Publications by authors named "Zhiyuan Fan"

80 Publications

Associations between cancer family history and esophageal cancer and precancerous lesions in high-risk areas of China.

Chin Med J (Engl) 2022 Jan 13. Epub 2022 Jan 13.

Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Background: Family clustering of esophageal cancer (EC) has been found in high-risk areas of China. However, the relationships between cancer family history and esophageal cancer and precancerous lesions (ECPL) have not been comprehensively reported in recent years. This study aimed to provide evidence for identification of high-risk populations.

Methods: This study was conducted in five high-risk areas in China from 2017 to 2019, based on the National Cohort of Esophageal Cancer. The permanent residents aged 40 to 69 years were examined by endoscopy, and pathological examination was performed for suspicious lesions. Information on demographic characteristics, environmental factors, and cancer family history was collected. Unconditional logistic regression was applied to evaluate odds ratios between family history related factors and ECPL.

Results: Among 33,008 participants, 6143 (18.61%) reported positive family history of EC. The proportion of positive family history varied significantly among high-risk areas. After adjusting for risk factors, participants with a family history of positive cancer, gastric and esophageal cancer or EC had 1.49-fold (95% confidence interval [CI]: 1.36-1.62), 1.52-fold (95% CI: 1.38-1.67), or 1.66-fold (95% CI: 1.50-1.84) higher risks of ECPL, respectively. Participants with single or multiple first-degree relatives (FDR) of positive EC history had 1.65-fold (95% CI: 1.47-1.84) or 1.93-fold (95% CI: 1.46-2.54) higher risks of ECPL. Participants with FDRs who developed EC before 35, 45, and 50 years of age had 4.05-fold (95% CI: 1.30-12.65), 2.11-fold (95% CI: 1.37-3.25), and 1.91-fold (95% CI: 1.44-2.54) higher risks of ECPL, respectively.

Conclusions: Participants with positive family history of EC had significantly higher risk of ECPL. This risk increased with the number of EC positive FDRs and EC family history of early onset. Distinctive genetic risk factors of the population in high-risk areas of China require further investigation.

Trial Registration: http://www.chictr.org.cn/, ChiCTR-EOC-17010553.
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http://dx.doi.org/10.1097/CM9.0000000000001939DOI Listing
January 2022

Prediction models for gastric cancer risk in the general population: a systematic review.

Cancer Prev Res (Phila) 2022 Jan 11. Epub 2022 Jan 11.

National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Risk prediction models for gastric cancer (GC) could identify high-risk individuals in the general population. The objective of this study was to systematically review the available evidence about the construction and verification of GC predictive models. We searched PubMed, Embase, and Cochrane Library databases for articles that developed or validated GC risk prediction models up to November 2021. Data extracted included study characteristics, predictor selection, missing data, and evaluation metrics. Risk of bias (ROB) was assessed using the Prediction model study Risk Of Bias Assessment Tool (PROBAST). We identified a total of 12 original risk prediction models that fulfilled the criteria for analysis. The area under the receiver operating characteristic curve ranged from 0.73 to 0.93 in derivation sets (n=6), 0.68 to 0.90 in internal validation sets (n=5), 0.71 to 0.92 in external validation sets (n=7). The higher-performing models usually include age, salt preference, Helicobacter pylori, smoking, BMI, family history, pepsinogen and sex. According to PROBAST, at least one domain with a high ROB was present in all studies mainly due to methodologic limitations in the analysis domain. In conclusion, although some risk prediction models including similar predictors have displayed sufficient discriminative abilities, many have a high ROB due to methodological limitations and are not externally validated efficiently. Future prediction models should adherence to well-established standards and guidelines to benefit GC screening.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0426DOI Listing
January 2022

Long-Term Recruitment of Endogenous M2 Macrophages by Platelet Lysate-Rich Plasma Macroporous Hydrogel Scaffold for Articular Cartilage Defect Repair.

Adv Healthc Mater 2021 Dec 30:e2101661. Epub 2021 Dec 30.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.

After cartilage damage, a large number of monocytes/macrophages infiltrate into adjacent synovium and the resident macrophages in synovial tissue transform to activated macrophages (M1), which secrete pro-inflammatory cytokines to induce sustained inflammation and chondrocyte apoptotic. However, current clinical therapies for cartilage repair can rarely achieve long-term anti-inflammatory regulation and satisfactory outcomes. Herein, a platelet lysate-rich plasma macroporous hydrogel (PLPMH) scaffold with around 100 µm pore size and 1.25 MPa Young's modulus is developed to sustainedly recruit and polarize endogenous anti-inflammatory macrophages (M2) for improving cartilage defect repair. PLPMH scaffold can steadily release sphingosine1-phosphate and proteins via gradual degradation, thus inducing M2 macrophages migration or resting (M0) macrophages migration and then polarization to M2 phenotype, and improving the secretion of anti-inflammatory cytokines. Furthermore, PLPMH scaffold exhibits negligible inflammatory responses in vivo and promotes endogenous M2 macrophage infiltration in large numbers and long-time duration to provide a local anti-inflammatory microenvironment, which even lasts for 42 d. In a rabbit model of cartilage defect, PLPMH scaffold increases the ratio of M2 macrophages and improves cartilage tissue regeneration. These studies support that PLPMH scaffold may have a great potential in articular cartilage tissue engineering by providing an anti-inflammatory and pro-regenerative microenvironment.
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http://dx.doi.org/10.1002/adhm.202101661DOI Listing
December 2021

Multifunctional Dendronized Polypeptides for Controlled Adjuvanticity.

Biomacromolecules 2021 Dec 17;22(12):5074-5086. Epub 2021 Nov 17.

