MOF-polymer composites with well-distributed gold nanoparticles for visual monitoring of homocysteine.

The distribution of gold nanoparticles (AuNPs) on the surface of a metal-organic framework (MOF) plays a crucial role in the catalytic performance of MOF-AuNP composites. This study describes how the physical adsorption (PH@AuNPs-on-U) and chemical modification of AuNPs on the surface of UiO-66-NH2 (U) affect the composites' catalytic efficiency. After 2-vinyl-4,4-dimethyl-2-oxazolin-5-one (VD) linked to poly(N-2-hydroxypropyl methacrylamide) (PH) with U (UVD-PH), UVD-PH@AuNPs composites were constructed with PH as the capping and reducing reagent. The composites exhibited higher peroxidase (POD)-like activity than PH@AuNPs-on-U for oxidising 3,3'5,5'-tetramethylbenzidine (TMB) with H2O2. The approach demonstrated that the proposed composite-based nanozymes could significantly enhance their catalytic activity and had a highly uniform distribution of PH@AuNPs on the surface of UVD. An assay with the nanozymes for visual detection of homocysteine (Hcy) was developed, displaying a good linear relationship (R2 = 0.998) ranging from 3.34 µM to 30.0 µM and a detection of limit of 0.3 µM. Additionally, the UVD-PH@AuNPs-TMB-H2O2 system successfully monitored serum Hcy after intraperitoneal injection in rats. This study paves a new way for developing MOF-AuNPs with highly uniform surface distribution of polymer@AuNPs to boost its catalytic activity and to detect drugs in real bio-samples.

Multicompartment Nanoparticles by Crystallization-Driven Self-Assembly of Star Polymers: Combining High Stability and Loading Capacity.

Herein novel multicompartment nanoparticles (MCNs) that combine high stability and cargo loading capacity are developed. The MCNs are fabricated by crystallization-driven self-assembly (CDSA) of a tailor-made 21 arm star polymer, poly(L-lactide)[poly(tert-butyl acrylate)-block-poly(ethylene glycol)]20 [PLLA(PtBA-b-PEG)20 ]. Platelet-like or spherical MCNs containing a crystalline PLLA core and hydrophobic PtBA subdomains are formed and stabilized by PEG. Hydrophobic cargos, such as Nile Red and chemotherapeutic drug doxorubicin, can be successfully encapsulated into the collapsed PtBA subdomains with loading capacity two orders of magnitude higher than traditional CDSA nanoparticles. Depolarized fluorescence measurements of the Nile Red loaded MCNs suggest that the free volume of the hydrophobic chains in the nanoparticles may be the key for regulating their drug loading capacity. In vitro study of the MCNs suggests excellent cytocompatibility of the blank nanoparticles as well as a dose-dependent cellular uptake and cytotoxicity of the drug-loaded MCNs.

Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy.

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss through activating microglial NADPH oxidase.

BACKGROUND: Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. METHODS: Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPH oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. RESULTS: In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100µg/cm2 induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10µg/cm2) and rotenone (2nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91phox, p47phox and p40phox); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47phox and p67phox translocation assembling active NADPH oxidase. CONCLUSION: ufCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to oxidative damage to DA neurons. Our findings delineated the potential role of ultrafine particles alone and in combination with pesticide rotenone in the pathogenesis of PD.

Neuroregulation of foraging behavior mediated by the olfactory co-receptor Orco in termites.

