Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment.

Nanocarriers have been widely studied and applied in the field of cancer treatment. However, conventional nanocarriers still suffer from complicated preparation processes, low drug loading, and potential toxicity of carriers themselves. To tackle the hindrance, carrier-free nanodrugs with biological activity have received increasing attention in cancer therapy. Extensive efforts have been made to exploit new self-assembly methods and mechanisms to expand the scope of carrier-free nanodrugs with enhanced therapeutic performance. In this review, we summarize the advanced progress and applications of carrier-free nanodrugs based on different types of assembly mechanisms and strategies, which involved noncovalent interactions, a combination of covalent bonds and noncovalent interactions, and metal ions-coordinated self-assembly. These carrier-free nanodrugs are introduced in detail according to their assembly and antitumor applications. Finally, the prospects and existing challenges of carrier-free nanodrugs in future development and clinical application are discussed. We hope that this comprehensive review will provide new insights into the rational design of more effective carrier-free nanodrug systems and advancing clinical cancer and other diseases (e.g., bacterial infections) infection treatment.

Correction to "Spatiotemporally dynamic therapy with shape-adaptive drug-gel for the improvement of tissue regeneration with ordered structure" [Bioact. Mater. 8 (2022) 165-176].

[This corrects the article DOI: 10.1016/j.bioactmat.2021.06.015.].

Multicomponent carrier-free nanodrugs for cancer treatment.

Nanocarriers can be used to deliver insoluble anticancer drugs to optimize therapeutic efficacy. However, the potential toxicity of nanocarriers cannot be ignored. Carrier-free nanodrugs are emerging safe drug delivery systems, which are composed of multiple components, such as drugs, bioactive molecules and functional ingredients, avoiding the usage of inert carrier materials and offering advantages that include high drug loading, low toxicity, synergistic therapy, versatile design, and easy surface functionalization. Therefore, how to design multicomponent carrier-free nanodrugs is becoming a priority. In this review, the common strategies for rapid construction of multicomponent carrier-free nanodrugs are briefly explored from the perspective of methodology. The properties of organic-organic, organic-inorganic and inorganic-inorganic multiple carrier-free nanosystems are analyzed according to wettability and in-depth understanding is provided. Further advances in the applications of multiple carrier-free nanodrugs are outlined in anticipation of grasping the intrinsic nature for the design and development of carrier-free nanodrugs.

Pea pod-mimicking hydroxyapatite nanowhisker-reinforced poly(lactic acid) composites with bone-like strength.

The anisotropic hierarchical structures of naturally derived materials have offered useful design principles for the fabrication of high-strength and functional materials. Herein, we unraveled a structure-by-bionics approach to construction of pea pod-mimicking architecture for poly(lactic acid) (PLA) composites impregnated with hydroxyapatite nanowhiskers (HANWs). The HANWs (length of 80-120 nm, diameter of ~30 nm) were customized using microwave-assisted aqueous biomineralization at minute level, which were incorporated into PLA microfibers by electrospinning with filler loadings of 10-30 wt%. The membranes comprising HANW-modified PLA microfibers were stacked and structured into composite films, strategically involving high-pressure compression at a relatively low temperature to impart the confined structuring mechanisms. It thus allowed partial melting and thinning of PLA microfibers into nanofibers, onto which the discrete HANWs were tightly adhered and embedded, showing distinguished architectural configurations identical with pea pod. More importantly, the mechanical properties and bioactivity were remarkably promoted, as demonstrated by the increments of over 54 % and nearly 72 % for the yield strength and elastic modulus (71.6 and 2547 MPa) of the structured composite loaded 30 wt% HANWs compared to those of pure PLA (46.4 and 1484 MPa), as accompanied by significant improvements in the bioactivity to nucleate and create apatite entities in mineral solution. The unusual combination of excellent biological characteristics and bone-like mechanical elasticity and extensibility make the structured PLA composites promising for guided bone/tissue regeneration therapy.

Significant enhancement of scintillation performance by inducing oxygen vacancies in alkali metal ion (A+ = Li+, Na+, K+)-incorporated (Lu, Sc)BO3:Ce.

