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A single-walled carbon nanohorns-based smart nanotheranostic: from photodynamic and photothermal therapy to endogenous enzyme-activated fluorescence imaging-guided photodynamic therapy. [Display omitted] Phototheranostics, a local non-invasive approach that integrates light-based diagnostics and therapeutics, enables precise treatment using nanotheranostic agents with minimal damage to normal tissues. However, ensuring high-efficiency ablation of cancer cells using phototheranostics for one time irradiation is highly challenging. Herein, we designed and synthesized a single-walled carbon nanohorns-based nanotheranostic agent, HA-IR808-SWNHs, by loading IR808, a photosensitizer, conjugated hyaluronic acid (HA) with an amide bond on the surface of single-walled carbon nanohorns (SWNHs) through noncovalent π − π interaction by the sonication method. The HA in HA-IR808-SWNHs improves the water dispersibility of SWNHs and endows SWNHs with targeting capabilities. Importantly, overexpressed endogenous hyaluronidase in cancer cells actively disassembles HA-IR808-SWNHs, forming small HA-IR808 fragments. The fragments exhibit a strong fluorescence signal and can be used to guide programmed photodynamic therapy for sequentially eliminating the residual living cancer cells. The current study confirms that HA-IR808-SWNHs is an endogenous enzyme-responsive nanotheranostic agent that can be employed to precisely track and ablate residual cancer cells in a spatiotemporal manner. The results strengthen the understanding of SWNH functionalization and expand its potential biomedical application, especially in cancer theranostics. [ABSTRACT FROM AUTHOR]

Abstract: Indocyanine green (ICG) is an effective light absorber for laser‐mediated photodynamic therapy. However, applications of ICG are limited due to its rapid degradation and poor photostability in water. Herein, we report the development of a multifunctional nanoplatform by coating ICG on the surface of single‐walled carbon nanohorns (SWNHs) through π–π stacking, obtaining SWNH‐ICGs with high solubility and stability under physiological conditions. The SWNH‐ICGs could be used as a single nanoplatform to simultaneously produce satisfactory hyperthermia and reactive oxygen species under near‐infrared (NIR) laser irradiation. In addition, the SWNH‐ICGs not only improved the photostability of ICG in different media, but also protected it from light degradation. The SWNH‐ICGs exhibited highly efficient thermal/photoacoustic (PA) imaging‐guided photothermal therapy (PTT) and photodynamic therapy (PDT) effects, even under low‐power laser irradiation (0.3 W cm−2) in vitro. Combined PTT and PDT effectively killed triple‐negative breast cancer 4T1 cells, demonstrating a markedly improved and synergistic therapeutic effect compared to PTT or PDT alone. Furthermore, significant tumor growth inhibition as well as tumor cell death were observed following PTT/PDT at 808 nm laser irradiation, confirming the synergistic effects of SWNH‐ICGs over free ICG in vivo. This facile and simple methodology for thermal/PA imaging‐guided PTT/PDT suggests that SWNH‐ICGs may serve as an effective nanoplatform for cancer therapy. [ABSTRACT FROM AUTHOR]

An efficient 'off-on' type fluorescent chemosensor, (E)-N′-(4-(diethylamino)-2-hydroxybenzylidene)-2-hydroxybenzohydrazide ( H L), based on Schiff base for the determination of Al has been designed, synthesized, and evaluated. Upon treated with Al, the fluorescence of H L was enhanced 45-fold due to the chelation-enhanced fluorescence (CHEF) effect based on the formation of a 1:1 complex between the chemosensor and Al. Other metal ions, such as Na, K, Mg, Ca, Cu, Ga, Zn, Cr, Cd, Ag, Fe, In, Mn, Pb, Co, and Ni had little effect on the fluorescence. The results demonstrate that the chemosensor H L has stronger affinity with Al than other metal ions. The detection limit of H L for sensing Al is 3.60 × 10 M in EtOH-HO (3:7, v/v) solution. And the recognizing behavior has been investigated both experimentally and computationally. [ABSTRACT FROM AUTHOR]

