Metal-Phenolic Networks for Chronic Wounds Therapy.

Chronic wounds are recalcitrant complications of a variety of diseases, with pathologic features including bacterial infection, persistent inflammation, and proliferation of reactive oxygen species (ROS) levels in the wound microenvironment. Currently, the use of antimicrobial drugs, debridement, hyperbaric oxygen therapy, and other methods in clinical for chronic wound treatment is prone to problems such as bacterial resistance, wound expansion, and even exacerbation. In recent years, researchers have proposed many novel materials for the treatment of chronic wounds targeting the disease characteristics, among which metal-phenolic networks (MPNs) are supramolecular network structures that utilize multivalent metal ions and natural polyphenols complexed through ligand bonds. They have a flexible and versatile combination of structural forms and a variety of formations (nanoparticles, coatings, hydrogels, etc.) that can be constructed. Functionally, MPNs combine the chemocatalytic and bactericidal properties of metal ions as well as the anti-inflammatory and antioxidant properties of polyphenol compounds. Together with the excellent properties of rapid synthesis and negligible cytotoxicity, MPNs have attracted researchers' great attention in biomedical fields such as anti-tumor, anti-bacterial, and anti-inflammatory. This paper will focus on the composition of MPNs, the mechanisms of MPNs for the treatment of chronic wounds, and the application of MPNs in novel chronic wound therapies.

Hyaluronic acid modified oral drug delivery system with mucoadhesiveness and macrophage-targeting for colitis treatment.

Based on the biocompatibility and macrophage targeting of natural polysaccharides, combined with the physiological and pathological characteristics of the gastrointestinal tract and colonic mucosa of ulcerative colitis (UC), we prepare dexamethasone (Dex)-loaded oral colon-targeted nano-in-micro drug delivery systems coated with multilayers of chitosan (CS), hyaluronic acid (HA), and finally Eudragit S100 (ECHCD MPs) using a layer-by-layer coating technique for UC treatment through regulating the M1/M2 polarization of intestinal macrophages. HA/CS/Dex nanoparticles (HCD NPs) are ingested by macrophages via CD44 receptor-mediated endocytosis to regulate M1-to-M2 macrophage polarization and exert anti-inflammatory effects. Moreover, ECHCD MPs show better colon-targeting properties than Dex-loaded chitosan nanoparticles (CD NPs) and HCD NPs which is demonstrated by stronger mucoadhesion to inflamed colon tissues. After oral administration, ECHCD MPs exert significant anti-UC effects. Therefore, ECHCD MPs are proven to be as promising oral colon-targeting drug delivery systems for Dex and have potential application in UC treatment.

A cathepsin B/GSH dual-responsive fluorinated peptide for effective siRNA delivery to cancer cells.

Small interfering RNA (siRNA) can be exploited to silence specific genes associated with cancer development, and successful siRNA therapy is highly dependent on the efficiency of the siRNA delivery vector. Herein, a well-designed novel redox- and enzyme-responsive fluorinated polyarginine (PFC-PR) was developed to be used as an anti-cancer siRNA carrier. The multiple guanidine groups could provide positive charges and bind with siRNA efficiently, and further fluorination modification enhanced the interaction with siRNA, resulting in a more stable PFC-PR/siRNA nanocomplex, improving serum tolerance, and promoting cellular uptake and endosome escape. Meanwhile, the PFC-PR was responsive to overexpressed cathepsin B and high levels of glutathione in cancer cells, conferring its ability to enhance siRNA release within cancer cells and making it cancer-targeting. Consequently, PFC-PR showed good biocompatibility and high gene silencing efficiency, which could inhibit cancer cell growth when delivered the siRNA targeting vascular endothelial growth factor, suggesting that it can be potentially used for anti-cancer gene therapy applications.

Effect of a rigid ankle foot orthosis and an ankle foot orthosis with an oil damper plantar flexion resistance on pelvic and thoracic movements of patients with stroke during gait.

