The Effect of Canagliflozin on High-Density Lipoprotein Cholesterol and Angiopoietin-Like Protein 3 in Type 2 Diabetes Mellitus.

Background: Diabetes mellitus is often accompanied by dyslipidemia. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM), have been reported to exert effects on lipid, while the results remain controversial. This study is aimed at exploring the effect of SGLT2 inhibitor canagliflozin on lipid profile. Methods: This study was a single-center, open-label, nonrandomized, prospective study. Metformin (500 mg three times per day) or canagliflozin (100 mg, once daily) was administered for 12 weeks. Fasting blood samples were collected before and 12 weeks after treatment. Serum lipid profile levels and angiopoietin-like protein 3 (ANGPTL3) were determined. In animal experiment, C57BL/6 J mice were divided into three groups including control, STZ + HFD, and STZ + HFD + canagliflozin. Lipid profile and plasma ANGPTL3 level were measured after 12 week's treatment. Moreover, the expression of ANGPTL3 was detected in the liver tissues. Results: There was a decreased trend in low-density lipoprotein cholesterol (LDL-c) and triglycerides (TG) after canagliflozin treatment, while canagliflozin significantly increased high-density lipoprotein cholesterol (HDL-c) level and decreased plasma ANGPTL3 level. In addition, the expression of ANGPTL3 in liver tissues decreased obviously in diabetic mice with canagliflozin treatment. Conclusions: Canagliflozin increases HDL-c level and suppresses ANGPTL3 expression in patients with T2DM and diabetic mice. The reduction of ANGPTL3 may contribute to the increase of HDL-c. However, the specific mechanism needs further research. This trial is registered with ChiCTR1900021231.

Appendectomy and risk of prostate cancer in the Health Professionals Follow-up Study.

BACKGROUND: Appendectomy is a common surgical procedure to treat appendicitis. Limited studies examined its association on prostate cancer, with one large cohort study suggesting significant increased risk of overall and advanced prostate cancer, especially among younger men. METHODS: A total of 49,104 men in the Health Professionals Follow-up Study were followed from 1986 to 2016. Cox proportional hazards models were applied to evaluate the association between self-reported history of appendectomy and risk of overall and subtype specific prostate cancer, adjusted for multiple risk factors. RESULTS: During 30 years of follow-up, we documented 7,253 overall prostate cancer including 579 advanced and 1,092 lethal events. Compared to men without appendectomy, those who reported at baseline having had appendectomy were not at higher risk of overall (hazard ratio (HR)=1.01, 95% CI = 0.95 to 1.07), advanced (HR=0.99, 95% CI = 0.81 to 1.23) or lethal (HR=1.04, 95% CI = 0.89 to 1.20) prostate cancer. The association remained null when stratified by age. CONCLUSIONS: We found no evidence of an association between appendectomy and risk of overall and clinically important prostate cancer. IMPACT: We showed that appendectomy was not associated with overall or advanced prostate cancer adjusted for multiple risk factors among a large population of men with 30 years of follow-up.

Predictors for early-onset psychotic symptoms in patients newly diagnosed with Parkinson's disease without psychosis at baseline: A 5-year cohort study.

AIMS: To investigate the risk factors for early-onset psychosis in Parkinson's disease (PD) in a cohort of patients from the Parkinson's Progression Markers Initiative. METHODS: Longitudinal data on motor and non-motor features, dopamine transporter (DAT) imaging, and cerebrospinal fluid (CSF) measurements were collected. The survival probability of psychotic symptoms, potential risk factors for psychosis development over a 5-year follow-up period, and the performance of the prediction model were evaluated. RESULTS: Among the 338 newly diagnosed patients with PD, 83 developed psychotic symptoms. Gastrointestinal autonomic dysfunction, presence of probable rapid-eye-movement sleep behavior disorder, and the ratio Aß42: total-tau could independently predict onset of psychosis in PD (hazard ratio (HR) = 1.157, 95% confidence interval (CI) 1.022-1.309, p = 0.021, HR = 2.596, 95% CI 1.287-5.237, p = 0.008, and HR = 0.842, 95% CI 0.723-0.980, p = 0.027, respectively). The combined model integrating baseline clinical predictors, DAT imaging, and CSF measurements achieved better sensitivity than the clinical predictors alone (area under the curve = 0.770 [95% CI 0.672-0.868] vs. 0.714 [95% CI 0.625-0.802], p = 0.098). CONCLUSION: We identified clinical and CSF predictors of early-onset psychosis in patients with PD. Our study provides evidence and implications for prognostic stratification and therapeutic approaches for PD psychosis.

