Nanoarchitectonics of Bimetallic Cu-/Co-Doped Nitrogen-Carbon Nanozyme-Functionalized Hydrogel with NIR-Responsive Phototherapy for Synergistic Mitigation of Drug-Resistant Bacterial Infections.

Superbug infections and transmission have become major challenges in the contemporary medical field. The development of novel antibacterial strategies to efficiently treat bacterial infections and conquer the problem of antimicrobial resistance (AMR) is extremely important. In this paper, a bimetallic CuCo-doped nitrogen-carbon nanozyme-functionalized hydrogel (CuCo/NC-HG) has been successfully constructed. It exhibits photoresponsive-enhanced enzymatic effects under near-infrared (NIR) irradiation (808 nm) with strong peroxidase (POD)-like and oxidase (OXD)-like activities. Upon NIR irradiation, CuCo/NC-HG possesses photodynamic activity for producing singlet oxygen(1O2), and it also has a high photothermal conversion effect, which not only facilitates the elimination of bacteria but also improves the efficiency of reactive oxygen species (ROS) production and accelerates the consumption of GSH. CuCo/NC-HG shows a lower hemolytic rate and better cytocompatibility than CuCo/NC and possesses a positive charge and macroporous skeleton for restricting negatively charged bacteria in the range of ROS destruction, strengthening the antibacterial efficiency. Comparatively, CuCo/NC and CuCo/NC-HG have stronger bactericidal ability against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AmprE. coli) through destroying the cell membranes with a negligible occurrence of AMR. More importantly, CuCo/NC-HG plus NIR irradiation can exhibit satisfactory bactericidal performance in the absence of H2O2, avoiding the toxicity from high-concentration H2O2. In vivo evaluation has been conducted using a mouse wound infection model and histological analyses, and the results show that CuCo/NC-HG upon NIR irradiation can efficiently suppress bacterial infections and promote wound healing, without causing inflammation and tissue adhesions.

Biocompatible N-carbazoleacetic acid decorated CuxO nanoparticles as self-cascading platforms for synergistic single near-infrared triggered phototherapy treating microbial infections.

In this work, positively charged N-carbazoleacetic acid decorated CuxO nanoparticles (CuxO-CAA NPs) as novel biocompatible nanozymes have been successfully prepared through a one-step hydrothermal method. CuxO-CAA can serve as a self-cascading platform through effective GSH-OXD-like and POD-like activities, and the former can induce continuous generation of H2O2 through the catalytic oxidation of overexpressed GSH in the bacterial infection microenvironment, which in turn acts as a substrate for the latter to yield ˙OH via Fenton-like reaction, without introducing exogenous H2O2. Upon NIR irradiation, CuxO-CAA NPs possess a high photothermal conversion effect, which can further improve the enzymatic activity for increasing the production rate of H2O2 and ˙OH. Besides, the photodynamic performance of CuxO-CAA NPs can produce 1O2. The generated ROS and hyperthermia have synergetic effects on bacterial mortality. More importantly, CuxO-CAA NPs are more stable and biosafe than Cu2O, and can generate electrostatic adsorption with negatively charged bacterial cell membranes and accelerate bacterial death. Antibacterial results demonstrate that CuxO-CAA NPs are lethal against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AREC) through destroying the bacterial membrane and disrupting the bacterial biofilm formation. MRSA-infected animal wound models show that CuxO-CAA NPs can efficiently promote wound healing without causing toxicity to the organism.

Construction of Mn-N-C nanoparticles with multienzyme-like properties and photothermal performance for the effective treatment of bacterial infections.

