Publications by authors named "Tao Xi"

192 Publications

Tanshinone IIA inhibits gastric cancer cell stemness through inducing ferroptosis.

Environ Toxicol 2021 Oct 18. Epub 2021 Oct 18.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.

Tanshinone IIA is the active constituent extracted from Salvia Miltiorrhza. Numerous studies have shown that Tanshinone IIA could inhibit tumor proliferation and metastasis, including gastric cancer. However, the effect of Tanshinone IIA on gastric cancer cell stemness stays unclear. Here, we found that Tanshinone IIA could reduce gastric cancer cell stemness through detecting spheroid-forming, flow cytometry analysis, and the expression of stemness markers (OCT3/4, ALDH1A1, and CD44). Mechanistically, Tanshinone IIA increased the level of lipid peroxides and decreased glutathione level in gastric cancer cells, both of which are the markers of ferroptosis. Similarly, ferroptosis inducers (erastin, sulfasalazine, and sorafenib) reduced gastric cancer cell stemness. Additionally, the inhibitory effects of Tanshinone IIA on GC cell stemness were reversed by ferroptosis inhibitor (Fer-1) or overexpression of SLC7A11, which is a critical ferroptosis inhibitor. Therefore, we revealed that Tanshinone IIA inhibited the stemness of gastric cancer cells partly through inducing ferroptosis.
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http://dx.doi.org/10.1002/tox.23388DOI Listing
October 2021

MicroRNA-9 as a paradoxical but critical regulator of cancer metastasis: Implications in personalized medicine.

Genes Dis 2021 Nov 23;8(6):759-768. Epub 2020 Oct 23.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, PR China.

Metastasis, is a development of secondary tumor growths at a distance from the primary site, and closely related to poor prognosis and mortality. However, there is still no effective treatment for metastatic cancer. Therefore, there is an urgent need to find an effective therapy for cancer metastasis. Plenty of evidence indicates that miR-9 can function as a promoter or suppressor in cancer metastasis and coordinate multistep of metastatic process. In this review, we summarize the different roles of miR-9 with the corresponding molecular mechanisms in metastasis of twelve common cancers and the multiple mechanisms underlying miR-9-mediated regulation of metastasis, benefiting the further research of miR-9 and metastasis, and hoping to bridge it with clinical applications.
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http://dx.doi.org/10.1016/j.gendis.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427239PMC
November 2021

Learning to Reconstruct CT Images from the VVBP-Tensor.

IEEE Trans Med Imaging 2021 Jun 17;PP. Epub 2021 Jun 17.

Deep learning (DL) is bringing a big movement in the field of computed tomography (CT) imaging. In general, DL for CT imaging can be applied by processing the projection or the image data with trained deep neural networks (DNNs), unrolling the iterative reconstruction as a DNN for training, or training a well-designed DNN to directly reconstruct the image from the projection. In all of these applications, the whole or part of the DNNs work in the projection or image domain alone or in combination. In this study, instead of focusing on the projection or image, we train DNNs to reconstruct CT images from the view-by-view backprojection tensor (VVBP-Tensor). The VVBP-Tensor is the 3D data before summation in backprojection. It contains structures of the scanned object after applying a sorting operation. Unlike the image or projection that provides compressed information due to the integration/summation step in forward or back projection, the VVBP-Tensor provides lossless information for processing, allowing the trained DNNs to preserve fine details of the image. We develop a learning strategy by inputting slices of the VVBP-Tensor as feature maps and outputting the image. Such strategy can be viewed as a generalization of the summation step in conventional filtered backprojection reconstruction. Numerous experiments reveal that the proposed VVBP-Tensor domain learning framework obtains significant improvement over the image, projection, and hybrid projection-image domain learning frameworks. We hope the VVBP-Tensor domain learning framework could inspire algorithm development for DL-based CT imaging.
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http://dx.doi.org/10.1109/TMI.2021.3090257DOI Listing
June 2021

MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis.

Stem Cell Res Ther 2021 06 5;12(1):325. Epub 2021 Jun 5.

School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.

Background: Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness.

Methods: Lentivirus infection was used to construct GC cells with ectopic expression of miR-375. In vitro and in vivo experiments, including analysis of tumor spheroid formation, CD44+ sub-population with stemness, stemness marker expression, and tumor-initiating ability, were performed to evaluate the effects of miR-375 on the stemness of GC cells. Furthermore, microarray and bioinformatics analysis were performed to search the potential targets of miR-375 in GC cells. Luciferase reporter, RNA immunoprecipitation, and RNA-FISH assays were carried out to verify the targeting of miR-375. Subsequently, combined with tissue microarray analysis, erastin-resistant GC cells, transmission electron microscopy, a series of agonists and oxidative stress markers, the underlying mechanisms contributing to miR-375-mediated effects were explored.