Methylseleninic acid inhibits human glioma growth in vitro and in vivo by triggering ROS-dependent oxidative damage and apoptosis.

Selenium-containing agents showed novel anticancer activity by triggering pro-oxidative mechanism. Studies confirmed that methylseleninic acid (MeSe) displayed broad-spectrum anti-tumor activity against kinds of human cancers. However, the anticancer effects and mechanism of MeSe against human glioma growth have not been explored yet. Herein, the present study showed that MeSeA dose-dependently inhibited U251 and U87 human glioma cells growth in vitro. Flow cytometry analysis indicated that MeSe induced significant U251 cells apoptosis with a dose-dependent manner, followed by the activation of caspase-7, caspase-9 and caspase-3. Immunofluorescence staining revealed that MeSe time-dependently caused reactive oxide species (ROS) accumulation and subsequently resulted in oxidative damage, as convinced by the increased phosphorylation level of Ser428-ATR, Ser1981-ATM, Ser15-p53 and Ser139-histone. ROS inhibition by glutathione (GSH) effectively attenuated MeSe-induced ROS generation, oxidative damage, caspase-3 activation and cytotoxicity, indicating that ROS was an upstream factor involved in MeSe-mediated anticancer mechanism in glioma. Importantly, MeSe administration in nude mice significantly inhibited glioma growth in vivo by inducing apoptosis through triggering oxidative damage. Taken together, our findings validated the possibility that MeSe as a selenium-containing can act as potential tumor chemotherapy agent for therapy of human glioma.

Proteomics revealed an association between ribosome-associated proteins and amyloid beta deposition in Alzheimer's disease.

Most scholars believe that amyloid-beta (Aß) has the potential to induce apoptosis, stimulate an inflammatory cascade, promote oxidative stress and exacerbate the pathological progression of Alzheimer's disease (AD). Therefore, it is crucial to investigate the deposition of Aß in AD. At approximately 6 months of age, APP/PS1 double transgenic mice gradually exhibit the development of plaques, as well as spatial and learning impairment. Notably, the hippocampus is specifically affected in the course of AD. Herein, 6-month-old APP/PS1 double transgenic mice were utilized, and the differentially expressed (DE) proteins in the hippocampus were identified and analyzed using 4D label-free quantitative proteomics technology and parallel reaction monitoring (PRM). Compared to wild-type mice, 29 proteins were upregulated and 25 proteins were downregulated in the AD group. Gene Ontology (GO) enrichment analysis of biological processes (BP) indicated that the DE proteins were mainly involved in 'ribosomal large subunit biogenesis'. Molecular function (MF) analysis results were primarily associated with '5.8S rRNA binding' and 'structural constituent of ribosome'. In terms of cellular components (CC), the DE proteins were mainly found in 'polysomal ribosome', 'cytosolic large ribosomal subunit', 'cytosolic ribosome', and 'large ribosomal subunit', among others. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the results were mainly enriched in the 'Ribosome signaling pathway'. The key target proteins identified were ribosomal protein (Rp)l18, Rpl17, Rpl19, Rpl24, Rpl35, and Rpl6. The PRM verification results were consistent with the findings of the 4D label-free quantitative proteomics analysis. Overall, these findings suggest that Rpl18, Rpl17, Rpl19, Rpl24, Rpl35, and Rpl6 may have potential therapeutic value for the treatment of AD by targeting Aß.

