Publications by authors named "Junyu Chen"

159 Publications

Autophagy Induced by Trehalose Alleviates Apoptosis of Human Aortic Endothelial Cells After Cryopreservation.

Biopreserv Biobank 2021 Sep 1. Epub 2021 Sep 1.

Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.

Cryoprotectants are crucial factors in cell cryopreservation. Trehalose (Tre), a nontoxic, nonreducing, and natural disaccharide, has the potential to protect cells as a cryoprotectant. As an inducer of autophagy, Tre can influence the development of many diseases and may also have an effect on cell cryopreservation through this mechanism. In this study, human aortic endothelial cells were preserved in different cryopreservation fluids with or without dimethyl sulfoxide and Tre was added. Subsequently, the expression of the main autophagy-related genes LC3, BECN, and P62, cell death and apoptosis, and the proliferation rate were measured in different groups after cryopreservation. Our data showed that Tre can improve the expression of the autophagy-related genes LC3 and BECN and reduce the expression of P62. Dead/alive staining and flow cytometry showed that cell death and cell apoptosis were reduced during cryopreservation with Tre. In addition, the cell proliferation rate after thawing was increased in the Tre group when compared with others. These results all indicated that there might be a connection between Tre-triggered autophagy and the protective role of Tre in cell cryopreservation. Furthermore, strategies to regulate autophagy to reduce apoptosis in this process should be investigated in future research.
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http://dx.doi.org/10.1089/bio.2021.0071DOI Listing
September 2021

Rabbit Monoclonal Antibody Specifically Recognizing a Linear Epitope in the RBD of SARS-CoV-2 Spike Protein.

Vaccines (Basel) 2021 Jul 28;9(8). Epub 2021 Jul 28.

National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, China.

To date, SARS-CoV-2 pandemic has caused more than 188 million infections and 4.06 million deaths worldwide. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein has been regarded as an important target for vaccine and therapeutics development because it plays a key role in binding the human cell receptor ACE2 that is required for viral entry. However, it is not easy to detect RBD in Western blot using polyclonal antibody, suggesting that RBD may form a complicated conformation under native condition and bear rare linear epitope. So far, no linear epitope on RBD is reported. Thus, a monoclonal antibody (mAb) that recognizes linear epitope on RBD will become valuable. In the present study, an RBD-specific rabbit antibody named 9E1 was isolated from peripheral blood mononuclear cells (PBMC) of immunized rabbit by RBD-specific single B cell sorting and mapped to a highly conserved linear epitope within twelve amino acids CNGVEGFNCYFP on RBD. 9E1 works well in Western blot on S protein and immunohistochemistry on the SARS-CoV-2 infected tissue sections. The results demonstrated that 9E1 can be used as a useful tool for pathological and functional studies of SARS-CoV-2.
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http://dx.doi.org/10.3390/vaccines9080829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402368PMC
July 2021

The Application of Polycaprolactone in Three-Dimensional Printing Scaffolds for Bone Tissue Engineering.

Polymers (Basel) 2021 Aug 17;13(16). Epub 2021 Aug 17.

Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Bone tissue engineering commonly encompasses the use of three-dimensional (3D) scaffolds to provide a suitable microenvironment for the propagation of cells to regenerate damaged tissues or organs. 3D printing technology has been extensively applied to allow direct 3D scaffolds manufacturing. Polycaprolactone (PCL) has been widely used in the fabrication of 3D scaffolds in the field of bone tissue engineering due to its advantages such as good biocompatibility, slow degradation rate, the less acidic breakdown products in comparison to other polyesters, and the potential for loadbearing applications. PCL can be blended with a variety of polymers and hydrogels to improve its properties or to introduce new PCL-based composites. This paper describes the PCL used in developing state of the art of scaffolds for bone tissue engineering. In this review, we provide an overview of the 3D printing techniques for the fabrication of PCL-based composite scaffolds and recent studies on applications in different clinical situations. For instance, PCL-based composite scaffolds were used as an implant surgical guide in dental treatment. Furthermore, future trend and potential clinical translations will be discussed.
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http://dx.doi.org/10.3390/polym13162754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400029PMC
August 2021

Atrazine Promoted Epithelial Ovarian Cancer Cells Proliferation and Metastasis by Inducing Low Dose Reactive Oxygen Species (ROS).

Iran J Biotechnol 2021 Apr 1;19(2):e2623. Epub 2021 Apr 1.

Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130041, China.

Background: Atrazine (ATZ) is a triazine herbicide that is widely used in agriculture and has been detected in surface and underground water. Recently, laboratory and epidemiological research have found that the bioaccumulation of ATZ in the environment leads to biotoxicity in the human immune and endocrine systems and results in tumor development.

Objective: To investigate the effects of ATZ exposure on epithelial ovarian cancer (EOC) cells and elucidate the potential mechanisms governing these effects.