In this work, we successfully constructed Mn-coordinated nitrogen-carbon nanoparticles (Mn-N-C NPs) exhibiting multienzyme-like activities. In a bacterial infectious microenvironment, the POD-like and OXD-like activities of Mn-N-C NPs could synergistically trigger the generation of ROS (˙OH and O2˙-), causing oxidative damage to the bacterial cell membrane for killing bacteria. Alternatively, in neutral or weak alkaline normal tissues, the excessive O2˙- could be converted into O2 and H2O2via the SOD-like ability of Mn-N-C NPs, and subsequently their CAT-like activity catalyzed excess H2O2 into H2O and O2 for protecting normal cells through the antioxidant defense. Mn-N-C NPs also possessed a good NIR-photothermal performance, which could enhance their POD-like and OXD-like activities. Furthermore, Mn-N-C NPs could facilitate the GSH oxidation process and disrupt the intrinsic balance in the bacterial protection microenvironment with the assistance of H2O2, which is beneficial for rapid bacterial death. Undoubtedly, the Mn-N-C NPs + H2O2 system showed the highest antibacterial activity when irradiated with an 808 nm laser, destroying the bacterial membrane and causing the efflux of proteins. Moreover, the Mn-N-C NPs + H2O2 system was immune to the development of bacterial resistance and could efficiently disrupt the formation of a bacterial biofilm with negligible cytotoxicity and low hemolysis ratio. Finally, Mn-N-C NPs exhibited an excellent antibacterial performance in vivo and could accelerate wound healing without cellular inflammation production. Therefore, due to their significant therapeutic effects, Mn-N-C NPs show great potential in fighting antibiotic-resistant bacteria.

Cuprous oxide-demethyleneberberine nanospheres for single near-infrared light-triggered photoresponsive-enhanced enzymatic synergistic antibacterial therapy.

In this work, novel cuprous oxide-demethyleneberberine (Cu2O-DMB) nanomaterials are successfully synthesized for photoresponsive-enhanced enzymatic synergistic antibacterial therapy under near-infrared (NIR) irradiation (808 nm). Cu2O-DMB has a spherical morphology with a smaller nanosize and positive ζ potential, can trap bacteria through electrostatic interactions resulting in a targeting function. Cu2O-DMB nanospheres show both oxidase-like and peroxidase-like activities, and serve as a self-cascade platform, which can deplete high concentrations of GSH to produce O2˙- and H2O2, then H2O2 is transformed into ˙OH, without introducing exogenous H2O2. At the same time, Cu2O-DMB nanospheres become photoresponsive, producing 1O2 and having an efficient photothermal conversion effect upon NIR irradiation. The proposed mechanism is that the generated ROS (O2˙-, ˙OH and 1O2) and hyperthermia can have synergetic effects for killing bacteria. Moreover, hyperthermia is not only beneficial for destroying bacteria, but also effectively enhances the efficiency of ˙OH production and accelerates GSH oxidation. Upon NIR irradiation, Cu2O-DMB nanospheres exhibit excellent antibacterial ability against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AREC) with low cytotoxicity and bare bacterial resistance, destroy the bacterial membrane causing an efflux of proteins and disrupt the bacterial biofilm formation. Animal experiments show that the Cu2O-DMB + NIR group can efficiently treat MRSA infection and promote wound healing. These results suggest that Cu2O-DMB nanospheres are effective materials for combating bacterial infections highly efficiently and to aid the development of photoresponsive enzymatic synergistic antibacterial therapy.

The Significance of PAX8-PPARγ Expression in Thyroid Cancer and the Application of a PAX8-PPARγ-Targeted Ultrasound Contrast Agent in the Early Diagnosis of Thyroid Cancer.

Objective: To investigate the significance of PAX8-PPARγ expression in thyroid cancer and the application of a PAX8-PPARγ-targeted ultrasound contrast agent in the early diagnosis of thyroid cancer. Methods: In this study, the expression of PAX8-PPARγ in thyroid cancer tissues, paracancer groups, and normal thyroid tissues was detected by western and immunohistochemical techniques; the effects of PAX8-PPARγ expression inhibition on thyroid cancer cell growth, clonogenic ability, and antiapoptosis were examined. The terminal carboxylactic acid/hydroxyacetic acid copolymer (PLGA-COOH) nanoparticles were prepared by the double emulsification solvent volatilization method. The in vitro cytotoxicity of the targeted contrast agent was detected by MTS and other methods; LD50 was used to evaluate its short-term in vivo toxicity after intraperitoneal injection in mice. Results: PAX8-PPARγ expression was significantly increased in thyroid cancer tissues, and the expression level of PAX8-PPARγ was closely correlated with TNM staging and lymph node metastasis (P < 0.05). In addition, PAX8-PPARγ was also expressed at high levels in thyroid cancer cell lines relative to normal thyroid cells. MTS experiments showed that the PAX8-PPARγ-targeted ultrasound nanocontrast agent had no significant toxic side effects on thyroid cells; countess observed that the contrast agent had no effect on cell survival and mortality; the LD50 assay showed that the targeted contrast agent had a wide safety range. Western blot showed the expression of caspase-3, BAX, and Bcl-2 in thyroid cancer cells, indicating that the nanocontrast agent has a good biosafety. In vitro targeting experiments showed that there were more nanospheres aggregated around the cells in the targeted contrast group. In vivo targeting imaging of nude mice revealed that the ultrasound signal was significantly enhanced in the targeted group compared with the nontargeted group after 20 min of LIFU irradiation. Conclusion: PAX8-PPARγ overexpression in thyroid cancer cell lines and thyroid cancer tissues promoted the proliferation and antiapoptotic ability of thyroid cancer cells and promoted the tumorigenic ability in nude mice in vivo. We successfully prepared a PAX8-PPARγ-targeted ultrasound nanocontrast agent, which has regular morphology, uniform size, and high stability, and its liquid-gas phase change can be promoted at lower temperature. Therefore, this contrast agent can achieve US-targeted imaging and temperature phase transition function, and may have enhanced ultrasound imaging potential.

