Sustained amphiregulin expression in intermediate alveolar stem cells drives progressive fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.

A Study on an Easy-Plane FeSi3.5 Composite with High Permeability and Ultra-Low Loss at the MHz Frequency Band.

An easy-plane FeSi3.5 composite with excellent magnetic properties and loss properties at MHz were proposed. The easy-plane FeSi3.5 composite has ultra-low loss at 10 MHz and 4 mT, about 372.88 kW/m3. In order to explore the reason that the Pcv of easy-plane FeSi3.5 composite is ultra-low, a none easy-plane FeSi3.5 composite, without easy-plane processing as a control group, measured the microstructure, and the magnetic and loss properties. We first found that the real reason why magnetic materials do not work properly at MHz due to overheat is dramatical increase of the excess loss and the easy-plane composite can greatly re-duce the excess loss by loss measurement and separation. The total loss of none easy-plane FeSi3.5 composite is much higher than that of easy-plane FeSi3.5 composite, where the excess loss is a major part in the total loss and even over 80% in the none easy-plane FeSi3.5 composite. The easy-plane FeSi3.5 composite can greatly reduce the total loss compared to the none easy-plane FeSi3.5 composite, from 2785.8 kW/m3 to 500.42 kW/m3 (3 MHz, 8 mT), with the main reduction being the excess loss, from 2435.2 kW/m3 to 204.93 kW/m3 (3 MHz, 8 mT), reduced by 91.58%. Furthermore, the easy-plane FeSi3.5 composite also has excellent magnetic properties, high permeability and ferromagnetic resonance frequencies. This makes the easy-plane FeSi3.5 composite become an excellent soft magnetic composite and it is possible for magnetic devices to operate properly at higher frequencies, especially at the MHz band and above.

Zein-induced immune response and modulation by size, pore structure and drug-loading: Application for sciatic nerve regeneration.

Zein is a biodegradable material with great potential in biomedical applications. However, as a plant-derived protein material, body's immune response is the key factor to determine its clinical performance. Herein, for the first time, the zein-induced immune response is evaluated systemically and locally, comparing with typical materials including alginate (ALG), poly(lactic-co-glycolic) acid (PLGA) and polystyrene (PS). Zein triggers an early inflammatory response consistent with the non-degradable PS, but this response decreases to the same level of the biosafe ALG and PLGA with zein degradation. Changing sphere sizes, pore structure and encapsulating dexamethasone can effectively modulate the zein-induced immune response, especially the pore structure which also inhibits neutrophil recruitment and promotes macrophages polarizing towards M2 phenotype. Thus, porous zein conduits with high and low porosity are further fabricated for the 15 mm sciatic nerve defect repair in rats. The conduits with high porosity induce more M2 macrophages to accelerate nerve regeneration with shorter degradation period and better nerve repair efficacy. These findings suggest that the pore structure in zein materials can alleviate the zein-induced early inflammation and promote M2 macrophage polarization to accelerate nerve regeneration. STATEMENT OF SIGNIFICANCE: Zein is a biodegradable material with great potential in biomedical applications. However, as a plant protein, its possible immune response in vivo is always the key issue. Until now, the systemic study on the immune responses of zein in vivo is still very limited, especially as an implant. Herein, for the first time, the zein-induced immune response was evaluated systemically and locally, comparing with typical biomaterials including alginate, poly(lactic-co-glycolic) acid and polystyrene. Changing sphere sizes, pore structure and encapsulating dexamethasone could effectively modulate the zein-induced immune response, especially the pore structure which also inhibited neutrophil recruitment and promoted macrophages polarizing towards M2 phenotype. Furthermore, the pore structure in zein nerve conduits was proved to alleviate the early inflammation and promote M2 macrophage polarization to accelerate nerve regeneration.

Genetic Algorithms to Automate the Design of Metasurfaces for Absorption Bandwidth Broadening.

In this paper, we present a method to automate the design of an efficient metasurface, which widens the bandwidth of the substrate. This strategy maximizes the potential of the substrate for the application of broad-band absorption. The design is achieved by utilizing the coding metasurface and a combination of two types of intelligent algorithms. First, inspired by the coding metasurface, a large number of structures are generated to act as potential metasurface unit patterns by randomly generating the associated binary codes. Then, the binary codes are directly substituted as optimization objects into a genetic algorithm to find the optimal metasurface. Finally, a neural network is introduced to replace the finite element analysis method to correlate the binary codes with the absorbing bandwidth. With the participation of neural networks, the genetic algorithm can find the optimal solution in a considerably short time. This method bypassed the prerequisite physical knowledge required in the process of metasurface design, which can be used for reference in other applications of the metasurface.