BACKGROUND: Impairments of trunk movements in gait of stroke are often reported. Ankle foot orthosis (AFO) is commonly used to improve gait of stroke; however, the effect of different types of AFOs on the pelvic and thoracic movements during gait in stroke has not been clarified. METHODS: Thirty-four patients with stroke were randomly allocated to undergo 2 weeks of gait training by physiotherapists while wearing a rigid AFO (RAFO) with a fixed ankle or an AFO with an oil damper (AFO-OD) that provides plantarflexion resistance and free dorsiflexion. A motion capture system was used for measurements of shod gait without AFO at baseline and with and without AFO after gait training. Two-way repeated ANOVA, Wilcoxon signed-rank test, and Mann-Whitney U test were performed for the data after the gait training to know the effect of different kinds of AFOs. RESULTS: Twenty-nine patients completed the study (AFO-OD group: 14, RAFO group: 15). Interactions were found in pelvic rotation angle, change of shank-to-vertical angle (SVA) in the stance, and paretic to non-paretic step length, which increased in AFO-OD group with AFOs (p < 0.05), while the SVA decreased in RAFO group with AFOs (p < 0.05). The main effects were found in pelvic rotation at the contralateral foot off, and thoracic tilt at foot off when an AFO was worn. The change of SVA in stance was positively correlated with the pelvic rotation in the AFO-OD group (r = 0.558). At initial contact, pelvic rotation was positively correlated with thoracic rotation in both groups. CONCLUSIONS: The findings in 29 patients with stroke showed that pelvic and thoracic movements especially the rotation were affected by the type of AFOs. Pelvic rotation and lower limb kinematics exhibited significant improvements with AFO-OD, reflecting more desirable gait performance. On the other hand, the increase in thoracic in-phase rotation might expose the effect of insufficient trunk control and dissociation movement. Trial registration UMIN000038694, Registered 21 November 2019, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_his_list.cgi?recptno=R000044048 .

Carbon-based zero valent iron catalyst for NOX removal at low temperatures: performance and kinetic study.

In order to solve the problem of nitrous oxide (NOX) removal at low temperatures, the carbon-based zero valent iron (C-ZFe) catalyst was prepared and studied. According to the kinetic study and the obtained kinetic parameters, the De-NOX reactor was designed to provide information for industrial applications. The box-behnken experimental design (BBD) was used to study the performance of C-ZFe, and the optimized operating parameters were obtained as the temperature was 408.15 K, the catalyst bed height was 140 cm (the space velocity was 459 h-1), the concentration of NO was 550 ppm, under which the NOX conversion was 72.7%. A kinetic model based on Langmuir-Hinshelwood (L-H) and Mars Van Krevelen mechanism was used to describe the kinetics for the reduction of NO by C-ZFe at low temperatures. Scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), surface area and pore size distribution measurements, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) results supported the validity of the model proposed. The gas-solid catalytic kinetic process of NO removal by C-ZFe was a quasi-first-order kinetic reaction, the apparent activation energy was 41.57 kJ/mol, and the pre-exponential factor was 2980 min-1.

Cu-VWT Catalysts for Synergistic Elimination of NOx and Volatile Organic Compounds from Coal-Fired Flue Gas.

A dual-function catalyst, designated as Cu5-VWT, has been constructed for the synergistic removal of NOx and volatile organic compounds under complex coal-fired flue gas conditions. The removal of toluene, propylene, dichloromethane, and naphthalene all exceeded 99% (350 °C), and the catalyst could effectively block the generation of polycyclic aromatic hydrocarbons. Mechanistic studies have shown that Cu sites on the Cu5-VWT catalyst facilitate catalytic oxidation, while V sites facilitate NOx reduction. Thus, toluene oxidation and NOx reduction can proceed simultaneously. The removal of total hydrocarbons and nonmethane total hydrocarbons from 1200 m3·h-1 real coal-fired flue gas by a monolithic catalyst were determined as 92 and 96%, respectively, much higher than those of 54 and 72% over a commercial VWT catalyst, indicating great promise for industrial application.

Mitochondrial Damage Response and Fate of Normal Cells Exposed to FLASH Irradiation with Protons.

Radiation therapy (RT) plays an important role in cancer treatment. The clinical efficacy of radiation therapy is, however, limited by normal tissue toxicity in areas surrounding the irradiated tumor. Compared to conventional radiation therapy (CONV-RT) in which doses are typically delivered at dose rates between 0.03-0.05 Gy/s, there is evidence that radiation delivered at dose rates of orders of magnitude higher (known as FLASH-RT), dramatically reduces the adverse side effects in normal tissues while achieving similar tumor control. The present study focused on normal cell response and tested the hypothesis that proton-FLASH irradiation preserves mitochondria function of normal cells through the induction of phosphorylated Drp1. Normal human lung fibroblasts (IMR90) were irradiated under ambient oxygen concentration (21%) with protons (LET = 10 keV/µm) delivered at dose rates of either 0.33 Gy/s or 100 Gy/s. Mitochondrial dynamics, functions, cell growth and changes in protein expression levels were investigated. Compared to lower dose-rate proton irradiation, FLASH-RT prevented mitochondria damage characterized by morphological changes, functional changes (membrane potential, mtDNA copy number and oxidative enzyme levels) and oxyradical production. After CONV-RT, the phosphorylated form of Dynamin-1-like protein (p-Drp1) underwent dephosphorylation and aggregated into the mitochondria resulting in mitochondria fission and subsequent cell death. In contrast, p-Drp1 protein level did not significantly change after delivery of similar FLASH doses. Compared with CONV irradiation, FLASH irradiation using protons induces minimal mitochondria damage; our results highlight a possible contribution of Drp1-mediated mitochondrial homeostasis in this potential novel cancer treatment modality.