Results: MiR-375 reduced the stemness of GC cells in vitro and in vivo. Mechanistically, SLC7A11 was identified as a direct target of miR-375 and miR-375 attenuated the stemness of GC cells mainly through triggering SLC7A11-dependent ferroptosis.

Conclusion: MiR-375 can trigger the ferroptosis through targeting SLC7A11, which is essential for miR-375-mediated inhibition on GC cell stemness. These results suggest that the miR-375/SLC7A11 regulatory axis could serve as a potential target to provoke the ferroptosis and thus attenuate the stemness of GC cells.
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http://dx.doi.org/10.1186/s13287-021-02394-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180146PMC
June 2021

Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression.

Front Immunol 2021 18;12:624725. Epub 2021 May 18.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.624725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167795PMC
September 2021

Helicobacter pylori induces gastric cancer via down-regulating miR-375 to inhibit dendritic cell maturation.

Helicobacter 2021 Aug 3;26(4):e12813. Epub 2021 May 3.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.

Background: Recent studies and clinical samples have demonstrated that Helicobacter pylori could induce the downregulation of miR-375 in the stomach and promote gastric carcinogenesis. However, whether the immune cells are affected by Helicobacter pylori due to the downregulation of miR-375 is unclear.

Materials And Methods: In this study, we constructed an overexpression and knockdown of miR-375 and Helicobacter pylori infection cell models in vitro. In addition, the maturity of dendritic cells (DCs) and the expression of IL-6, IL-10, and VEGF at the transcriptional and translational levels were analyzed. Changes in the JAK2-STAT3 signaling pathway were detected. In vivo, the number changes in CD4+ T and CD8+ T cells and the size changes of tumors via models of transplantable subcutaneous tumors were also analyzed.

Results: A cell model of Helicobacter pylori and gastric cancer was used to identify the expression of miR-375 and the maturity of dendritic cells. This study found that Helicobacter pylori could downregulate miR-375, which regulates the expression of cytokines IL-6, IL-10, and VEGF in the stomach. MiR-375 regulated the expression of cytokines IL-6, IL-10, and VEGF through the JAK2-STAT3 signaling pathway in vitro. In addition, we found that Helicobacter pylori regulates the maturation of dendritic cells through miR-375. These results were further verified in vivo, and miR-375 diminishes tumor size was also demonstrated. This study showed that immature DCs caused a decrease in the number of CD4+ and CD8+ T cells.

Conclusions: This study demonstrated that Helicobacter pylori can inhibit miRNA-375 expression in the stomach. Downregulated miR-375 activates the JAK2-STAT3 pathway. Activating the JAK2-STAT3 signaling pathway promotes the secretion of IL-6, IL-10, and VEGF, leading to immature differentiation of DCs and induction of gastric cancer.
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http://dx.doi.org/10.1111/hel.12813DOI Listing
August 2021

Downsampled Imaging Geometric Modeling for Accurate CT Reconstruction via Deep Learning.

IEEE Trans Med Imaging 2021 Apr 21;PP. Epub 2021 Apr 21.

X-ray computed tomography (CT) is widely used clinically to diagnose a variety of diseases by reconstructing the tomographic images of a living subject using penetrating X-rays. For accurate CT image reconstruction, a precise imaging geometric model for the radiation attenuation process is usually required to solve the inversion problem of CT scanning, which encodes the subject into a set of intermediate representations in different angular positions. Here, we show that accurate CT image reconstruction can be subsequently achieved by downsampled imaging geometric modeling via deep-learning techniques. Specifically, we first propose a downsampled imaging geometric modeling approach for the data acquisition process and then incorporate it into a hierarchical neural network, which simultaneously combines both geometric modeling knowledge of the CT imaging system and prior knowledge gained from a data-driven training process for accurate CT image reconstruction. The proposed neural network is denoted as DSigNet, i.e., downsampled-imaging-geometry-based network for CT image reconstruction. We demonstrate the feasibility of the proposed DSigNet for accurate CT image reconstruction with clinical patient data. In addition to improving the CT image quality, the proposed DSigNet might help reduce the computational complexity and accelerate the reconstruction speed for modern CT imaging systems.
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http://dx.doi.org/10.1109/TMI.2021.3074783DOI Listing
April 2021

HET0016 attenuates the stemness of breast cancer cells through targeting CYP4Z1.

Mol Carcinog 2021 06 18;60(6):413-426. Epub 2021 Apr 18.

Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.

