Ligand-induced Assembly of Copper Nanoclusters with Enhanced Electrochemical Excitation and Radiative Transition for Electrochemiluminescence.

Copper nanoclusters (CuNCs) are emerging electrochemiluminescence (ECL) emitters with unique molecule-like electronic structures, high abundance, and low cost. However, the synthesis of CuNCs with high ECL efficiency and stability in a scalable manner remains challenging. Here, we report a facile gram-scale approach for preparing self-assembled CuNCs (CuNCsAssy ) induced by ligands with exceptionally boosted anodic ECL and stability. Compared to the disordered aggregates that are inactive in ECL, the CuNCsAssy shows a record anodic ECL efficiency for CuNCs (10 %, wavelength-corrected, relative to Ru(bpy)3 Cl2 /tripropylamine). Mechanism studies revealed the unusual dual functions of ligands in simultaneously facilitating electrochemical excitation and radiative transition. Moreover, the assembly addressed the limitation of poor stability of conventional CuNCs. As a proof of concept, an ECL biosensor for alkaline phosphatase detection was successfully constructed with an ultralow limit of detection of 8.1×10-6  U/L.

Sfrp2 regulates the WNT/ß-catenin pathway to slow the development of aldosterone-producing adenoma.

Background: To explore a new drug therapy for aldosterone-producing adenoma (APA), and investigate whether Sfrp2 (secreted frizzled-related protein 2) can influence the development of adrenal APA by regulating the WNT/ß-catenin pathway. Methods: Tissue samples from APA patients were collected to detect the expression of Sfrp2 and ß-catenin in APA. NCI-H295R cells were cultured with WNT/ß-catenin pathway inhibitors to detect cell proliferation and aldosterone secretion. Then, the expression of Sfrp2 was altered to determine the effect of Sfrp2 expression on WNT/ß-catenin pathway activity and aldosterone adenocarcinoma cells. Finally, a mouse APA model was established, and the mice were intravenously injected with WNT/ß-catenin pathway inhibitors or transfected with the Sfrp2 gene. The activity of the WNT/ß-catenin pathway, blood pressure, aldosterone secretion, and cell growth in the mice were then observed. Results: ß-catenin was overexpressed in APA tissues, while Sfrp2 was underexpressed. Sfrp2 can negatively regulate ß-catenin expression and control the activity of the WNT/ß-catenin pathway. Increased Sfrp2 expression inhibited the activity of the WNT/ß-catenin pathway, which suppressed aldosterone secretion and APA cell proliferation. The in vivo experiments also demonstrated that inhibition of WNT/ß-catenin pathway activity in mice reduced the arterial pressure and aldosterone concentration. The increased expression of Sfrp2 can inhibit the WNT/ß-catenin pathway in mice, and can also reduce arterial pressure and APA tissue growth. Conclusions: Sfrp2 can inhibit the WNT/ß-catenin signaling pathway by suppressing the expression of ß-catenin, thus controlling the concentration of aldosterone and hindering APA development. This study provides a novel therapeutic target for the treatment of APA and a new direction for future research.

Ligands engineering of gold nanoclusters with enhanced photoluminescence for deceptive information encryption and glutathione detection.

Gold nanoclusters (Au NCs) have appeared as an essential alternative to traditional quantum dots and fluorescent molecules for the development of intelligent stimuli-responsive photoluminescence (PL), but the low PL emission of Au NCs restricts their broad applications. Herein, we reported a simple yet effective strategy for preparing Au NCs with high PL by ligands engineering of 4-hydroxy-2-mercapto-6-methylpyrimidine (MTU) and L-Arginine (Arg). Owing to the rigidified shell and the ligand-to-metal charge transfer (LMCT) effects, it was found that the assembly of Arg ligand on MTU-protected Au NCs (Arg/MTU-Au NCs) led to a significantly enhanced PL in the alkaline solution up to 30 times. Moreover, utilizing the tunable LMCT, the Arg/MTU-Au NCs displayed rapid responses to multi-type ionic interaction in a reversible manner, such as H+/OH- and Cu2+/glutathione (GSH) pairs. Inspired by these intriguing ions-responsive LMCT and the associated switchable PL emission, the Arg/MTU-Au NCs were successfully used as excellent stimuli-responsive PL probes for intriguing deceptive information encryption and biosensing as well. This work would provide new insight into regulating the PL emission of Au NCs by ligands engineering and advance their potential applications in information encryption and bioassay.

