Regio- and stereoselective [3 + 2] cycloaddition reaction: access to isoxazole-dispirobisoxindoles featuring three contiguous stereocenters.

A novel methodology toward the diversity-oriented asymmetric construction of densely functionalized isoxazole-dispirobisoxindoles was developed. This approach is distinguished by an organocatalytic stereo- and appealing ß-regioselective [3 + 2] cycloaddition reaction of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles and 3-isothiocyanato oxindoles. Complex polycyclic oxindoles 3 featuring two different oxindole moieties and three contiguous stereocenters were smoothly afforded in up to 96% yield, 96% ee, and >20 : 1 dr. The described method, which is different from our previous work of α-regioselective asymmetric annulation of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles, is the first ß-regioselective asymmetric annulation.

Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKα/NF-κB pathway.

Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in tumor cell growth process. However, its role and molecular mechanism in liver cancer is still not fully understood. In this study, we found that MALAT1 was significantly expressed in liver cancer cell lines. And knockdown of MALAT1 suppressed proliferation, migration and invasion of HepG2 cells, accompanied with decrease of Rho-associated coiled-coil-forming protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALAT1 deletion sensitized HepG2 cells to 5-FU-induced cell cycle arrest in G1 phase, as evidenced by the significant reduction in Cyclin D1 and CDK4 and increase in p53, p21 and p27 protein levels. In addition, MALAT1 knockdown triggered 5-FU induced apoptosis in HepG2 cells by inducing intrinsic apoptosis-related signals, including Cyto-c, Apaf-1, cleaved Caspase-9/-7/-3 and poly (ADP-ribose) polymerase (PARP). Furthermore, phosphorylated nuclear factor-κB (p-NF-κB) was also down-regulated by MALAT1 silence. Importantly, suppression of IKKα/NF-κB significantly elevated apoptosis and reduced liver cancer cell viability in MALAT1-knockdown cells with 5-FU incubation. The nude mice transplantation model also confirmed the promoted sensitivity of MALAT1-silenced HepG2 cells to 5-FU by blocking tumor cell proliferation and inducing apoptosis. Therefore, our data supplied a potential mechanism by which knockdown of MALAT1 might play an important role in augmenting sensitivity of HepG2 cells to 5-FU in therapeutic approaches, demonstrating suppressing of MALAT1 may serve as a combination with chemotherapeutic agents in liver cancer treatment.

[Preparation of cell penetrating peptide TAT and cleavable PEGco-modified liposomes loaded with paclitaxel and its in vitro apoptosis assay].

The preparation method, serum stability, efficiency of cellular uptake and apoptosis induction of the cell penetrating peptide TAT and cleavable PEG co-modified liposomes loaded with paclitaxel (C-TAT-Lipo) were investigated. The best preparation procedure was performed by orthogonal test based on single factor screening method. First, the paclitaxel (PTX)-loaded liposomes were prepared by filming-rehydration method, evaluated with entrapment efficiency and polydispersity index. The morphology of C-TAT-Lipo was characterized by transmission electron microscopy. Turbidity variations were monitored in the presence of fetal bovine serum (FBS) to evaluate the serum stability of the liposomes developed here. Next, the efficiency of cellular uptake of different Rho-PE-labeled liposomes on B16F1 cells in vitro was evaluated by confocal laser scanning microscopy (CLSM) and flow cytometry. The quantitative analysis of apoptosis induced by different PTX-loaded liposomes was performed by Annexin V-FITC/PI double staining. The optimal formulation was as follows: Chol : lipid: 1 : 8 (molar ratio); drug : lipid: 1 : 40 (mass ratio); lipid concentration: 3 mmol x L(-1); temperature of hydration: 25 degrees C. The mean size and polydispersity index of C-TAT-Lipo were about (97.97 +/- 3.68) nm and 0.196 +/- 0.037, the zeta potential was (-0.89 +/- 0.45) mV, the entrapment efficiency of paclitaxel was (90.16 +/- 1.53)%. The particle sizes did not exhibit significant variations in 50% FBS over 24 h at 37 degrees C. The efficiency of cellular uptake of the C-TAT-Lipo increased 1.40 fold following the cleavage of PEG. Apoptosis analysis showed 59.3% increase of the apoptosis and necrosis profile of C-TAT-Lipo after the detachment of PEG shells, which was markedly higher than that of N-TAT-LP with or without glutathione and SL, respectively. The results indicate that the C-TAT-Lipo is successfully prepared by filming-rehydration method and shows significant antitumor activities.

Bioactive Metal Ion-Coordinated Dynamic Hydrogel with Antibacterial, Immunomodulatory, and Angiogenic Activities for Infected Wound Repair.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Progress of uric acid in cardiovascular disease.