Department of Chemistry, University of California, Irvine, California 92697, United States.

Vaccination has been playing an important role in treating both infectious and cancerous diseases. Nevertheless, many diseases still lack proper vaccines due to the difficulty to generate sufficient amounts of antigen-specific antibodies or T cells. Adjuvants provide an important route to improve and direct immune responses. However, there are few adjuvants approved clinically and many of them lack the clear structure/adjuvanticity relationship. Here, we synthesized and evaluated a series of dendronized polypeptides (denpols) functionalized with varying tryptophan/histidine (W/H) molar ratios of 0/100, 25/75, 50/50, 75/25, and 100/0 as tunable synthetic adjuvants. The denpols showed structure-dependent inflammasome activation in THP1 monocytic cells and structure-related activation and antigen cross-presentation in bone marrow-derived dendritic cells. We used the denpols with bacterial pathogen antigens , which showed both high and tunable adjuvating activities, as demonstrated by the antigen-specific antibody and T cell responses. The denpols are easy to make and scalable, biodegradable, and have highly adjustable chemical structures. Taken together, denpols show great potential as a new and versatile adjuvant platform that allows us to adjust adjuvanticity based on structure-activity correlation with the aim to fine-tune the immune response, thus advancing vaccine development.
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http://dx.doi.org/10.1021/acs.biomac.1c01052DOI Listing
December 2021

Tailoring the physicochemical properties of nanomaterials for immunomodulation.

Adv Drug Deliv Rev 2022 Jan 3;180:114039. Epub 2021 Nov 3.

Department of Materials Science and Engineering, Drexel University, Philadelphia, PA 19104, USA. Electronic address:

Immunomodulation is poised to revolutionize the treatment of cancer, autoimmune diseases, and many other inflammation-related disorders. The immune system in these conditions can be either activated or suppressed by nanocarriers loaded with bioactive molecules. Although immunomodulation via these therapeutics has long been recognized, and a broad range of nanocarriers have been designed to accommodate varied usages, less studies have focused on the effects of nanomaterial physicochemical properties on immune responses, especially the immunity altered by nanocarrier materials alone. Conclusions are sometimes seemly inconsistent due to the complexities of nanomaterials and the immune system. An in-depth understanding of the nanocarrier-induced immune responses is essential for clinical applications. In this review, we summarize recent studies of the immune responses influenced by nanomaterial physicochemical properties with an emphasis on the intrinsic features of nanomaterials that modulate the innate and adaptive immunities. We then provide our perspectives on the design of nanomaterials for immunomodulation.
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http://dx.doi.org/10.1016/j.addr.2021.114039DOI Listing
January 2022

Biomimetic microcavity interfaces for a label-free capture of pathogens in the fluid bloodstream by vortical crossflow filtration.

Nanoscale 2021 Sep 23;13(36):15220-15230. Epub 2021 Sep 23.

Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.

Bacterial sepsis is a lethal disease triggered by microbial pathogens. The blood pathogen load is a major contributor to both disease severity and mortality in patients with sepsis blood. Therefore, it is crucial to reduce the load of pathogens, in particular the drug-resistant pathogens. In this work, inspired by the crossflow filtration mechanism in suspension-feeding fish, we developed a biomimetic microcavity interface to mimic a porous gill-raker surface as a blood-cleansing dialyzer for sepsis therapy, which can rapidly, safely and efficiently clear bacteria from the fluidic blood. The microcavity interface consists of microcavity arrays, the innerface of which contains nanowire forests. By precisely controlling the pore size of the microcavity and directing the axial travel of the fluid, the bacteria can be isolated from the whole blood without disturbing any blood components or blocking the blood cell transportation. In addition, the three-dimensional nanowire forests assist in the formation of vortices with reduced blood flow velocity and increased resistance to bacterial deposition . Functional modification is not required to recognize the bacteria specifically in our designed dialyzer. Moreover, the microcavity interface clears over 95% bacteria from a fluid blood sample without inducing protein adsorption or complement and platelet activation when contacting the fluid blood. The study supports this biomimetic microcavity interface to be a promising extracorporeal blood-cleansing device in clinical settings.
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http://dx.doi.org/10.1039/d1nr03350fDOI Listing
September 2021

Evaluation of the Impact of Intratumoral Heterogeneity of Esophageal Cancer on Pathological Diagnosis and P16 Methylation and the Representativity of Endoscopic Biopsy.

Front Oncol 2021 17;11:683876. Epub 2021 Aug 17.

National Cancer Registry Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: P16 methylation is expected to be potential diagnostic and therapeutic targets for esophageal cancer (EC). The intratumoral heterogeneity (ITH) of EC has been mentioned but has not been quantitatively measured yet. We aimed to clarify the impact of ITH on pathological diagnosis and P16 methylation, and the concordance between endoscopic biopsy and the corresponding surgically resected tissue.

Methods: We designed a systematic sampling method (SSM) compared with a general sampling method (GSM) to obtain EC tumor tissue, tumor biopsy, and normal squamous epithelium biopsy. MethyLight assay was utilized to test P16 methylation. All specimens obtained by the SSM were pathologically diagnosed.

Results: A total of 81 cases were collected by the GSM, and 91.4% and 8.6% of them were esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EADs), respectively. Nine SSM cases were 100.0% ESCCs. The positive rates of P16 methylation of the GSM tumor and normal tissues were 63.0% (51/81) and 32.1% (26/81), respectively. For SSM samples, tumor tissues were 100.0% (40/40) EC and 85.0% (34/40) P16 methylated; tumor biopsy was 64.4% (29/45) diagnosed of EC and 68.9% P16 methylated; the corresponding normal biopsies were 15.7% (8/51) dysplasia and 54.9% (28/51) P16 methylated. The concordance of pathological diagnosis and P16 methylation between tumor biopsy and the corresponding tumor tissue was 75.0% and 62.5%, respectively.

