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Despite the potential indicating role of tyrosinase (TYR) in cutaneous melanoma, how to capture the real changes of TYR in suspicious skin remains a major challenge. Unlike the traditional human serum test, this study reports a sensing platform that incorporates a wearable microneedle (MN) patch and trimetallic Au@Ag-Pt nanoparticles (NPs) for surface-enhanced Raman scattering (SERS) and colorimetric dual-mode detecting TYR in human skin in situ toward potential melanoma screening. In the presence of TYR, catechol immobilized on MN is preferentially oxidized to benzoquinone, which competitively impedes the interaction of MN and Au@Ag-Pt NPs, triggering the SERS-colorimetric signal reciprocal switch. Using a B16F10 mouse melanoma model, our platform is capable of noninvasively piercing the skin surface and detecting TYR levels before and during anti-PD-1 antibody treatment, which would be highly informative for prognostic judgment and illness monitoring of melanoma. Through in situ sensing for capturing the metabolic changes of TYR in advance, this platform was successfully applied to discriminate the melanoma subjects from skin moles and normal ones (p < 0.001), as well as screen potential melanoma from lactate dehydrogenase (LDH)-negative patients. Melanoma growth and prognosis can still be monitored through recording the continuous change of TYR levels. More importantly, the well-defined flexible and stretchable characteristics of the MN patch allow robustly adhering to the skin without inducing chemical or physical irritation. We believe this platform integrating MN-based in situ sensing, TYR responsiveness, and SERS/colorimetric dual-readout strategy will have high clinical importance in early diagnosis and monitoring of cutaneous melanoma.

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How to actively target tumor sites manipulating the controllable release of the encapsulated anticancer drugs and photosensitizers for synergistic anticancer therapy remains a big challenge. In this study, a cancer cell-targeted, near-infrared (NIR) light-triggered and anticancer drug loaded liposome system (LPs) was developed for synergistic cancer therapy. Photosensitizer indocyanine green (ICG) and chemotherapy drug Curcumin (CUR) were coencapsulated into the liposomes, followed by the surface conjugation of GE11 peptide for epidermal growth factor receptor (EGFR) targeting on the cancer cell surface. Strictly controlled by NIR light, GE11 peptide modified and CUR/ICG-loaded LPs (GE11-CUR/ICG-LPs) could introduce hyperthermia in EGFR overexpressed A549 cancer cells for photothermal therapy, which could also trigger the increased release of CUR for enhanced cancer cell inhibition. GE11-CUR/ICG-LPs synergized photochemotherapy could induce reactive oxygen species (ROS) generation and cytoskeleton disruption to activate stronger apoptotic signaling events than the photothermal therapy or chemotherapy alone by regulating Bax/Bcl-2 and PI3K/AKT pathways. This EGFR-targeted drug-delivery nanosystem with NIR sensitivity may potentially serve in more effective anticancer therapeutics with reduced off-target effects.

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The integration of ultrasound (US) contrast enhancement with oxygen-loading nanoagents provide the synergistic strategy for simultaneously US imaging and hypoxic microenvironment modulation. Herein, we synthesize pentafluorobutane (PFB)-loading methoxy poly(ethylene glycol)-b-poly(l-lactide) (PLLA) nanoparticle as the novel US-contrast-enhanced agent and demonstrate that PFB@PLLA effectively loads oxygen. We characterize the nanosize, phase-transformation property and oxygen-loading amount of PFB@PLLA and investigate the effectiveness of these nanoagents in US-contrast-enhanced imaging. The PFB@PLLA displays a perfect temperature-responsive phase-transition property and its liquid-to-gas phase transition temperature is 45°C, which produces microbubbles in the targeted regions. Moreover, PFB@PLLA loads high amount of oxygen and US-triggering PFB@PLLA reoxygenation effectively inhibits the expression of hypoxia-related proteins (HIF-1α and CAIX), reduces lactate secretion and glycolysis, which modulates hypoxic microenvironment and inhibits cancer cell migration and invasion in vitro. This study demonstrates that the US contrast-enhanced activity of PFB@PLLAs and the promising utility of oxygen-loading nanoagents to improve hypoxic microenvironment.