Due to the global prevalence of hyperuricemia (HUA), there is growing interest in research on uric acid (UA). HUA is a common condition that has various adverse consequences, including gout and kidney disease. However, recent studies have also implicated UA in the development of cardiovascular diseases (CVD) such as atrial fibrillation (AF) and coronary heart disease (CHD). Experimental and clinical research has extensively demonstrated the detrimental effects of elevated serum UA levels on cardiovascular health. Furthermore, serum UA levels have been identified as predictors of CVD outcomes following percutaneous coronary intervention (PCI) and catheter ablation. Additionally, the use of UA-lowering therapy holds important implications for the management of CVD. This review aims to consolidate the current evidence on the relationship between serum UA and CVD.

Bibliometric and visualized analysis of hydrogels in organoids research.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

A Decision-Making System for Low Carbon Manufacturing.

Based on the stochastic market demand of products, this paper studies the low-carbon manufacturing decisions making of manufacturing enterprises considering downward substitution and green technology input under the carbon cap-and-trade policy. The results show that the government's carbon trade policy will have a great impact on the production of manufacturing enterprises. Therefore, manufacturing enterprises must attach importance to the constraints of the government's carbon emission reduction policies. In terms of it, there are strategies for manufacturing enterprises such as adjusting the output, trading the carbon emission right, and so on. On this case, green technology input can increase the expected profit of manufacturing enterprises, especially in the case of downward substitution.

Optimized thyroid transcription factor-1 core promoter-driven microRNA-7 expression effectively inhibits the growth of human non-small-cell lung cancer cells.

Targeted gene therapy has become a promising approach for lung cancer treatment. In our previous work, we reported that the targeted expression of microRNA-7 (miR-7) operated by thyroid transcription factor-1 (TTF-1) promoter inhibited the growth of human lung cancer cells in vitro and in vivo; however, the intervention efficiency needed to be further improved. In this study, we identified the core promoter of TTF-1 (from -1299 bp to -871 bp) by 5' deletion assay and screened out the putative transcription factors nuclear factor-1 (NF-1) and activator protein-1 (AP-1). Further analysis revealed that the expression level of NF-1, but not AP-1, was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer (NSCLC) cells. Moreover, the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter. Of note, we optimized four distinct sequences to form additional NF-1-binding sites (TGGCA) in the sequence of TTF-1 core promoter (termed as optTTF-1 promoter), and verified the binding efficiency of NF-1 on the optTTF-1 promoter by electrophoretic mobility shift assay (EMSA). As expected, the optTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro, accompanied by a reduced transduction of NADH dehydrogenase (ubiquinone) 1α subcomplex 4 (NDUFA4)/protein kinase B (Akt) pathway. Consistently, optTTF-1 promoter-driven miR-7 expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC. Finally, no significant changes were detected in the biological indicators or the histology of some important tissues and organs, including heart, liver, and spleen. On the whole, our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells, providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.

Detection of dental caries in oral photographs taken by mobile phones based on the YOLOv3 algorithm.

BACKGROUND: The aim of this study was to explore the value of using the YOLOv3 algorithm for detection and diagnosis of dental caries in oral photographs taken with mobile phones. METHODS: Oral photographs taken with the mobile phones of 570 patients were used as 3 datasets: the augmented images (n=3,990), the enhanced images (n=3,990), and the combined augmented and enhanced images (n=7,980). Oral photographs taken by mobile phones from another 70 patients were used as an independent test set. We used the YOLOv3 network for migration learning for modelling. Diagnostic precision, recall, F1-score, and mean average precision (mAP) were calculated to obtain the detection and diagnostic performance of the YOLOv3 algorithm. RESULTS: After 3 independent training, the mAP value of the original group YOLOv3 algorithm was 56.20%, in which the precision for primary caries recognition was 76.92%, recall was 49.59%, and F1-score was 0.60; the precision for secondary caries recognition was 91.67%, recall was 52.38%, and F1-score was 0.67. The mAP value of the enhance group algorithm was 66.69%, in which the precision for primary caries identification was 81.82%, recall was 52.07%, and F1-score was 0.64, and the precision for secondary caries identification was 100%, recall was 33.33%, and F1-score was 0.50. The mAP value of the comprehensive group algorithm was 85.48%, in which the precision for primary caries identification was 93.33%, recall was 69.42%, F1-score was 0.80, and the F1-score for secondary caries identification was 0.50; precision was 100%, recall was 52.38%, and F1-score was 0.69. CONCLUSIONS: The caries detection capability based on the YOLOv3 algorithm highlights the potential utility of deep learning in caries detection and diagnosis. Comparing the 3 experiments, the detection of the model trained after using image augmented and enhancement techniques was significantly improved.

Thyroid Transcription Factor-1: Structure, Expression, Function and Its Relationship with Disease.