Intact polyaniline coating as a conductive guidance is beneficial to repairing sciatic nerve injury.

Endowing the conduit with conductivity has been an effective way to stimulate nerve growth and functional recovery. Here, conducting polyaniline (PANi) was used to construct a conductive guidance by coating on the surface of microtubes inserted in a three-dimensional zein nerve conduit to study the repairing efficacy on peripheral nerve injury. PANi nanoparticles with a size of 20-30 nm were synthesized and coated on the surface of microtubes through layer-by-layer deposition. Then, conduits including microtubes with and without PANi coating were implanted into rats to bridge a 10-mm sciatic nerve defect and autograft as the control group. After 2 months, the conduit with PANicoating improved the recovery of proximal compound muscle action potential significantly in the regenerated nerve compared to the conduit without PANi coating, which was not inferior to the autograft group. However, the repairing efficacy was changed reversely at the fourth month postimplantation. PANi coating fragmented to form debris within or around the regenerated nerves while microtubes seem to degrade completely as observed by H&E staining. In vitro degradation experiment confirmed this process. The PANi nanoparticles could induce cytotoxicity and reactive oxygen species (ROS) generation of both NIH 3T3 cells and macrophage cell line RAW 264.7. These in vitro and in vivo results implied that the nondegradable PANi may occupy the regeneration space and stimulate the inflammatory response in later implantation in vivo. While there was no such risk if the PANi coating keeps in an intact film. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:128-142, 2020.

Expression and Clinical Significance of POLR1D in Colorectal Cancer.

PURPOSE: RNA polymerase I subunit D (POLR1D) is involved in the synthesis of ribosomal RNA precursors and small RNAs, but its mechanism in the development and progression of colorectal cancer (CRC) remains ambiguous. Thus, this research aimed to investigate POLR1D's expression and significance in human CRC patients and evaluate its association with clinicopathological characteristics. METHODS: Matched fresh-frozen cancerous and non-cancerous tissues were collected from 100 patients diagnosed with CRC. Immunohistochemical, Western blot, and quantitative real-time polymerase chain reaction analyses were adopted to validate the correlation between POLR1D expression and clinicopathological parameters in CRC tissues and adjacent normal tissues (ANTs). RESULTS: POLR1D expression in CRC tissues was significantly higher than in the ANTs. χ2 test and Spearman's correlative analysis showed that a high POLR1D expression is significantly associated with clinical stage, Dukes stage, tumor differentiation, depth of invasion, and metastasis (p < 0.05). It is not correlated with gender, age, and tumor location and size (p > 0.05). Kaplan-Meier survival curves show that the overall survival (OS) time for the low expression group is remarkably longer than for the high expression group (p < 0.0015). Univariate and multivariate analyses indicate that a high POLR1D expression is an independent prognostic factor for poor OS (p = 0.000). CONCLUSION: The findings of this study strongly indicate that POLR1D plays a pivotal role in the occurrence and progression of CRC. It might be an independent adverse prognostic factor for CRC patients and could serve as a potential therapeutic target for clinical diagnosis in CRC and anticancer drug development.

Exosomes derived from mesenchymal stem cells reverse EMT via TGF-ß1/Smad pathway and promote repair of damaged endometrium.