Correlation of slow-wave sleep with motor and nonmotor progression in Parkinson's disease.

OBJECTIVE: This study aimed to explore the association between slow-wave sleep and the progression of motor and nonmotor symptoms in patients with PD. METHODS: Data were collected from the Parkinson's Progression Markers Initiative study. Slow-wave sleep, also known as deep non-rapid eye movement (DNREM) sleep, was objectively assessed using the Verily Study Watch. Motor function was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III score, Hoehn and Yahr stage, freezing of gait, motor fluctuations, and dyskinesia severity. Comprehensive assessments were conducted on nonmotor symptoms, including depression, anxiety, global cognitive function, and autonomic dysfunction. Statistical analyses involved repeated-measures analysis of variance and linear regression. RESULTS: A total of 102 patients with PD were included in the study, with a median follow-up duration of 3.4 years. In the long DNREM sleep duration group (n = 55), better motor function (DNREM × time interaction: F(1,100) = 4.866, p = 0.030), less severe sexual dysfunction (p = 0.026), and improved activities of daily living (p = 0.033) were observed at the last follow-up visit compared with the short DNREM sleep duration group (n = 47). Reduced DNREM sleep duration is a risk factor for motor progression (ß = -0.251, p = 0.021; 95% confidence interval = -0.465 to -0.038). INTERPRETATION: The findings suggest an association between longer DNREM sleep duration and slower motor and nonmotor progression in patients with PD.

Self-Assembly Protein Superstructures as a Powerful Chemodynamic Therapy Nanoagent for Glioblastoma Treatment.

Glioblastoma (GBM) remains a formidable challenge in oncology. Chemodynamic therapy (CDT) that triggers tumor cell death by reactive oxygen species (ROS) could open up a new door for GBM treatment. Herein, we report a novel CDT nanoagent. Hemoglobin (Hb) and glucose oxidase (GOx) were employed as powerful CDT catalysts. Instead of encapsulating the proteins in drug delivery nanocarriers, we formulate multimeric superstructures as self-delivery entities by crosslinking techniques. Red blood cell (RBC) membranes are camouflaged on the protein superstructures to promote the delivery across blood-brain barrier. The as-prepared RBC@Hb@GOx nanoparticles (NPs) offer superior biocompatibility, simplified structure, and high accumulation at the tumor site. We successfully demonstrated that the NPs could efficiently produce toxic ROS to kill U87MG cancer cells in vitro and inhibit the growth of GBM tumor in vivo, suggesting that the new CDT nanoagent holds great promise for treating GBM.

Wavelength selective photoactivated autocatalytic oxidation of 5,12-dihydrobenzo[b]phenazine and its application in metal-free synthesis.

Photochemical stability of 5,12-dihydrobenzo[b]phenazine (DHBP) was investigated with LEDs with central emission wavelengths in a range of 365 to 595 nm. Photochemical conversion of DHBP to benzo[b]phenazine (BP) was observed with wavelengths upto 516 nm. Light of 490 and 516 nm is not absorbed by DHBP, but photoactivated autocatalytic oxidation of DHBP to BP with these wavelengths was confirmed. The reaction rate is in a range of 111-208 µg min-1 with these LEDs. The mechanism of the reaction was examined and the experimental results exclude the intermolecular interaction such as the Förster resonance energy transfer, the intermolecular charge transfer, the photoinduced electron transfer and the formation of an exciplex. The formation of the reactive oxygen species was verified with electron paramagnetic resonance, which indicates its potential in the synthesis. When sunlight was used as the light source, the oxidation rate of 1 mg mL-1 DHBP was 393 µg min-1. Same autocatalytic oxidation was also observed on similar compounds and it can be used for producing metal-free organic substances for semiconductors.

Enhanced Plasmon-Induced Resonance Energy Transfer (PIRET)-Mediated Photothermal and Photodynamic Therapy Guided by Photoacoustic and Magnetic Resonance Imaging.

