Coenzyme-depleting nanocarriers for enhanced redox cancer therapy under hypoxia.

Cancer cells show unique redox homeostasis. Glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play essential roles as coenzymes of multiple key antioxidant enzymes. Coenzyme depletion offers a unique opportunity for cancer treatment by inducing oxidative stress. Here, we report an innovative hybrid nanocarrier for cancer redox therapy via selective depletion of GSH and NADPH. The nanocarrier core is a sorafenib-loaded porous zeolitic imidazole framework (ZIF-65), and the shell is epigallocatechin gallate (EGCG)-Fe3+ complex (EF). The nitroimidazole ligand in ZIF-65 could selectively deplete NADPH under hypoxia. Sorafenib diminished GSH by inhibiting cystine import and GSH biosynthesis. EGCG can reduce Fe3+ to Fe2+, which aids the generation of hydroxyl radicals via the Fenton reaction. The reversible coordination between nitroimidazole and Zn2+, EGCG, and Fe3+ enables triggered cargo release in acidic lysosomes. Tailored nanocarriers induced the depletion of both coenzymes (GSH and NADPH) and boosted reactive oxygen species in a 4T1 murine cancer cell line. The altered redox balance eventually resulted in efficient apoptotic cell death. The current work offers a novel means of redox cancer therapy via the selective depletion of key antioxidant enzymes in hypoxic cells.

Surface Plasmon Effect Dominated High-Performance Triboelectric Nanogenerator for Traditional Chinese Medicine Acupuncture.

Available, effectively converting low-frequency vibration into available electricity, triboelectric nanogenerator (TENG) is always research hot nowadays. However, the enhancing effect of the existing methods for the output have all sorts of drawbacks, i.e., low efficiency and unstable, and its practical applications still need to be further explored. Here, leveraging core-shell nanoparticles Ag@SiO2 doping into tribo-materials generates the surface plasmon effect to boost the output performance of the TENG. On one hand, the shell alleviated the seepage effect from conventional nanoparticles; on the other hand, the surface plasmon effect enabled the core-shell nanoparticles to further boost the output performance of TENG. We circumvent the limitations and present a TENG whose output power density can be up to 4.375 mW/cm2. Points is that this article novelty investigate the high-performance TENG applicating for traditional Chinese medicine and develop a pratical self-powered acupuncture system. This technology enables rapid, routine regulation of human health at any age, which has potential applications in nearly any setting across healthcare platforms alike.

One-step synthesis of garlic peel derived biochar by concentrated sulfuric acid: Enhanced adsorption capacities for Enrofloxacin and interfacial interaction mechanisms.

This study put forward a one-step carbonization method by concentrated sulfuric acid to prepare garlic peel derived biochar, and the synthetic conditions were optimized by L16(45) orthogonal experiments. Notably, in order to study the differences between the proposed synthetic method and the conventional pyrolysis method, the concentrated sulfuric acid carbonized garlic peels biochar (CSGPB) was compared with pyrolysis derived garlic peel biochar (HTGPB) in characterization and adsorption capacities for Enrofloxacin (ENR). Results showed that CSGPB exhibited more graphite-like structures with more active functional groups on the surface, and the equilibrium adsorption capacity of CSGPB (142.3 mg g-1) was 13.7 times of HTGPB (10.4 mg g-1) under identical conditions. Moreover, the adsorption behaviors including adsorption kinetics, isotherms and thermodynamics of CSGPB for ENR were fully investigated and discussed. Based on the above experiments, density functional theory (DFT) simulations were performed to reveal the interfacial interaction and adsorption mechanism. Results showed π-π interaction between quinolone moieties of ENR and graphite-like structures in CSGPB might be the dominant mechanism. As for the functional groups, the adsorption energies were -40.46, -15.21 and -5.96 kJ mol-1 for -SO3H, -OH and -COOH, respectively, which indicated -SO3H was the most active functional groups on the surface of CSGPB. This study provided a new sustainable perspective for the design of efficient biochars, and explored the interfacial interaction mechanism of antibiotics removal on biochars.

Boosting the Ferroptotic Antitumor Efficacy via Site-Specific Amplification of Tailored Lipid Peroxidation.

Ferroptosis is an iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive cancer cells. The ferroptosis-inducing molecules are tailored lipid peroxides whose efficacy is compromised in hypoxic solid tumor and lack of tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill cancer cells via accumulating hydrogen peroxide (H2O2) only in tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of hydroxyl radicals and oxygen in the tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with lipid-coated calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting lipid peroxide repair enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of hydroxyl radicals, lipid peroxides, and depleted glutathione under hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 ± 0.2 µM) in the model 4 T1 cells. In the 4 T1 tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid tumors without inducing additional side effects.

All-active antitumor micelles via triggered lipid peroxidation.

