Thermal accelerated urease-driven hyaluronan-targeted melanin nano-missile for bio-radar detection and chemodrug-free phototherapy.

Polymer-based nanomotors are attracting increasing interest in the biomedical field due to their microscopic size and kinematic properties which support overcoming biological barriers, completing cellular uptake and targeted blasting in limited spaces. However, their applications are limited by the complex viscous physiological environment and lack of sufficient biocompatibility. This manuscript firstly reports a natural melanin nano-missile of MNP@HA-EDA@Urease@AIE PS (MHUA) based on photothermally accelerated urease-driven to achieve chemodrug-free phototherapy. Compared to conventional nano-missiles that only provide driving force, this photothermally accelerated urease-driven nanomotor is independent of chemodrug to maximise biocompatibility, and achieve ideal therapeutic effect through targeted PTT/PDT. In particular, the thermal effect can not only boost the catalytic activity of urease but also achieve ideally anti-tumor effect. In addition, guided by and AIE PS, the nanomotor can generate 1O2 to achieve PDT and be traced in real time serving as an effective fluorescent bio-radar for intracellular self-reporting during cancer treatment. Finally, the targeting ability of MUHA is provided by hyaluronan. Taken together, this MHUA platform provides a simple and effective strategy for target/fluorescence radar detective-guided PTT/PDT combination, and achieves good therapeutic results without chemodrug under thermal accelerated strategy, providing a new idea for the construction of chemodrug-free nanomotor-therapy system.

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice.

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 µM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 µM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.

Thermal-Accelerated Urease-Driven Bowl-Like Polydopamine Nanorobot for Targeted Photothermal/Photodynamic Antibiotic-Free Antibacterial Therapy.

The problem of antibiotic resistance seriously affects the treatment of bacterial infections, so there is an urgent need to develop novel antibiotic-independent antimicrobial strategies. Herein, a urease-driven bowl-like mesoporous polydopamine nanorobot (MPDA@ICG@Ur@Man) based on single-wavelength near-infrared (NIR) remote photothermal acceleration to achieve antibiotic-free phototherapy(photothermal therapy, PTT, plus photodynamic therapy, PDT) is first reported. The smart nanorobots can perform active movement by decomposing urea to produce carbon dioxide and ammonia. Particularly, the elevated local temperature during PTT can increase urease activity to enhance the autonomous movement and thus increase the contact between the antimicrobial substance and bacteria. Compared with a nanomotor propelled by urea only, the diffusion coefficient (De) of photothermal-accelerated nanorobots is increased from 1.10 to 1.26 µm2 s-1. More importantly, urease-driven bowl-like nanorobots with photothermal enhancement can specifically identify Escherichia coli (E. coli) and achieve simultaneous PTT/PDT at a single wavelength with 99% antibactericidal activity in vitro. In a word, the urease-driven bowl-like nanorobots guided by photothermal-accelerated strategy could provide a novel perspective for increasing PTT/PDT antibacterial therapeutic efficacy and be promising for various antibiotic-free sterilization applications.

Photothermal-accelerated urease-powered human serum albumin nanomotor for rapid and efficient photothermal and photodynamic cancer combination therapy.

Nanomotors, as a new type of micro-device, show good performance in terms of rapid transportation and deep penetration through their autonomous motion. However, their ability to efficiently break physiological barriers still remains a great challenge. Herein, we first developed a thermal-accelerated urease driven human serum albumin (HSA) nanomotor based on photothermal intervention (PTI) to achieve chemotherapy drugfree-phototherapy. The HANM@FI (HSA-AuNR@FA@Ur@ICG) is composed of a main body of biocompatible HSA, modified by gold nanorods (AuNR) and loaded with functional molecules of folic acid (FA) and indocyanine green (ICG). It promotes its own motion by breaking down urea to produce carbon dioxide and ammonia. In particular, the nanomotor is conveniently operated via near-infrared combined photothermal therapy (PTT)/ photodynamic therapy (PDT) to achieve an accelerated De value from 0.73 µm2s-1 to 1.01µm2s-1, and ideal tumor ablation at the same time. In contrast to customary urease-driven nanodrug-stacked engine, this HANM@FI has both targeting and imaging-guided capabilities, and finally achieves superior anti-tumor effects without chemotherapy drugs, through a "two-in-one" (motor mobility plus unique phototherapy in chemotherapy-drugfree phototherapy) strategy. This PTI effect with urease-driven nanomotors may offer further possibilities for future clinical applications of nanomedicines by enabling deep penetration and a subsequent chemotherapy-drugfree combination therapy strategy.

Enhanced photo-hypoxia-activated combination therapy traced by AIE photosensitizer and targeted by hyaluronic acid: Disulphide bond interference of detoxification barrier.