Clinical Study on Long-Term Sinus Reversion Rate and Left Atrial Function Recovery of Mitral Valve Disease with Atrial Fibrillation under Modified Surgical Radiofrequency Ablation.

We aimed to study the long-term sinus reversion rate and recovery of left atrial function after modified surgical radiofrequency ablation for permanent atrial fibrillation caused by mitral valve disease. From March 2014 to May 2020, 35 patients who underwent modified surgical radiofrequency ablation during cardiac valve surgery in our hospital were selected as the study group, and 25 normal individuals without cardiac structural changes were selected as the control group. The time of modified surgical radiofrequency ablation and long-term sinus reversion rate were measured, and left atrial anteroposterior, superoinferior, left and right diameters, left atrial ejection fraction, left atrial filling index, and left atrial ejection force were measured before and 6 months after surgery. The mean ablation time was 23.2 min, and the long-term sinus reversion rate was 80.0%. The left atrium diameter decreased and the left atrium ejection fraction increased after the operation (P < 0.05). The left atrium filling index and ejection force were significantly increased in 28 patients with sinus reversion (P < 0.05). The decrease in left atrial diameter and the increase in left atrial ejection fraction were correlated with sinus conversion after surgery (P < 0.05). The modified operation is simple, the curative effect is definite, and the sinus reversion rate is high, which is beneficial to the restoration of left atrial structure, ejection function, and hemodynamic function.

Long Non-Coding RNA CRYBG3 Promotes Lung Cancer Metastasis via Activating the eEF1A1/MDM2/MTBP Axis.

The occurrence of distant tumor metastases is a major barrier in non-small cell lung cancer (NSCLC) therapy, and seriously affects clinical treatment and patient prognosis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to be crucial regulators of metastasis in lung cancer. The aim of this study was to reveal the underlying mechanisms of a novel lncRNA LNC CRYBG3 in regulating NSCLC metastasis. Experimental results showed that LNC CRYBG3 was upregulated in NSCLC cells compared with normal tissue cells, and its level was involved in these cells' metastatic ability. Exogenously overexpressed LNC CRYBG3 increased the metastatic ability and the protein expression level of the metastasis-associated proteins Snail and Vimentin in low metastatic lung cancer HCC827 cell line. In addition, LNC CRYBG3 contributed to HCC827 cell metastasis in vivo. Mechanistically, LNC CRYBG3 could directly combine with eEF1A1 and promote it to move into the nucleus to enhance the transcription of MDM2. Overexpressed MDM2 combined with MDM2 binding protein (MTBP) to reduce the binding of MTBP with ACTN4 and consequently increased cell migration mediated by ACTN4. In conclusion, the LNC CRYBG3/eEF1A1/MDM2/MTBP axis is a novel signaling pathway regulating tumor metastasis and may be a potential therapeutic target for NSCLC treatment.

The long noncoding RNA CRYBG3 induces aneuploidy by interfering with spindle assembly checkpoint via direct binding with Bub3.

Aneuploidy is a hallmark of genomic instability that leads to tumor initiation, progression, and metastasis. CDC20, Bub1, and Bub3 form the mitosis checkpoint complex (MCC) that binds the anaphase-promoting complex or cyclosome (APC/C), a crucial factor of the spindle assembly checkpoint (SAC), to ensure the bi-directional attachment and proper segregation of all sister chromosomes. However, just how MCC is regulated to ensure normal mitosis during cellular division remains unclear. In the present study, we demonstrated that LNC CRYBG3, an ionizing radiation-inducible long noncoding RNA, directly binds with Bub3 and interrupts its interaction with CDC20 to result in aneuploidy. The 261-317 (S3) residual of the LNC CRYBG3 sequence is critical for its interaction with Bub3 protein. Overexpression of LNC CRYBG3 leads to aneuploidy and promotes tumorigenesis and metastasis of lung cancer cells, implying that LNC CRYBG3 is a novel oncogene. These findings provide a novel mechanistic basis for the pathogenesis of NSCLC after exposure to ionizing radiation as well as a potential target for the diagnosis, treatment, and prognosis of an often fatal disease.