Abstract: A new selective fluorescent sensor for Cu2+ and S2−, 2-hydroxy-N′-((quinolin-2-yl)methylene)benzohydrazide (HL), based on 2-methylquinoline derivative has been designed, synthesized and evaluated. The fluorescence of the sensor HL was quenched by Cu2+ with a 1:1 binding ratio, behaving as an “on–off” type sensor even in the presence of a wide range of biological cations. Once binding with Cu2+, it can display high selectivity for S2−. Among the various anions, only sulfide anion induces the revival of fluorescence of HL, resulting in “off–on” type sensing of sulfide anion. The signal transduction occurs via reversible formation–separation of complex L–Cu and CuS. With the addition of Cu2+, sensor HL give rise to a colorless to yellow color change. The resulting yellow solution switches to colorless immediately upon the addition of S2−; however, no changes were observed in the presence of other anions, including CN−, NO3 −, P2O7 4−, various forms of sulfate, and some other reactive sulfur species (RSS) including SCN−, l-methionine (l-Me) and l-cysteine (l-Cys). Notably, the color change is so distinct that the recycling process can be seen clearly by the naked eye. [Copyright &y& Elsevier]

Abstract: A new fluorescent sensor for Zn2+ based on 2-methylquinoline has been designed and synthesized. The sensor (1) demonstrates a Zn2+-specific emission enhancement linearly by a factor of 14 with a 1:1 binding ratio even in the presence of a wide range of biological cations. This can be correlated to the efficient Zn2+ binding of 1 and to the participation of relevant amine functions in the metal coordination which promotes a good chelation-enhanced fluorescence (CHEF) effect and prevents the photoinduced electron transfer (PET) effect. Although the addition of Cd2+ also induced an emission enhancement to a certain extent, this enhancement was less pronounced as compared to that of Zn2+, which was further demonstrated by DFT calculations. [Copyright &y& Elsevier]

Thrombocytopenia and thrombosis following treatment with the integrin alphaIIbbeta3 antagonist eptifibatide are rare complications caused by patient antibodies specific for ligand-occupied alphaIIbbeta3. Whether such antibodies induce platelet clearance by simple opsonization, by inducing mild platelet activation, or both is poorly understood. To gain insight into the mechanism by which eptifibatide-dependent antibodies initiate platelet clearance, we incubated normal human platelets with patient serum containing an alphaIIbbeta3-specific, eptifibatide-dependent antibody. We observed that in the presence of eptifibatide, patient IgG induced platelet secretion and aggregation as well as tyrosine phosphorylation of the integrin beta3 cytoplasmic domain, the platelet FcgammaRIIa Fc receptor, the protein-tyrosine kinase Syk, and phospholipase Cgamma2. Each activation event was inhibited by preincubation of the platelets with Fab fragments of the FcgammaRIIa-specific mAb IV.3 or with the Src family kinase inhibitor PP2. Patient serum plus eptifibatide did not, however, activate platelets from a patient with a variant form of Glanzmann thrombasthenia that expressed normal levels of FcgammaRIIa and the alphaIIbbeta3 complex but lacked most of the beta3 cytoplasmic domain. Taken together, these data suggest a novel mechanism whereby eptifibatide-dependent antibodies engage the integrin beta3 subunit such that FcgammaRIIa and its downstream signaling components become activated, resulting in thrombocytopenia and a predisposition to thrombosis. [ABSTRACT FROM AUTHOR]

Defects in apoptotic pathways can promote cancer development and cause cancers to become resistant to chemotherapy. The cell adhesion and signaling molecule PECAM-1 has been shown to potently suppress apoptosis in a variety of cellular systems. PECAM-1 expression has been reported on a variety of human malignancies—especially hematopoietic and vascular cell cancers—but the significance of this expression has not been fully explored. The ability of PECAM-1 to inhibit apoptosis makes it an attractive candidate as a molecule that may promote cancer development and/or confer resistance to chemotherapeutic treatment. The exact mechanisms by which PECAM-1 mediates its cytoprotection have not been fully defined, but its anti-apoptotic effects have been shown to require both homophilic binding and intracellular signaling via its immunoreceptor tyrosine-based inhibitory motif (ITIM) domains. In this review, we will discuss the data regarding PECAM-1's anti-apoptotic effects and ways in which this cytoprotection may be clinically relevant to the development and/or treatment of hematologic malignancies that express this vascular cell-specific surface molecule. [ABSTRACT FROM AUTHOR]

Abstract: Invited for the cover of this issue is the group of Xing‐Can Shen at the Guangxi Normal University. The image depicts how SWNH‐ICGs efficiently inhibit the growth of tumor cells under NIR light irradiation. Read the full text of the article at 10.1002/chem.201802611. [ABSTRACT FROM AUTHOR]

