Tuning Fe3O4 for sustainable cathodic heterogeneous electro-Fenton catalysis by acetylated chitosan.

Peroxidase-like catalysts are safe and low-cost candidates to tackle the dilemma in constructing sustainable cathodic heterogeneous electro-Fenton (CHEF) catalysts for water purification, but the elusive structure-property relationship of enzyme-like catalysts constitutes a pressing challenge for the advancement of CHEF processes in practically relevant water and wastewater treatment. Herein, we probe the origins of catalytic efficiency in the CHEF process by artificially tailoring the peroxidase-like activity of Fe3O4 through a series of acetylated chitosan-based hydrogels, which serve as ecofriendly alternatives to traditional carbon shells. The optimized acetylated chitosan wrapping Fe3O4 hydrogel on the cathode shows an impressive activity and stability in CHEF process, overcoming the complicated and environmentally unfavored procedures in the electro-Fenton-related processes. Structural characterizations and theoretical calculations reveal that the amide group in chitosan can modulate the intrinsic redox capacity of surficial Fe sites on Fe3O4 toward CHEF catalysis via the neutral hydrogen bond. This work provides a sustainable path and molecule-level insight for the rational design of high-efficiency CHEF catalysts and beyond.

Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1.

Recent recognition that TGF-ß signaling disruption is involved in the development of aortic aneurysms has led to renewed investigations into the role of TGF-ß biology in the aortic wall. We previously found that the type I receptor of TGF-ß (TGFBR2) receptor contributes to formation of ascending aortic aneurysms and dissections (AADs) induced by smooth muscle cell (SMC)-specific, postnatal deletion of Tgfbr1 (Tgfbr1iko). Here, we aimed to decipher the mechanistic signaling pathway underlying the pathogenic effects of TGFBR2 in this context. Gene expression profiling demonstrated that Tgfbr1iko triggers an acute inflammatory response in developing AADs, and Tgfbr1iko SMCs express an inflammatory phenotype in culture. Comparative proteomics profiling and mass spectrometry revealed that Tgfbr1iko SMCs respond to TGF-ß1 stimulation via robust up-regulation of cyclophilin A (CypA). This up-regulation is abrogated by inhibition of TGFBR2 kinase activity, small interfering RNA silencing of Tgfbr2 expression, or inhibition of SMAD3 activation. In mice, Tgfbr1iko rapidly promotes CypA production in SMCs of developing AADs, whereas treatment with a CypA inhibitor attenuates aortic dilation by 56% (P = 0.003) and ameliorates aneurysmal degeneration (P = 0.016). These protective effects are associated with reduced aneurysm-promoting inflammation. Collectively, these results suggest a novel mechanism, wherein loss of type I receptor of TGF-ß triggers promiscuous, proinflammatory TGFBR2 signaling in SMCs, thereby promoting AAD formation.-Zhou, G., Liao, M., Wang, F., Qi, X., Yang, P., Berceli, S. A., Sharma, A. K., Upchurch, G. R., Jr., Jiang, Z. Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1.

Exosomes derived from human umbilical cord mesenchymal stem cells accelerate growth of VK2 vaginal epithelial cells through MicroRNAs in vitro.