Construction of Carbon Dots with Wavelength-Tunable Electrochemiluminescence and Enhanced Efficiency.

Tuning the electrochemiluminescence (ECL) wavelength of carbon dots (CDs) with enhanced efficiency is essential for multiplexed biosensing, bioimaging, and energy applications but remains challenging. Herein, we reported a facile route to finely modulate the ECL wavelength of CDs from 425 to 645 nm, the widest range ever reported, along with a more than 5-fold enhancement of ECL efficiency via phosphorous (P) incorporation. The molecular mechanism was explored experimentally and theoretically, which revealed the unusual dual roles of P dopants in the form of P-C and P-O bonding, that is, importing shallow trapping states and promoting an effective intramolecular charge transfer. This work would allow unlocking the key factors of ECL kinetics for heteroatom-doped CDs appearing out of reach and open a new avenue for the rational design of nanocarbon for desirable applications.

Quantum dots for electrochemiluminescence bioanalysis - A review.

Electrochemiluminescence (ECL) bioanalysis has become increasingly important in various fields from bioanalysis to clinical diagnosis due to its outstanding merits, including low background signal, high sensitivity, and simple instrumentation. Quantum dots (QDs) are a significant theme in ECL bioanalysis since their excellent optical, electrochemical properties, and ease of functionalization endow them with versatile roles and new mechanisms of signal transduction in ECL. Herein, this review details recent advances of QDs-based ECL bioanalysis by using QDs as ECL emitters, coreactants, or ECL resonance energy transfer donors/acceptors, mainly focused on their optical and electrochemical properties and ECL reaction mechanism. In the end, we will discuss the current limitations and future developments in QDs ECL bioanalysis to address the requirement about selectivity, sensitivity, toxicity, and emerging applications.

Biomimetic smart nanoplatform for dual imaging-guided synergistic cancer therapy.

Developing an integrated multimodal diagnosis and therapeutics nanoplatform is of great importance to enhance the outcome of cancer therapy. Herein, we report a highly efficient and biocompatible nanoplatform based on the assembly of a graphene oxide (GO) and metal-organic framework (MOF) Fe-porphyrin, which was coated with a folate-functionalized erythrocyte membrane (FA-EM@GO-MOF). The nanoplatform could be targeted to cancer cells precisely, and could avoid immune elimination and had prolonged blood circulation due to the presence of FA-EM on its surface. The presence of GO and paramagnetic Fe ions endowed the nanoplatform with robust fluorescence imaging and T2-weighted magnetic resonance imaging capacities. The porous structure and large surface area of GO-MOF make it desirable for drug delivery in chemotherapy. More importantly, with one operation, under the same laser (808 nm) irradiation, both photothermal therapy and photodynamic therapy could be triggered for efficient synergistic treatment by using MOF as a photosensitizer. This synergistic anticancer therapy promoted the generation of tumor-associated antigens and evoked an antitumor immune response. In vitro and in vivo therapy studies highlighted that the as-fabricated biomimetic nanoplatform for dual imaging-guided synergistic cancer therapy was highly effective yet straightforward, paving a new avenue for cancer diagnosis and therapy.

A Dual Functional Self-Enhanced Electrochemiluminescent Nanohybrid for Label-Free MicroRNA Detection.

The development of electrochemiluminescent (ECL) emitters with both intense ECL and excellent film-forming properties is highly desirable for biosensing applications. Herein, a facile one-pot preparation strategy was proposed for the synthesis of a self-enhanced ECL emitter by co-doping Ru(bpy)32+ and (diethylaminomethyl)triethoxysilane (DEAMTES) into an in situ-produced silica nanohybrid (DEAMTES@RuSiO2). DEAMTES@RuSiO2 not only possessed improved ECL properties but also exhibited outstanding film-forming ability, which are both critical for the construction of ECL biosensors. By coupling branched catalytic hairpin assembly with efficient signal amplification peculiarity, a label-free ECL biosensor was further constructed for the convenient and highly sensitive detection of miRNA-21. The as-fabricated ECL biosensor displayed a detection limit of 8.19 fM, much lower than those in previous reports for miRNA-21 and showed superior reliability for detecting miRNA-21-spiked human serum sample, demonstrating its potential for applications in miRNA-associated fundamental research and clinical diagnosis.