Conclusion: The SSM we designed was efficient in measuring the ITH of EC. We found inadequate concordance between tumor biopsy and tissue in pathological diagnosis and P16 methylation.
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http://dx.doi.org/10.3389/fonc.2021.683876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416173PMC
August 2021

Monitoring the effects of chemical stimuli on live cells with metasurface-enhanced infrared reflection spectroscopy.

Lab Chip 2021 10 12;21(20):3991-4004. Epub 2021 Oct 12.

School of Applied and Engineering Physics, Cornell University, Ithaca, New York, 14853 USA.

Infrared spectroscopy has found wide applications in the analysis of biological materials. A more recent development is the use of engineered nanostructures - plasmonic metasurfaces - as substrates for metasurface-enhanced infrared reflection spectroscopy (MEIRS). Here, we demonstrate that strong field enhancement from plasmonic metasurfaces enables the use of MEIRS as a highly informative analytic technique for real-time monitoring of cells. By exposing live cells cultured on a plasmonic metasurface to chemical compounds, we show that MEIRS can be used as a label-free phenotypic assay for detecting multiple cellular responses to external stimuli: changes in cell morphology, adhesion, and lipid composition of the cellular membrane, as well as intracellular signaling. Using a focal plane array detection system, we show that MEIRS also enables spectro-chemical imaging at the single-cell level. The described metasurface-based all-optical sensor opens the way to a scalable, high-throughput spectroscopic assay for live cells.
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http://dx.doi.org/10.1039/d1lc00580dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511245PMC
October 2021

Identification of biomarkers associated with metabolic cardiovascular disease using mRNA-SNP-miRNA regulatory network analysis.

BMC Cardiovasc Disord 2021 07 23;21(1):351. Epub 2021 Jul 23.

Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China.

Background: CVD is the leading cause of death in T2DM patients. However, few biomarkers have been identified to detect and diagnose CVD in the early stage of T2DM. The aim of our study was to identify the important mRNAs, micro (mi)RNAs and SNPs (single nucleotide polymorphisms) that are associated with metabolic cardiovascular disease.

Materials And Methods: Expression profiles and GWAS data were obtained from Gene Expression Omnibus (GEO) database. MiRNA-sequencing was conducted by Illumina HiSeq 2000 platform in T2DM patients and T2DM with CVD patients. EQTL analysis and gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. MRNA-miRNA co-expression network and mRNA-SNP-miRNA interaction network were established and visualized by Cytoscape 3.7.2.

Results: In our study, we identified 56 genes and 16 miRNAs that were significantly differentially expressed. KEGG analyses results indicated that B cell receptor signaling pathway and hematopoietic cell lineage were included in the biological functions of differentially expressed genes. MRNA-miRNA co-expression network and mRNA-SNP-miRNA interaction network illustrated that let-7i-5p, RASGRP3, KRT1 and CEP41 may be potential biomarkers for the early detection and diagnosis of CVD in T2DM patients.

Conclusion: Our results suggested that downregulated let-7i-5p, and upregulated RASGRP3, KRT1 and CEP41 may play crucial roles in molecular mechanisms underlying the initiation and development of CVD in T2DM patients.
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http://dx.doi.org/10.1186/s12872-021-02166-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305867PMC
July 2021

Generation of even and odd high harmonics in resonant metasurfaces using single and multiple ultra-intense laser pulses.

Nat Commun 2021 Jul 7;12(1):4185. Epub 2021 Jul 7.

School of Applied and Engineering Physics, Cornell University, Ithaca, NY, USA.

High harmonic generation (HHG) opens a window on the fundamental science of strong-field light-mater interaction and serves as a key building block for attosecond optics and metrology. Resonantly enhanced HHG from hot spots in nanostructures is an attractive route to overcoming the well-known limitations of gases and bulk solids. Here, we demonstrate a nanoscale platform for highly efficient HHG driven by intense mid-infrared laser pulses: an ultra-thin resonant gallium phosphide (GaP) metasurface. The wide bandgap and the lack of inversion symmetry of the GaP crystal enable the generation of even and odd harmonics covering a wide range of photon energies between 1.3 and 3 eV with minimal reabsorption. The resonantly enhanced conversion efficiency facilitates single-shot measurements that avoid material damage and pave the way to study the controllable transition between perturbative and non-perturbative regimes of light-matter interactions at the nanoscale.
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http://dx.doi.org/10.1038/s41467-021-24450-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263774PMC
July 2021

Surveillance of premalignant gastric cardia lesions: A population-based prospective cohort study in China.

Int J Cancer 2021 11 7;149(9):1639-1648. Epub 2021 Jul 7.

Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

In our study, we aimed to assess the long-term risk of gastric cardia adenocarcinoma (GCA) for patients with different histological cardia lesions to inform future guidelines for GCA screening in China. We conducted a population-based prospective study among 9740 subjects who underwent upper endoscopy screening during 2005 to 2009 and followed until December 2017. Cumulative incidence and mortality rates of GCA were calculated by the baseline histological diagnoses, and the hazard ratios (HRs), overall and by age and sex, were analyzed by Cox proportional hazards models. During a median follow-up of 10 years, we identified 123 new GCA cases (1.26%) and 31 GCA deaths (0.32%). The age-standardized incidence and mortality rates of GCA were 128.71/100 000 and 35.69/100 000 person-years, and cumulative incidence rate in patients with cardia high-grade dysplasia (CHGD), cardia low-grade dysplasia (CLGD) and atrophic carditis (AC)/cardia intestinal metaplasia (CIM) was 25%, 3.05% and 1.58%, respectively. The progression rate and cancer risk of GCA increased monotonically with each step in Correa's cascade. Individuals aged 50 to 69 years had 4.4 times higher GCA incidence than those aged 40 to 49 years. Patients with CLGD had a significantly higher 3-year GCA incidence than the normal group, while patients with AC/CIM had a comparable GCA risk during 3-year follow-up but a higher risk at 5-year intervals. Our results suggested a postponed starting age of 50 years for GCA screening, immediate treatment for patients with CHGD, a 3-year surveillance interval for patients with CLGD, and a lengthened surveillance interval of 5 years for patients with AC/CIM.
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http://dx.doi.org/10.1002/ijc.33720DOI Listing
November 2021