Materials And Methods: The human EOC cell lines Skov3 and A2780 were used in this study to explore the effects and mechanisms of ATZ exposure on EOC. The mouse embryonic osteoblastic precursor MC3T3-E1 cells served as the control cells to determine the effects of ATZ on cancer cell lines. After exposure to ATZ, the MTT assay, flow cytometry, the colony formation assay, immunohistochemical staining, the cell scratch assay, and the Transwell assay were used to evaluate the proliferative activity, invasion, and migration capabilities of EOC cell lines. Moreover, flow cytometry was also applied to detect the level of reactive oxygen species (ROS) in these two EOC cell lines, as well as the MC3T3-E1 cells. To further illustrate the underlying mechanisms governing the effect of ATZ on EOC, real-time PCR and Western blotting were employed to assess the transcription and the expression level of Stat3 signaling pathway-related genes in Skov3 and MC3T3-E1 cells.

Results: The results showed that following ATZ treatment, the cell proliferation, migration, and invasion potencies of Skov3 and A2780 cells were increased compared to those of the control group. Meanwhile, the ROS levels of EOC and MC3T3-E1 cells were notably elevated after ATZ treatment. In Skov3 cells, the expression levels of p53 and p21 were downregulated, while those of Cyclin E, vascular endothelial growth factor (VEGF), matrix metallopeptidase 2 (MMP2), MMP9, signal transducers and activators of transcription 3 (Stat3), and p-Stat3 were upregulated by ATZ treatment. In MC3T3-E1 cells, however, ATZ treatment did not affect the level of p53/p21 mRNA compared to the control groups. Moreover, there was no significant change in the expression levels of Stat3 and p-Stat3 in MC3T3-E1 cells exposed to ATZ. This phenomenon was observed while the proliferation rate was enhanced in MC3T3-E1 cells by ATZ.

Conclusions: The results of this study suggest that ATZ effectively promotes the proliferation and metastasis of EOC cells through the Stat3 signaling pathway by inducing low levels of ROS. Additionally, although ATZ might also induce proliferative potential in normal cells, the mechanisms governing its effects in these cells might be different from those in EOC cells.
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http://dx.doi.org/10.30498/IJB.2021.2623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358173PMC
April 2021

Optimising PHBV biopolymer production in haloarchaea via CRISPRi-mediated redirection of carbon flux.

Commun Biol 2021 08 25;4(1):1007. Epub 2021 Aug 25.

State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People's Republic of China.

The haloarchaeon Haloferax mediterranei is a potential strain for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) production, yet the production yield and cost are the major obstacles hindering the use of this archaeal strain. Leveraging the endogenous type I-B CRISPR-Cas system in H. mediterranei, we develop a CRISPR-based interference (CRISPRi) approach that allows to regulate the metabolic pathways related to PHBV synthesis, thereby enhancing PHBV production. Our CRISPRi approach can downregulate the gene expression in a range of 25% to 98% depending upon the target region. Importantly, plasmid-mediated CRISPRi downregulation on the citrate synthase genes (citZ and gltA) improves the PHBV accumulation by 76.4% (from 1.78 to 3.14 g/L). When crRNA cassette integrated into chromosome, this further shortens the PHBV fermentation period and enhances PHA productivity by 165%. Our transcriptome analysis shows that repression of citrate synthase genes redirects metabolic flux from the central metabolic pathways to PHBV synthesis pathway. These findings demonstrate that the CRISPRi-based gene regulation is a transformative toolkit for fine-tuning the endogenous metabolic pathways in the archaeal system, which can be applied to not only the biopolymer production but also many other applications.
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http://dx.doi.org/10.1038/s42003-021-02541-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387396PMC
August 2021

Doyle-Kirmse reaction using 3,3-difluoroallyl sulfide and N-sulfonyl-1,2,3-triazole: an efficient access to gem-difluoroallylated multifunctional quaternary carbon.

Org Biomol Chem 2021 Aug 2;19(32):6974-6978. Epub 2021 Aug 2.

Faculty of Science, Kunming University of Science and Technology, Jingming South Road 727, Chenggong District, Kunming 650500, P. R. of China.

A Doyle-Kirmse reaction of N-sulfonyl-1,2,3-triazole with 3,3-difluoroallyl sulfide through a Rh(ii)-catalyzed [2,3]-sigmatropic rearrangement has been developed, which provides an efficient access to multifunctional quaternary centers containing aryl, imino, thio, and brominated gem-difluoroallyl groups. The reaction features broad substrate scope with moderate to excellent yields. The applicability of the method is confirmed by gram-scale synthesis and further transformations.
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http://dx.doi.org/10.1039/d1ob01129dDOI Listing
August 2021

Fluorosulfuryl Isocyanate Enabled SuFEx Ligation of Alcohols and Amines.

Angew Chem Int Ed Engl 2021 09 18;60(39):21195-21199. Epub 2021 Aug 18.

Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai, 200032, P. R. China.