Facile Preparation of WO3-x Dots with Remarkably Low Toxicity and Uncompromised Activity as Co-reactants for Clinical Diagnosis by Electrochemiluminescence.

The exceptional nature of WO3-x dots has inspired widespread interest, but it is still a significant challenge to synthesize high-quality WO3-x dots without using unstable reactants, expensive equipment, and complex synthetic processes. Herein, the synthesis of ligand-free WO3-x dots is reported that are highly dispersible and rich in oxygen vacancies by a simple but straightforward exfoliation of bulk WS2 and a mild follow-up chemical conversion. Surprisingly, the WO3-x dots emerged as co-reactants for the electrochemiluminescence (ECL) of Ru(bpy)32+ with a comparable ECL efficiency to the well-known Ru(bpy)32+ /tripropylamine (TPrA) system. Moreover, compared to TPrA, whose toxicity remains a critical issue of concern, the WO3-x dots were ca. 300-fold less toxic. The potency of WO3-x dots was further explored in the detection of circulating tumor cells (CTCs) with the most competitive limit of detection so far.

Nitrogen, phosphorus and sulfur tri-doped carbon dots are specific and sensitive fluorescent probes for determination of chromium(VI) in water samples and in living cells.

A rapid, sensitive, and selective fluorometric assay is described for the determination of chromium(VI) in real waters and living cells. The method is making use of nitrogen, phosphorus, and sulfur tri-doped carbon dots (NPS-CDs) which have absorption/emission maxima at 360/505 nm/nm. Cr(VI) has an absorption maximum at 350 nm and causes an inner filter effect (IFE) on the blue fluorescence of the NPS-CDs. The NPS-CDs were hydrothermally synthesized using p-aminobenzenesulfonic acid and tetrakis(hydroxymethyl)phosphonium chloride as precursors. The NPS-CDs were characterized by transmission electron microscopy, X-ray diffraction, and several spectroscopic methods. They are biocompatible and negligibly cytotoxic when tested with HeLa cells and MCF-7 cells even after 48 h of incubation. The NPS-CDs were used as fluorescent probes for Cr(VI). The detection limit is 0.23 µM (three times standard deviation versus slope), and the linear response covers the 1 to 500 µM chromate concentration range. The NPS-CDs were applied to the determination of Cr(VI) in real waters and living cells (HeLa and MCF-7) and gave satisfying results. Graphical abstractSchematic representation of hydrothermal synthesis of nitrogen, phosphorus, and sulfur tri-doped carbon dots (NPS-CDs) for Cr(VI) detection via inner filter effect (IFE). NPS-CDs were applied to the determination of Cr(VI) in living cells (HeLa and MCF-7) with satisfying results.

Nitrogen, Cobalt Co-doped Fluorescent Magnetic Carbon Dots as Ratiometric Fluorescent Probes for Cholesterol and Uric Acid in Human Blood Serum.

Detection of cholesterol and uric acid biomarkers is of great importance for clinical diagnosis of several serious diseases correlated with their variations in human blood serum. In this study, a new kind of well selective and highly sensitive ratiometric fluorescent probe for cholesterol and uric acid determination in human blood serum was innovatively developed on the basis of the inner filter effect (IFE) process of nitrogen, cobalt co-doped carbon dots (N,Co-CDs) with 2,3-diaminophenazine (DAP). DAP was the oxidative product during the oxidation reaction between o-phenylenediamine and H2O2. Fluorescent magnetic N,Co-CDs possessing blue emission and magnetic property were prepared through a facile one-pot hydrothermal strategy by using citric acid, diethylenetriamine, and cobalt(II) chloride hexahydrate as precursors. N,Co-CDs exhibited good ferromagnetic property and excellent optical properties even in extremely harsh environmental conditions, implying the huge potential applications of such N,Co-CDs in biological areas. On the basis of the IFE process between N,Co-CDs and DAP, N,Co-CDs were applied to establish ratiometric fluorescent probes for the indirect detection of cholesterol and uric acid that participated in enzyme-catalyzed H2O2-generation reactions. The established IFE-based fluorescent probes exhibited relatively low detection limits of 3.6 nM for cholesterol and 3.4 nM for uric acid, respectively. The fluorescent probe was successfully utilized for the determination of cholesterol and uric acid in human blood serum with satisfying results, which provided an informed perspective on the applications of such doped CDs to explore the specific and sensitive nanoprobe in disease diagnoses and clinical therapy.