[Research on entity relationship extraction of Chinese medical literature and application in diabetes medical literature].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2021 Jun;38(3):563-573

College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong 518118, P.R.China.

The medical literature contains a wealth of valuable medical knowledge. At present, the research on extraction of entity relationship in medical literature has made great progress, but with the exponential increase in the number of medical literature, the annotation of medical text has become a big problem. In order to solve the problem of manual annotation time such as consuming and heavy workload, a remote monitoring annotation method is proposed, but this method will introduce a lot of noise. In this paper, a novel neural network structure based on convolutional neural network is proposed, which can solve a large number of noise problems. The model can use the multi-window convolutional neural network to automatically extract sentence features. After the sentence vectors are obtained, the sentences that are effective to the real relationship are selected through the attention mechanism. In particular, an entity type (ET) embedding method is proposed for relationship classification by adding entity type characteristics. The attention mechanism at sentence level is proposed for relation extraction in allusion to the unavoidable labeling errors in training texts. We conducted an experiment using 968 medical references on diabetes, and the results showed that compared with the baseline model, the present model achieved good results in the medical literature, and F1-score reached 93.15%. Finally, the extracted 11 types of relationships were stored as triples, and these triples were used to create a medical map of complex relationships with 33 347 nodes and 43 686 relationship edges. Experimental results show that the algorithm used in this paper is superior to the optimal reference system for relationship extraction.
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http://dx.doi.org/10.7507/1001-5515.202001009DOI Listing
June 2021

Prediction model of objective response after neoadjuvant chemotherapy in patients with locally advanced gastric cancer.

Am J Transl Res 2021 15;13(3):1568-1579. Epub 2021 Mar 15.

Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200025, China.

Background: Neoadjuvant chemotherapy (NAC) plays an important role in the therapeutic strategy of locally advanced gastric cancer (LAGC). However, the response of LAGC after NAC varies among different patients. The objective response after NAC has proven to be an excellent indicator for benefiting from NAC, yet effective predictors of objective response are still lacking. The present study aimed to identify potential predictors of objective response in LAGC patients treated with NAC.

Methods: Clinicopathological data from 267 patients with LAGC who received NAC and met the inclusion criteria between July 2009 and December 2018 were retrospectively reviewed. Patients were randomly divided into the training and test sets at a 2:1 ratio. Univariate analysis was used to investigate whether any factors were correlated with objective response in the training set. Multivariate logistic regression analysis was applied to find independent predictors. A risk score model was then constructed based on the independent predictors, and its performance in predicting objective response was validated in the test set.

Results: Univariate analysis found that gender, age, short axis diameter of the largest regional lymph node (LN), serum total protein content, CEA detection value, tumor location, tumor differentiation, signet ring cell carcinoma component and Borrmann type were potential predictors for objective response. In multivariate logistic regression analysis, gender, LN and signet ring cell carcinoma component were independent predictors for objective response. Based on independent predictors, we developed a prediction model for objective response.

Conclusions: We found gender, LN and signet ring cell carcinoma component were independent predictors for objective response. The prediction model is a good tool to predict the objective response for LAGC patients treated with NAC, which can be applied to guide clinical practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014384PMC
March 2021

Acellular fish skin enhances wound healing by promoting angiogenesis and collagen deposition.

Biomed Mater 2021 04 9;16(4). Epub 2021 Apr 9.

Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, People's Republic of China.

Acellular matrix is a type of promising biomaterial for wound healing promotion. Although acellular bovine and porcine tissues have proven effective, religious restrictions and risks of disease transmission remain barriers to their clinical use. Acellular fish skin (AFS), given its similarity to human skin structure and without the aforementioned disadvantages, is thus seen as an attractive alternative. This study aims to fabricate AFS from the skin of black carp (), evaluate its physical and mechanical properties and assess its impact on wound healing. The results showed that AFS has a highly porous structure, along with high levels of hydrophilicity, water-absorption property and permeability. Furthermore, physical characterization showed the high tensile strength of AFS in dry and wet states, and high stitch tear resistance, indicating great potential in clinical applications. Cell Counting Kit-8 was used to test the viability of L929 cells when culturing in the extracts of AFS. Compared with the control group, there is no significant difference in optical density value when culturing in the extracts of AFS at days 1, 3 and 7 (*> 0.05).wound healing evaluation then highlighted its promotion of angiogenesis and collagen synthesis, its function in anti-inflammation and acceleration in wound healing. Therefore, this study suggests that AFS has potential as a promising alternative to mammal-derived or traditional wound dressing.
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http://dx.doi.org/10.1088/1748-605X/abef7aDOI Listing
April 2021

Applications of biomaterials for immunosuppression in tissue repair and regeneration.

Acta Biomater 2021 05 17;126:31-44. Epub 2021 Mar 17.

Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China. Electronic address:

The immune system plays an essential role in tissue repair and regeneration. Regardless of innate or adaptive immune responses, immunosuppressive strategies such as macrophage polarization and regulatory T (Treg) cell induction can be used to modulate the immune system to promote tissue repair and regeneration. Biomaterials can improve the production of anti-inflammatory macrophages and Treg cells by providing physiochemical cues or delivering therapeutics such as cytokines, small molecules, microRNA, growth factors, or stem cells in the damaged tissues. Herein, we present an overview of immunosuppressive modulation by biomaterials in tissue regeneration and highlight the mechanisms of macrophage polarization and Treg cell induction. Overall, we foresee that future biomaterials for regenerative strategies will entail more interactions between biomaterials and the immune cells, and more mechanisms of immunosuppression related to T cell subsets remain to be discovered and applied to develop novel biomaterials for tissue repair and regeneration. STATEMENT OF SIGNIFICANCE: Immunosuppression plays a key role in tissue repair and regeneration, and biomaterials can interact with the immune system through their biological properties and by providing physiochemical cues. Here, we summarize the studies on biomaterials that have been used for immunosuppression to facilitate tissue regeneration. In the first part of this review, we demonstrate the crucial role of macrophage polarization and induction of T regulatory (Treg) cells in immunosuppression. In the second part, distinct approaches used by biomaterials to induce immunosuppression are introduced, which show excellent performance in terms of promoting tissue regeneration.
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http://dx.doi.org/10.1016/j.actbio.2021.03.019DOI Listing
May 2021

Tumor suppressor lnc-CTSLP4 inhibits EMT and metastasis of gastric cancer by attenuating HNRNPAB-dependent Snail transcription.

Mol Ther Nucleic Acids 2021 Mar 10;23:1288-1303. Epub 2021 Feb 10.

Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Tumor metastasis is a crucial impediment to the treatment of gastric cancer (GC), and the epithelial-to-mesenchymal transition (EMT) program plays a critical role for the initiation of GC metastasis. Thus, the aim of this study is to investigate the regulation of lnc-CTSLP4 in the EMT process during GC progression. We found that lnc-CTSLP4 was significantly downregulated in GC tumor tissues compared with adjacent non-tumor tissues, and its levels in GC tumor tissues were closely correlated with tumor local invasion, TNM stage, lymph node metastasis, and prognosis of GC patients. Loss- and gain-of-function assays indicated that lnc-CTSLP4 inhibited GC cell migration, invasion, and EMT , as well as peritoneal dissemination . Mechanistic analysis demonstrated that lnc-CTSLP4 could bind with Hsp90α/heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) complex and recruit E3-ubiquitin ligase ZFP91 to induce the degradation of HNRNPAB, thus suppressing the transcriptional activation of Snail and ultimately reversing EMT of GC cells. Taken together, our results suggest that lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3 ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC.
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http://dx.doi.org/10.1016/j.omtn.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907227PMC
March 2021

ATP5B promotes the metastasis and growth of gastric cancer by activating the FAK/AKT/MMP2 pathway.

FASEB J 2021 04;35(4):e20649

Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.

Adenosine triphosphate (ATP) in the tumor microenvironment serves a vital role during tumor progression. ATP synthase F1 β subunit (ATP5B) is one of the most important subunits of ATP synthase and increases cellular ATP levels. ATP5B reportedly participates in carcinogenesis in several tumors. However, the regulatory mechanisms of ATP5B remain poorly understood in gastric cancer (GC). Here, we determined that high ATP5B expression in tumor tissues of GC is positively correlated with age, the tumor size, the TNM stage, lymph node metastasis, and patients' poor prognosis. The overexpression of ATP5B in GC cells elevated the cellular ATP content and promoted migration, invasion and proliferation. The levels of MMP2 expression, phosphorylated FAK, and phosphorylated AKT were increased after ATP5B overexpression in GC cells. Additionally, ATP5B overexpression increased the extracellular ATP level through the secretion of intracellular ATP and activated the FAK/AKT/MMP2 signaling pathway. ATP5B-induced downstream pathway activation was induced through the plasma membrane P2X7 receptor. Inhibitors of P2X7, FAK, AKT, and MMP2 suppressed the proliferative, migratory, and invasive capabilities of GC cells. In conclusion, our experiments indicate that ATP5B contributes to tumor progression of GC via FAK/AKT/MMP2 pathway. ATP5B, therefore, may be a biomarker of poor prognosis and a potential therapeutic target for GC.
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http://dx.doi.org/10.1096/fj.202000608RDOI Listing
April 2021

Epidermal growth factor/epidermal growth factor receptor moves into the osteoblasts' cell nuclei where it is involved to regulate STAT5's signaling.

Biofactors 2021 May 27;47(3):351-362. Epub 2021 Jan 27.

Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Epidermal growth factor (EGF) has vital biological impacts on the osteoblasts. However, the knowledge on the cellular properties of EGF/EGFR (epidermal growth factor receptor) on osteoblasts is scanty. As such, we explored the EGF/EGFR's cell behavior in the osteoblast (MC3T3-E1 cell) using the indirect immunofluorescence assay, Western-blot, and fluorescence resonance energy transfer. Our findings revealed that EGF could internalize into the cytoplasm under EGFR mediation. Besides, the co-localization analysis demonstrated that caveolin played a critical role in EGFR's endocytosis. We also analyzed the cytoplasmic trafficking pathway of EGF/EGFR in MC3T3-E1 cell. The colocalization analysis showed that EGFR entered into Rab5, Rab4, and Rab9-positive endosomes. More importantly, we found that EGFR could move into the MC3T3-E1 cells' nuclei. Based on this, we investigated the EGFR's nuclear-localized functions, and the results suggested that nuclear-localized EGFR has important biological functions. This work lays a foundation for further study on EGF/EGFR's biological functions on the osteoblasts.
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http://dx.doi.org/10.1002/biof.1709DOI Listing
May 2021

PEGylation enables subcutaneously administered nanoparticles to induce antigen-specific immune tolerance.

