The use of untargeted and widely targeted metabolomics to distinguish between asphyxia and sudden cardiac death as the cause of death in rats: A preliminary study

It is important to determine the cause of death in the case of asphyxia. However, it is difficult to conclude death by asphyxia, especially when the deceased has underlying heart disease, because there are often no specific and representative corpse signs for both asphyxia and sudden cardiac death (SCD). The aim of the present work was to investigate the potential of metabolomics to discriminate asphyxia from SCD as the cause of death. A total of thirty male Sprague–Dawley rats were used to construct models of asphyxia, SCD (interfering cause of death), and cervical dislocation (control). Untargeted and widely targeted metabolomics approaches were used to obtain rat pulmonary metabolic profiles in this study. First, the metabolic alterations resulting from asphyxia were explored. There were significant changes found in carbohydrate metabolism, the endocrine system, and the sensory system. Second, we screened potential biomarkers and built classification models to determine the cause of death. Moreover, some biomarkers remained differentiated at 24 h and 48 h postmortem, so the cause of death could still be determined after death. This study showed the application potential of metabolomics to investigate the metabolic changes occurring in the process of death, as well as to determine the cause of death on the basis of metabolic differences even after death.     

Topical application of zein-silk sericin nanoparticles loaded with curcumin for improved therapy of dermatitis

Atopic dermatitis is characterized by leukocyte migration into the skin dermis and typically driven by excessive chemokine production at the site of inflammation. Conventional topical formulations such as gels, creams, and ointments are insufficient for this treatment because of low penetration of drug molecules into the targeted skin tissues. Herein, using a simple, green, sustainable strategy, we have developed novel primary zein nanoparticles embedded in curcumin (Cur) and coated with silk sericin (ZHSCs) for the topical delivery of Cur to penetrate into the dermis and exercise anti-dermatitis effects on the lesion with minimal side-effects. Transdermal delivery experiments and porcine skin fluorescence imaging indicated that ZHSCs facilitate the penetration of Cur across the epidermis layer of skin to reach deep-seated sites. Notably, ZHSCs = 1:0.25 (zein-to-silk sericin mass ratios of 1:0.25) markedly elevated the skin permeability and cumulative turnover of Cur transferred, which were provided a greater than a 3.8-fold increase relative to free Cur. The special nanoparticles of ZHS = 1:0.25 possessed the deepest localization depth and experience a transition of the particle structure and core-shell separation after penetrating into the dermis of skin. In a cell model of dermatitis induced by tumor necrosis factor α/interferon γ co-stimulation, compared with free Cur, Cur-loaded ZHS nanoparticles down-regulated the generation of inflammatory cytokines and chemokines in keratinocytes through suppression of the nuclear translocation of NF-κBp65 and hence exerted an anti-dermatitis effect. This strategy may provide new avenues and direction for the demanding issues of valid topical delivery systems.     

Dendritic polyurethane-based prodrug as unimolecular micelles for precise ultrasound-activated localized drug delivery

Ultrasound has been recognized as an exciting tool to enhance the therapeutic efficacy in tumor chemotherapy owing to the triggered drug release, facilitated intracellular drug delivery, and improved spatial precision. Aiming for a precise localized drug delivery, novel dendritic polyurethane-based prodrug (DOX-DPU-PEG) was fabricated with a drug content of 18.9% here by conjugating DOX onto the end groups of the functionalized dendritic polyurethane via acid-labile imine bonds. It could easily form unimolecular micelles around 38 nm. Compared with the non-covalently drug-loaded unimolecular micelles (DOX@Ph-DPU-PEG), they showed excellent pH/ultrasound dual-triggered drug release performance, with drug leakage of only 4% at pH 7.4, but cumulative release of 14% and 88% at pH 5.0 without and with ultrasound, respectively. The ultrasound responsiveness was attributed to the unique strawberry-shaped topological structure of the DOX-DPU-PEG, in which DOX was embedded in the skin layer of the hydrophobic DPU cores. With ultrasound, the DOX-DPU-PEG unimolecular micelles possessed enhanced tumor growth inhibition than free DOX but showed no obvious cytotoxicity on the tumor cells without ultrasound. Such feature makes them promising potential for precise localized drug delivery.     