Traditional antitumor nanomedicines have been suffering from the poor tumor targeting (ca. 1%) by the enhanced permeability and retention (EPR) effect, and the low drug loading (<5%). It was postulated that engineering all-active nanoplatform could increase the therapeutic efficacy to enable the nanocarrier function as both vehicle and active ingredient. To achieve this, a photosensitizer, Ce6 was encapsulated within polymeric micelles with unsaturated fatty acids as the building blocks. Upon light irradiation, the singlet oxygen produced by Ce6 induced lipid peroxidation, resulting in the generation of both active free radicals and aldehydes. These supplementary radicals could exert cytotoxic effect for direct killing tumor cells. The aldehyde end-products induced significant cell cycle arrest at G2 phase in 4T1 cells. The peroxidation process also facilitated the on-demand disassembly of micelles and rapid release of Ce6 to maximize the therapeutic effect of singlet oxygen. These all-active micelles showed a significantly enhanced cytotoxicity with the half maximal inhibitory concentration (IC50) of 0.6 ±â€¯0.2 µg/mL in contrast to the control micelles at 3.4 ±â€¯0.5 µg/mL. The improved antitumor efficacy of the all-active micelles was also demonstrated in the 4T1 tumor-bearing mice in vivo. The current work provides a facile approach to enhance the antitumor efficacy of PDT nanomedicine using the biocompatible fatty acids, which can be applied to various antitumor drugs and unsaturated lipids.

Vitamin D status and related factors in newborns in Shanghai, China.

With the increasing recognition of the importance of the non-skeletal effects of vitamin D (VitD), more and more attention has been drawn to VitD status in early life. However, the VitD status of newborns and factors that influence VitD levels in Shanghai, China, remain unclear. A total of 1030 pregnant women were selected from two hospitals in Shanghai, one of the largest cities in China located at 31 degrees north latitude. Umbilical cord serum concentrations of 25-hydroxy vitamin D [25(OH)D] were measured by LC-MS-MS, and questionnaires were used to collect information. The median cord serum 25(OH)D concentration was 22.4 ng/mL; the concentration lower than 20 ng/mL accounted for 36.3% of the participants, and the concentration lower than 30 ng/mL for 84.1%. A multivariable logistic regression model showed that the determinants of low 25(OH)D status were being born during autumn or winter months and a lack of VitD-related multivitamin supplementation. The relative risk was 1.7 for both autumn (95% CI, 1.1-2.6) and winter (95% CI, 1.1-2.5) births (p < 0.05). VitD-related multivitamin supplementation more than once a day during pregnancy reduced the risk of VitD deficiency [adjusted OR (aOR) = 0.6, 95% CI (0.45-1.0) for VitD supplementation] (p < 0.05). VitD deficiency and insufficiency are common in newborns in Shanghai, China, and are independently associated with season and VitD supplementation. Our findings may assist future efforts to correct low levels of 25(OH)D in Shanghai mothers and their newborn children.

A cascade amplification strategy based on rolling circle amplification and hydroxylamine amplified gold nanoparticles enables chemiluminescence detection of adenosine triphosphate.

A highly sensitive and selective chemiluminescent (CL) biosensor for adenosine triphosphate (ATP) was developed by taking advantage of the ATP-dependent enzymatic reaction (ATP-DER), the powerful signal amplification capability of rolling circle amplification (RCA), and hydroxylamine-amplified gold nanoparticles (Au NPs). The strategy relies on the ability of ATP, a cofactor of T4 DNA ligase, to trigger the ligation-RCA reaction. In the presence of ATP, the T4 DNA ligase catalyzes the ligation reaction between the two ends of the padlock probe, producing a closed circular DNA template that initiates the RCA reaction with phi29 DNA polymerase and dNTP. Therein, many complementary copies of the circular template can be generated. The ATP-DER is eventually converted into a detectable CL signal after a series of processes, including gold probe hybridization, hydroxylamine amplification, and oxidative gold metal dissolution coupled with a simple and sensitive luminol CL reaction. The CL signal is directly proportional to the ATP level. The results showed that the detection limit of the assay is 100 pM of ATP, which compares favorably with those of other ATP detection techniques. In addition, by taking advantage of ATP-DER, the proposed CL sensing system exhibits extraordinary specificity towards ATP and could distinguish the target molecule ATP from its analogues. The proposed method provides a new and versatile platform for the design of novel DNA ligation reaction-based CL sensing systems for other cofactors. This novel ATP-DER based CL sensing system may find wide applications in clinical diagnosis as well as in environmental and biomedical fields.

Pharmacokinetic evaluation of intranasally administered vinyl polymer-coated lorazepam microparticles in rabbits.

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 µm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 µm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 µm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9 min; MP2, T (max) 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.

Using Chou's pseudo amino acid composition based on approximate entropy and an ensemble of AdaBoost classifiers to predict protein subnuclear location.

The knowledge of subnuclear localization in eukaryotic cells is essential for understanding the life function of nucleus. Developing prediction methods and tools for proteins subnuclear localization become important research fields in protein science for special characteristics in cell nuclear. In this study, a novel approach has been proposed to predict protein subnuclear localization. Sample of protein is represented by Pseudo Amino Acid (PseAA) composition based on approximate entropy (ApEn) concept, which reflects the complexity of time series. A novel ensemble classifier is designed incorporating three AdaBoost classifiers. The base classifier algorithms in three AdaBoost are decision stumps, fuzzy K nearest neighbors classifier, and radial basis-support vector machines, respectively. Different PseAA compositions are used as input data of different AdaBoost classifier in ensemble. Genetic algorithm is used to optimize the dimension and weight factor of PseAA composition. Two datasets often used in published works are used to validate the performance of the proposed approach. The obtained results of Jackknife cross-validation test are higher and more balance than them of other methods on same datasets. The promising results indicate that the proposed approach is effective and practical. It might become a useful tool in protein subnuclear localization. The software in Matlab and supplementary materials are available freely by contacting the corresponding author.