Thyroid transcription factor-1 (TTF-1/NKx2.1) is a member of the NKx2 tissue-specific transcription factor family, which is expressed in thyroid follicle, parathyroid gland, alveolar epithelium, and diencephalon which originated from ectoderm, and participates in the differentiation, development, and functional maintenance of the above organs. Recent studies have shown that the abnormal expression of TTF-1 is closely related to the occurrence of a variety of human diseases and can be used as a potential new target for the diagnosis and treatment of related diseases. In this article, in order to strengthen the systematic understanding of TTF-1 and promote the progress of related research, we reviewed the structure, expression regulation, biological functions of TTF-1, and its role in the occurrence and development of human-related clinical diseases. Meanwhile, we prospect the future research direction of TTF-1, which might ultimately contribute to the understanding of the pathogenesis of related clinical diseases and the development of new prevention and treatment strategies.

Downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 inhibits osteogenesis of BMSCs through p53 in type 2 diabetes mellitus.

The bone marrow mesenchymal stem cells (BMSCs)-mediated abnormal bone metabolism can delay and impair the bone remodeling process in type 2 diabetes mellitus (T2DM). Our previous study demonstrated that the downregulation of brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1), a circadian clock protein, inhibited the Wnt/ß-catenin pathway via enhanced GSK-3ß in diabetic BMSCs. In this article, we confirmed that the downregulated BMAL1 in T2DM played an inhibitory role in osteogenic differentiation of BMSCs. Upregulation of BMAL1 in the diabetic BMSCs significantly recovered the expression pattern of osteogenic marker genes and alkaline phosphatase (Alp) activity. We also observed an activation of the p53 signaling pathways, exhibited by increased p53 and p21 in diabetic BMSCs. Downregulation of p53 resulting from overexpression of BMAL1 was detected, and when we applied p53 gene silencing (shRNA) and the p53 inhibitor, pifithrin-α (PFT-α), the impaired osteogenic differentiation ability of diabetic BMSCs was greatly restored. However, there was no change in the level of expression of BMAL1. Taken together, our results first revealed that BMAL1 regulated osteogenesis of BMSCs through p53 in T2DM, providing a novel direction for further exploration of the mechanism underlying osteoporosis in diabetes.

The role of Nrf2/PIWIL2/purine metabolism axis in controlling radiation-induced lung fibrosis.

NF-E2-related factor 2 (Nrf2) is a key transcription factor recently implicated in the control of radiation-induced lung fibrosis (RILF). However, the molecular mechanism of Nrf2 in the pathogenesis of RILF is still unclear. The purpose of this study was to evaluate the regulatory effect and mechanism of Nrf2 in the pathogenesis of RILF. The effects of different Nrf2 expression levels on RILF were explored in vitro and in vivo. The RILF model of Nrf2 knockout mice was established for in vivo study. In the study of the mechanism of action, ChIP-seq assay and metabolomics analysis were performed. The discovered mechanism of Nrf2-mediated RILF alleviation was further validated in vitro and in vivo. We found that overexpression of Nrf2 significantly alleviated the fibrosis caused by irradiation in vivo and in vitro. Conversely, Nrf2 silencing strongly aggravated the development of RILF. Mechanistically, Nrf2 signaling increased the expression of piwi-like RNA-mediated gene silencing 2 (PIWIL2), leading to the alteration of purine metabolism and contributing to the relief of RILF. These results suggest that Nrf2 promotes the attenuation of RILF in vivo and in vitro by directly targeting PIWIL2 and activating purine metabolism.

T Helper 9 Cells: A New Player in Immune-Related Diseases.

The helper T cell 9 (Thelper-9, Th9), as a functional subgroup of CD4+T cells, was first discovered in 2008. Th9 cells expressed transcription factor PU.1 and cytokine interleukin-9 (IL-9) characteristically. Recent researches have shown that the differentiation of Th9 cells was coregulated by cytokine transforming growth factor ß, IL-4, and various transcription factors. Th9 cells, as a new player, played an important role in various immune-related diseases, including tumors, inflammatory diseases, parasite infection, and other diseases. In this article, we summarize the related research progress and discuss the possible prospect.

Thalidomide (THD) alleviates radiation induced lung fibrosis (RILF) via down-regulation of TGF-ß/Smad3 signaling pathway in an Nrf2-dependent manner.

Radiation-induced lung fibrosis (RILF) is a complication of radiotherapy in thoracic cancer patients. Thalidomide (THD) has a therapeutic effect on fibrotic and inflammatory disorders. The purpose of the current study was to investigate the therapeutic effect of THD on RILF in mice and better understand the underlying regulatory mechanisms of the therapeutic effect. We found that THD mitigated the fibrosis caused by irradiation in mice. The action of THD on RILF was related to the elevation of low levels reactive oxygen species (ROS), which inhibited the transforming growth factor­ß (TGF­ß)/Smad3 signaling pathway through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Analysis of the therapeutic effect of THD using Nrf2-/- mouse model confirmed the role of Nrf2 in vivo. In addition, no radioprotective effect of THD on thoracic cancer cell lines was observed. In conclusion, these data showed that THD attenuated RILF in mice, which was mediated by Nrf2-dependent down-regulation of the TGF-ß/Smad3 pathway, suggesting THD as a potential novel agent for RILF prevention.