Dispositional Negative Emotionality in Childhood and Adolescence Predicts Structural Variation in the Amygdala and Caudal Anterior Cingulate During Early Adulthood: Theoretically and Empirically Based Tests.

Substantial evidence implicates the amygdala and related structures in the processing of negative emotions. Furthermore, neuroimaging evidence suggests that variations in amygdala volumes are related to trait-like individual differences in neuroticism/negative emotionality, although many questions remain about the nature of such associations. We conducted planned tests of the directional prediction that dispositional negative emotionality measured at 10-17 years using parent and youth ratings on the Child and Adolescent Dispositions Scale (CADS) would predict larger volumes of the amygdala in adulthood and conducted exploratory tests of associations with other regions implicated in emotion processing. Participants were 433 twins strategically selected for neuroimaging during wave 2 from wave 1 of the Tennessee Twins Study (TTS) by oversampling on internalizing and/or externalizing psychopathology risk. Controlling for age, sex, race-ethnicity, handedness, scanner, and total brain volume, youth-rated negative emotionality positively predicted bilateral amygdala volumes after correction for multiple testing. Each unit difference of one standard deviation (SD) in negative emotionality was associated with a .12 SD unit difference in larger volumes of both amygdalae. Parent-rated negative emotionality predicted greater thickness of the left caudal/dorsal anterior cingulate cortex (ß = 0.28). Associations of brain structure with negative emotionality were not moderated by sex. These results are striking because dispositions assessed at 10-17 years of age were predictive of grey matter volumes measured 12-13 years later in adulthood. Future longitudinal studies should examine the timing of amygdala/cingulate associations with dispositional negative emotionality to determine when these associations emerge during development.

Sex differences in associations of socioemotional dispositions measured in childhood and adolescence with brain white matter microstructure 12 years later.

Predictive associations were estimated between socioemotional dispositions measured at 10-17 years using the Child and Adolescent Dispositions Scale (CADS) and future individual differences in white matter microstructure measured at 22-31 years of age. Participants were 410 twins (48.3% monozygotic) selected for later neuroimaging by oversampling on risk for psychopathology from a representative sample of child and adolescent twins. Controlling for demographic covariates and total intracranial volume (TICV), each CADS disposition (negative emotionality, prosociality, and daring) rated by one of the informants (parent or youth) significantly predicted global fractional anisotropy (FA) averaged across the major white matter tracts in brain in adulthood, but did so through significant interactions with sex after false discovery rate (FDR) correction. In females, each 1 SD difference in greater parent-rated prosociality was associated with 0.43 SD greater FA (p < 0.0008). In males, each 1 SD difference in greater parent-rated daring was associated with 0.24 SD lower FA (p < 0.0008), and each 1 SD difference in greater youth-rated negative emotionality was associated with 0.18 SD greater average FA (p < 0.0040). These findings suggest that CADS dispositions are associated with FA, but associations differ by sex. Exploratory analyses suggest that FA may mediate the associations between dispositions and psychopathology in some cases. These associations over 12 years could reflect enduring brain-behavior associations in spite of transactions with the environment, but could equally reflect processes in which dispositional differences in behavior influence the development of white matter. Future longitudinal studies are needed to resolve the causal nature of these sex-moderated associations.