STUDY QUESTION: Could human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) accelerate vaginal epithelium cell (VK2) growth? SUMMARY ANSWER: HucMSC-Ex play a significant role in promoting proliferation of VK2 cells by accelerating the cell cycle and inhibiting apoptosis through exosomal microRNAs in vitro. WHAT IS KNOWN ALREADY: Numerous studies have reported that MSC-Ex play an important role in tissue injury repair. STUDY DESIGN, SIZE, DURATION: hucMSC and exosomes isolated from their conditioned medium were used to treat a vaginal epithelial cell line (VK2). Normal human fibroblasts (HFF-1) were used as negative control to hucMSC. PARTICIPANTS/MATERIALS, SETTING, METHODS: VK2 cells were co-cultured with hucMSC whose paracrine effect on the viability, cell cycle and cell apoptosis of VK2 vaginal epithelial cells was further assessed by the CCK-8 assay and flow cytometry. HucMSC-Ex isolated from culture medium by ultracentrifuge were characterized by transmission electron microscopy, nanoparticle tracking analysis and Western blot. HucMSC-Ex at different concentrations and HFF-1 exosomes were used to treat VK2 cells. High-throughput RNA sequencing was utilized to reveal the profile of microRNAs in hucMSC, hucMSC-Ex, HFF-1 and HFF-1 exosomes and GO analysis was applied to demonstrate their functions. To evaluate the function of these specific microRNAs in hucMSC-Ex, VK2 cells were treated with RNA-interfered-hucMSC-Ex (RNAi-hucMSC-Ex) and their proliferation was measured by Label-free Real-time Cellular Analysis System. MAIN RESULTS AND THE ROLE OF CHANCE: The study showed that hucMSC stimulate VK2 cell growth possibly through a paracrine route by promoting cell cycle and inhibiting apoptosis. Compared with control and low dose groups, hucMSC-Ex of high concentration (more than 1000 ng/ml) significantly increased VK2's growth after treatment in a dose-depended manner (P < 0.05). HucMSC-Ex raised the proportion of cells in S-phase and reduced the percentage of apoptotic cells in VK2 cells in comparison with the HFF-1 exosomes and control groups (P < 0.05). microRNAs, including miR-100 (16.92%), miR-146a (9.21%), miR-21 (6.67%), miR-221 (6.39%) and miR-143 (4.63%), were found to be specifically enriched (P < 0.05) in hucMSC-Ex and their functions concentrated on cell cycle, development and differentiation. Collectively, our findings indicate that hucMSC-Ex may play a significant role in accelerating VK2's proliferation by promoting cell cycle and inhibiting apoptosis through exosomal microRNAs in vitro. LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Our study did not confirm the function of hucMSC-Ex or specifically enriched exosomal microRNAs in vivo. miR-100 and miR-146a are well-known immunomodulatory miRNAs that participate in the regulation of inflammatory disorders and may enhance the therapeutic effect of hucMSC-Ex by promoting the surgical injury repair after vaginal reconstruction. But whether it acts through anti-inflammatory responses needs further study. WIDER IMPLICATIONS OF THE FINDINGS: This finding supports the potential use of hucMSC-Ex as a cell-free therapy of Meyer-Rokitansky-Küster-Hauser syndrome (MRKHS) after vaginoplasty. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Chinese National Nature Sciences Foundation (grant number 91440107, 81471416 and 81771524) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19040102). All authors state that there is no conflict of interest to disclose.

Cathode-Introduced Atomic H* for Fe(II)-Complex Regeneration to Effective Electro-Fenton Process at a Natural pH.

Promotion of iron solubility using ligands is the preliminary step in the homogeneous electro-Fenton (EF) process at a mild pH, but the chelate efficiencies of most organic ligands are unsatisfactory, resulting in insufficient Fe(II) availability. In this study, atomic H* was, for the first time, introduced to the EF process to accelerate the regeneration of the Fe(II)-complex at a mild pH using a Ni-deposited carbon felt (Ni-CF) cathode. The introduction of atomic H* significantly elevated total organic carbon (TOC) abatement of ciprofloxacin (CIP) from 42% (CF) to 81% (Ni-CF) at a natural pH. In the presence of humic acids (HAs), atomic H* introduced via Ni-CF enhanced the CIP degradation rate to 10 times that of the CF at a mild pH. The electron spin resonance (ESR), density functional theory (DFT) calculations, electrochemical characterization, and in situ electrochemical Raman study clearly demonstrated that the atomic H* generated from the Ni-CF cathode was highly efficient at reducing Fe(III)-complexes at a natural pH. Additionally, the Ni-CF could generate atomic H* without significant nickel leaching. Thus, the atomic H* could continuously facilitate iron cycling and, consequently, enhance pollutant mineralization via the homogeneous EF process at a mild pH in an environmentally friendly manner.

The role of oral oil administration in displaying the chylous tubes and preventing chylous leakage in laparoscopic para-aortic lymphadenectomy.