An "all-in-one" phototheranostic nanoplatform based on a single NIR-II light-responsive Schottky-type Bi 2 S 3-x -Au heterostructure for photoacoustic imaging-guided sonodynamic therapy-enhanced photodynamic/photothermal therapy. [Display omitted] Bismuth sulfide is widely used as an n -type semiconductor material in photocatalytic reactions. However, bismuth sulfide has poor absorption in the near-infrared region and low charge separation efficiency, limiting its application in phototherapy and sonodynamic therapy (SDT). In this study, we successfully synthesized an "all-in-one" phototheranostic nanoplatform, namely Bi 2 S 3-x -Au@HA, based on a single second near-infrared (NIR-II) light-responsive Schottky-type Bi 2 S 3-x -Au heterostructure for photoacoustic (PA) imaging-guided SDT-enhanced photodynamic therapy (PDT)/photothermal therapy (PTT). Bi 2 S 3-x -Au@HA exhibits excellent NIR-II plasmonic and photothermal properties, rendering it with NIR-II PA imaging capabilities for accurate diagnosis. Additionally, the high-density sulfur vacancies constructed on the Bi 2 S 3 surface cause it to possess a reduced band gap (1.21 eV) that can act as an electron trap. Using the density functional theory, we confirmed that the light and ultrasound-induced electrons are more likely to aggregate on the Au nanoparticle surface through interfacial self-assembly, which promotes electron-hole separation and enhances photocatalytic activity with increased reactive oxygen species (ROS) generation. With a further modification of hyaluronic acid (HA), Bi 2 S 3-x -Au@HA can selectively target cancer cells through HA and CD44 protein interactions. Both in vitro and in vivo experiments demonstrated that Bi 2 S 3-x -Au@HA effectively suppressed tumor growth through SDT-enhanced PTT/PDT under a single NIR-II laser and ultrasound irradiation with negligible toxicity. Our findings provide a framework for fabricating Schottky-type heterostructures as single NIR-II light-responsive nanotheranostic agents for PA imaging-guided cancer phototherapy. [ABSTRACT FROM AUTHOR]

Hemin-functionalized WS2 nanosheets (hemin/WS2-NSs) were first obtained by hemin assembled on the surface of few-layered WS2 nanosheets (WS2-NSs) via van der Waals interactions. Significantly, this new material possessed the advantages of both hemin and WS2 nanosheets and exhibited some unique properties. Firstly, hemin/WS2-NSs had intrinsic peroxidase-like activity, which could effectively catalyze oxidation of the substrate 3,3′,5,5′-tetramethylbenzidine (TMB) by H2O2 to produce a typical blue colored reaction. Secondly, the activity of hemin/WS2-NSs was much higher than the activity of hemin or WS2-NSs alone. The catalytic activity followed the typical Michaelis–Menten kinetics and was dependent on the temperature, pH, H2O2 concentration, as well as reaction time. Based on this finding, a new highly sensitive and selective colorimetric method for H2O2 and glucose detection was developed. This method was simple and inexpensive for glucose detection using glucose oxidase (GOx) and hemin/WS2-NSs with a linear range of 0.5 × 10−5 to 2.0 × 10−4 mol L−1 with a detection limit of 1.5 × 10−6 mol L−1. The good catalytic activity and low-cost make the hemin/WS2-NSs a useful biocatalyst for a wide range of potential applications in environmental chemistry, biotechnology and clinical diagnostics. [ABSTRACT FROM AUTHOR]