InP/ZnS quantum dot-based fluorescent probe for directly sensitive and selective detection of horseradish peroxidase.

InP/ZnS quantum dot (QD)-based fluorescent probe for directly sensitive and selective detection of horseradish peroxidase (HRP) was reported herein. Fluorescence of InP/ZnS QDs was statically quenched by HRP, due to the ground state complex formation of InP/ZnS QDs with HRP. Such ground state complex formation between InP/ZnS QDs and HRP reduced both the α-helix content and the melting temperature of HRP. Several key factors including InP/ZnS QDs concentration, buffer pH value, ionic strength, reaction temperature, and reaction time those affected the analytical performance of InP/ZnS QDs in HRP determination were investigated thoroughly. Under the optimal conditions, fluorescence intensity of InP/ZnS QDs was linearly decreased with the increasing of HRP concentration during the range of 1.0 × 10-9 M âˆ¼ 3.0 × 10-8 M (0.01 U ml-1 âˆ¼ 0.3 U ml-1) with the detection limit as low as 1.2 × 10-10 M (1.2 mU ml-1). The present method showed excellent selectivity for HRP over some amino acids, nucleotides, and common proteins. This method was utilized to detect HRP in synthetic samples successfully.

Tumor necrosis factor-related apoptosis-inducing ligand regulate the accumulation of extracelluar matrix in pulmonary artery by activating the phosphorylation of Smad2/3.

Introduction: Previous studies have found that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was involved in the progression of pulmonary hypertension (PH), and TRAIL knocking (KO) has an inhibitory effect on PH, but its mechanism is not completely clear. Methods: The effects of TRAIL on the accumulation of extracelluar matrix (ECM), which is one of the most important processes of vascular remodeling, were observed in mice and isolated pulmonary artery smooth muscle cells (PASMCs). In vivo, mice were divided into four groups: Control group (n = 5), hypoxia-induced PH mice group (n = 8), anti-TRAIL antibody (TRAIL-Ab) treatment group (n = 8) and IgG antibody (IgG) group (n = 8). The effects of TRAIL-Ab on ECM expression in hypoxic induced PH were researched; in vivo, PASMCs were divided into three groups: Control group, hypoxia-induced group, TRAIL-Ab group. Expressions of p-Smad2/3 and p-Smad1/5/8 were compared among the three groups. Results: Hypoxia-induced PH mice had significant increases in right ventricle systolic pressure (RVSP) (P < 0.001), right ventricular hypertrophy (RVH) (P = 0.007), vascular stenosis (P < 0.001) compared with controls. Mice with anti-TRAIL antibody had lower levels in RVSP (P < 0.001), RVH (P < 0.001), vascular stenosis (P < 0.001) than PH mice. Besides, the TRAIL-Ab significantly inhibited the phosphorylation of Smad2/3 compared with hypoxia-induced group. Conclusion: TRAIL regulates the accumulation of ECM in pulmonary artery by activating pSmad2/3.

Red emission nitrogen, boron, sulfur co-doped carbon dots for "on-off-on" fluorescent mode detection of Ag+ ions and l-cysteine in complex biological fluids and living cells.

Herein, a simple and efficient fluorescent assay for Ag+ ions and l-cysteine (L-Cys) in complex biological fluids and living cells was first developed based on the fluorescent "on-off-on" mode of red emission nitrogen, boron, sulfur co-doped carbon dots (NBS-CDs). Red emission NBS-CDs were prepared via one-step hydrothermal synthesis by using 3-aminobenzeneboronic acid and 2,5-diaminobenzenesulfonic acid as precursors. Such NBS-CDs exhibited excellent optical properties and relatively high absolute fluorescent quantum yield compared with some reported NBS-CDs. Due to the strong quenching ability of Ag+ ions on the fluorescence of NBS-CDs, red emission NBS-CDs were used for the determination of Ag+ ions with high sensitivity and excellent selectivity. The fluorescence of NBS-CDs was recovered after the interaction between Ag+ ions and L-Cys, which realized the specific determination of L-Cys in human urine samples and human plasma samples. The established NBS-CDs-based fluorescent "on-off-on" sensor offered a relatively low detection limits of 0.35 µM for Ag+ ions and 0.045 µM for L-Cys based on three times signal-to-noise criteria. Notably, this strategy was applied for the visual detections of Ag+ ions and L-Cys in living human cancer cells (HeLa cells and MCF-7 cells). This method is simple, high sensitive, and excellent selectivity, which provided a new insight on the potential applications of NBS-CDs to develop the biosensor in clinical diagnosis and other biologically related areas.