Olfaction is critical for survival because it allows animals to look for food and detect pheromonal cues. Neuropeptides modulate olfaction and behaviors in insects. While how the neuroregulation of olfactory recognition affects foraging behavior in termites is still unclear. Here, we analyzed the change after silencing the olfactory co-receptor gene (Orco) and the neuropeptide Y gene (NPY), and then investigated the impact of olfactory recognition on foraging behavior in Odontotermes formosanus under different predation pressures. The knockdown of Orco resulted in the reduced Orco protein expression in antennae and the decreased EAG response to trail pheromones. In addition, NPY silencing led to the damaged ability of olfactory response through downregulating Orco expression. Both dsOrco- and dsNPY-injected worker termites showed significantly reduced walking activity and foraging success. Additionally, we found that 0.1 pg/cm trail pheromone and nestmate soldiers could provide social buffering to relieve the adverse effect of predator ants on foraging behavior in worker termites with the normal ability of olfactory recognition. Our orthogonal experiments further verified that Orco/NPY genes are essential in manipulating termite olfactory recognition during foraging under different predation pressures, suggesting that the neuroregulation of olfactory recognition plays a crucial role in regulating termite foraging behavior.

Encapsulation of an enzyme-immobilized smart polymer membrane in a metal-organic framework for enhancement of catalytic performance.

Encapsulation of enzymes within porous materials has shown great promise for protecting enzymes from denaturation, increasing their tolerance to harsh environments and promoting their industrialization. However, controlling the conformational freedom of the encapsulated enzymes to enhance their catalytic performance remains a great challenge. To address this issue, herein, following immobilization of GOx and HRP on a thermo-responsive porous poly(styrene-maleic-anhydride-N-isopropylacrylamide) (PSMN) membrane, a GOx-HRP@PSMN@HZIF-8 composite was fabricated by encapsulating GOx-HRP@PSMN in hollow ZIF-8 (HZIF-8) with liposome (L) as the sacrificial template. The improved conformational freedom for enzymes arising from the hollow cavity formed in ZIF-8 through the removal of L enhanced the mass transfer and dramatically promoted the catalytic activity of the composite. Interestingly, at high temperature, the coiled PN moiety in PSMN provided the confinement effect for GOx-HRP, which also significantly boosted the catalytic performance of the composites. Compared to the maximum catalytic reaction rates (Vmax) of GOx-HRP@PSMN@LZIF-8, the free enzyme and GOx-HRP@ZIF-8, the Vmax of the GOx-HRP@PSMN@HZIF-8 composite exhibited an impressive 17.8-fold, 10.8-fold and 6.0-fold enhancement at 37 °C, respectively. The proposed composites successfully demonstrated their potential as catalytic platforms for the colorimetric detection of glucose in a cascade reaction. This study paves a new way for overcoming the current limitations of immobilizing enzymes in porous materials and the use of smart polymers for the potential fabrication of enzyme@polymer@MOF composites with tunable conformational freedom and confinement effect.

Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management.

Bone-modifying agents (BMA) are extensively used in treating patients with prostate cancer with bone metastases. However, this increases the risk of medication-related osteonecrosis of the jaw (MRONJ). The safety of long-term BMA administration in clinical practice remains unclear. We aimed to determine the cumulative incidence and risk factors of MRONJ. One hundred and seventy-nine patients with prostate cancer with bone metastases treated with BMA at our institution since 2008 were included in this study. Twenty-seven patients (15%) had MRONJ during the follow-up period (median, 19 months; interquartile range, 9-43 months). The 2-year, 5-year, and 10-year cumulative MRONJ incidence rates were 18%, 27%, and 61%, respectively. Multivariate analysis identified denosumab use as a risk factor for MRONJ, compared with zoledronic acid use (HR 4.64, 95% CI 1.93-11.1). Additionally, BMA use at longer than one-month intervals was associated with a lower risk of MRONJ (HR 0.08, 95% CI 0.01-0.64). Furthermore, six or more bone metastases (HR 3.65, 95% CI 1.13-11.7) and diabetes mellitus (HR 5.07, 95% CI 1.68-15.2) were risk factors for stage 2 or more severe MRONJ. MRONJ should be considered during long-term BMA administration in prostate cancer patients with bone metastases.

Circadian Rhythms of Locomotor Activity Mediated by Cryptochrome 2 and Period 1 Genes in the Termites Reticulitermes chinensis and Odontotermes formosanus.