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The authors describe a dual-mode (colorimetric-fluorometric) nanoprobe for H2O2 that was fabricated by covering molybdenum disulfide nanosheets (MoS2 NS) with ortho-phenylenediamine (OPD). The probe (OPD-MoS2 NS) was applied to the optical determination of H2O2, to the quantitation of cell numbers, and to the detection of intracellular concentrations of H2O2. Oxidation by H2O2 leads to a colored and fluorescent product (oxidized OPD) with absorption/excitation/fluorescence peaks at 450/450/557 nm. The nanoprobe can detect H2O2 in down to 500 nM concentrations, and HeLa cells at levels of 100 cells mL-1. The detection limit for intracellular H2O2 is in the 5.5 to 12.6 µM concentration range when the method is applied to cells at levels of 102-106 cells mL-1. Due to its good biocompatibility and easy cell uptake, the nanoprobe also permits sensitive fluorometric imaging of intracellular H2O2. It can also comparatively discriminate the change of intracellular oxidation state in living cancerous and normal cells. Graphical abstract Editor, we provided image with high resolution. Please find it in a folder name "MIAC-D-18-00081" in the FTP site. A dual-mode (colorimetric-fluorometric) detection nanoplatform based on OPD-modified MoS2 nanosheets is used to quantitatively detect H2O2, cell numbers and intracellular H2O2. The MoS2 nanoprobes also permit sensitive fluorescence imaging of intracellular H2O2, and can discriminate intracellular oxide states in living cancerous and normal cells.

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Acute myocardial infarction (AMI) initiation and progression follow complex molecular and structural changes in the nanoarchitecture of platelets. However, it remains poorly understood how the transformation from health to AMI alters the ultrastructural and biomechanical properties of platelets within the platelet activation microenvironment. Here, we show using an atomic force microscope (AFM) that platelet samples, including living human platelets from the healthy and AMI patient, activated platelets from collagen-stimulated model, show distinct ultrastructural imaging and stiffness profiles. Correlative morphology obtained on AMI platelets and collagen-activated platelets display distinct pseudopodia structure and nanoclusters on membrane. In contrast to normal platelets, AMI platelets have a stiffer distribution resulting from complicated pathogenesis, with a prominent high-stiffness peak representative of platelet activation using AFM-based force spectroscopy. Similar findings are seen in specific stages of platelet activation in collagen-stimulated model. Further evidence obtained from different force measurement region with activated platelets shows that platelet migration is correlated to the more elasticity of pseudopodia while high stiffness at the center region. Overall, ultrastructural and nanomechanical profiling by AFM provides quantitative indicators in the clinical diagnostics of AMI with mechanobiological significance.

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A rapid, facile assay for sensitive cytosensing of breast cancer cells should help to guide potential medical evaluation for breast cancer. Here, we report development of novel resonance Rayleigh scattering (RRS) cytosensor for cell recognitions and folate (FA) receptor expression analyses on living cells. Using FA-conjugated gold nanoparticles (FA-AuNPs) as nanoprobes, the constructed nanoprobes-assembled recognition interface could increase the binding capacity for cell recognition, amplify Au-aggregates-enhanced RRS signal, and then enhance the sensitivity for membrane antibody assay. FA-AuNPs-based RRS measurements enabled a distinct 34-times-enhancement in RRS intensities after incubation with human breast cancer cells, compared with normal cells. Receptor-targeted cytosensor was used to quantitatively detect human breast cancer MCF-7, liver cancer HepG2 and normal cells, which expressing different amount of FA receptor, respectively. The detection limit for MCF-7 cells was 12 cells/mL with good selectivity and reproducibility. Furthermore, the proposed cytosensor allowed for dynamic evaluation of FA receptor expression on different living cells after dihydroartemisinin stimulus. This assay platform shows the good potential for clinical diagnostics and antibody-targeted drug screening.

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Simple and sensitive determination of chromium (III) ions (Cr(3+)) has potential applications for detecting trace contamination in environment. Here, the assay is based on the enhancement of resonance Rayleigh scattering (RRS) by Cr(3+)-induced aggregation of citrate-capped gold nanoparticles (AuNPs). Transmission electron microscopy (TEM) and UV-vis absorption spectroscopy were employed to characterize the nanostructures and spectroscopic properties of the Cr(3+)-AuNP system. The experiment conditions, such as reaction time, pH value, salt concentration and interfering ions, were investigated. The combination of signal amplification of Cr(3+)-citrate chelation with high sensitivity of RRS technique allow a selective assay of Cr(3+) ions with a detection limit of up to 1.0 pM. The overall assay can be carried out at room temperature within only twenty minutes, making it suitable for high-throughput routine applications in environment and food samples.

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Organogermanium(IV) (Ge) is considered to play an important role in the anti-oxidative activities of some Chinese medicines. Here, a new chrysin-organogermanium (Chry-Ge) complex was synthesized and investigated for its potential biological activities. The radicals-sensitive Ge-O bond was introduced to Chry-Ge complex to enhance bioactivities of organic Ge or Chry. Results showed that Chry-Ge complex possessed great anti-oxidative activities, showing stronger hydroxyl scavenging effects than their corresponding ligands. We also demonstrated Chry-Ge complex inhibited ROS-dependent oxidative damage in cells. Moreover, the morphological and biophysical recoveries in oxidation-damaged cells induced by Chry-Ge complex were characterized by atomic force microscopy. All these results collectively suggested that Chry-Ge complex has synergetic effect for radicals scavenging and could be served as promising pharmacologically active agent against anti-oxidative treatment.