J Control Release 2021 03 12;331:164-175. Epub 2021 Jan 12.

Department of Materials Science and Engineering, Drexel University, Philadelphia, PA 19104, USA; School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA. Electronic address:

The development of nanomaterials to induce antigen-specific immune tolerance has shown promise for treating autoimmune diseases. While PEGylation has been widely used to reduce host immune responses to nanomaterials, its tolerogenic potential has not been reported. Here, we report for the first time that a subcutaneous injection of PEGylated poly(lactide-co-glycolide) (PLGA) nanoparticles containing auto-antigen peptide MOG without any tolerogenic drugs is sufficient to dramatically ameliorate symptoms after disease onset in an antigen-specific manner in a mouse model of multiple sclerosis. Neither free MOG nor particles without PEG exhibit this efficacy. Interestingly, mechanistic studies indicate that PEGylation of nanoparticles does not reduce dendritic cell activation through direct nanoparticle-cell interactions. Instead, PEGylated nanoparticles induce lower complement activation, neutrophil recruitment, and co-stimulatory molecule expression on dendritic cells around the injection sitecompared to non-PEGylated PLGA nanoparticles, creating a more tolerogenic microenvironment in vivo. We further demonstrate that the locally recruited dendritic cells traffic to lymphoid organs to induce T cell tolerance. These results highlight the critical role of surface properties of nanomaterials in inducing immune tolerance via subcutaneous administration.
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http://dx.doi.org/10.1016/j.jconrel.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968989PMC
March 2021

Comparative bioinformatics analysis between proteomes of rabbit aneurysm model and human intracranial aneurysm with label-free quantitative proteomics.

CNS Neurosci Ther 2021 01 3;27(1):101-112. Epub 2021 Jan 3.

Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Aims: This study aimed to find critical proteins involved in the development of intracranial aneurysm by comparing proteomes of rabbit aneurysm model and human aneurysms.

Methods: Five human intracranial aneurysm samples and 5 superficial temporal artery samples, and 4 rabbit aneurysm samples and 4 control samples were collected for protein mass spectrometry. Four human intracranial aneurysm samples and 4 superficial temporal artery samples, and 6 rabbit aneurysm samples and 6 control samples were used for immunochemistry.

Results: Proteomic analysis revealed 180 significantly differentially expressed proteins in human intracranial aneurysms and 716 significantly differentially expressed proteins in rabbit aneurysms. Among them, 57 proteins were differentially expressed in both species, in which 24 were increased and 33 were decreased in aneurysms compared to the control groups. Proteins were involved in focal adhesion and extracellular matrix-receptor interaction pathways. We found that COL4A2, MYLK, VCL, and TAGLN may be related to aneurysm development.

Conclusion: Proteomics analysis provided fundamental insights into the pathogenesis of aneurysm. Proteins related to focal adhesion and extracellular matrix-receptor interaction pathways play an important role in the occurrence and development of intracranial aneurysm.
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http://dx.doi.org/10.1111/cns.13570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804895PMC
January 2021

Adaptive Se-Te Metathesis Controlled by Cucurbituril-Based Host-Guest Interaction.

Chem Asian J 2020 Dec 6;15(24):4321-4326. Epub 2020 Nov 6.

Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China.

Regulating the reactivity and equilibrium of a dynamic reaction is essential for adaptive chemistry and functional materials. Herein, cucurbituril-based host-guest interaction was embedded into the dynamic metathesis between diselenide and ditelluride to establish an equilibrium-adaptive system. In this system, cucurbit[6]uril (CB[6]) selectively bound with diselenide while cucurbit[7]uril (CB[7]) bound with not only diselenide but also ditelluride and exchange product. The dynamic nature of diselenide bond was locked after forming the inclusion complex with CB[6]. Based on this selective locking effect, the Se-Te products were reversed back to diselenide and ditelluride reactants, which was an equilibrium regulating process. Therefore, by combining CB[6]-based host-guest interaction and dynamic diselenide chemistry, the reactivity of diselenide bond and the equilibrium of Se-Te metathesis was successfully regulated.
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http://dx.doi.org/10.1002/asia.202001224DOI Listing
December 2020

Ultrashort all-fiber Fabry-Perot interferometer fabricated by a CO laser.

Appl Opt 2020 Oct;59(28):8959-8963

We proposed and demonstrated a method to fabricate ultrashort all-fiber Fabry-Perot interferometers by splicing a standard single-mode fiber and another single-mode fiber with a concave surface constructed by a laser pulse. The geometric parameters of the concave surface could be controlled flexibly by adjusting the laser pulse and the relative position between the laser beam and the optical fiber. In our experiments, the minimum depth of the concave surfaces is 0.12 µm, which offers a means of fabricating an all-fiber Fabry-Perot interferometer with submicrometer cavity length. Moreover, the ultralow-roughness concave surface fabricated by a laser pulse is beneficial to improve the fringe visibility of the interferometer. These advantages make it attractive for practical applications.
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http://dx.doi.org/10.1364/AO.402999DOI Listing
October 2020

Engineering long-circulating nanomaterial delivery systems.

Curr Opin Biotechnol 2020 12 12;66:131-139. Epub 2020 Aug 12.