MiR-874 inhibits metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting SOX12.

MicroRNA-874 (miR-874), a novel cancer-associated microRNA (miRNA), has been reported to play a suppressive role in multiple malignancies. However, its function in cell migration and invasion in hepatocellular carcinoma (HCC) and the mechanisms responsible remain unclear. Here, we found miR-874 to be significantly downregulated in HCC tissues and cell lines. Moreover, this decreased expression strongly correlated with clinical stage and lymph node metastasis. Accordingly, ectopic expression of miR-874 in HCC cells markedly inhibited their migration, invasion, and epithelial-mesenchymal transition (EMT). Concerning the underlying mechanism, SRY (sex-determining region Y) -box 12 (SOX12) was identified as a direct target of miR-874, and its expression was found to be inversely correlated with that of this miRNA in HCC cells. Importantly, SOX12 knockdown had an inhibitory effect on HCC cells similar to that caused by miR-874 overexpression, whereas SOX12 overexpression in these cells negated the suppressive effects of miR-874 on migration, invasion, and EMT. Overall, these findings demonstrate that miR-874 inhibits metastasis and EMT in HCC by targeting SOX12, suggesting that this miRNA may constitute a promising therapeutic target for this disease.

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents.

Phosphatidylinostitol-3-kinase (PI3K) is the potential anticancer target in the PI3K/Akt/ mTOR pathway. Here we reviewed the ATP-competitive small molecule PI3K inhibitors in the past few years, including the pan Class I PI3K inhibitors, the isoform-specific PI3K inhibitors and/or the PI3K/mTOR dual inhibitors.

Combing NLR, V20 and mean lung dose to predict radiation induced lung injury in patients with lung cancer treated with intensity modulated radiation therapy and chemotherapy.

The purpose was to evaluate the predictive value of baseline neutrophil to lymphocyte ratio (NLR) level in the incidence of grade 3 or higher radiation induced lung injury (RILI) for lung cancer patients. A retrospectively analysis with 166 lung cancer patients was performed. All of the enrolled patients received chemoradiotherapy at our hospital between April 2014 and May 2016. The Cox proportional hazard model was used to identify the potential risk factors for RILI. In this cohort, the incidence of grade 3 or higher RILI was 23.8%. Univariate analysis showed that radiation dose, volume at least received 20Gy (V20), mean lung dose and NLR were significantly associated with the incidence of grade 3 or higher RILI (P = 0.012, 0.008, 0.012, and 0.039, respectively). Multivariate analysis revealed that total dose ≥ 60 Gy, V20 ≥ 20%, mean lung dose ≥ 12 Gy, and NLR ≥ 2.2 were still independent predictive factors for RILI (P = 0.010, 0.043, 0.028, and 0.015, respectively). A predictive model of RILI based on the identified risk factors was established using receiver operator characteristic curves. The results demonstrated that the combination analysis of V20, mean lung dose and NLR was superior to either of the variables alone. Additionally, we found that the constraint of V20 and mean lung dose were meaningful for patients with higher baseline NLR level. If the value of V20 and mean lung dose lower than the threshold value, the incidence of grade 3 or higher RILI for the high NLR level patients could be decreased from 63.3% to 8.7%. Our study showed that radiation dose, V20, mean lung dose and NLR were independent predictors for RILI. Combination analysis of V20, mean lung dose and NLR may provide a more accurate model for RILI prediction.

[Nitrate and nitrite contents of drinking water in some areas of Shanxi Province].

OBJECTIVE: To understand the nitrate and nitrite contents of drinking water in Shanxi Province, China. METHODS: Water samples were collected from Pingding and Taigu counties and Taiyuan City. The nitrate and nitrite contents were determined following the 'Drinking water hygienic standard-2001'. RESULTS: The median nitrate content of drinking water was 3.5 mg/L, and the proportion of samples above national hygienic standard for drinking water was 4.0% in study areas. The median nitrite content of well water samples(5.l mg/L) was higher than that of tape water (2.7 mg/L). The median content of nitrite was 0.004 mg/L for all samples, and the median content of spring water was highest (0.017 mg/L) than that of other sources. Conclusion The contents of nitrate and nitrite in drinking water were similar to that reported form other regions. Maternal nitrate exposure from drinking water may not be among the important risk factors of high prevalence of birth defects in Shanxi Province.