BACKGROUND AND OBJECTIVES: This study is aimed to investigate the possibility of preoperative oral oil administration in displaying the chylous tubes and preventing chylous leakage in laparoscopic para-aortic lymphadenectomy. MATERIALS AND METHODS: In this retrospective nonrandomized study, of the 30 patients with gynecological malignancies who had indications for laparoscopic para-aortic lymphadenectomy up to renal vessels, 15 were administered preoperative oral oil (oil a administration) (control group) at our hospital between September 2017 and June 2018. The chylous tube displaying rates, incidences of chylous leakage, and other perioperative data of the two groups were compared. RESULTS: Successful display of chylous tubes was observed in 93.3% (14/15) patients in the oil administration group. The chylous leakage was zero in the oil administration group, and 33.3% (5/15) in the control group. The postoperative drainage duration (4.1 ± 1.0 days vs 7.6 ± 1.4 days, P = 0.000), somatostatin application time (0 day vs 5.9 ± 0.8 days), and postoperative hospital stay (6.0 ± 2.3 days vs 9.1 ± 2.1 days, P = 0.001) were significantly shorter in the oil administration group. The total cost is lower in the oil administration group (4972.52 ± 80.54 dollars vs 6260.80 ± 484.47 dollars, P = 0.000). CONCLUSIONS: Preoperative oil administration is a feasible and effective method to display the chylous tubes and to prevent the chylous leakage in para-aortic lymphadenectomy.

MiR-146a Aggravates LPS-Induced Inflammatory Injury by Targeting CXCR4 in the Articular Chondrocytes.

BACKGROUND/AIMS: Osteoarthritis (OA) as a degenerative disease is a major problem in ageing populations. To better understand the molecular mechanisms in the pathogenesis of OA, this study explored the role of microRNA (miR)-146a in the articular chondrocytes. METHODS: The articular chondrocyte line ATDC5 was used to simulate inflammatory injury by LPS administration in vitro. Cell viability, apoptosis, mRNA expressions and productions of inflammatory factors were assessed, respectively. Mir-146a and Cxcr4 mRNA expressions were measured by qRT-PCR. Targeting effect of miR-146a on Cxcr4 3'UTR was assessed by luciferase activity analysis. Protein expression levels of CXCR4 and main factors in PI3K/AKT, Wnt/ß-catenin signal pathways were measured by western blotting. RESULTS: LPS exposure suppressed cell viability, prompted apoptosis of ATDC5 cells, and stimulated expression and release of inflammatory factors. MiR-146a was upregulated in LPS-induced cells. Overexpression of miR-146a further aggravated LPS-induced inflammatory injury, while it was reduced after miR-146a was knocked down. CXCR4 expression was negatively regulated by miR-146a. CXCR4 was a direct target of miR-146a and thus involved in regulatory effect of miR-146a on the injured chondrocytes, which was also related with phosphorylation levels of PI3K/AKT and expressions of Wnt/ß-catenin signal factors. CONCLUSION: miR-146a promoted inflammatory response of articular chondrocytes via targeting CXCR4 and suppressing CXCR4 expression. Overexpression of CXCR4 could attenuate the inflammatory injury. Our findings provided novel evidence which might be useful for further studies exploring therapeutic approaches for OA via targeting miR-146a.

Adipocyte-Derived Extracellular Vesicles: Small Vesicles with Big Impact.

While increasing numbers of studies have established that adipose tissue plays a vital role in balancing energy intake and energy expenditure as both an energy and an endocrine organ, the detailed functions of adipose tissue remain unclear. Adipose tissues are complex, with multiple resident cell populations that communicate to diverse cells and organs via local and systemic metabolic, thermal, and inflammatory signaling. In normal physiology, adipose tissue-derived extracellular vesicles mediate the regulation of energy storage/consumption in adipose tissue, liver, and muscle. In a pathological sense, fat-derived extracellular vesicles can promote the progression of obesity, endocrine diseases, cancer, and reproductive system disorders. In this review, we demonstrate that adipocyte-derived extracellular vesicles function not only in physiological balance but also in the pathological process. We aim to illustrate the impact of adipocyte-derived extracellular vesicles and their value in understanding both homeostasis and disorders.

The biological roles of CD24 in ovarian cancer: old story, but new tales.