Ours and other previous studies have shown that CYP4Z1 is specifically and highly expressed in breast cancer, and acts as a promoter for the stemness of breast cancer cells. Here, we explored whether targeting CYP4Z1 could attenuate the stemness of breast cancer cells using HET0016, which has been confirmed to be an inhibitor of CYP4Z1 by us and others. Using the transcriptome-sequencing analysis, we found that HET0016 suppressed the expression of cancer stem cell (CSC) markers and stem cell functions. Additionally, HET0016 indeed reduced the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44 /CD24 subpopulation with stemness, mammary-spheroid formation, and tumor-initiating ability. Moreover, HET0016 suppressed the metastatic capability through in vitro and in vivo experiments. Furthermore, we confirmed that HET0016 suppressed CYP4Z1 activity, and HET0016-induced inhibition on the stemness and metastasis of breast cancer cells was rescued by CYP4Z1 overexpression. Thus, our results demonstrate that HET0016 can attenuate the stemness of breast cancer cells through targeting CYP4Z1.
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http://dx.doi.org/10.1002/mc.23302DOI Listing
June 2021

[The Role of Virtual Reality Technology in Medical Education in the Context of Emerging Medical Discipline].

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 Mar;52(2):182-187

School of Stomatology Ningxia Medical University, Yinchuan 750001, China.

According to Healthy China, a national strategy of the Government of China, new requirements were put forward for high-quality medical education, high-level surgical research, and precise clinical diagnosis and treatment. In the context of Emerging Medical Discipline, a strategic blueprint of medical education in China, this paper reviews the concept and core value of virtual reality (VR) and its significant role in the medical industry. On that basis, we explore the role of VR technology in medical training against the background of Emerging Medicine Discipline. Furthermore, typical cases are presented to help analyze and illustrate in detail the important role of VR technology in the teaching and training of stomatological and clinical procedures, skills assessment, online self-directed training, and clinical thinking skills training. We herein summarize useful information from past experience so as to help build innovative models of medical education in the context of Emerging Medical Discipline.
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http://dx.doi.org/10.12182/20210260301DOI Listing
March 2021

Quantifying Axial Spine Images Using Object-Specific Bi-Path Network.

IEEE J Biomed Health Inform 2021 08 5;25(8):2978-2987. Epub 2021 Aug 5.

Automatic estimation of indices from medical images is the main goal of computer-aided quantification (CADq), which speeds up diagnosis and lightens the workload of radiologists. Deep learning technique is a good choice for implementing CADq. Usually, to acquire high-accuracy quantification, specific network architecture needs to be designed for a given CADq task. In this study, considering that the target organs are the intervertebral disc and the dural sac, we propose an object-specific bi-path network (OSBP-Net) for axial spine image quantification. Each path of the OSBP-Net comprises a shallow feature extraction layer (SFE) and a deep feature extraction sub-network (DFE). The SFEs use different convolution strides because the two target organs have different anatomical sizes. The DFEs use average pooling for downsampling based on the observation that the target organs have lower intensity than the background. In addition, an inter-path dissimilarity constraint is proposed and applied to the output of the SFEs, taking into account that the activated regions in the feature maps of two paths should be different theoretically. An inter-index correlation regularization is introduced and applied to the output of the DFEs based on the observation that the diameter and area of the same object express an approximately linear relation. The prediction results of OSBP-Net are compared to several state-of-the-art machine learning-based CADq methods. The comparison reveals that the proposed methods precede other competing methods extensively, indicating its great potential for spine CADq.
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http://dx.doi.org/10.1109/JBHI.2021.3070235DOI Listing
August 2021

MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment.

Biochem Biophys Res Commun 2021 Jan 22;542:65-72. Epub 2021 Jan 22.

Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases. Department of Preventive Dentistry, Stomatology Hospital, Xi'an Jiaotong University, Xi'an, 710004, China. Electronic address:

Dental fluorosis is characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation. Excess fluoride could have effects on the ERK signaling, which is essential for the ameloblasts differentiation and tooth development. MAP kinase phosphatase-1 (MKP-1) plays a critical role in regulating ERK related kinases. However, the role of MKP-1 in ameloblast and the mechanisms of MKP-1/ERK signaling in the pathogenesis of dental fluorosis are incompletely understood. Here, we adopted an in vitro fluorosis cell model using murine ameloblasts-like LS8 cells by employing sodium fluoride (NaF) as inducer. Using this system, we demonstrated that fluoride exposure led to an inhibition of p-MEK and p-ERK1/2 with a subsequent increase in MKP-1 expression in a dose-dependent manner. We further identified, under high dose fluoride, MKP-1 acted as a negative regulator of the fluoride-induced p-ERK1/2 signaling, leading to downregulation of CREB, c-myc, and Elk-1. Our results identify a novel MKP-1/ERK signaling mechanism that regulates dental fluorosis and provide a framework for studying the molecular mechanisms of intervention and fluorosis remodeling under normal and pathological conditions. MKP-1 inhibitors may prove to be a benefit therapeutic strategy for dental fluorosis treatment.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.100DOI Listing
January 2021

X-ray microtomosynthesis of unstained pathology tissue samples.