Department of Materials Science and Engineering, Drexel University, Philadelphia, PA 19104, USA. Electronic address:

One of the grand challenges at the forefront of bionanomaterials is their quick clearance in blood circulation. Progress has been made in understanding nanomaterial-biological system interactions and in developing new strategies to extend the blood circulation time of nanomaterials. Here, we first review interactions between the complement system and nanomaterials as well as clearance pathways in major organs such as the liver, spleen, and kidneys. We then discuss new approaches to prolong the blood circulation of nanomaterials with a focus on grafting polymers and biomimetic camouflages including cell membrane coating and hybrid vesicles. In the end, we provide insights into the pros and cons of these approaches and our perspectives for advancing this field.
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http://dx.doi.org/10.1016/j.copbio.2020.07.006DOI Listing
December 2020

Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway.

J Neuroinflammation 2020 Jun 16;17(1):191. Epub 2020 Jun 16.

Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road Middle, Shanghai, 200040, People's Republic of China.

Background: The regulation of vascular smooth muscle cell (VSMC) phenotype plays an important role in intracranial aneurysm (IA) formation and progression. However, the underlying mechanism remains unclear. Metformin is a 5' AMP-activated protein kinase (AMPK) agonist that has a protective effect on vasculature. The present study investigated whether metformin modulates VSMC phenotype switching via the AMPK/acetyl-CoA carboxylase (ACC) pathway during IA pathogenesis.

Methods: Adult male Sprague-Dawley rats (n = 80) were used to establish an elastase-induced IA model. The effects of metformin on AMPK activation and VSMC phenotype modulation were examined. We also established a platelet-derived growth factor (PDGF)-BB-induced VSMC model and analyzed changes in phenotype including proliferation, migration, and apoptosis as well as AMPK/ACC axis activation under different doses of metformin, AMPK antagonist, ACC antagonist, and their combinations.

Results: Metformin decreased the incidence and rupture rate of IA in the rat model and induced a switch in VSMC phenotype from contractile to synthetic through activation of the AMPK/ACC pathway, as evidenced by upregulation of VSMC-specific genes and decreased levels of pro-inflammatory cytokines. AMPK/ACC axis activation inhibited the proliferation, migration, and apoptosis of VSMCs, in which phenotypic switching was induced by PDGF-BB.

Conclusions: Metformin protects against IA formation and rupture by inhibiting VSMC phenotype switching and proliferation, migration, and apoptosis. Thus, metformin has therapeutic potential for the prevention of IA.
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http://dx.doi.org/10.1186/s12974-020-01868-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298751PMC
June 2020

Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer.

Gastric Cancer 2020 11 9;23(6):974-987. Epub 2020 May 9.

Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Increasing evidence indicates that angiogenesis plays an important role in tumor progression. The function of cathepsin L (CTSL), an endosomal proteolytic enzyme, in promoting tumor metastasis is well recognized. The mechanisms by which CTSL has promoted the angiogenesis of gastric cancer (GC), however, remains unclear.

Methods: The nuclear expression levels of CTSL were assessed in GC samples. The effects of CTSL on GC angiogenesis were determined by endothelial tube formation analysis, HUVEC migration assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the CDP/Cux/VEGF-D pathway was analyzed by angiogenesis antibody array, Western blot, co-immunoprecipitation (Co-IP) and dual-luciferase reporter assay.

Results: In this study, we found that the nuclear CTSL expression level in GC was significantly higher than that in adjacent nontumor gastric tissues and was a potential important clinical prognostic factor. Loss- and gain-of-function assays indicated that CTSL promotes the tubular formation and migration of HUVEC cells in vitro. The CAM assay also showed that CTSL promotes angiogenesis of GC in vivo. Mechanistic analysis demonstrated that CTSL can proteolytically process CDP/Cux and produce the physiologically relevant p110 isoform, which stably binds to VEGF-D and promotes the transcription of VEGF-D, thus contributing to the angiogenesis of GC.

Conclusion: The findings of the present study suggested that CTSL plays a constructive role in the regulation of angiogenesis in human GC and could be a potential therapeutic target for GC.
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http://dx.doi.org/10.1007/s10120-020-01080-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567730PMC
November 2020

Tunable Structural Color Patterns Based on the Visible-Light-Responsive Dynamic Diselenide Metathesis.

Adv Mater 2020 Mar 6;32(12):e1907569. Epub 2020 Feb 6.

Key Lab of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, China.

Structural color materials with reversible stimuli-responsiveness to external environment have been widely used in sensors, encryption, display, and other fields. Compared with other stimuli, visible light is highly controllable both temporally and spatially with less damage to materials, which is more suitable for structural color patterning. Herein, a new diselenide-containing shape memory material is prepared and used for creating patterns via visible light stimulus. In this system, the structural color originates from birefringence of stretched materials, whose shapes can be fixed while maintaining the mechanical stress. The fixed stress can be released by diselenide metathesis under visible light irradiation. By regulating the wavelength or irradiation time with a commercial projector, the pattern with tunable structural colors is realized and the structural color pattern can be erased and rewritten arbitrarily. During the patterning process, the optical signal is first stored as mechanical signal and then transformed back to optical signal. It is a new method for preparing visible-light-responsive structural color material and has great potential in display devices, anticounterfeiting labels, and data storage.
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http://dx.doi.org/10.1002/adma.201907569DOI Listing
March 2020

Smartphone Biosensor System with Multi-Testing Unit Based on Localized Surface Plasmon Resonance Integrated with Microfluidics Chip.

Sensors (Basel) 2020 Jan 13;20(2). Epub 2020 Jan 13.

State Key Laboratory of Integrated Optoelectronics, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.