CD24 is a glycosylphosphatidylinositol linked molecular which expressed in diverse malignant tumor cells, particular in ovarian carcinoma cells and ovarian carcinoma stem cells. The CD24 expression is associated with increased metastatic potential and poor prognosis of malignancies. CD24 on the surface of tumor cells could interact with Siglec-10 on the surface of immune cells, to mediate the immune escape of tumor cells. Nowadays, CD24 has been identified as a promising focus for targeting therapy of ovarian cancer. However, the roles of CD24 in tumorigenesis, metastasis, and immune escape are still not clearly demonstrated systematically. In this review, we i) summarized the existing studies on CD24 in diverse cancers including ovarian cancer, ii) illustrated the role of CD24-siglec10 signaling pathway in immune escape, iii) reviewed the existing immunotherapeutic strategies (targeting the CD24 to restore the phagocytic effect of Siglec-10 expressing immune cells) based on the above mechanisms and evaluated the priorities in the future research. These results might provide support for guiding the CD24 immunotherapy as the intervention upon solid tumors.

Ferrous ion enhanced Fenton-like degradation of emerging contaminants by sulfidated nanosized zero-valent iron with pH insensitivity.

In this study, the performance and mechanism of the integrated sulfidated nanosized zero-valent iron and ferrous ions (S-nZVI/Fe2+) system for oxygen activation to remove emerging contaminants (ECs) were comprehensively explored. The S-nZVI/Fe2+ system exhibited a 2.4-8.2 times of increase in the pseudo-first order kinetic rate constant for the oxidative degradation of various ECs compared to the S-nZVI system under aerobic conditions, whereas negligible removal was observed in both nZVI and nZVI/Fe2+ systems. Moreover, remarkable EC mineralization efficiency and benign detoxification capacity were also demonstrated in the S-nZVI/Fe2+ system. We revealed that dosing Fe2+ promoted the corrosion of S-nZVI by maintaining an acidic solution pH, which was conducive to O2 activation by dissolved Fe2+ and surface-absorbed Fe(II) to produce •OH. Furthermore, the generation of H* was enhanced for the further reduction of Fe(III) and H2O2 to Fe(II) and •O2-, resulting in the improvement of consecutive single-electron O2 activation for •OH production. Additionally, bisphenol A (BPA) degradation by S-nZVI/Fe2+ was positively correlated with the S-nZVI dosage, with an optimum S/Fe molar ratio of 0.15. The Fenton-like degradation process by S-nZVI/Fe2+ was pH-insensitive, indicating its robust performance over a wide pH range. This study provides valuable insights for the practical implementation of nZVI-based technology in achieving high-efficiency removal of ECs from water.

Enhanced reductive reactivity of zero-valent iron (ZVI) for pollutant removal by natural organic matters (NOMs) under aerobic conditions: Correlation between NOM properties and ZVI activity.

While ubiquitous natural organic matters (NOMs) are capable of enhancing zero-valent iron (ZVI) performance under aerobic conditions, there is limited understanding of how the properties of NOMs affect the reactivity of ZVI towards contaminants removal. Here, the corresponding activity of ZVI under aerobic conditions was investigated in the presence of humic acid (HA), fulvic acid (FA), bovine serum albumin (BSA). It was found that three models of NOMs were all effective in promoting diatrizoate (DTA) reduction via depassivating ZVI. Interestingly, fast adsorption of NOM onto ZVI surface initially caused inconspicuous impact or visible inhibition on hydrophilic DTA reduction depending on their hydrophobicity. However, subsequent exposure of more reactive sites with high hydrophilicity arising from the detachment of surfaced NOM-associated iron oxide finally contributed to the enhanced consumption of Fe0 with the ability: HA > FA ≈ BSA, and 1-2 times increase in DTA removal kinetic rate following the order: HA > FA > BSA. It further revealed that there were two key factors in determining DTA removal under aerobic conditions, including the ability of NOMs to boost Fe0 consumption as contributed by their aromaticity degree and amino groups, and the hydrophobicity of NOMs to initially affect the property of ZVI surfaces.

Life Modifications and PCOS: Old Story But New Tales.