J Microsc 2021 Jul 18;283(1):9-20. Epub 2021 Feb 18.

National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

In pathology protocols, a tissue block, such as one containing a mouse brain or a biopsy sample from a patient, can produce several hundred thin sections. Substantial time may be required to analyse all sections. In cases of uncertainty regarding which sections to focus on, noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sub-10 µm resolution. We explored a novel x-ray tomosynthesis method as a way to maximise contrast-to-noise ratio, a determinant of tissue visibility. It provided a z-stack of thousands of images at 7.3 μm resolution (10% contrast, half-period of 68.5 line pairs/mm), in scans of 5-15 minutes. When compared with micro-CT scans, the straight-line tomosynthesis scan did not need to rotate the sample, which allowed flat samples, such as paraffin blocks, to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this mode maximised the photon flux density through the sample, which helped in maximising the contrast-to-noise ratio. The tradeoff of tomosynthesis is incomplete 3D information. The microtomosynthesis scanner has scanned 110 unstained human and animal tissue samples as part of their respective pathology protocols. In all cases, the z-stack of images showed tissue structures that guided sectioning or provided correlative structural information. We describe six examples that presented different levels of visibility of soft tissue structures. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.
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http://dx.doi.org/10.1111/jmi.13003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248055PMC
July 2021

Silk fibroin hydrogel as mucosal vaccine carrier: induction of gastric CD4+TRM cells mediated by inflammatory response induces optimal immune protection against .

Emerg Microbes Infect 2020 Dec;9(1):2289-2302

School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.

Tissue-resident memory T (T) cells, located in the epithelium of most peripheral tissues, constitute the first-line defense against pathogen infections. Our previous study reported that gastric subserous layer (GSL) vaccination induced a "pool" of protective tissue-resident memory CD4+T (CD4+T) cells in the gastric epithelium. However, the mechanistic details how CD4+T cells form in the gastric epithelium are unknown. Here, our results suggested that the vaccine containing CCF in combination with Silk fibroin hydrogel (SF) broadened the distribution of gastric intraepithelial CD4+T cells. It was revealed that the gastric intraepithelial T cells were even more important than circulating memory T cells against infection by . It was also shown that gastric-infiltrating neutrophils were involved as indispensable mediators which secreted CXCL10 to chemoattract CXCR3+CD4+T cells into the gastric epithelium. Blocking of CXCR3 or neutrophils significantly decreased the number of gastric intraepithelial CD4+T cells due to reduced recruitment of CD4+T cells. This study demonstrated the protective efficacy of gastric CD4+T cells against infection, and highlighted the influence of neutrophils on gastric intraepithelial CD4+T cells formation.
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http://dx.doi.org/10.1080/22221751.2020.1830719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594714PMC
December 2020

MiR-375 inhibits the stemness of breast cancer cells by blocking the JAK2/STAT3 signaling.

Eur J Pharmacol 2020 Oct 30;884:173359. Epub 2020 Jul 30.

School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Longmian Road 639, Nanjing, 211198, PR China. Electronic address:

The relapse of breast cancer could be due to the existence of breast cancer stem cells (BCSCs). Other and our researches have indicated the suppressive roles of miR-375 in various tumors, however, its roles in breast cancer stemness remain confusing. Here, we constructed breast cancer cells with miR-375 stable overexpression via lentivirus infection. Flow cytometry, Western blot, mammosphere formation, cell colony formation and CCK8 as well as in vivo assays were performed to identify the role of miR-375 in the stemness of breast cancer cells. Luciferase reporter, RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were utilized to elucidate the mechanism whereby miR-375 exerts its effects. It was found that miR-375 not only reduced the stemness, but also decreased adriamycin resistance of breast cancer cells. These results were characterized by the decrease of BCSC rate, mammosphere-forming and tumor-initiating ability, and IC value of adriamycin, and weakened by JAK2 re-expression. This work indicates that miR-375 suppresses the stemness of breast cancer cells through targeting JAK2.
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http://dx.doi.org/10.1016/j.ejphar.2020.173359DOI Listing
October 2020

Transcriptional Factor Yin Yang 1 Promotes the Stemness of Breast Cancer Cells by Suppressing miR-873-5p Transcriptional Activity.