A dendrite-free and stable anode for high-performance Li-O2 batteries by prestoring Li in reduced graphene oxide coated three-dimensional nickel foam.

Li-based reduced (r)GO-Ni (Li/rGO-Ni) was prepared by a thermal-infusion method. Li/rGO-Ni based symmetric cells have high cycling stability and small voltage hysteresis at various current densities. Furthermore, the Li/rGO-Ni based Li-O2 batteries exhibit good performances.

Radiation Exposure-Induced Changes in the Immune Cells and Immune Factors of Mice With or Without Primary Lung Tumor.

Recent studies have demonstrated that radiation activates in situ antitumor immunity and consequently induced a synergistic effect of radiotherapy and immunotherapy. However, studies related to radiation-induced changes in immune system of tumor-bearing mice are limited, which are of great significance to improve the efficacy of radioimmunotherapy. In this study, we first established a primary lung tumor mouse model using urethane. Then part of the right lung of the mouse was exposed to X-ray irradiation with a computed tomography-guided small animal irradiator and the changes of immune cells in both peripheral blood and spleen were determined by flow cytometry. Besides, the levels of both cytokines and immunoglobulins in mouse serum were detected by a protein chip. We found that B lymphocytes increased while CD8+ T lymphocytes reduced significantly. Interleukin-3 (IL-3), IL-6, regulated upon activation, normally T-expressed, and presumably secreted factor (RANTES), and vascular endothelial growth factor (VEGF) were found to be decreased after tumor formation, and the similar results have also been observed with kappa, IgG3, IgE, IgM, and IgG2a. After irradiation, lower concentrations of IgD, kappa, and IgM were found in the serum. Our findings indicate that localized tumor irradiation caused some obvious changes like inhibiting the ability of innate immunity, and these changes may be useful in predicting prognosis.

Overexpression of Ras-Related C3 Botulinum Toxin Substrate 2 Radiosensitizes Melanoma Cells In Vitro and In Vivo.

Radioresistance is the major obstacle in the radiotherapy of the malignant melanoma. Thus, it is of importance to increase the radiosensitivity of melanoma cells. In the present study, the radioresistant melanoma cell line OCM-1 with inducible overexpression of Ras-related C3 botulinum toxin substrate 2 was established based on a radiation-inducible early growth response gene (Egr-1) promoter. The effects of Ras-related C3 botulinum toxin substrate 2 overexpression on the radiosensitivity of melanoma cells exposed to either X-rays or carbon ion beams were evaluated in cultured cells as well as xenograft tumor models. In addition, both reactive oxygen species yield and the NADPH oxidase activity were measured in the irradiated melanoma cells. It was found that the radiation-inducible overexpression of Ras-related C3 botulinum toxin substrate 2 sensitized the melanoma cells to both X-rays and carbon ion irradiation by enhancing the NADPH oxidase activity and the subsequent reactive oxygen species production. Besides, the overexpression of Ras-related C3 botulinum toxin substrate 2 enhanced the tumor-killing effect of radiotherapy in xenograft tumors significantly. The results of this study indicate that Ras-related C3 botulinum toxin substrate 2 is promising in increasing the radiosensitivity of melanoma cells, which provides experimental evidence and theoretical basis for clinical radiosensitization of the malignant melanoma.

LNC CRYBG3 inhibits tumor growth by inducing M phase arrest.

Long noncoding RNAs (lncRNAs) are usually associated with tumor development and progression and some of them are dysregulated in various human cancers. The mechanisms underlying their dysregulation are worth further study. Here, we demonstrate that the expression level of LNC CRYBG3 is correlated with 1501 aberrantly expressed proteins in A549 cells (non-small cell lung cancer (NSCLC) cells). LNC CRYBG3 overexpression results in M phase arrest and promoted cell death, whereas LNC CRYBG3 knockdown did not elicit the opposite effects. The overexpression of LNC CRYBG3 inhibits cell proliferation both in vitro and in vivo. Moreover, it upregulates the expression of cyclin B1 and the phosphorylation of H3, whereas it inhibited the expression of cyclin-dependent kinase 6 and cyclin D1. Taken together, these findings suggest that LNC CRYBG3 regulates the cell cycle process of A549 cells, suggesting its potential application for the treatment of this disease.

Anti-cancer effects of CQBTO, a chloroquine, and benzo(e)triazine oxide conjugate.