The treatment efficacy of anticancer drugs in complex physiological environments is still restricted by multi-drug resistance. To overcome this issue, a nanodrug system of HA-SS@CuS@ZIF-8@TPZ&TBMACN (HSCZTT) that breaks through the detoxification barrier for tirapazamine (TPZ) delivery was developed in this manuscript. In addition to the photothermal effect aroused by CuS in HSCZTT, which can damage tumour cells, TBMACN with photostable fluorescence in the aggregate state can also generate sufficient reactive oxygen species (ROS) to destroy tumour cells. The continuous consumption of oxygen in PDT aggravates the hypoxic environment of tumours, which further activates the TPZ released in the acidic microenvironment of the tumour to achieve apoptosis of the tumour cells. The HSCZTT can not only target the CD44 receptor overexpressed on the surface of the cancer cell, but can also effectively consume a large amount of glutathione (GSH) through the disulphide bond-modified hyaluronic acid, which serves as a targeted disulphide bond, interfering with the detoxification barrier. Our finding presents a rational strategy to overcome multidrug resistance for the improved efficacy of anticancer drugs by the targeting of Hyaluronic acid (HA), release of the drug by the acid response of ZIF-8, breakthrough of the detoxification barrier, precise positioning of the drug release and combined treatment with phototherapy and hypoxia-activated chemotherapy.

FvWRKY48 binds to the pectate lyase FvPLA promoter to control fruit softening in Fragaria vesca.

The regulatory mechanisms that link WRKY gene expression to fruit ripening are largely unknown. Using transgenic approaches, we showed that a WRKY gene from wild strawberry (Fragaria vesca), FvWRKY48, may be involved in fruit softening and ripening. We showed that FvWRKY48 is localized to the nucleus and that degradation of the pectin cell wall polymer homogalacturonan, which is present in the middle lamella and tricellular junction zones of the fruit, was greater in FvWRKY48-OE (overexpressing) fruits than in empty vector (EV)-transformed fruits and less substantial in FvWRKY48-RNAi (RNA interference) fruits. Transcriptomic analysis indicated that the expression of pectate lyase A (FvPLA) was significantly downregulated in the FvWRKY48-RNAi receptacle. We determined that FvWRKY48 bound to the FvPLA promoter via a W-box element through yeast one-hybrid, electrophoretic mobility shift, and chromatin immunoprecipitation quantitative polymerase chain reaction experiments, and ß-glucosidase activity assays suggested that this binding promotes pectate lyase activity. In addition, softening and pectin degradation were more intense in FvPLA-OE fruit than in EV fruit, and the middle lamella and tricellular junction zones were denser in FvPLA-RNAi fruit than in EV fruit. We speculated that FvWRKY48 maybe increase the expression of FvPLA, resulting in pectin degradation and fruit softening.

A triple-stimulus responsive melanin-based nanoplatform with an aggregation-induced emission-active photosensitiser for imaging-guided targeted synergistic phototherapy/hypoxia-activated chemotherapy.

Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency (η = 37%), desired cytocompatibility, and excellent synergistic therapeutic efficacy. The proposed nanoplatform not only extends the application scope of melanin materials with AIE-active PSs, but also offers useful insights into developing multistimulus as well as multimodal synergistic tumor treatment.

Study of the thermal pain threshold latency of acupoints based on Fei Teng Ba Fa / 针灸推拿医学（英文版）

Objective:By applying moxibustion to the eight confluent points in different periods of time,to observe the changes in thermal pain threshold latency of acupoints based on Fei Teng Ba Fa.Methods:A total of 468 healthy college student volunteers received moxibustion at the eight confluent points in three different periods of time,i.e.Chen (7:00-9:00),Wu (11:00-13:00) and Xu (19:00-21:00).The thermal pain threshold latency was adopted to measure the changes in pain threshold of the eight confluent points under different conditions (different periods of time,different genders,different acupoints and different states of the acupoints) based on Fei Teng Ba Fa.Results:Finally,thirty subjects dropped out and 438 subjects were included.The comparison of thermal pain threshold latencies of the eight confluent points in the same opening or closing state based on Fei Teng Ba Fa:latencies of the closing points and adjunct points were significantly different in different periods of time (P＜0.05);the latencies of the males were significantly longer than those of the females (P＜0.05);there was no significant difference in the latency between the left and right sides (P＞0.05);in the female group,there was a significant difference in the latency between the lower-limb points and the upper-limb points (P＜0.05).The comparison of thermal point threshold latencies of the eight confluent points in different opening or closing state:in the period of Wu (11:00-13:00),the latencies of the opening points were significantly longer than those of the closing points and adjunct points (P＜0.05);for men,their opening and closing points had significantly longer thermal pain threshold latencies than their adjunct points (P＜0.05);despite the gender,the latencies of the upper limb opening and closing points were significantly longer than the latency of the adjunct points (P＜0.05);in the female group,the latencies of the lower-limb opening points were significantly shorter than those of the lower-limb closing and adjunct points (P＜0.05).Conclusion:Based on Fei Teng Ba Fa,the pain thresholds of the eight confluent points vary in different periods of time,gender,acupoint location and opening/closing state,which can be taken as the evidence of making time-based acupuncture-moxibustion prescriptions.

Bioactive metabolites from biotransformation of paeonol by the white-rot basidiomycete Coriolus versicolor.

Biotransformation of paeonol (1) with the white-rot basidiomycete Coriolus versicolor afforded two metabolites, 2,4-dihydroxyacetophenone (2) and 2,5-dihydroxy-4-methoxyacetophenone (3), which were identified by spectroscopic methods. Compound 3 showed higher antioxidative, antibacterial, antifungal activities than 1 or 2. The results demonstrate for the first time that C. versicolor has the capacities to catalyze hydroxylation and demethylation reactions on the aromatic compound.