Mol Ther Nucleic Acids 2020 Sep 24;21:527-541. Epub 2020 Jun 24.

School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address:

Transcription factor Yin Yang 1 (YY1) is upregulated in multiple tumors and plays essential roles in tumor proliferation and metastasis. However, the function of YY1 in breast cancer stemness remains unclear. Herein, we found that YY1 expression was negatively correlated with the overall survival and relapse-free survival of breast cancer patients and positively correlated with the expression of stemness markers in breast cancer. Overexpression of YY1 increased the expression of stemness markers, elevated CD44CD24 cell sub-population, and enhanced the capacity of cell spheroid formation and tumor-initiation. In contrast, YY1 knockdown exhibited the opposite effects. Mechanistically, YY1 decreased microRNA-873-5p (miR-873-5p) level by recruiting histone deacetylase 4 (HDAC4) and HDAC9 to miR-873-5p promoter and thus increasing the deacetylation level of miR-873-5p promoter. Sequentially, YY1 activated the downstream PI3K/AKT and ERK1/2 pathways, which have been confirmed to be suppressed by miR-873-5p in our recent work. Moreover, the suppressed effect of YY1/miR-873-5p axis on the stemness of breast cancer cells was partially dependent on PI3K/AKT and ERK1/2 pathways. Finally, it was found that the YY1/miR-873-5p axis is involved in the chemoresistance of breast cancer cells. Our study defines a novel YY1/miR-873-5p axis responsible for the stemness of breast cancer cells.
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http://dx.doi.org/10.1016/j.omtn.2020.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381513PMC
September 2020

RNA-binding proteins in tumor progression.

J Hematol Oncol 2020 07 11;13(1):90. Epub 2020 Jul 11.

School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.

RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.
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http://dx.doi.org/10.1186/s13045-020-00927-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353687PMC
July 2020

Emerging agents that target signaling pathways in cancer stem cells.

J Hematol Oncol 2020 05 26;13(1):60. Epub 2020 May 26.

School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.

Cancer stem cells (CSCs) contribute to the initiation, recurrence, and metastasis of cancer; however, there are still no drugs targeting CSCs in clinical application. There are several signaling pathways playing critical roles in CSC progression, such as the Wnt, Hedgehog, Notch, Hippo, and autophagy signaling pathways. Additionally, targeting the ferroptosis signaling pathway was recently shown to specifically kill CSCs. Therefore, targeting these pathways may suppress CSC progression. The structure of small-molecule drugs shows a good spatial dispersion, and its chemical properties determine its good druggability and pharmacokinetic properties. These characteristics make small-molecule drugs show a great advantage in drug development, which is increasingly popular in the market. Thus, in this review, we will summarize the current researches on the small-molecule compounds suppressing CSC progression, including inhibitors of Wnt, Notch, Hedgehog, and autophagy pathways, and activators of Hippo and ferroptosis pathways. These small-molecule compounds emphasize CSC importance in tumor progression and propose a new strategy to treat cancer in clinic via targeting CSCs.
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http://dx.doi.org/10.1186/s13045-020-00901-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249421PMC
May 2020

Chip-based serum proteomics approach to reveal the potential protein markers in the sub-acute stroke patients receiving the treatment of Ginkgo Diterpene Lactone Meglumine Injection.

J Ethnopharmacol 2020 Oct 13;260:112964. Epub 2020 May 13.

State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang, 222000, China.

Ethnopharmacological Relevance: Ginkgo biloba L. is a kind of traditional Chinese medicinal material with a long history. Its main active ingredients, ginkgolides, can be used for the treatment of stroke and other cardio-cerebrovascular diseases. Ginkgo Diterpene Lactone Meglumine Injection (GDLI), a modernized TCM, has attracted much attention because of its neuroprotective and anti-inflammatory properties.

Aim Of The Study: To uncover the effects of GDLI on ischemic stroke patients, as well as the underlying biomarkers involved in sub-acute stroke.

Materials And Methods: We used a state-of-the-art targeted proteomics chip to investigate the association between numerous serum proteins (1101 proteins) and the sub-acute phase post-ischemic stroke. Then, the relative proteins of anti-apoptosis, anticoagulant, and neuroprotection of GDLI were verified in animal models.