Phototherapy, including photothermal and photodynamic therapy, has attracted extensive attention due to its noninvasive nature, low toxicity, and high anticancer efficiency. The charge-separation mechanism of plasmon-induced resonance energy transfer (PIRET) has been increasingly employed to design nanotheranotic agents. Herein, we developed a novel and smart PIRET-mediated nanoplatform for enhanced, imaging-guided phototherapy. Prussian blue (PB) was incorporated into a Au@Cu2O nanostructure, which was then assembled with poly(allylamine) (PAH)-modified black phosphorus quantum dots (Au@PB@Cu2O@BPQDs/PAH nanocomposites). The hybrid nanosystem exhibited great absorption in the near-infrared region, as well as the ability to self-supply O2 by catalyzing hydrogen peroxide and convert O2 into singlet oxygen (1O2) under 650 nm laser light (0.5 W/cm2) irradiation. In vitro and in vivo assays showed that the generated heat and toxic 1O2 from Au@PB@Cu2O@BPQDs/PAH nanocomposites could effectively kill the cancer cells and suppress tumor growth. Moreover, the unique properties of the PB-modified nanosystem allowed for synergistic therapy with the aid of T1-weighed magnetic resonance imaging (T1-weighted magnetic resonance imaging) and photoacoustic imaging. This study presented a suitable way to fabricate smart PIRET-based nanosystems with enhanced photothermal therapy/photodynamic therapy efficacy and dual-modality imaging functionality. The great biocompatibility and low toxicity ensured their high potential for use in cancer therapy.

Distinct correlation between (CN2)x units and pores: a low-cost method for predesigned wide range control of micropore size of porous carbon.

Flexible control of the micropore size of carbon was achieved in a cost-efficient way by predesigned quantitative correlation between the sizes of extendable (CN2)x nanosized modulators and the generated micropore sizes ranged from 0.2 to 2.3 nm, with effectiveness for boosting the electrochemical performance systematically.

Dialysed caramel as an effective fluorophore for the simultaneous detection of three nitrophenols.

Low-cost and nontoxic fluorescent reagents are important for on-site analysis performed by non-professionals. In this work, a cheap and widely available food additive, caramel was used as an effective fluorescence reagent for the sensitive detection of 2,4,6-trinitrophenol (TNP), 2,4-dinitrophenol (DNP) and 4-nitrophenol (4-NP). Through a simple dialysis, fluorescent components of a commercial caramel were harvested with a yield as high as 60%. The structural characterization demonstrated that the fluorescent components were dehydrated oligomers of carbohydrates. Their fluorescence can be quenched by these nitrophenols. The quenching mechanism was speculated as inner filter effect. At pH 8, a linear range of 0.2-22 µM and a detection limit of 90 nM could be achieved for TNP. Based on the difference of their quenching efficiency at different pHs, TNP, DNP and 4-NP can be simultaneously determined by solving the linear equations obtained at pH 3, 5 and 8. Successful detection of these nitrophenols in the water and soil samples was performed with relative standard deviations of 1.1-5.9% and recoveries of 95-108% of spiked standards.

Fluorometric determination of doxycycline based on the use of carbon quantum dots incorporated into a molecularly imprinted polymer.

A fluorometric assay is described for doxycycline detection. It is based on the use of nitrogen-doped carbon quantum dots (NCQDs) coated with molecularly imprinted polymers (MIPs). The NCQDs were prepared by a one-step hydrothermal reaction using citric acid and ethylenediamine (EDA) as the starting materials. Afterwards, the NCQDs were incorporated into the polymer that was molecularly imprinted with doxycycline. It is found that doxycycline quenches the fluorescence of the NCQDs, and that the functional groups on the surface of NCQDs play an important role in terms of quenching efficiency. A larger fraction of carboxyl groups presented on the surface of NCQDs leads to a higher quenching efficiency due to the enhanced electron transfer from NCQD to doxycycline. The NCQDs@MIP composite can specifically and rapidly recognize doxycycline. Fluorescence drops linearly in the 5 to 50 µM doxycycline concentration range, and the limit of detection is 87 nM. This method was successfully applied to the determination of doxycycline in spiked pig serum where it gave recovery rates of >94%. Graphical abstract Schematic illustration for fabricating a fluorescent sensor based on nitrogen-doped carbon quantum dots (NCQDs) and molecularly imprinted polymers (MIPs). The sensor integrates the merits of the high sensitivity of NCQD and good selectivity of MIPs, and can be significantly quenched upon interaction with doxycycline.