Background: Due to mTOR (mammalian/mechanistic target of rapamycin) gene-loss mice die during embryonic development, the role of mTOR in platelets has not been evaluated using gene knockout technology.Methods: A mouse model with megakaryocyte/platelet-specific deletion of mTOR was established, and be used to evaluate the role of mTOR in platelet activation and thrombus formation.Results: mTOR-/- platelets were deficient in thrombus formation when grown on low-concentration collagen-coated surfaces; however, no deficiency in thrombus formation was observed when mTOR-/- platelets were perfused on higher concentration collagen-coated surfaces. In FeCl3-induced mouse mesenteric arteriole thrombosis models, wild-type (WT) and mTOR-/- mice displayed significantly different responses to low-extent injury with respect to the ratio of occluded mice, especially within the first 40 min. Additionally, mTOR-/- platelets displayed reduced aggregation and dense granule secretion (ATP release) in response to low doses of the glycoprotein VI (GPVI) agonist collagen related peptide (CRP) and the protease-activated receptor-4 (PAR4) agonist GYPGKF-NH2; these deficiencies were overcame by stimulation with higher concentration agonists, suggesting dose dependence of the response. At low doses of GPVI or PAR agonist, the activation of αIIbβ3 in mTOR-/- platelets was reduced. Moreover, stimulation of mTOR-/- platelets with low-dose CRP attenuated the phosphorylation of S6K1, S6 and Akt Ser473, and increased the phosphorylation of PKCδ Thr505 and PKCε Ser729. Using isoform-specific inhibitors of PKCs (δ, ɛ, and α/β), we established that PKCδ/ɛ, and especially PKCδ but not PKCα/β or PKCθ, may be involved in low-dose GPVI-mediated/mTOR-dependent signaling.Conclusion: These observations indicate that mTOR plays an important role in GPVI-dependent platelet activation and thrombus formation. [ABSTRACT FROM AUTHOR]

Cys is a common and important sulfur-containing amino acid in living organisms, whose intracellular level changes are associated with a variety of diseases. To specifically detect Cys without interference from other thiol species has considerable significance. However, only selective fluorescent probes are available for cysteine detection; other thiol species can also have certain interference in the sensing process. Herein, we report an irreversible fluorescent probe for the specific detection of cysteine without interference from other thiol species both in living cells and zebrafish. The FR-NIR-Cys probe exhibits a large emission wavelength shift (up to 84 nm) and a significant ratio fluorescence enhancement (up to 41-fold) in the far-red and near-infrared region. Furthermore, we demonstrate that FR-NIR-Cys with good cell permeability can be employed in the far-red to near-infrared imaging of Cys in living cells and zebrafish. [ABSTRACT FROM AUTHOR]

IgG immune complexes contribute to the etiology and pathogenesis of numerous autoimmune disorders, including heparin-induced thrombocytopenia, systemic lupus erythematosus, rheumatoid- and collagen-induced arthritis, and chronic glomerulonephritis. Patients suffering from immune complex-related disorders are known to be susceptible to platelet-mediated thrombotic events. Though the role of the Fc receptor, FcγRIIa, in initiating platelet activation is well understood, the role of the major platelet adhesion receptor, integrin αIIbβ3, in amplifying platelet activation and mediating adhesion and aggregation downstream of encountering IgG immune complexes is poorly understood. The goal of this investigation was to gain a better understanding of the relative roles of these two receptor systems in immune complex-mediated thrombotic complications. Human platelets, and mouse platelets genetically engineered to differentially express FcγRIIa and αIIbβ3, were allowed to interact with IgG-coated surfaces under both static and flow conditions, and their ability to spread and form thrombi evaluated in the presence and absence of clinically-used fibrinogen receptor antagonists. Although binding of IgG immune complexes to FcγRIIa was sufficient for platelet adhesion and initial signal transduction events, platelet spreading and thrombus formation over IgG-coated surfaces showed an absolute requirement for αIIbβ3 and its ligands. Tyrosine kinases Lyn and Syk were found to play key roles in IgG-induced platelet activation events. Taken together, our data suggest a complex functional interplay between FcγRIIa, Lyn, and αIIbβ3 in immune complex-induced platelet activation. Future studies may be warranted to determine whether patients suffering from immune complex disorders might benefit from treatment with anti-αIIbβ3-directed therapeutics. [ABSTRACT FROM AUTHOR]

