Differential cytotoxicity to human cells in vitro of tire wear particles emitted from typical road friction patterns: The dominant role of environmental persistent free radicals.

Tire wear particles (TWPs) have been recognized as one of the major sources of microplastics (MPs), however, effects of initial properties and photochemical behavior of TWPs on cytotoxicity to human cells in vitro have not been reported. Therefore, here, three TWPs generated from typical wear of tires and pavements (i.e., rolling friction (R-TWPs) and sliding friction (S-TWPs)) and cryogenically milled tire tread (C-TWPs), respectively, and their photoaging counterparts were used to study the reasons for their differential cytotoxicity to 16HBE cells in vitro. Results showed in addition to changes of surface structure and morphology, different preparation methods could also induce formation of different concentration levels of environmental persistent free radicals (EPFRs) (from 1.24 to 3.06 × 1017 spins/g with g-factors ranging 2.00307-2.00310) on surfaces of TWPs, which contained 7.3%-65.8% of reactive EPFRs (r-EPFRs). Meanwhile, photoaging for 90 d could strengthen formation of EPFRs (from 4.03 to 4.61 × 1017 spins/g) with containing 74.7%-78.1% r-EPFRs on surfaces of TWPs and improve their g-factor indexes (ranging 2.00309-2.00313). At 100 µg mL-1 level, compared to C-TWPs, both R-TWPs and S-TWPs (whether photoaging or not) carried higher intensity EPFRs could significantly inhibit 16HBE cells proliferation activity, cause more cells oxidative stress and induce more cell apoptosis/necrosis and secretion of inflammatory factor (P < 0.05). However, regardless of how TWPs were prepared, photoaged or not, exposure at a concentration of 1 µg mL-1 appeared to be non-acute cytotoxic. Correlation analysis suggested dominant toxicity of TWPs was attributed to the formation of r-EPFRs on their surfaces, which could promote accumulation of excess reactive oxygen species in cells and the massive deposition of intracellular particles. This study provides direct evidence of TWPs cytotoxicity, and underlining the need for a better understanding of the influences of initial properties and photochemical characteristics on risk assessment of TWPs released into the environment.

Peptide-modified bioresponsive chondroitin sulfate micelles for targeted doxorubicin delivery in triple-negative breast cancer.

Triple-negative breast cancer is an offensive tumor that is highly challenging to cure. In this study, we developed novel polymeric nanoparticles that target dual receptors and respond to reducing conditions for chemotherapeutic drug release in the treatment of triple-negative breast cancer. Then we synthesized and characterized a targeted peptide-grafted chondroitin sulfate A-ss-deoxycholic acid (TCSSD) copolymer and prepare doxorubicin (DOX)-loaded TCSSD (TCSSD-D) micelles high-loading content. The bioresponsive drug release of TCSSD-D nanoparticles was demonstrated in a glutathione-containing phosphate buffer solution. We found that TCSSD-D effectively targeted CD44 and P-selectin receptors both in vitro and in vivo. TCSSD-D micelles were higher cytotoxicity and cellular uptake than unmodified DOX-containing micelles in MDA-MB-231 cells. Furthermore, TCSSD-D micelles showed the strongest suppression of tumor growth among three DOX-based formulations in triple-negative MDA-MB-231-bearing nude mice. These results suggest that amphiphilic TCSSD nanoparticles can serve as a targeted and intelligent delivery vehicle for triple-negative breast cancer therapy.

An injectable hydrogel based on Bi2Se3 nanosheets and hyaluronic acid for chemo-photothermal synergistic therapy.

To resolve poor accumulation caused by systemic administration, injectable and responsive hydrogels are the prospective drug delivery systems for localized tumor treatment, owning to negligible invasiveness and accurate administration. Herein, an injectable hydrogel, based on dopamine (DA) crosslinked hyaluronic acid and Bi2Se3 nanosheets (NSs) loading with doxorubicin (DOX) coated with polydopamine (Bi2Se3-DOX@PDA), was developed for synergistic chem-photothermal cancer therapy. The ultrathin functional Bi2Se3-DOX@PDA NSs could be responsive to the weak acidic condition and photothermal effect under NIR laser irradiation, achieving controlled release of DOX. Moreover, nanocomposite hydrogel based on hyaluronic acid matrix could be precisely administrated through intratumoral injection since its injectability and self-healing capacity, remaining at injected sites for at least 12 days. Furthermore, the excellent therapeutics effect of Bi2Se3-DOX@PDA nanocomposite hydrogel was demonstrated on 4 T1 xenograft tumor with outstanding injectability and negligible systemic side-effect. In short, the construction of Bi2Se3-DOX@PDA nanocomposite hydrogel paves a prospective path for local treatment of cancers.

Mechanical properties of emulsified recycled cement-stabilized macadam based on step-by-step filling gradation design.