Polycystic ovary syndrome (PCOS) is defined as a kind of endocrine and metabolic disorder that affects female individuals of reproductive age. Lifestyle modifications, including diet modifications, exercise, and behavioral modification, appear to alleviate the metabolic dysfunction and improve the reproductive disorders of PCOS patients (particularly in obese women). Therefore, lifestyle modifications have been gradually acknowledged as the first-line management for PCOS, especially in obese patients with PCOS. However, the mechanism of lifestyle modifications in PCOS, the appropriate composition of diet modifications, and the applicable type of exercise modifications for specific female populations are rarely reported. We conducted a systematic review and enrolled 10 randomized controlled trials for inclusion in a certain selection. In this review, we summarized the existing research on lifestyle modifications in PCOS. We aimed to illustrate the relationship between lifestyle modifications and PCOS (referring to hyperandrogenism, insulin resistance as well as obesity) and also considered the priorities for future research. These results might be an invaluable tool to serve as a guide in lifestyle modifications as the intervention for PCOS and other related endocrine disorders.

Generation of iodinated trihalomethanes during chloramination in the presence of solid copper corrosion products.

Copper water pipelines are widely used in water distribution systems, but the effects of solid copper corrosion products (CCPs) including CuO, Cu2O and Cu2(OH)2CO3 on the generation of iodinated trihalomethanes (I-THMs) during chloramination remain unknown. This study found that the formation of I-THMs during chloramination of humic acid (HA) was inhibited by the presence of CuO and Cu2O, but promoted with the addition of Cu2(OH)2CO3. The negative effect of CuO and Cu2O is mainly exerted by promoting the decay of both NH2Cl and HOI. Although Cu2(OH)2CO3 also accelerated the decomposition of NH2Cl and HOI, it was found that the complexes formed between Cu2(OH)2CO3 and HA facilitated, through carboxyl functional groups, the reaction between HA and HOI, leading to an enhancement of I-THM generation during chloramination, which was further confirmed by model compound experiments. Additionally, this study demonstrated that the effects of solid CCPs on I-THM generation during chloramination were solid CCP- and HA-concentration dependent, but almost unaffected by different initial I- and Br- concentrations. This study provides new insights into the health risks caused by the corrosion of copper water pipelines, especially in areas intruded by sea water.

Vaginal Microbial Environment Skews Macrophage Polarization and Contributes to Cervical Cancer Development.

As a common female reproductive system malignancy, cervical cancer (CC) disturbs numerous women's health. This study demonstrates the role of the vaginal microbial environment (Peptostreptococcus anaerobius) in cervical cancer. Functional assays, including cell proliferation assay, tube formation assay, and immunofluorescence staining, revealed the effect of Peptostreptococcus anaerobius-treated macrophages on cell proliferation and the angiogenesis process. The tube formation assay disclosed the function of Peptostreptococcus anaerobius-treated macrophages on angiogenesis. In vivo assays were also established to explore the impact of Peptostreptococcus anaerobius-treated macrophages on tumor migration. The results revealed that Peptostreptococcus anaerobius-induced macrophages boosted cervical cancer migration and angiogenesis both in vitro and in vivo. Then, this study unveiled that Peptostreptococcus anaerobius-induced macrophage secreted VEGF to stimulate the angiogenesis in cervical cancer. As a whole, Peptostreptococcus anaerobius-induced macrophage facilitates cervical cancer development through modulation of VEGF expression.

Gut and Vaginal Microbiomes in PCOS: Implications for Women's Health.

PCOS is defined as a kind of endocrine and metabolic disorder which affects females at reproductive ages, is becoming much more common, nowadays. Microbiomes are known as microorganisms that inhabit the body to play a vital role in human health. In recent years, several basic and clinical studies have tried to investigate the correlation between the reproductive health/disorder and microbiomes (gut microbiomes and vaginal microbiomes). However, the mechanism is still unclear. In this review, we reviewed the relationship between PCOS and microbiomes, including gut/vaginal microbiomes compositions in PCOS, mechanism of microbiomes and PCOS, and then collectively focused on the recent findings on the influence of microbiomes on the novel insight regarding the therapeutic strategies for PCOS in the future clinical practice.

Exosome Mediated Cytosolic Cisplatin Delivery Through Clathrin-Independent Endocytosis and Enhanced Anti-cancer Effect via Avoiding Endosome Trapping in Cisplatin-Resistant Ovarian Cancer.