• The origin of unusual non-MLC mechanism is unveiled by DFT calculation. • The crucial role of spectator ligands in MLC catalysis is illuminated. • MLC catalyst based d7 metal center is designed and evaluated theoretically. Pincer complexes based on first-row transition metals have a wide range of applications in the field of homogeneous catalysis. However, the variable coordination geometry and electronic structure bring about complicated influencing factors, which restricts the deep understanding of the catalytic mechanisms. Herein, a detailed theoretical study based on the density functional theory (DFT) was conducted to illuminate the mechanistic preference of the isomerization of allyl alcohol catalyzed by the Co(II) pincer catalyst developed by de Vries et al. (Chem. Eur. J., 25 (2019) 7820–7825). Three different coordination geometries, two spin states (doublet and quartet) and corresponding pathways were taken into consideration. The calculation results suggest that the Co(II)-PNP catalyst prefers the inner-sphere migratory insertion mechanism at doublet state instead of metal-ligand cooperation (MLC) mechanism, which is consistent with the experimental results. Although the catalyst bears the N H functional ligands, the π−basic spectator ligands lead to the changeable coordination geometries, resulting in the emergence of spin crossover process with high energy barrier. Based on these findings, we designed a series of model catalysts and evaluated their catalytic activity on a theoretical level. The results indicate that π−acidic ligands and rigid tetradentate ligands can effectively avoid the occurrence of spin crossover processes and ensure that the Co(II) catalyst follows the MLC mechanism at low spin state. In addition, the activity of the catalyst can be precisely adjusted by changing the ligand substituents electronic effect. These findings and predictions are expected to provide guidance for future catalyst design. [Display omitted] [ABSTRACT FROM AUTHOR]

The Ig-ITIM family member PECAM-1 is expressed in vascular and endothelial cells, and its functions include suppression of mitochondria-dependent apoptosis. Previous studies have identified distinct PECAM-1 cytoplasmic domain splice variants at the mRNA, but not protein, level. Several relatively abundant mRNA isoforms lack exon 15 (Δ15) and would theoretically encode a protein with a truncated cytoplasmic domain and a unique C-terminal sequence. Using a novel rabbit polyclonal antibody that specifically recognizes Δ 15 PECAM-1, we found that the Δ 15 PECAM-1 isoform was expressed in human tissues, including brain, testes and ovary. This isoform was also expressed on the cell surface of human platelets, human umbilical vein endothelial cells (HUVECs) and the Jurkat T-cell leukemia, human erythroleukemia (HEL) and U937 histiocytic lymphoma cell lines. Furthermore, murine platelets and lung lysates demonstrated abundant amounts of exon-15-deficient PECAM-1. Functional studies revealed that Δ 15 PECAM-1 retains both its homophilic binding capacity and its ability to signal by means of its immunoreceptor tyrosine-based inhibitory motif (ITIM) domains. Δ 15 PECAM-1 was unable, however, to protect against apoptosis induced by overexpression of Bax or treatment with the chemotherapy agent etoposide. These studies suggest a novel role for the PECAM-1 C-terminus in cytoprotective signaling and highlight a need for further characterization of expression of PECAM-1 isoforms in normal and malignant tissues. [ABSTRACT FROM AUTHOR]

Background: Protein phosphorylation & dephosphorylation are ubiquitous cellular processes that allow for the nuanced and reversible regulation of protein activity. Protein phosphatase 2A (PP2A) is a multifunction phosphatase that is well expressed in all cell types of kidney during early renal development, though its functions in kidney remains to be elucidated. Methods: PP2A conditional knock-out mice was generated with PP2A fl/fl mice that were crossed with Podocin-Cre mice. The phenotype of Pod-PP2A–KO mice (homozygous for the floxed PP2A allele with Podocin-Cre) and littermate PP2A fl/fl controls (homozygous for the PP2A allele but lacking Podocin-Cre) were further studied. Primary podocytes isolated from the Pod-PP2A-KO mice were cultured and they were then employed with sing label-free nano-LC − MS/MS technology on a Q-exactive followed by SIEVE processing to identify possible target molecular entities for the dephosphorylation effect of PP2A, in which Western blot and immunofluorescent staining were used to analyze further. Results: Pod-PP2A–KO mice were developed with weight loss, growth retardation, proteinuria, glomerulopathy and foot process effacement, together with reduced expression of some slit diaphragm molecules and cytoskeleton rearrangement of podocytes. Y box protein 1 (YB-1) was identified to be the target molecule for dephosphorylation effect of PP2A. Furthermore, YB-1 phosphorylation was up-regulated in the Pod-PP2A–KO mice in contrast to the wild type controls, while total and un-phosphorylated YB-1 both was moderately down-regulated in podocytes from the Pod-PP2A-KO mice. Conclusion: Our study revealed the important role of PP2A in regulating the development of foot processes and fully differentiated podocytes whereas fine-tuning of YB-1 via a post-translational modification by PP2A regulating its activity might be crucial for the functional integrity of podocytes and glomerular filtration barrier. [ABSTRACT FROM AUTHOR]