Since the recycling of waste original cement-stabilized macadam (OCSM) base has important environmental and economic significance, the addition of emulsified asphalt to OCSM to form emulsified recycled OCSM (ER-OCSM) can improve the flexibility of recycled mixtures. However, the influence of emulsified asphalt on the mechanical performance of such mixtures remains to be investigated. This study presents a gradation design and ER-OCSM established using the step-by-step filling method and investigated the mechanical properties of the ER-OCSM mixture. The apparent characteristics, crushing value and needle-like particle content of the OCSM milling material were tested. Based on step-by-step filling theory, the appropriate test method to achieve a uniform and dense state according to the characteristics of different aggregates was selected, and the dense skeleton gradation design method for recycled cement macadam was obtained. The mechanical properties of the ER-OCSM were analyzed by performing indoor physical laboratory tests. The natural gradation of the OCSM milling material exceeded the gradation range recommended in the Technical Guide for the Promotion of Science and Technology of the Construction Project of the Main Highway in Jiangsu Province (Trial), but the designed gradations were basically within the range. At the same age and temperature, the flexural strength and dynamic elastic modulus of the ER-OCSM decreased gradually with an increase in the emulsified asphalt content. Because ER-OCSM had temperature-sensitive characteristics, the adhesiveness of the asphalt between particles in the mixture decreased with increasing temperature, which was manifested as the unconfined compressive strength, flexural tensile strength and dynamic elastic modulus decreasing with an increase in temperature (the decrease was slight within 5-25°C but noticeable within 25-60°C). Furthermore, a higher emulsified asphalt content caused a more noticeable decrease. The flexural strength of the tested ER-OCSM showed noticeable correlations with the splitting strength, unconfined compressive strength and dynamic elastic modulus. The proper addition of emulsified asphalt can reduce the rigidity of ER-OCSM. However, the emulsified asphalt content should be strictly controlled; otherwise, the mechanical properties of the material will decrease greatly, adversely impacting the comprehensive road use performance.

Tension force-induced bone formation in orthodontic tooth movement via modulation of the GSK-3ß/ß-catenin signaling pathway.

Orthodontic force-induced osteogenic differentiation and bone formation at tension sites play a critical role in orthodontic tooth movement. However, the molecular mechanism underlying this phenomenon is poorly understood. In the current study, we investigated the involvement of the GSK-3ß/ß-catenin signaling pathway, which is critical for bone formation during tooth movement. We established a rat tooth movement model to test the hypothesis that orthodontic force may stimulate bone formation at the tension site of the moved tooth and promote the rate of tooth movement via regulation of the GSK-3ß/ß-catenin signaling pathway. Our results showed that continued mechanical loading increased the distance between the first and second molar in rats. In addition, the loading force increased bone formation at the tension site, and also increased phospho-Ser9-GSK-3ß expression and ß-catenin signaling pathway activity. Downregulation of GSK-3ß activity further increased bone parameters, including bone mineral density, bone volume to tissue volume and trabecular thickness, as well as ALP- and osterix-positive cells at tension sites during tooth movement. However, ICG-001, the ß-catenin selective inhibitor, reversed the positive effects of GSK-3ß inhibition. In addition, pharmaceutical inhibition of GSK-3ß or local treatment with ß-catenin inhibitor did not influence the rate of tooth movement. Based on these results, we concluded that GSK-3ß/ß-catenin signaling contributes to the bone remodeling induced by orthodontic forces, and can be used as a potential therapeutic target in clinical dentistry.

New approach to treating spinal cord injury using PEG-TAT-modified, cyclosporine-A-loaded PLGA/polymeric liposomes.

Cyclosporine-A (CsA) is an immunosuppressant agent that has shown effectiveness as a neuroprotective drug; however, it does not readily cross the blood-spinal cord barrier (BSCB), which constrains the clinical applications of CsA for the treatment of spinal cord injury (SCI). Our group recently tested the ability of novel polyethylene glycol (PEG)-transactivating-transduction protein (TAT)-modified CsA-loaded cationic multifunctional polymeric liposome-poly(lactic-co-glycolic acid) (PLGA) core/shell nanoparticles (PLGA/CsA NPs) to transport and deliver CsA across the BSCB to treat SCI. The PLGA/CsA NPs were successfully constructed. In vitro drug release studies have demonstrated that the sustained release of CsA from PLGA/CsA NPs occurs over ∼25 h. The in vivo study presented here showed that injured animals that received PLGA/CsA NPs through the tail vein, exhibited a significant up-regulation of growth-associated protein-43 (GAP-43) expression and an increased number of GAP-43-stained neurons compared with animals that received CsA or the vehicle alone. The improvement in neurological function was also evaluated by the Basso-Beattie-Bresnahan (BBB) open-field test. Moreover, fluorescein isothiocyanate (FITC)-attached PLGA/CsA NPs were successfully aggregated in the intact spinal cord 4 h after injection. Our data suggest that PLGA/CsA NPs have the potential for use as a new treatment method for SCI.

Enzymological Characterization of Atm, the First Laccase from Agrobacterium sp. S5-1, with the Ability to Enhance In Vitro digestibility of Maize Straw.

Laccase is an enzyme that catalyzes oxidation of phenolic compounds, diamines and aromatic amines. In this study, a novel laccase-like gene (atm) in a ligninolyitic isolate Agrobacterium sp. S5-1 from soil humus was identified and heterologously expressed in Escherichia coli. Atm exhibited its maximal activity at pH 4.5 and at 50°C. This enzyme was tolerant to high temperature, a broad range of pH, heavy metal ions (Co3+, Mn2+, Cu2+ and Ni2+, 20 mM) and all tested organic solvents. Furthermore, Atm significantly (p<0.05) increased dry matter digestibility of maize straw from 23.44% to 27.96% and from 29.53% to 37.10% after 8 or 24 h of digestion and improved acid detergent fiber digestibility from 5.81% to 10.33% and from 12.80% to 19.07% after 8 or 24 h of digestion, respectively. The combination of Atm and fibrolytic enzymes significantly (p<0.05) enhanced neutral detergent fiber digestibility from 19.02% to 24.55% after 24 h of digestion respectively. Results showed treatment with Atm effectively improved in vitro digestibility of maize straw, thus suggesting that Atm has an application potential for bioconversion of lignin rich agricultural byproducts into animal feed and cellulosic ethanol.

Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery.

To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (∼50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.