Results: Compared with the serum from healthy volunteers, we identified 15 up-regulated proteins and 26 down-regulated proteins (FC ≥ 1.5) involved in inflammatory response, immune response, and nervous system development in the sub-acute ischemic stroke. The pro-inflammatory proteins, such as IL17, MSP-R, G-CSF-R, TLR3, MIP-3β, TNFRSF19, and TNFRSF12, were significantly increased in serum, illustrating that the chronic inflammatory state was evident in the sub-acute stage of ischemic stroke. However, the common pro-inflammatory proteins, such as IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and IL-10, known to be up-regulated in acute stroke, had close or lightly lower levels than healthy humans (FC ≥ 1.5, P > 0.05). And some cytokines (IL3, CCL13, TNFRSF3, IL10 R beta, HLA-A, IL-1 F8/FIL1 eta, TNFRSF8, CCL18) were also markedly down-regulated in the sub-acute phase of stroke. These proteins are highly associated with the onset of stroke-induced immunosuppression and post-stroke infection. Moreover, we noticed that Ginkgo Diterpene Lactone Meglumine Injection (GDLI) treatment for 14 days was helpful to the recovery of patients in the subacute period. After the treatment of GDLI, it was observed that several inflammatory cytokines (i.e. IL-17 and IL-28A), chemokine (i.e. CCL14), and Coagulation Factor III were reduced. Meanwhile, the anti-inflammatory cytokines (IL-10 R alpha, GREMLIN, and Activin C) and neurotrophic factors (Neurturin and IGFBP2) were found to be up-regulated in stroke patients through self-control observation. Finally, we identified the IGFBP2 as a novel marker in the animal models.

Conclusions: In summary, the potential markers in sub-acute stroke patients were highly different from known protein markers in the acute phase of ischemic stroke. The serum protein IGFBP2 could be novel biomarkers for the treatment of GDLI in sub-acute stroke patients. Our present findings provide an innovative insight into the novel treatment of GDLI in ischemic stroke therapy.
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http://dx.doi.org/10.1016/j.jep.2020.112964DOI Listing
October 2020

Perivascular Lymphocyte Clusters Induced by Gastric Subserous Layer Vaccination Mediate Optimal Immunity against Helicobacter through Facilitating Immune Cell Infiltration and Local Antibody Response.

J Immunol Res 2020 11;2020:1480281. Epub 2020 Jan 11.

School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.

Background: vaccination-induced local inflammatory response resulted in the establishment of a pool of tissue-resident memory T (T) cells and new vessels after the resolution of inflammation. T cells have received increasing attention; however, the role of new vessels in protective response is still unknown.

Materials And Methods: We performed the laparotomy to access the stomach and injected alum-based vaccine into the gastric subserous layer (GSL). At 28 days post vaccination, a parabiosis mouse model along with depletion of anti-CD90.2 antibody was employed to explore the function of perivascular lymphocyte clusters in recall responses. The composition of the gastric lymphocyte clusters was analyzed by immunofluorescence staining. Antibody responses were detected using ELISA. Gastric lymphocytes were analyzed using flow cytometry.

Results: GSL vaccination induced the formation of new vessels in the inflamed region. These new vessels were different from native vessels in that they were generally accompanied by perivascular lymphocyte clusters that mainly consisted of CD90-expressing cells. Additionally, histological analysis revealed the presence of CD4 and CD8 T cells in the perivascular lymphocyte clusters. Administration of a dose of an anti-CD90.2 antibody to GSL-vaccinated mice resolved these clusters. The efficacy of protection was compared in the parabiosis mice. Upon challenge, the presence of perivascular lymphocyte clusters was responsible for the fast recall response, as depletion of these clusters by CD90.2 antibody administration resulted in decreased expressions of VCAM-1, Madcam-1, and TNF-, as well as lower recruitment of proinflammatory immune cells, decreased antibody levels, and poor protection.

Conclusions: Our research demonstrates that vaccination-induced regional inflammatory response contributes to optimal recall response not only by establishing a CD4 T pool but also by creating an "expressway," i.e., perivascular lymphocyte cluster.
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http://dx.doi.org/10.1155/2020/1480281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201474PMC
March 2021

Multiple Axial Spine Indices Estimation via Dense Enhancing Network With Cross-Space Distance-Preserving Regularization.

IEEE J Biomed Health Inform 2020 11 4;24(11):3248-3257. Epub 2020 Nov 4.