The incorporation of Sc3+ can stabilize calcite-phase LuBO3:Ce3+ to grow large-sized single crystals but leads to the significant degradation of scintillation performance. In the present work, alkali metal ion (A+ = Li+, Na+, K+)-incorporated (Lu, A, Sc)BO3:Ce was rapidly synthesized in batches via a high-throughput sol-gel method. The aliovalent substitution of Lu3+ with A+ is balanced by the generation of oxygen vacancies by forming complexes. Thanks to the increased oxygen vacancies, the luminescence and XEL intensity of (Lu, Li, Sc)BO3:Ce are significantly enhanced by 2.2 times and 1.9 times, respectively. Further, the incorporation of A+ is attributed to the improved transition efficiency of charge carriers. The prepared scintillation screen fabricated with LASBO:Ce and PMMA shows that the spatial resolution can reach 8.6 lp mm-1, indicating its potential application in efficient and low-cost non-destructive X-ray detection. This work is of great significance in improving the luminescence and scintillation performance of (Lu, Sc)BO3:Ce single crystals and thin films and their application in the scintillation field.

Awe and Prosocial Behavior: The Mediating Role of Presence of Meaning in Life and the Moderating Role of Perceived Social Support.

Although awe has been shown to increase prosocial behavior, there is limited knowledge about the mechanisms underlying this relationship, and about this relationship during unique periods. To bridge these gaps, this study examined the influence of awe on prosocial behaviors, the mediating role of the presence of meaning in life, and the moderating role of perceived social support. Based on longitudinal surveys from 676 Chinese college students we showed that: (1) awe was positively associated with prosocial behavior; (2) the presence of meaning in life mediated this association, and; (3) these associations were moderated by perceived social support. Specifically, the positive relationship between awe and the presence of meaning in life was only significant for college students with low perceived social support; and the positive relationship between the presence of meaning in life and prosocial behavior was stronger for college students with high perceived social support.

Intercropping Walnut and Tea: Effects on Soil Nutrients, Enzyme Activity, and Microbial Communities.

The practice of intercropping, which involves growing more than one crop simultaneously during the same growing season, is becoming more important for increasing soil quality, land-use efficiency, and subsequently crop productivity. The present study examined changes in soil physicochemical properties, enzymatic activity, and microbial community composition when walnut (Juglans spp.) was intercropped with tea (Camellia sinensis L.) plants in a forest and compared with a walnut and tea monocropping system. The results showed that walnut-tea intercropping improved the soil nutrient profile and enzymatic activity. The soil available nitrogen (AN), available phosphorus (AP), available potassium (AK), organic matter (OM) content, and sucrase activity were significantly boosted in intercropped walnut and tea than in monocropping forests. The interaction between crops further increased bacterial and fungal diversity when compared to monoculture tea forests. Proteobacteria, Bacteroidetes, Firmicutes, Chlamydiae, Rozellomycota, and Zoopagomycota were found in greater abundance in an intercropping pattern than in monoculture walnut and tea forest plantations. The walnut-tea intercropping system also markedly impacted the abundance of several bacterial and fungal operational taxonomic units (OTUs), which were previously shown to support nutrient cycling, prevent diseases, and ameliorate abiotic stress. The results of this study suggest that intercropping walnut with tea increased host fitness and growth by positively influencing soil microbial populations.

Spatiotemporally dynamic therapy with shape-adaptive drug-gel for the improvement of tissue regeneration with ordered structure.

A spatiotemporally dynamic therapy (SDT) is proposed as a powerful therapeutic modality that provides spatially dynamic responses of drug-carriers for adapting to the wound microenvironment. Herein, dynamic chitosan-poly (ethylene glycol) (CP) Schiff-base linkages are employed to perform SDT by directly converting a liquid drug Kangfuxin (KFX) into a gel formation. The obtained KFX-CP drug-gel with shape-adaptive property is used to treat a representative oral mucositis (OM) model in a spatiotemporally dynamic manner. The KFX-CP drug-gel creates an instructive microenvironment to regulate signaling biomolecules and endogenous cells behavior, thereby promoting OM healing by the rule of dynamically adjusting shape to fit the irregular OM regions first, and then provides space for tissue regeneration, over KFX potion control and the general hydrogel group of CP hydrogel and KFX-F127. Most interestingly, the regenerated tissue has ordered structure like healthy tissue. Therefore, the SDT provides a new approach for the design of next generation of wound dressing and tissue engineering materials.

Combating Biofilms by a Self-Adapting Drug Loading Hydrogel.