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A rapid, easy assay for monitoring dynamics of T-cell activation should help to guide potential medical evaluation of immune responses or immunopathogenesis. Here, we report development of novel electrochemical cytosensors for dynamic analyses of T-cell activation markers on living cells. Gold nanoparticles-doped polyaniline nanofiber (Au/PANI-NFs) composite was greenly prepared by in situ one-step chemical inertness of PANI-NFs with gold nanoparticles to fabricate impedance-based electrochemical biosensors. Transmission electron micrographs indicated that the gold nanoparticles were uniformly anchored along with the structure of PANI-NF surface, displaying fibrillar morphology with a ~60 nm diameter. Au/PANI-NFs-based cytosensors coated with anti-CD Ab molecules could provide biomimetic interface for multiple immunosensing of T-cell surface activation markers (CD69, CD25, and CD71). The dual signal amplification of Au nanoparticle and PANI-NFs-based electrochemical impedance spectroscopic (EIS) measurements enabled the cytosensors considerably sensitive, with a detection limit of 1×10(4) cells/ml of activated T-cells. The activation-targeted cytosensors detected early, middle and late stages for expression of activation markers CD69, CD25, and CD71 at 8 h, 24 h, and 36 h, respectively, after concanvalin A stimulation of T cells. The quantitative results consisted with those derived from flow cytometric analysis. Furthermore, activation-targeted cytosensor allowed for dynamic analysis of the immune inhibition of T-cell activation by immune regulatory drug icariin (ICA). Thus, Au/PANI-NFs-based cytosensors offer simple and fast approach for non-destructive, quantitative evaluation of T-cell activation markers, with considerable specificity, reproducibility, and low background noise.

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Quercetin is a popular flavonoid in plant foods, herbs, and dietary supplement. Germanium, a kind of trace elements, can enhance the body immunity. This study investigated the hydroxyl-radical-scavenging mechanism of the quercertin-germanium (IV) (Qu-Ge) complex to human erythrocytes, especially the effects on ultrastructure and mechanical properties of cell membrane, plasma membrane potential and intracellular free Ca(2+) concentration. Results showed that QuGe(2), a kind of the Qu-Ge complex, could reduce the oxidative damage of erythrocytes, change the cell-surface morphology, and partly recover the disruption of plasma membrane potential and intracellular free Ca(2+) level. Atomic force microscopy (AFM) was used to characterize the changes of the cell morphology, cell-membrane ultrastructure and biophysical properties at nanoscalar level. QuGe(2) has triggered the antioxidative factor to inhibit cellular damage. These results can improve the understanding of hydroxyl-radical-scavenging mechanism of human erythrocytes induced by the Qu-Ge complex, which can be potentially developed as a new antioxidant for treatment of oxidative damage.

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A novel strategy based on antigen-antibody interaction was developed by means of backfilling transferrin on antibody functionalized gold nanoparticles surfaces in the present study. Nano gold particles were immobilized with cysteamine layer by self-assembly, whose surfaces were chemically coupled with anti-transferrin antibodies by using EDCX, forming the anti-transferrin-Au immuno-probes. The particles and the nano-probes were characterized by the integrated tools of resonance Rayleigh scattering (RRS), UV-Vis absorption spectra, transmission electron microscopy (TEM) and laser light scattering. The result showed that the nano-probe with the ability of specific recognition of transferrin had good immune activity. The RRS peak at 470 nm was amplified obviously by using this signal amplification, and the antigen recognition was monitored via the enhancement of 470 nm RRS intensity when this binding event occurred. The result showed that the amplification strategy led to a dramatic improvement of the detection sensitivity of transferrin, and the detection of transferrin featured a linear range of 0.85 to 33.9) x 10(-10) mol x L(-1) with the detection limit of 8.5 x 10(-11) mol x L(-1).

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Holotransferrin, the iron (III) transport protein in the blood, can significantly increase the anticancer activity of artemisinin, which is isolated from the Chinese plant qinghaosu. This paper investigates the action process of holotransferrin-induced electrocatalytic reduction of artemisinin by spectroscopic and electrochemical techniques. Results show that holotransferrin(Fe(III)) is the electrochemical sites of holotransferrin, which can catalyze the reduction of artemisinin through lowering the overpotential by about 80 mV. Compared with the different electrochemical behaviors of artemisinin with apotransferrin and holoprotein (apotransferrin in the presence of Fe(III)), respectively, it demonstrates that holotransferrin(Fe(III)) plays an important role in the electrocatalytic reduction of artemisinin, which can catalyze the cleavage of the endoperoxide bridge in artemisinin. A reliable two-step process is proposed to explain that artemisinin is activated by holotransferrin(Fe(III))-mediated electrocatalytic reduction. These results can provide further information for better understanding the anticancer action of holotransferrin-conjugated artemisinin.

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