Development of Lysosome-Targeted Fluorescent Probes for Cys by Regulating the Boron-dipyrromethene (BODIPY) Molecular Structure

Our previous discovery suggested that substituents on the 1,7 positions delicately modulate the sensing ability of the meso-arylmercapto boron-dipyrromethene (BODIPY) to biothiols. In this work, the impact of delicate modulations on the sensing ability is investigated. Therefore, 1,7-dimethyl, 3,5-diaryl substituted BODIPY is designed and developed and its conformationally restricted species with a meso-arylmercapto moiety ( DM-BDP-SAr and DM-BDP-R-SAr ) as selective fluorescent probes for Cys. Moreover, the lysosome-target probes ( Lyso-S and Lyso-D ) based on DM-BDP-SAr carrying one or two morpholinoethoxy moieties were developed. They were able to detect Cys selectively in vitro with low detection limits. Both Lyso-S and Lyso-D localized nicely in lysosomes in living HeLa cells and exhibited red fluorescence for Cys. Moreover, a novel fluorescence quenching mechanism was proposed from the calculations by density functional theory (DFT). The probes may go through intersystem crossing (from singlet excited state to triplet excited state) to result in fluorescence quenching.     

Redox‐responsive Fluorescent Nanoparticles Based on Diselenide‐containing AIEgens for Cell Imaging and Selective Cancer Therapy

A fluorescent, diselenide‐containing 9,10‐distyrylanthracene (DSA) derivative (SeDSA) with aggregation‐induced emission (AIE) characteristic was successfully synthesized and SeDSA nanoparticles (NPs) were prepared through a nanoprecipitation method. SeDSA could coassemble with an antitumor prodrug, diselenide‐containing paclitaxel (SePTX), which could be obtained by precipitation, to form SeDSA‐SePTX Co‐NPs (Co‐NPs). Molecular dynamics (MD) simulations reveal that the driving forces for the self‐assembly behaviors of SeDSA NPs and SePTX NPs are π–π interactions and hydrophobic interactions, respectively, while the driving forces for Co‐NPs include hydrophobic interactions between SeDSA and SePTX, π–π interactions between SeDSA molecules and hydrophobic interactions between SePTX molecules. Meanwhile, Se‐Se bonds play a crucial role in balancing the intramolecular forces. These diselenide‐containing nanoparticles (SeDSA NPs, SePTX NPs and Co‐NPs) exhibit a high stability under physiological conditions and excellent reduction‐sensitivity in the presence of the redox agent glutathione (GSH) because of the selenium‐sulfur exchange reaction between diselenide and GSH. Both SeDSA NPs and Co‐NPs show strong orange fluorescence emissions on the account of the AIE feature of SeDSA and they were easily internalized by HeLa and HepG2 cells. Distinctively, the Co‐NPs combine the advantage of SeDSA and SePTX for cell imaging and antineoplastic activity, and exhibit selectivity of cytotoxicities between neoplasia cells and normal cells. This study highlights the development of diselenide‐containing AIEgens as a unique approach to prepare uniform and stable fluorescent nanoparticles for the application in cell imaging and tumor treatment.     

Decision diagrams for solving traveling salesman problems with pickup and delivery in real time

The Traveling Salesman Problem with Pickup and Delivery seeks a minimum cost path with pickups preceding deliveries. It is important in on-demand last-mile logistics, such as ride sharing and meal delivery. We examine the use of low-width Decision Diagrams in a branch-and-bound with and without Assignment Problem inference duals as a primal heuristic for finding good solutions within strict time budgets. We show these diagrams can be more effective than similarly structured hybrid Constraint Programming techniques for real-time decision making.     