BACKGROUND: Intrauterine adhesion (IUA) is one of the most serious complications in patients with endometrial repair disorder after injury. Currently, there is no effective treatment for IUA. Stem cell is the main candidate of new therapy, which functions mainly through paracrine mechanism. Stem-derived exosomes (Exo) play an important role in tissue injury. Here, we mainly aim to study the effect of bone marrow mesenchymal stem cell (BMSC)-derived Exo on repairing endometrium of IUA animal models and its effect on TGF-ß1 induced EMT in endometrial epithelial cells (EECs). METHODS: Totally, 64 female rabbits were randomly divided into Sham operation group, model group, BMSC treatment group, and Exo treatment group. EMT in EECs was induced by TGF-ß1. Then, EECs were treated with Exo (25 µg/ml, 50 µg/ml, 100 µg/ml) for 24 h. HE staining and Masson staining were used to evaluate the changes in glandular number and fibrosis area. The expression levels of CK19 and VIM were detected by immunohistochemistry. Western blotting was used to detect the expression of CK19, VIM, FSP-1, E-cadherin, TGF-ß1, TGF-ß1R, Smad 2, and P-Smad 2. RT-PCR was used to detect mRNA expression levels of CK19, VIM, FSP-1, E-cadherin, TGF-ß1, TGF-ß1R, and Smad 2. RESULTS: Compared with the model group, the number of endometrial glands was significantly increased and endometrial fibrosis area was significantly decreased in BMSC and Exo groups (P < 0.05). CK19 level significantly increased whereas VIM level significantly decreased after treatment of BMSCs and Exo (P < 0.05). Additionally, the expressions of TGF-ß1, TGF-ß1R, and Smad2 mRNA were all significantly decreased after BMSC and Exo treatment (P < 0.05). Besides, phosphorylation levels of TGF-ß1, TGF-ß1R, and Smad2 were also significantly decreased in BMSC and Exo treatment groups (P < 0.05). Furthermore, there was no significant difference between BMSC and Exo treatment groups (P > 0.05). EMT was induced in EECs by 60 ng/ml TGF-ß1 for 24 h. After Exo treatment for 24 h, mRNA expressions of CK-19 and E-cadherin increased, while those of VIM, FSP-1, TGF-ß1, and Smad2 decreased. Additionally, protein expressions of CK-19 and E-cadherin increased, while those of VIM, FSP-1, TGF-ß1, Smad2, and P-Smad2 decreased. CONCLUSIONS: BMSC-derived Exo is involved in the repair of injured endometrium, with similar effect to that of BMSC, and can reverse EMT in rabbit EECs induced by TGF-ß1. BMSC-derived Exo may promote endometrial repair by the TGF-ß1/Smad signaling pathway.

Fabrication of Stable and Well-Dispersed Polyaniline-Polypyrrolidone Nanocomposite for Effective Photothermal Therapy.

Well-dispersed polyaniline (PANi) nanoparticles were successfully synthesized by simple oxidative polymerization of aniline in a two-phase system in the presence of poly(vinylpyrrolidone) (PVP) as a polymer shell agent, and citric acid was used as a doping acid instead of inorganic acids due to its better biocompatibility. TEM showed that the nanocomposites of PANi and PVP (PANi@PVP) assembled into core-shell like nanostructures uniformly. MTT results indicated that the PANi@PVP nanoparticles supported the survival of cells; IC50 could reach about 2.5 mg/mL, much higher than the IC50 value reported for PANi nanoparticles without PVP. Furthermore, in the presence of PVP, only exceeding PANi (>1.5 mg/mL) resulted in a comparable production of intracellular reactive oxygen species (ROS), the induction of apoptosis in PC-12 cells, and a weaker DNA fragmentation. TEM of PC-12 cell sections displayed that the cell morphological changes associated with the apoptosis were induced when exposed to a very high dose of PANi@PVP (3 mg/mL). The well-dispersed PANi@PVP combined with NIR irradiation achieved excellent photothermal conversion performance, which could kill cancer cell BEL-7402 in vitro effectively. Reflecting this well-dispersed property, the tumors in cancer bearing KM mice disappeared thoroughly after a single subcutaneous injection of PANi@PVP nanoparticles and subsequent NIR laser irradiation.

Design and optimization of a biodegradable porous zein conduit using microtubes as a guide for rat sciatic nerve defect repair.

Various degradable biomaterials have been used to bridge injured peripheral nerve defect; however, drawbacks such as poor mechanical properties, inappropriate degradation rate, and toxic degradation products continue to limit the application of them in nerve repair. Considering the unique properties of zein, such as its biocompatibility, biodegradability and ease of fabrication, we report the use of zein conduits to repair injured rat sciatic nerves with a 10-mm defect. Three-dimensional zein conduits were designed with/without pores, and with/without microtubes including in the lumen of conduits. Zein conduit with microtubes yielded satisfactory results in sciatic function index (SFI), proximal compound muscle action potentials, density of myelinated nerve fibres and myelin thickness, which were not inferior to autograft but slightly superior to the hollow conduit at the 4th month post-implantation. The conduits degraded almost completely within two months, which was shorter than the suggested period of four months. Thus, the use of a porous conduit with microtubes inside as the guidance may play important roles in successful repair. Notably, the regulatory body will more likely approve designs employing a single component, such as the natural polymer zein.