A bacterial biofilm is one of the main reasons that many diseases are difficult to cure. Herein, a teicoplanin (TPN)-loaded self-adapting chitosan-based hydrogel (CPH) system, called TPN-CPH, was prepared by encapsulating antibacterial TPN into CPH. This TPN-CPH can effectively combat preformed biofilms in vitro of Staphylococcus aureus (S. aureus). It has a good therapeutic effect on full-thickness cutaneous wounds in vivo of mice infected with biofilms. In addition, TPN-CPH can accelerate wound healing by self-adapting the wound and providing a moist environment. The operation process of TPN-CPH is simple, and no external stimulation such as light and heat is needed in the treatment process, making it more convenient for clinical application. Furthermore, this is a challenge to use self-adapting hydrogels to adapt the micro-size channels of biofilms. TPN-CPH provides a chitosan-based self-adapting hydrogel system for loading drugs to kill bacteria in biofilms, and thus it is promising for infection control.

The use of methylprednisolone in COVID-19 patients: A propensity score matched retrospective cohort study.

PURPOSE: To evaluate the efficacy and safety of methylprednisolone in treating the coronavirus disease 2019 (COVID-19) patients. METHODS: A retrospective cohort study was conducted, and all COVID-19 patients were recruited who were admitted to the Yichang Third People's Hospital from February 1st to March 31st, 2020. One-to-one propensity score matching (PSM) was used for minimizing confounding effects. The primary outcome was hospital mortality, with the secondary outcomes being the time needed for a positive SARS-CoV-2 nucleic acid test to turn negative and the length of hospital stay. RESULTS: Totaling 367 patients with COVID-19 hospitalized at the Yichang Third People's Hospital were identified, of whom 276 were mild or stable COVID-19, and 67 were serious or critically ill. Among them, 255 patients were treated using methylprednisolone, and 188 did not receive any corticosteroid-related treatment. After PSM, no statistically significant difference was found in the baseline characteristics between the two groups. Regarding the outcomes, there also were no statistically significant difference between the two groups. Patients without the use of methylprednisolone were more quickly to obtain negative results of their nasopharyngeal swab tests of SARS-CoV-2 nucleic acid after treatment, compared to those receiving methylprednisolone. CONCLUSION: Methylprednisolone could not improve the prognosis of patients with COVID-19, and the efficacy and safety of the use of methylprednisolone in patients with COVID-19 still remain uncertain, thus the use of corticosteroids clinically in patients with COVID-19 should be with cautions.

Dynamic agent of an injectable and self-healing drug-loaded hydrogel for embolization therapy.

Embolic agents are crucial for trans-catheter arterial embolization (TAE) in the treatment of various unresectable malignant tumors. Although solid particles, liquid oils, and some polymeric hydrogels have proved their capacities for embolic therapies, the low efficiency, time sensitivity, and cytotoxicity are still considered as challenges. In this study, we developed a three-component dynamic self-healing hydrogel to overcome these limitations. With the help of the Schiff-base bonding, both glycol-chitosan and carbazochrome, containing amine groups, react with dibenzaldehyde-terminated poly(ethylene-glycol) (DF-PEG), forming the dynamic self-healing hydrogels under a mild condition within 200 s. 1H NMR and rheology test were used to characterize the Schiff-base formation and mechanical strength. Controlled-release of carbazochrome from different gelator concentrations of DF-PEG was also studied. Furthermore, in vivo evaluation of the embolization on rats showed the superior embolic effects of the injectable and self-healing hydrogel. Therefore, this new dynamic agent demonstrated the potential for application as a simple, inexpensive, and tunable embolic agent for cancer treatment and drug delivery system.

Self-Adapting Hydrogel to Improve the Therapeutic Effect in Wound-Healing.

Smart materials that can respond to multistimuli have been broadly studied. However, the smart materials that can spontaneously answer the ever-changing inner environment of living bodies have not been reported. Here, we report a strategy based on the dynamic chemistry to develop possible self-adapting solid materials that can automatically change shape without external stimuli, as organisms do. The self-adapting property of a chitosan-based self-healing hydrogel has been rediscovered since its dynamic Schiff-base network confers the unique mobility to that solid gel. As a result, the hydrogel can move slowly, like an octopus climbing through a narrow channel, only following the natural forces of surface tension and gravity. The fascinating self-adapting feature enables this hydrogel as an excellent drug carrier for the in vivo wound treatment. In a healing process of the rat-liver laceration, this self-adapting hydrogel demonstrated remarkable superiority over traditional drug delivery methods, suggesting the great potential of this self-adapting hydrogel as a promising new material for biomedical applications. We believe the current research revealed a possible strategy to achieve self-adapting materials and may pave the way toward the further development, study, and application of new-generation smart materials.