Detecting biomarkers is an efficient method to diagnose and monitor patients' stages. For more accurate diagnoses, continuously detecting and monitoring multiple biomarkers are needed. To achieve point-of-care testing (POCT) of multiple biomarkers, a smartphone biosensor system with the multi-testing-unit (SBSM) based on localized surface plasmon resonance (LSPR) integrated multi-channel microfluidics was presented. The SBSM could simultaneously record nine sensor units to achieve the detection of multiple biomarkers. Additional 72 sensor units were fabricated for further verification. Well-designed modularized attachments consist of a light source, lenses, a grating, a case, and a smartphone shell. The attachments can be well assembled and attached to a smartphone. The sensitivity of the SBSM was 161.0 nm/RIU, and the limit of detection (LoD) reached 4.2 U/mL for CA125 and 0.87 U/mL for CA15-3 through several clinical serum specimens testing on the SBSM. The testing results indicated that the SBSM was a useful tool for detecting multi-biomarkers. Comparing with the enzyme-linked immunosorbent assays (ELISA) results, the results from the SBSM were correlated and reliable. Meanwhile, the SBSM was convenient to operate without much professional skill. Therefore, the SBSM could become useful equipment for point-of-care testing due to its small size, multi-testing unit, usability, and customizable design.
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http://dx.doi.org/10.3390/s20020446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014366PMC
January 2020

Mutation position is an important determinant for predicting cancer neoantigens.

J Exp Med 2020 04;217(4)

Genentech, South San Francisco, CA.

Tumor-specific mutations can generate neoantigens that drive CD8 T cell responses against cancer. Next-generation sequencing and computational methods have been successfully applied to identify mutations and predict neoantigens. However, only a small fraction of predicted neoantigens are immunogenic. Currently, predicted peptide binding affinity for MHC-I is often the major criterion for prioritizing neoantigens, although little progress has been made toward understanding the precise functional relationship between affinity and immunogenicity. We therefore systematically assessed the immunogenicity of peptides containing single amino acid mutations in mouse tumor models and divided them into two classes of immunogenic mutations. The first comprises mutations at a nonanchor residue, for which we find that the predicted absolute binding affinity is predictive of immunogenicity. The second involves mutations at an anchor residue; here, predicted relative affinity (compared with the WT counterpart) is a better predictor. Incorporating these features into an immunogenicity model significantly improves neoantigen ranking. Importantly, these properties of neoantigens are also predictive in human datasets, suggesting that they can be used to prioritize neoantigens for individualized neoantigen-specific immunotherapies.
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http://dx.doi.org/10.1084/jem.20190179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144530PMC
April 2020

LncRNA TUG1 functions as a ceRNA for miR-6321 to promote endothelial progenitor cell migration and differentiation.

Exp Cell Res 2020 03 11;388(1):111839. Epub 2020 Jan 11.

Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, People's Republic of China; Neurosurgery Institute of Fudan University, Shanghai, People's Republic of China. Electronic address:

Endothelial progenitor cell (EPC) recruitment and angiogenesis play crucial roles in aneurysm neck endothelialization, but the mechanisms of EPC recruitment and angiogenesis are still unclear. Recent studies have shown that long noncoding RNAs (lncRNAs) can regulate the function and differentiation of cells in various ways. LncRNA TUG1 is involved in liver cancer and glioma-mediated angiogenesis. The aim of this study was to investigate the role of lncRNA TUG1 in regulating EPC migration and differentiation. Overexpression and knockdown of lncRNA TUG1 with lentivirus, scratch assays, Transwell assays and tube formation assays using EPCs isolated from rat bone marrow showed that lncRNA TUG1 overexpression promoted EPC migration, invasion and differentiation. Moreover, ELISAs showed that lncRNA TUG1 overexpression increased VEGF expression. Bioinformatics prediction, luciferase assays, Western blots and RIP assays indicated that lncRNA TUG1 functions as a ceRNA (competing endogenous RNA) for miR-6321 and that miR-6321 inhibits EPC migration and differentiation through its target, ATF2. As a potential therapeutic target, lncRNA TUG1 may play a vital role in the pathogenesis of aneurysms.
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http://dx.doi.org/10.1016/j.yexcr.2020.111839DOI Listing
March 2020

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function.

J Neuroinflammation 2019 Oct 4;16(1):185. Epub 2019 Oct 4.

Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumiqi Rd., Shanghai, 200040, People's Republic of China.

Background: Oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation influence intracranial aneurysm (IA) formation and progression. Oxidative stress plays an important role in phenotype switching, and nuclear factor erythroid 2-related factor 2 (Nrf-2) is one of the main antioxidant systems. Unfortunately, little is known about how Nrf-2 signaling influences VSMC phenotype switches during IA pathogenesis.

Methods: We examined the effect of Nrf-2 activation IA on formation and progression in an elastase-induced rat IA model. We also developed a hydrogen peroxide (HO)-induced VSMC oxidative damage model. Then, we analyzed VSMC phenotype changes in the setting of Nrf-2 activation or inhibition in vitro. The proliferation, migration ability, and apoptosis rate of VSMCs were tested. Lastly, we measured the expression levels of antioxidant enzymes and inflammatory cytokines downstream of Nrf-2.

Results: Nrf-2 activation suppressed IA formation and progression in vivo. We confirmed Nrf-2 nuclear translocation and a VSMC switch from the contractile to synthetic phenotype. Nrf-2 activation inhibited the proliferation, migratory ability, and apoptosis rate enhanced by HO. Quantitative real-time polymerase chain reaction (PCR) and western blot analysis revealed that Nrf-2 activation promoted antioxidant enzymes and VSMC-specific marker gene expressions but decreased pro-inflammatory cytokine levels.

Conclusion: These results suggest that Nrf-2 exerts protective effects against IA development by preventing VSMCs from changing to a synthetic phenotype.
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http://dx.doi.org/10.1186/s12974-019-1568-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778377PMC
October 2019
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