Background: Ovarian carcinoma is one of the most common gynecologic malignancies, cisplatin resistance has become a key obstacle to the successful treatment of ovarian cancer because ovarian carcinomas are liable to drug resistance. To find an effective drug carrier is an urgent need. Methods: Exosomes and loading-cisplatin exosomes are isolated using differential centrifugation and characterized by transmission, electron, nanoparticle tracking analysis. The anti-cancer effect of cisplatin was detected under the circumstance of delivered by exosomes or without exosomes in vitro and in vivo. Using proteome analysis and bioinformatics analysis, we further discovered the pathways in exosomes delivery process. We employed a con-focal immunofluorescence analysis, to evaluate the effects of milk-exosomes deliver the cisplatin via avoiding endosomal trapping. Results: Exosomes and exosome-cisplatin were characterized including size, typical markers including CD63, Alix and Tsg101. The anti-cancer effect of cisplatin was enhanced when delivered by exosome in vitro and in vivo. Mechanistic studies shown that exosomes deliver cisplatin mostly via clathrin-independent endocytosis pathway. Exosomes deliver cisplatin into cisplatin-resistant cancer cells clathrin-independent endocytosis and enhance the anti-cancer effect through avoiding endosome trapping. Conclusion: Cisplatin could be delivered by exosome through clathrin-independent endocytosis, and could evade the endosome trapping, diffused in the cytosol evenly. Our study clarifies the mechanism of exosomes mediated drug delivery against resistant cancer, indicates that exosomes can be a potential nano-carrier for cisplatin against cisplatin resistant ovarian cancer, which validates and enriches the theory of intracellular exosome trafficking.

The Emerging Roles and Therapeutic Potential of Extracellular Vesicles in Infertility.

Infertility is becoming much more common and affects more couples. The past years witnessed the rapid development of the diagnosis and treatment upon infertility, which give numerous coupled more opportunities become parents. Extracellular vesicles are known as nano-sized membrane vesicles to play a major role in intracellular communication. In recent years, several basic and clinical studies have tried to investigate the correlation between the reproductive health/disorder and extracellular vesicles. However, the mechanism is still unclear. In this review, we reviewed the relationship between reproductive physiology and extracellular vesicles, and then collectively focused on the recent findings on the relationship between extracellular and infertility, and its consequent influence on the novel insight regarding the therapeutic strategies for infertility in the future clinical practice.

Adipocytes-Derived Extracellular Vesicle-miR-26b Promotes Apoptosis of Cumulus Cells and Induces Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is a refractory reproductive disease and also a kind of endocrine and metabolic disease. Adipocyte cells can produce a mass of extracellular vesicles and orchestrate the status of other types cells. The objective of this study was to determine the effects of adipocyte-derived extracellular vesicles-miR-26b on cumulus cells (CCs) and development of PCOS. Methods: The crosstalk mediated by extracellular vesicle-miR-26b between adipocytes and CCs was determined in CC cells co-cultured with mature adipocytes or incubated with extracellular vesicle isolated from mature adipocytes. CCK-8 assay and flow cytometry were conducted in CCs treated with or without extracellular vesicles; microRNA (miRNA) sequencing was conducted for clarifying the key molecular. Hormone levels and ovary ovulation ability were conducted with animal experiment. Results: The results revealed that miR-26b was upregulated in extracellular vesicles derived from mature adipocytes. Adipocyte-derived extracellular vesicles inhibited viability and promoted apoptosis in CCs via targeting JAG1. Furthermore, extracellular vesicles derived from mature adipocyte disrupted the ovary ovulation and impaired the hormone levels. Conclusions: These results identify a novel signaling pathway that adipocytes-derived extracellular vesicles-miR-26b promotes cell apoptosis in CCs and disrupted the ovary ovulation in the development of PCOS. The study indicates that adipose tissue-derived extracellular vesicles-miR-26b may play a key role in the PCOS and also provides insight into developing new therapeutic strategies for PCOS.

Selective recognition of uracil and its derivatives using a DNA repair enzyme structural mimic.