AIM: Autophagy is a self-protective process, and it confers cancer cells resistance against radio-chemotherapeutics. To induce cancer cell death, a series of compounds of 3-((4-((7-chloroquinolin-4-yl)amino)butyl)amino)-7-substituted benzo[e][1,2,4]triazine 1-oxide or CQBTO containing two critical chemical groups were designed and synthesized. One compound, benzo[e][1,2,4]triazine 1-oxide, yielded free radicals to trigger autophagy, and the other one, chloroquine (CQ), was an inhibitor of autophagy. We hypothesized that the compounds could kill cancer cells effectively by inducing incomplete autophagy. METHODS: In vitro cultured non-small cell lung carcinoma cells and primary lung tumors in mice in vivo were used to test the lethal effects of CQBTO on cancer cells and toxicity to normal tissues. Cell viability was examined using the CCK8 assay. Genomic instability was determined with the cytochalasin B-blocked micronucleus assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Western blotting and immunofluorescence were used to detect the induction and localization of LC3, a biomarker for autophagy. RESULTS: Compared with CQ, three CQBTO compounds were lethal to lung cancer cells, and CQBTO-3 was the most effective. The LD50 for CQBTO-3 was 21 µΜ in A549 cells and 21.5 µΜ in Calu-1 cells, which was lower than that of CQBTO-2 or CQBTO-1. Induction of LC3 foci and an increase in the LC3II/LC3I ratio demonstrated the induction of autophagy by CQBTO-3 in A549 cells, whereas no obvious micronuclei or cell cycle arrest was observed. No detectable toxicity to normal mice was observed. CQBTO-3 improved the quality of mouse life, reduced the number and size of existing tumors, and suppressed tumor formation. CONCLUSION: CQBTO-3 is a potential chemical compound for lung cancer treatment.

RAC2 promotes abnormal proliferation of quiescent cells by enhanced JUNB expression via the MAL-SRF pathway.

Radiation-induced lung injury (RILI) occurs most often in radiotherapy of lung cancer, esophageal cancer, and other thoracic cancers. The occurrence of RILI is a complex process that includes a variety of cellular and molecular interactions, which ultimately result in carcinogenesis. However, the underlying mechanism is unknown. Here we show that Ras-related C3 botulinum toxin substrate 2 (RAC2) and transcription factor jun-B (JUNB) were upregulated in non-small cell carcinoma (NSCLC) tissues and were associated with poor prognoses for NSCLC patients. Ionizing radiation also caused increased expression of RAC2 in quiescent stage cells, and the reentry of quiescent cells into a new cell cycle. The activity of the serum response factor (SRF) was activated by RAC2 and other Rho family genes (RhoA, ROCK, and LIM kinase). Consequently, JUNB acted as an oncogene and induced abnormal proliferation of quiescent cells. Together, the results showed that RAC2 can be used as a target gene for radiation protection. A better understanding of the RAC2 and JUNB mechanisms in the molecular etiology of lung cancer will be helpful in reducing cancer risks and side effects during treatment of this disorder. Our study therefore provides a new perspective on the involvement of RAC2 and JUNB as oncogenes in the tumorigenesis of NSCLC.

Long Noncoding RNA CRYBG3 Blocks Cytokinesis by Directly Binding G-Actin.

The dynamic interchange between monomeric globular actin (G-actin) and polymeric filamentous actin filaments (F-actin) is fundamental and essential to many cellular processes, including cytokinesis and maintenance of genomic stability. Here, we report that the long noncoding RNA LNC CRYBG3 directly binds G-actin to inhibit its polymerization and formation of contractile rings, resulting in M-phase cell arrest. Knockdown of LNC CRYBG3 in tumor cells enhanced their malignant phenotypes. Nucleotide sequence 228-237 of the full-length LNC CRYBG3 and the ser14 domain of ß-actin is essential for their interaction, and mutation of either of these sites abrogated binding of LNC CRYBG3 to G-actin. Binding of LNC CRYBG3 to G-actin blocked nuclear localization of MAL, which consequently kept serum response factor (SRF) away from the promoter region of several immediate early genes, including JUNB and Arp3, which are necessary for cellular proliferation, tumor growth, adhesion, movement, and metastasis. These findings reveal a novel lncRNA-actin-MAL-SRF pathway and highlight LNC CRYBG3 as a means to block cytokinesis and to treat cancer by targeting the actin cytoskeleton.Significance: Identification of the long noncoding RNA LNC CRYBG3 as a mediator of microfilament disorganization marks it as a novel therapeutic antitumor strategy. Cancer Res; 78(16); 4563-72. ©2018 AACR.