Adaptive Chitosan Hollow Microspheres as Efficient Drug Carrier.

Smart drug carrier with function-oriented adaptations is highly desired due to its unique properties in medical applications. Herein, adaptive chitosan hollow microspheres (CHM) are fabricated by employing interfacial Schiff-base bonding reaction. Hydrophilic macromolecules of glycol chitosan are fixed at the oil/water interface through numerous hydrophobic small molecules of borneol 4-formylbenzoate, forming the CHM with a positively charged surface and lipophilic cavity. These CHM have an average size of 400-1000 nm after passing through the 0.22 µm apertures of filter paper. This phenomenon combined with SEM measurements demonstrates its remarkable shape-adaptive behavior. Furthermore, the CHM present a pH-dependence of structural stability. When pH value reduces from 7.06 to 5.01, the CHM begin to lose their integrity. All those characteristics make the CHM an intelligent drug carrier, especially for water-insoluble anticancer drugs, paclitaxel (PTX) in particular. Both cell uptake and cell cytotoxicity assays suggest that the PTX-loaded CHM are highly efficient on HepG2 and A549 cells. Therefore, rather than most of the traditional materials, these adaptive CHM show great potential as a novel drug carrier.

Regulation of skeletal muscle protein synthetic and degradative signaling by alanyl-glutamine in piglets challenged with Escherichia coli lipopolysaccharide.

OBJECTIVE: The aim of this study was to investigate the effects of alanyl-glutamine (Ala-Gln) on skeletal muscle protein synthetic and degradative signaling in piglets challenged with Escherichia coli lipopolysaccharide (LPS). METHODS: Piglets were arranged in a 2 × 2 factorial design and the main effects were LPS challenge (0 or 100 units) and diets (0.62% Ala or 0.5% Ala-Gln). After treatment with either Ala or Ala-Gln for 10 d, piglets were injected twice with either saline or LPS on days 11 and 15. RESULTS: During days 11 to 15 (postchallenge), LPS challenge affected the growth performance of piglets. Ala-Gln supplementation tended to alleviate the reduction of the average daily weight gain (P = 0.071) and the average daily feed intake (P = 0.087) of the LPS-challenged piglets. LPS challenge increased the concentrations of cytokines in plasma (P < 0.05), however, Ala-Gln supplementation prevented the elevation of cortisol induced by LPS challenge (P < 0.05). Moreover, Ala-Gln supplementation increased the mRNA expressions of insulin-like growth factor-1 signaling and Akt (P < 0.05). Ala-Gln supplementation also increased the phosphorylation abundance of the mammalian target of rapamycin, eIF-4 E binding protein 1 and ribosomal protein S6 kinase 1 (P < 0.05). Additionally, Ala-Gln supplementation down-regulated the mRNA abundances of toll-like receptor 4 (TLR4), muscle atrophy F-box, and muscle RING finger 1, which are associated with protein degradation induced by LPS challenge. CONCLUSION: Ala-Gln supplementation had beneficial effects in improving protein synthesis signaling of skeletal muscle, and reversed the deleterious changes of signaling molecules in muscle atrophy mainly through down-regulation of Akt/FOXO and TLR4 signaling pathways induced by LPS challenge.

[Value of fractional nitric oxide concentration in exhaled breath in assessing level of asthma control in children].

OBJECTIVE: To investigate the value of fractional nitric oxide concentration in exhaled breath (FeNO) in assessing the level of asthma control in children. METHODS: A total of 226 asthmatic children were divided into controlled asthma (n= 86), partially controlled asthma (n=63), and uncontrolled asthma groups (n=77). Ninety healthy children were enrolled as controls. FeNO was measured for both asthmatic and healthy children using the Swedish-designed NIOX system. RESULTS: The control group had an FeNO of 14±6 ppb, the controlled asthma group had an FeNO of 29±26 ppb, the partially controlled asthma group had an FeNO of 32±30 ppb, and the uncontrolled asthma group had an FeNO of 40±32 ppb. The three asthma groups showed significantly higher FeNO than the control group (P<0.05). The uncontrolled asthma group showed significantly higher FeNO than the controlled asthma group (P<0.05), but there were no significant differences in FeNO between the partially controlled and uncontrolled asthma groups and between the partially controlled and controlled asthma groups (P>0.05). CONCLUSIONS: Asthmatic children have significantly higher FeNO than healthy children, and FeNO is correlated with the level of asthma control.