Automatic estimation of axial spine indices is clinically desired for various spine computer aided procedures, such as disease diagnosis, therapeutic evaluation, pathophysiological understanding, risk assessment, and biomechanical modeling. Currently, the spine indices are manually measured by physicians, which is time-consuming and laborious. Even worse, the tedious manual procedure might result in inaccurate measurement. To deal with this problem, in this paper, we aim at developing an automatic method to estimate multiple indices from axial spine images. Inspired by the success of deep learning for regression problems and the densely connected network for image classification, we propose a dense enhancing network (DE-Net) which uses the dense enhancing blocks (DEBs) as its main body, where a feature enhancing layer is added to each of the bypass in a dense block. The DEB is designed to enhance discriminative feature embedding from the intervertebral disc and the dural sac areas. In addition, the cross-space distance-preserving regularization (CSDPR), which enforces consistent inter-sample distances between the output and the label spaces, is proposed to regularize the loss function of the DE-Net. To train and validate the proposed method, we collected 895 axial spine MRI images from 143 subjects and manually measured the indices as the ground truth. The results show that all deep learning models obtain very small prediction errors, and the proposed DE-Net with CSDPR acquires the smallest error among all methods, indicating that our method has great potential for spine computer aided procedures.
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http://dx.doi.org/10.1109/JBHI.2020.2977224DOI Listing
November 2020

Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases.

Am J Physiol Heart Circ Physiol 2020 04 21;318(4):H820-H829. Epub 2020 Feb 21.

Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Estrogen deficiency is considered to be an important factor leading to cardiovascular diseases (CVDs). Indeed, the prevalence of CVDs in postmenopausal women exceeds that of premenopausal women and men of the same age. Recent research findings provide evidence that estrogen plays a pivotal role in the regulation of calcium homeostasis and therefore fine-tunes normal cardiomyocyte contraction and relaxation processes. Disruption of calcium homeostasis is closely associated with the pathological mechanism of CVDs. Thus, this paper maps out and summarizes the effects and mechanisms of estrogen on calcium handling proteins in cardiac myocytes, including L-type Ca channel, the sarcoplasmic reticulum Ca release channel named ryanodine receptor, sarco(endo)plasmic reticulum Ca-ATPase, and sodium-calcium exchanger. In so doing, we provide theoretical and experimental evidence for the successful design of estrogen-based prevention and treatment therapies for CVDs.
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http://dx.doi.org/10.1152/ajpheart.00734.2019DOI Listing
April 2020

MicroRNA-9 and breast cancer.

Biomed Pharmacother 2020 Feb 30;122:109687. Epub 2019 Dec 30.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address:

Breast cancer is the most common cancer in women worldwide and seriously impairs patients' physical and mental health. Its incidence has been predicted to rise further. Mounting evidence indicates that microRNAs (miRNAs) play key roles in tumorigenesis and development. It is worth noting that miR-9 exerts critical functions in the initiation and progression of breast cancer, and the present research displays opposite roles of miR-9 in breast cancer. This article mainly reviews the roles of miR-9 in breast cancer progression.
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http://dx.doi.org/10.1016/j.biopha.2019.109687DOI Listing
February 2020

Galactooligosaccharides protects against DSS-induced murine colitis through regulating intestinal flora and inhibiting NF-κB pathway.

Life Sci 2020 Feb 24;242:117220. Epub 2019 Dec 24.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Background/aims: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism.

Main Methods: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot.

Key Findings: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways.

Significance: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2019.117220DOI Listing
February 2020

Ozone alleviates ischemia/reperfusion injury by inhibiting mitochondrion-mediated apoptosis pathway in SH-SY5Y cells.

Cell Biol Int 2020 Apr 21;44(4):975-984. Epub 2020 Jan 21.

Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Changsha, 410005, P.R. China.

Cerebral ischemia/reperfusion (I/R) injuries are common and often cause severe complications. Ozone has been applied for protecting I/R injury in animal models of several organs including cerebra, but the detailed mechanism remains unclear. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase measurement were used to determine the influence of ozone on cell activity and damage of SH-SY5Y cells. Some redox items such as catalase (CAT), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay. The mitochondrial membrane potential (ΔΨ ) was determined by JC-1 assay. Cytochrome-c (cyt-c) level in the cytoplasm and mitochondrion was measured by western blotting. Apoptosis was determined by flow cytometry, and some apoptosis-related molecules were detected by quantitative real-time polymerase chain reaction and western blotting. Ozone alleviated oxidative damage by increasing GSH-Px, SOD, CAT, and decreasing MDA. Ozone decreased mitochondrial damage caused by I/R injury and inhibited the release of cyt-c from mitochondrion to cytoplasm in SH-SY5Y cells. The cell apoptosis caused by I/R was inhibited by ozone, and ozone could decrease apoptosis by increasing the ratio of Bcl-2/Bax and inhibiting caspase signaling pathway in SH-SY5Y cells. Ozone has the ability of maintaining redox homeostasis, decreasing mitochondrion damage, and inhibiting neurocytes apoptosis induced by I/R. Therefore, ozone may be a promising protective strategy against cerebral I/R injury.
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http://dx.doi.org/10.1002/cbin.11294DOI Listing
April 2020

[Sparse-view CT image restoration multiscale wavelet residual network].