Carbon dots doped with nitrogen and boron as ultrasensitive fluorescent probes for determination of α-glucosidase activity and its inhibitors in water samples and living cells.

An ultrasensitive fluorometric assay is described for the determination of the activity of the enzyme α-glucosidase in waters and living cells. Carbon dots doped with nitrogen and boron (N,B-CDs) were prepared that have excitation/emission peaks at 400/510 nm and a fluorescence quantum yield of 47%. 4-Nitrophenylglucoside is added and then hydrolyzed by α-glucosidase to form yellow 4-nitrophenol which screens off fluorescence due to an inner filter effect. The method was applied to the determination of α-glucosidase activity and has a 3 mU mL-1 detection limit. It was subsequently applied to the determination of the α-glucosidase inhibitor acarbose which can be determined in a concentration as low as 10 nM (at three times the standard deviation versus slope). The method was also applied to the determination of α-glucosidase activity and acarbose in living HeLa cells and MCF-7 cells. The method is simple, sensitive, and excellently selective. Graphical abstract N,B-CDs as ultrasensitive fluorescence probe for α-glucosidase activity and its inhibitor in waters and living cells based on IFE.

Serum levels of tumor necrosis factor-related apoptosis-inducing ligand correlate with the severity of pulmonary hypertension.

Pulmonary hypertension (PH) is a rapidly progressive disease that eventually leads to right heart failure and death. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs) play an important role in the survival, migration, and proliferation of vascular smooth muscle cells. However, the association between serum TRAIL levels and PH is unknown. In this study, we assayed the serum soluble TRAIL (sTRAIL) levels in 78 patients with PH and 80 controls. The sTRAIL concentrations were elevated in the PH patients compared with the controls (138.76 ± 6.60 pg/mL vs. 80.14 ± 3.38 pg/mL, p < 0.0001). The presence of sTRAIL levels of >103 pg/mL could discriminate PH patients from healthy individuals, with a sensitivity of 75.6% and specificity of 81.2%. Moreover, elevated sTRAIL concentrations were associated with eventual pathological complications; this is consistent with the finding that sTRAIL levels decreased in patients who responded to treatment. In a hypoxia-induced PH mouse model, sTRAIL levels were significantly higher compared with those in normoxia mice, and clearly decreased when the mice were treated with treprostinil. The sTRAIL levels were positively correlated with right ventricular systolic pressure and the index of right ventricular hypertrophy. In conclusion, serum sTRAIL could be a biomarker for diagnosis and effective therapy for PH patients.

Impact of weight gain following smoking cessation on one-year outcome after drug-eluting stent implantation.

BACKGROUND: Weight gain following smoking cessation increases cardiovascular risk, but its effects on prognosis after percutaneous coronary intervention (PCI) remain unclear. This study aimed to investigate the relationship between weight gain post smoking cessation and one-year clinical outcome in patients who underwent PCI with drug-eluting stent (DES). METHODS: A total of 895 consecutive male smoking patients were divided into quitters (n = 437) and continuers (n = 458) according to their smoking status after PCI. Weight gain, major adverse cardiac events (MACE, including cardiac deaths, myocardial infarction and revascularization), and recurrent angina were recorded during follow-up for one year. RESULTS: Average weight gain in quitters was more than that in continuers (1.5 kg vs. -0.03 kg, P < 0.001). Weight was unchanged or increased by more than 1.5 kg in 78.17% of continuers, while 50.57% of quitters had a weight gain of less than 1.5 kg. Compared with continuers, MACE in quitters was significantly reduced after PCI (6.12% vs. 4.81%, P = 0.049), especially recurrent angina (13.97% in continuers vs. 9.84% in quitters, P = 0.027). After adjusting for weight gain and other factors, smoking cessation was independently associated with a lower risk of MACE and recurrent angina (OR = 0.73, P = 0.035). However, weight gain > 1.5 kg (OR = 1.55, P = 0.026) could curtail the benefits from smoking cessation. CONCLUSIONS: Weight gain may reduce the benefits of smoking cessation after PCI with DES implantation. Thus, although smoking cessation is recommended after PCI, weight control should also be highly encouraged for these patients.