Preparation of microcarriers based on zein and their application in cell culture.

Microcarriers with a large surface area have attracted much attention in the field of large-scale cell culture. The preparation of microcarriers is mainly based on methods such as emulsification, suspension polymerization, solvent evaporation, organic phase separation (cohesion) and spray drying. Many of these require the use of organic solvents. In general, organic solvents are considered to be toxic and not conducive to environmental protection. In this study, zein microcarriers were successfully prepared via a novel method in which only glycerol was used as the dispersing medium. The size of these microcarriers was controllable, and the preparation process was simple to perform. Vero cells, commonly used in the production of vaccines, were cultured on the surface of the zein microcarriers to evaluate the microcarriers' performance in cell culture. The cells could attach and spread on the surface, without any difference compared with cells on the surface of Cytodex 1. The cell density reached its maximum on the fourth day, which was approximately 10 times the initial density. This is the first report that zein can be used as a microcarrier for the mass production of a large-scale suspension cell culture, which shows the potential of zein as a replacement for commercial non-degradable materials.

Two cholesterol derivative-based PEGylated liposomes as drug delivery system, study on pharmacokinetics and drug delivery to retina.

In this study, two cholesterol derivatives, (4-cholesterocarbonyl-4'-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and 4-cholesterocarbonyl-4'-(N,N-diethylamine butyloxyl) azobenzene (ACB), one of which is positively charged while the other is neutral, were synthesized and incorporated with phospholipids and cholesterol to form doxorubicin (DOX)-loaded liposomes. PEGylation was achieved by including 1,2-distearoyl-sn-glycero-3-phosphatiylethanol-amine-N-[methoxy-(polyethylene glycol)-2000 (DSPE-PEG2000). Our results showed that PEGylated liposomes displayed significantly improved stability and the drug leakage was decreased compared to the non-PEGylated ones in vitro. The in vivo study with rats also revealed that the pharmacokinetics and circulation half-life of DOX were significantly improved when liposomes were PEGylated (p < 0.05). In particular, the neutral cholesterol derivative ACB played some role in improving liposomes' stability in systemic circulation compared to the conventional PC liposome and the positively charged CAB liposome, with or without PEGylation. In addition, in the case of local drug delivery, the positively charged PEG-liposome not only delivered much more of the drug into the rats' retinas (p < 0.001), but also maintained much longer drug retention time compared to the neutral PEGylated liposomes.

Hydrothermal syntheses and characterizations of two novel frameworks constructed from polyoxometalates, metals and organic units.

Two novel compounds have been hydrothermally synthesized and characterized by IR spectra and single crystal X-ray diffraction analyses. Crystal structure analyses reveal that and exhibit novel 2-D framework structures constructed from tungsten polyoxoanions, metal ions and 4,4-byp units, respectively.

First examples of extended structures based on {PMo(12)Sb(2)O(40)} polyoxoanions.

Three novel heteropolyanions [PMo(12)Sb(2)O(40)][Cu(enMe)(2)].4H(2)O (), [PMo(12)Sb(2)O(40)][Ni(enMe)(2)].4H(2)O (2) and [PMo(12)Sb(2)O(40)][Cu(en)(2)].H(3)O.H(2)O (3) (enMe = 1,2-diaminopropane, en = ethylene diamine) have been synthesized and characterized by IR spectroscopy, X-ray photoelectron spectroscopy (XPS), thermogravimetric analyses and elemental analyses. Single-crystal X-ray diffraction analyses reveal that these three compounds represent the first examples of compounds based on the novel polyoxoanion {PMo(12)Sb(2)O(40)} and different transition metal coordination complexes. 1 and 2 are isostructural and both exhibit novel 1-D structures. In contrast to 1 and 2, 3 exhibits a substantially distinct novel 1-D structure. In addition, 3 is the first example of an extended structure constructed from polyoxoanions and Cu(+) transition metal coordination complexes.

Synthesis and characterization of a novel POM compound containing two different layers stacked alternately.

A novel POM compound containing the first Sb bicapped Keggin anion {SiMo(12)O(40)Sb(2)} and two different layers constructed from these anions stacked alternately has already been hydrothermally synthesized.