 respectively,which showed a decreasing tendency.Conclusion Effective infection prevention and control measures have obvious effect on promoting management of rational use of antimicrobial agents,it is helpful for reducing the clinical use density of antimicrobial agents.

Coexistence of Amyotrophic Lateral Sclerosis in the Proband of an X-Linked Charcot-Marie-Tooth Disease Type 1 Pedigree in China

No abstract available.