Detection of hemoglobin using hybrid molecularly imprinted polymers/carbon quantum dots-based nanobiosensor prepared from surfactant-free Pickering emulsion.

A simple fluorescent nanobiosensor based on molecularly imprinted polymers (MIPs) and carbon quantum dots (CQDs) was developed for hemoglobin (Hb) detection. The nanocomposites were synthesized by a novel one-pot surfactant-free Pickering emulsion method, in which imprinted cavities complementary to Hb were formed at the surface of the particles for target recognition, while CQDs were incorporated in the core as the fluorescence probe. We innovatively used the Hb template as emulsifier to help stabilize the emulsion droplets. The method eliminated the need of surfactant, which greatly simplified Pickering emulsion synthesis procedures, and significantly enhanced the fidelity of molecular imprinting. Moreover, the method provided an easy way to integrate fluorescent probes with MIPs in a single step. The nanobiosensor was utilized for determination of Hb via fluorescence quenching, and high selectivity and sensitivity were achieved. Under the optimized conditions, a linear range of 0.77-7.7 nM and a detection limit of 0.77 nM were obtained. The resulting nanocomposites were also successfully applied to detect Hb in the serum samples, which showed good recoveries ranging from 86.8% to 93.9%.

Asn391Thr Mutation of ß-Myosin Heavy Chain in a Hypertrophic Cardiomyopathy Family.

The present study was performed to identify the genetic abnormalities in a family with familial hypertrophic cardiomyopathy.Peripheral blood samples were collected from 22 members of a Chinese family with hypertrophic cardiomyopathy and 307 healthy controls. A total of 26 candidate pathogenic genes were analyzed in the proband using targeted capture sequencing. Identified mutations were analyzed using Sanger sequencing in all family members and healthy controls.A missense mutation (c.1172A>C, p. Asn391Thr) in exon 12 of MYH7 was identified in eight family members, among which six of them were hypertrophic cardiomyopathy carriers. Three carriers presented with cardiac dysfunction. Four members of this pedigree died suddenly, three of whom were diagnosed with hypertrophic cardiomyopathy.From the results of this study, we concluded that the Asn391Thr mutation of MYH7 is a malignant mutation for HCM and that mutation carriers should get effective treatment to prevent sudden death.

Molecularly imprinted nanoparticles for inhibiting ribonuclease in reverse transcriptase polymerase chain reaction.

Molecularly imprinted nanoparticles (nanoMIPs) are synthesized via a solid-phase approach using RNase as the template. The feasibility of employing the nanoMIPs as RNase inhibitor is successfully demonstrated in reverse transcriptase polymerase chain reaction (RT-PCR) assays, suggesting the tailor-made nanomaterials are very promising for use in routine biological assays.

Dispersive solid-phase imprinting of proteins for the production of plastic antibodies.

We describe a novel dispersive solid-phase imprinting technique for the production of nano-sized molecularly imprinted polymers (nanoMIPs) as plastic antibodies. The template was immobilized on in-house synthesized magnetic microspheres instead of conventional glass beads. As a result, high-affinity and template-free MIPs were produced in higher yields.

A multifunctional molecularly imprinted polymer-based biosensor for direct detection of doxycycline in food samples.