Novel drug‐eluting soy‐protein structures for wound healing applications

Naturally derived materials are becoming widely used in the biomedical field. Soy protein has advantages over the various types of natural proteins employed for biomedical applications due to its low price, nonanimal origin, and relatively long storage time and stability. In the current study, novel drug‐eluting soy‐protein films for wound healing applications were developed and studied. The films were prepared using the solvent casting technique. The analgesic drug bupivacaine and two types of wide range antibiotics (gentamicin and clindamycin) were incorporated into the soy‐protein films. The effect of drug incorporation and plasticizers content on the films' mechanical properties, drug release profiles, and cell viability was studied. Drug incorporation had a softening effect of the films, lowering mechanical strength and increasing ductility. Release profiles of bupivacaine and clindamycin exhibited high burst release of 80% to 90% of encapsulated drug within 6 hours, followed by continuous release in a decreasing rate for a period of 2 to 4 days. Gentamicin release was prolonged, probably due to interaction between the gentamicin and the polymer chains. Hybrid soy‐protein/poly (Dl‐lactic‐co‐glycolic acid) (PDLGA) microspheres structure showed potential for long and sustained release of bupivacaine. Films with no drugs and films loaded with gentamicin were found to be noncytotoxic for human fibroblasts, while bupivacaine and clindamycin were found to have some effect on cell growth. In conclusion, our new drug‐loaded soy‐protein films combine good mechanical properties and biocompatibility, with desired drug release profiles, and can therefore be potentially very useful as burn and ulcer dressings.     

Hydrogen-Bond Cyclization Programming of Ultrasensitive Esters and Its Application in Gene Delivery

The ester bond as a universal linker has recently been applied in gene delivery systems owing to its efficient gene release by electrostatic repulsion after its cleavage. However, the ester bond is nonlabile and is difficult to cleave in cells. This work reports a method in which a secondary amine was introduced to the β-position of the ester bond to generate a hydrogen-bond cyclization (HBC) structure that can make the ester bond hydrolysis ultrafast. A series of molecules comprising ultrasensitive esters that can be activated by H₂O₂ were synthesized, and it was found that those able to form an HBC structure showed complete ester hydrolysis within 5 h in both water and phosphate-buffered saline solution, which was several times faster than other methods reported. Then, a series of amphiphilic poly(amidoamine) dendrimers were constructed, comprising the ultrasensitive ester groups for gene delivery; it was found that they could effectively release genes under quite a low concentration of H₂O₂ (<200 μm ) and transport them into the nucleus within 2 h in Hela cells with high safety. Their gene transfection efficiencies were higher than that of PEI_25k. The results demonstrated that the hydrogen-bond-induced ultrasensitive esters could be powerfully applied to construct gene delivery systems.     

Recent developments in Pickering emulsions for biomedical applications

Pickering emulsions, stabilised by organic or inorganic particles, offer long-term dispersibility of liquid droplets and resistance to coalescence. The versatility of stabilising particles and their ability to encapsulate and release cargo with high internal payload capacity makes them attractive in a wide variety of applications, ranging from catalysis to the cosmetic and food industry. While these properties make them an equally promising material platform for pharmaceutical and clinical applications, the development of Pickering emulsions for healthcare is still in its infancy. Herein, we summarise and discuss recent progress in the development of Pickering emulsions for biomedical applications, probing their design for passive diffusion-based release as well as stimuli-responsive destabilisation. We further comment on challenges and future directions of this exciting and rapidly expanding area of research.     

Fe3O4 – Glutathione stabilized Ag nanoparticles: A new magnetically separable robust and facile catalyst for aqueous phase reduction of nitroarenes

The heterostructured Ag nanoparticles decorated Fe₃O₄ Glutathione (Fe₃O₄‐Glu‐Ag) nanoparticles (NPs) were synthesized by sonicating glutathione (Glu) with magnetite and further surface immobilization of silver NPs on it. The ensuing magnetic nano catalyst is well characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), powder X‐ray diffraction (PXRD), thermogravimetric analysis (TGA). The prepared Fe₃O₄‐Glu‐Ag nanoparticles have proved to be an efficient and recyclable nanocatalyst with low catalyst loading for the reduction of nitroarenes and heteronitroarenes to respective amines in the presence of NaBH₄ using water as a green solvent which could be easily separated at the end of a reaction using an external magnet and can be recycled up to 5 runs without any significant loss in catalytic activity. Gram scale study for the reduction of 4‐NP has also being carried out successfully and it has been observed that this method can serve as an efficient protocol for reduction of nitroarenes on industrial level.