Locomotor activity rhythms are crucial for foraging, mating and predator avoidance in insects. Although the circadian rhythms of activity have been studied in several termite species, the molecular mechanisms of circadian rhythms in termites are still unclear. In this study, we found that two termite species, R. chinensis and O. formosanus, exhibited clear circadian rhythms of locomotor activity in constant darkness along with rhythmically expressed core clock genes, Cry2 and Per1. The knockdown of Cry2 or Per1 expression in the two termite species disrupted the circadian rhythms of locomotor activity and markedly reduced locomotor activity in constant darkness, which demonstrates that Cry2 and Per1 can mediate the circadian rhythms of locomotor activity in termites in constant darkness. We suggest that locomotor activity in subterranean termites is controlled by the circadian clock.

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll-Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity.

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.

Physical Fitness with Regular Lifestyle Is Positively Related to Academic Performance among Chinese Medical and Dental Students.

OBJECTIVE: The purpose of this study was to examine the relationship between physical fitness, lifestyle, and academic performance of Chinese college students and investigate the differences among medical and dental students on their lifestyle. METHODS: This study was conducted with 316 students enrolled from 2012 to 2014 at Tongji University. Scores from the college physical test were used to represent the students' physical fitness condition. Lifestyle was measured by some variables extracted from the students' behavior data provided by the university's information center. Academic performance was measured by the average score of basic courses and the average score of professional courses. Demographic information, including age, gender, nation, and family background, was also obtained. Separate multiple linear regression analysis was performed for modeling academic performance and physical fitness with a p value threshold of 0.05. RESULTS: A total of 212 (45.97% females) medical students and 104 (58.65% females) dental students participated in this study. Physical fitness score (medical: r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. r = 0.34, p value threshold of 0.05. CONCLUSION: Physical fitness, library usage, and the regularity of lifestyle are significant contributors to academic performance among Chinese medical and dental students. Moreover, medical students are shown to have less rest time compared to dental students.

Paradoxical bulging of mentalis after botulinum toxin type A injection.

BACKGROUND: Botulinum toxin type A (BTA) injection is a widely-used procedure to correct cosmetic problems caused by muscular hyperactivity. "Cobblestone chin" refers to the appearance of remarkable chin creases caused by mentalis contraction. AIMS: The aim of this case report is to raise the awareness of paradoxical bulging after BTA injection in mentalis. PATIENT/METHODS: A 26-year-old female asked for cosmetic correction of the "cobblestone chin". BTA injection was performed routinely to the mentalis muscle. However, on the second day after injection, an unusual paradoxical bulging at chin was presented. RESULTS: We speculated that the imbalanced relaxation of mentalis caused by improper injection and uneven diffusion of BTA is responsible for the bulging. After a supplementary injection of BTA in the remaining hyperactive muscle fibers based on the ultrasound examination, the bulging was relieved and chin contour improved significantly. CONCLUSION: Injection of BTA in mentalis should cover the whole thickness of the muscle to prevent imbalanced paralysis and paradoxical chin bulging, especially in severe mentalis hyperactivity cases.

Urethane-based low-temperature curing, highly-customized and multifunctional poly(glycerol sebacate)-co-poly(ethylene glycol) copolymers.