In this study, we developed a new type of multifunctional molecularly imprinted polymer (MIP) composite as an all-in-one biosensor for the low-cost, rapid and sensitive detection of doxycycline in pig plasma. The MIP composite consisted of a magnetic core for ease of manipulation, and a shell of fluorescent MIPs for selective recognition of doxycycline. By simply incorporating a small amount of fluorescent monomer (fluorescein-O-acrylate), the fluorescent MIP layer was successfully grafted onto the magnetic core via a surface imprinting technique. The resultant MIP composites showed significant doxycycline-dependent fluorescence quenching in an aqueous environment. Good linearity ranging from 0.2 to 6 µM was achieved, and the limit of detection was determined to be 117 nM. The biosensor also showed good selectivity towards doxycycline when compared to other common antibiotic residues. The multifunctional MIP composites were used to directly extract doxycycline from spiked pig plasma samples and quantify the antibiotics based on the quenched fluorescence signals. Recoveries of doxycycline were found in the range of 88-107%.

A facile molecularly imprinted polymer-based fluorometric assay for detection of histamine.

Histamine is a biogenic amine naturally present in many body cells. It is also a contaminant that is mostly found in spoiled food. The consumption of foods containing high levels of histamine may lead to an allergy-like food poisoning. Analytical methods that can routinely screen histamine are thus urgently needed. In this paper, we developed a facile and cost-effective molecularly imprinted polymer (MIP)-based fluorometric assay to directly quantify histamine. Histamine-specific MIP nanoparticles (nanoMIPs) were synthesized using a modified solid-phase synthesis method. They were then immobilized in the wells of a microplate to bind the histamine in aqueous samples. After binding, o-phthaldialdehyde (OPA) was used to label the bound histamine, which converted the binding events into fluorescent signals. The obtained calibration curve of histamine showed a linear correlation ranging from 1.80 to 44.98 µM with the limit of detection of 1.80 µM. This method was successfully used to detect histamine in spiked diary milk with a recovery rate of more than 85%.

One-Pot Green Synthesis of Biocompatible Graphene Quantum Dots and Their Cell Uptake Studies.

Graphene-based quantum dots (GQDs) are attractive fluorophores due to their excellent photoluminescence properties, water solubility, low cost, and low toxicity. However, the lack of simple, efficient, and environmental-friendly synthesis methods often limits their biological applications. Herein, we explore a novel, one-pot, green synthesis approach for the fabrication of fluorescent GQDs without involving any harsh reagents. Graphene oxide is used as a precursor, and a 2 h hydrothermal synthesis is carried out with assistance of hydrogen peroxide; no further post purification steps are required. The effects of reaction conditions on the characteristics of GQDs are comprehensively investigated. The as-synthesized GQDs show a high photostability and excellent biocompatibility as revealed by cell viability assays for three different cell lines, namely, macrophages, endothelial cells, and a model cancer cell line. The detailed studies of cellular uptake mechanisms suggest that for all of the three cell lines the major internalization route for GQDs is caveolae-mediated endocytosis followed by clathrin-mediated endocytosis at a less extent. Our results demonstrate the great potential of the as-synthesized GQDs as fluorescent nanoprobes. The study also provides unique insight into the cell-GQDs interactions, which is highly valuable for bioimaging and other related applications such as diagnostics and drug delivery.

Online Flowing Colloidosomes for Sequential Multi-analyte High-Throughput SERS Analysis.

3D plasmonic colloidosomes are superior SERS sensors owing to their high sensitivity and excellent tolerance to laser misalignment. Herein, we incorporate plasmonic colloidosomes in a microfluidic channel for online SERS detection. Our method resolves the poor signal reproducibility and inter-sample contamination in the existing online SERS platforms. Our flow system offers rapid and continuous online detection of 20 samples in less than 5 min with excellent signal reproducibility. The isolated colloidosomes prevent cross-sample and channel contamination, allowing accurate quantification of samples over a concentration range of five orders of magnitude. Our system demonstrates high-resolution multiplex detection with fully preserved signal and Raman features of individual analytes in a mixture. High-throughput multi-assay analysis is performed, which highlights that our system is capable of rapid identification and quantification of a sequence of samples containing various analytes and concentrations.