Nan Fang Yi Ke Da Xue Xue Bao 2019 Nov;39(11):1320-1328

School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China.

Objective: Sparse-view CT has the advantages of accelerated data collection and reduced radiation dose, but data missing arising from the data collection process causes serious streaking artifact and noise in the images reconstructed using the traditional filtering back projection algorithm (FBP). To solve this problem, we propose a multi-scale wavelet residual network (MWResNet) to restore sparse-view CT images.

Methods: The MWResNet was based on the combination of deep learning and traditional model in MWCNN, and the wavelet network was combined with the residual block to enhance the network's ability to embed image features and speed up network training. The network proposed herein was trained using the real spiral geometry CT image data, namely the Low-dose CT Grand Challenge dataset. The results of the proposed networks were visually and quantitatively compared to that by other existing networks, including the image restoration iterative residual convolution network (IRLNet), residual coding-decoding convolutional neural network (REDCNN) and the FBP convolutional neural network (FBPConvNet).

Results: The results demonstrated that the proposed method was superior to other competing methods in terms of visual inspection and quantitative comparison.

Conclusions: The MWResNet network is an effective method for suppressing noise and artifacts and maintaining edges details in the sparse-view CT images.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2019.11.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926081PMC
November 2019

[Sparse-view helical CT reconstruction based on tensor total generalized variation minimization].

Nan Fang Yi Ke Da Xue Xue Bao 2019 Oct;39(10):1213-1220

School of Biomedical Engineering, Southern Medical University//Guangzhou Key Laboratory of Medical Radioimaging and Detection Technology, Guangzhou 510515, China.

Objective: We propose a sparse-view helical CT iterative reconstruction algorithm based on projection of convex set tensor total generalized variation minimization (TTGV-POCS) to reduce the X-ray dose of helical CT scanning.

Methods: The three-dimensional volume data of helical CT reconstruction was viewed as the third-order tensor. The tensor generalized total variation (TTGV) was used to describe the structural sparsity of the three-dimensional image. The POCS iterative reconstruction framework was adopted to achieve a robust result of sparse-view helical CT reconstruction. The TTGV-POCS algorithm fully used the structural sparsity of first-order and second-order derivation and the correlation between the slices of helical CT image data to effectively suppress artifacts and noise in the image of sparse-view reconstruction and better preserve image edge information.

Results: The experimental results of XCAT phantom and patient scan data showed that the TTGVPOCS algorithm had better performance in reducing noise, removing artifacts and maintaining edges than the existing reconstruction algorithms. Comparison of the sparse-view reconstruction results of XCAT phantom data with 144 exposure views showed that the TTGV-POCS algorithm proposed herein increased the PSNR quantitative index by 9.17%-15.24% compared with the experimental comparison algorithm; the FSIM quantitative index was increased by 1.27%-9.30%.

Conclusions: The TTGV-POCS algorithm can effectively improve the image quality of helical CT sparse-view reconstruction and reduce the radiation dose of helical CT examination to improve the clinical imaging diagnosis.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2019.10.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867954PMC
October 2019

Corrigendum to "Oral Helicobacter pylori vaccine-encapsulated acid-resistant HP55/PLGA nanoparticles promote immune protection" [Eur. J. Pharm. Biopharm. 111 (2017) 33-43].

Eur J Pharm Biopharm 2019 12 7;145:96-97. Epub 2019 Nov 7.

School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, People's Republic of China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.ejpb.2019.10.006DOI Listing
December 2019

Corrigendum to "MALAT1 induced migration and invasion of human breast cancer cells by competitively binding miR-1 with cdc42" [Biochem. Biophys. Res. Commun. 472 (1) (2016) 262-9].

Biochem Biophys Res Commun 2020 Jan 8;521(2):541-543. Epub 2019 Nov 8.

School of Life Science and Technology, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, People's Republic of China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.bbrc.2019.10.189DOI Listing
January 2020

Corrigendum to "Pseudogene CYP4Z2P 3'UTR promotes angiogenesis in breast cancer." [Biochem. Biophys. Res. Commun. 2014 oct 24, 453(3), 545-51].

Biochem Biophys Res Commun 2020 Jan 28;521(2):546-547. Epub 2019 Oct 28.

Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.bbrc.2019.10.131DOI Listing
January 2020

Corrigendum to 'MiR-873/PD-L1 axis regulates the stemness of breast cancer cells' EBioMedicine 41 (2019) 395-407.

EBioMedicine 2019 11 24;49:389-390. Epub 2019 Oct 24.

School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, People's Republic of China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945241PMC
November 2019
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