During DNA repair, uracil DNA glycosylase (UDG) pulls unwanted uracil into its active site through hydrogen bonding and pi-pi stacking interactions. The reason why UDG binds only uracil tightly--and not its derivatives, such as thymine--remains unclear. In this study, we synthesized the stable, water-soluble receptor 1a as a structural mimic of the active site in UDG. Compound 1a contains a 2,6-bis(glycylamino)pyridine group, which mimics the amino acid residues of UDG that interact with uracil through a hydrogen-bonding network; it also possesses a pyrene moiety as a pi-pi stacking interaction element and fluorescent probe that mimics the aromatic groups (phenyl and fluorescent indolyl units) found in the active site of UDG. Receptor 1a binds selectively to uracil and derivatives (including thymine, 5-formyluracil, 5-fluorouracil, and 5-nitrouracil) and some DNA and RNA nucleosides (including thymidine and uridine) through hydrogen bonding and pi-pi stacking interactions. Interestingly, a plot of log K(b) with respect to the values of pK(a) of the N(3)H units of uracil and its derivatives was linear, with a negative slope (beta) of -0.24 +/- 0.03. Thus, compounds featuring lower values of pK(a) for their N(3)H units provided greater apparent binding constants for their complexes with receptor 1a, suggesting acidity-dependent binding of uracil and its derivatives to this receptor; notably, uracil bound more tightly than did thymine. Our study provides some insight into how uracil and its derivatives in DNA are bound by DNA repair enzymes through hydrogen bonding and pi-pi stacking interactions.

Euxanthone represses the proliferation, migration, and invasion of glioblastoma cells by modulating STAT3/SHP-1 signaling.

Glioblastoma is one of the most prevalent primary malignant brain tumors. Glioblastoma often develops resistance to conventional chemoradiotherapy, and thus, new ways to treat glioblastoma are urgently required. The aim of this study was to investigate the effect of euxanthone on the anticancer activities of glioblastoma and its potential mechanism. The U87 and U251 glioblastoma cell lines were cultured in media containing different concentrations of euxanthone. CCK-8 and colony formation assay were used to evaluate the cell proliferation. Cell migration and invasion were evaluated by wound healing and Transwell assays. Flow cytometry was used to assess the cell cycle and apoptosis rate. TUNEL assay was also employed to evaluate the apoptosis rate. Gene and protein expressions were determined by RT-qPCR and western blotting, respectively. A xenograft model was established to evaluate the efficacy of euxanthone in vivo. Euxanthone significantly repressed cell viability, migration, invasion, and epithelial-to-mesenchymal transition of U87 and U251 cells; and increased the rate of apoptosis. Western blotting results revealed that the levels of p21, p27, cleaved caspase-3, Bax, TIMP-3, and E-cadherin were upregulated while, the levels of CDK4, CDK6, pro-caspase-3, Bcl-2, MMP-2, MMP-9, N-cadherin, and Vimentin were downregulated by euxanthone. In addition, the expression of p-STAT3 was decreased, while the expression of SHP-1 was upregulated by euxanthone. We proposed that euxanthone could repress the malignant behavior of glioblastoma cells through suppression of STAT3 phosphorylation and activation of SHP-1. Further, in vivo data demonstrated that euxanthone repressed tumor growth and promoted apoptosis.

Numerical analysis and application of the construction method for the small interval tunnel in the turn line of metro.

The surrounding rock may become unstable or even fall down and the initial support may crack and be destroyed when the construction method of the underground excavation tunnel is not properly selected in the turn line of metro. . A section of the Santunbei turn line of Urumqi Metro Line 1# was taken as the engineering background. The proposed construction method was analyzed by numerical simulation. Numerical analysis shows that the final surface settlement caused by the proposed construction method is 3.0 mm and the horizontal convergence is 3.2 mm. It also turns out that the proposed construction method causes less deformation, and the method can be applied to the construction of the small interval tunnel in the Santunbei turn line of metro. The rationality of the method and numerical model was further verified by comparison between the monitored data of surface settlement, horizontal convergence and vault sinking, and numerical simulation results. Finally, the deformation and stress of the six construction methods were compared. The deformation and stress caused by the six construction methods are almost the same. It indicates that the construction spacing between the left and right tunnels does not affect the safety of tunnel construction. Therefore, the appropriate construction spacing could be selected according to the resource configuration, instead of deformation and stress.