Poly (glycerol sebacate) (PGS), a tough elastomer, has been widely explored in tissue engineering due to the desirable mechanical properties and biocompatibility. However, the complex curing procedure (high temperature and vacuum) and limited hydrophilicity (∼90° of wetting angle) greatly impede its functionalities. To address these challenges, a urethane-based low-temperature setting, PEGylated PGS bioelastomer was developed with and without solvent. By simultaneously tailoring PEG and hexamethylene diisocyanate (HDI) contents, the elastomers X-P-mUs (X referred to the PEG content and m referred to HDI content) with a broad ranging mechanical properties and customized hydrophilicity were constructed. The X-P-mUs synthesized exhibited adjustable tensile Young's modulus, ultimate tensile strength and elongation at break in the range of 1.0 MPa-14.2 MPa, 0.3 MPa-7.6 MPa and 53.6%-272.8%, with the water contact angle varying from 28.6° to 71.5°, respectively. Accordingly, these elastomers showed favorable biocompatibility in vitro and mild host response in vivo. Furthermore, the potential applications of X-P-mU elastomers prepared with solvent-base and solvent-free techniques in biomedical fields were investigated. The results showed that these X-P-mU elastomers with high molding capacity at mild temperature could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity, demonstrating that the X-P-mU elastomers could be tailored as potential building blocks for diverse applications in biomedical research. STATEMENT OF SIGNIFICANCE: Poly(glycerol sebacate) (PGS), a tough biodegradable elastomer, has received great attentions in biomedical field. But the complex curing procedure and limited hydrophilicity greatly hamper its functionality. Herein, a urethane-based low-temperature setting, PEGylated PGS (PEGS-U) bioelastomer with highly-customized mechanical properties, hydrophilicity and biodegradability was first explored. The synthesized PEGS-U showed favorable biocompatibility both in vitro and in vivo. Furthermore, the PEGS-U elastomer could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity. This versatile, user-tunable bioelastomers should be a promising biomaterials for biomedical applications.

A drug delivery hydrogel system based on activin B for Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Activins are members of the superfamily of transforming growth factors and have many potential neuroprotective effects. Herein, at the first place, we verified activin B's neuroprotective role in a PD model, and revealed that activin B's fast release has limited function in the PD therapy. To this end, we developed a multi-functional crosslinker based thermosensitive injectable hydrogels to deliver activin B, and stereotactically injected the activin B-loaded hydrogel into the striatum of a mouse model of PD. The histological evaluation showed that activin B can be detected even 5 weeks post-surgery in PD mice implanted with activin B-loaded hydrogels, and activin B-loaded hydrogels can significantly increase the density of tyrosine hydroxylase positive (TH(+)) nerve fibers and reduce inflammatory responses. The behavioral evaluation demonstrated that activin B-loaded hydrogels significantly improved the performance of the mice in the PD model. Meanwhile, we found that hydrogels can slightly induce the activation of microglia cells and astrocytes, while cannot induce apoptosis in the striatum. Overall, our data demonstrated that the developed activin B-loaded hydrogels provide sustained release of activin B for over 5 weeks and contribute to substantial cellular protection and behavioral improvement, suggesting their potential as a therapeutic strategy for PD.

A poly(glycerol sebacate)-coated mesoporous bioactive glass scaffold with adjustable mechanical strength, degradation rate, controlled-release and cell behavior for bone tissue engineering.

Various requirements in the field of tissue engineering have motivated the development of three-dimensional scaffold with adjustable physicochemical properties and biological functions. A series of multiparameter-adjustable mesoporous bioactive glass (MBG) scaffolds with uncrosslinked poly(glycerol sebacate) (PGS) coating was prepared in this article. MBG scaffold was prepared by a modified F127/PU co-templating process and then PGS was coated by a simple adsorption and lyophilization process. Through controlling macropore parameters and PGS coating amount, the mechanical strength, degradation rate, controlled-release and cell behavior of the composite scaffold could be modulated in a wide range. PGS coating successfully endowed MBG scaffold with improved toughness and adjustable mechanical strength covering the bearing range of trabecular bone (2-12MPa). Multilevel degradation rate of the scaffold and controlled-release rate of protein from mesopore could be achieved, with little impact on the protein activity owing to an "ultralow-solvent" coating and "nano-cavity entrapment" immobilization method. In vitro studies indicated that PGS coating promoted cell attachment and proliferation in a dose-dependent manner, without affecting the osteogenic induction capacity of MBG substrate. These results first provide strong evidence that uncrosslinked PGS might also yield extraordinary achievements in traditional MBG scaffold. With the multiparameter adjustability, the composite MBG/PGS scaffolds would have a hopeful prospect in bone tissue engineering. The design considerations and coating method of this study can also be extended to other ceramic-based artificial scaffolds and are expected to provide new thoughts on development of future tissue engineering materials.