Fluorosulfuryl isocyanate (FSI, FSO NCO) is established as a reliable bis-electrophilic linker for stepwise attachment of an alcohol bearing module to an amine bearing module and thence a new module RO-C(=O)-NH-SO -NR'R'' is created. FSI's isocyanate motif fuses directly and quickly with alcohols and phenols, affording fluorosulfuryl carbamates in nearly quantitative yield. A new reagent and process to deliver the FSI-derived fluorosulfuryl carbamate fragment to amines are also developed. The resulting S -F motifs from step-1 are remarkably stable, given the great structural complexities in diverse products. In the step-2 reaction with amines, the best yield of the S-N linked products arise with water alone. This "on water" interfacial reactivity phenomenon is crucial, revealing the latent reactivity of S -F probe for potential covalent capture of proteins in vivo which is important in today's drug discovery. The scope of the SuFEx chemistry is largely expanded thereby and the facile entry to these phosphate-like connections should prove useful to click chemistry across diverse fields.
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http://dx.doi.org/10.1002/anie.202105583DOI Listing
September 2021

5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer's disease.

Cell Rep 2021 Apr;35(4):109042

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. Electronic address:

5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer's disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids.
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http://dx.doi.org/10.1016/j.celrep.2021.109042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106871PMC
April 2021

Analysis of the association between KIN17 expression and the clinical features/prognosis of epithelial ovarian cancer, and the effects of KIN17 in SKOV3 cells.

Oncol Lett 2021 Jun 15;21(6):475. Epub 2021 Apr 15.

Department of Recovery, Nursing School of Jilin University, Changchun, Jilin 130012, P.R. China.

DNA double-strand breaks (DSBs) are an important mechanism of chemotherapy in epithelial ovarian cancer (EOC). Kin17 DNA and RNA binding protein (KIN17) serves a crucial role in DSB repair. In the present study, the association between KIN17 and EOC, and the effects of KIN17 on EOC cells were evaluated. A bioinformatics method was used to determine the mRNA expression levels of KIN17 in EOC and its association with EOC prognosis including overall survival (OS) and progression free survival (PFS) time. Western blotting and immunohistochemical staining were used to evaluate the expression levels of KIN17 in EOC samples. Kaplan-Meier and Cox regression analyses were utilized to analyze risk factors for the OS of patients with EOC. A Cell Counting Kit-8 assay was performed to explore the roles of KIN17 in SKOV3 cells. Both the transcription and expression of KIN17 were upregulated in EOC tissues. Furthermore, the OS of patients with EOC with high mRNA expression levels of KIN17 was shorter than that of patients with EOC with low expression levels. High KIN17 expression was an independent risk factor for EOC prognosis. Furthermore, KIN17 knockdown inhibited the proliferation of SKOV3 cells, enhanced the sensitivity of the cells to cisplatin and inhibited the migration ability of the cells. These results suggested that KIN17 may act as an ideal candidate for therapy and as a prognostic biomarker of EOC, although the underlying mechanisms require further exploration.
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http://dx.doi.org/10.3892/ol.2021.12736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063336PMC
June 2021

Learning fuzzy clustering for SPECT/CT segmentation via convolutional neural networks.

Med Phys 2021 Jul 28;48(7):3860-3877. Epub 2021 May 28.

Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, USA.

Purpose: Quantitative bone single-photon emission computed tomography (QBSPECT) has the potential to provide a better quantitative assessment of bone metastasis than planar bone scintigraphy due to its ability to better quantify activity in overlapping structures. An important element of assessing the response of bone metastasis is accurate image segmentation. However, limited by the properties of QBSPECT images, the segmentation of anatomical regions-of-interests (ROIs) still relies heavily on the manual delineation by experts. This work proposes a fast and robust automated segmentation method for partitioning a QBSPECT image into lesion, bone, and background.

Methods: We present a new unsupervised segmentation loss function and its semi- and supervised variants for training a convolutional neural network (ConvNet). The loss functions were developed based on the objective function of the classical Fuzzy C-means (FCM) algorithm. The first proposed loss function can be computed within the input image itself without any ground truth labels, and is thus unsupervised; the proposed supervised loss function follows the traditional paradigm of the deep learning-based segmentation methods and leverages ground truth labels during training. The last loss function is a combination of the first and the second and includes a weighting parameter, which enables semi-supervised segmentation using deep learning neural network.

Experiments And Results: We conducted a comprehensive study to compare our proposed methods with ConvNets trained using supervised, cross-entropy and Dice loss functions, and conventional clustering methods. The Dice similarity coefficient (DSC) and several other metrics were used as figures of merit as applied to the task of delineating lesion and bone in both simulated and clinical SPECT/CT images. We experimentally demonstrated that the proposed methods yielded good segmentation results on a clinical dataset even though the training was done using realistic simulated images. On simulated SPECT/CT, the proposed unsupervised model's accuracy was greater than the conventional clustering methods while reducing computation time by 200-fold. For the clinical QBSPECT/CT, the proposed semi-supervised ConvNet model, trained using simulated images, produced DSCs of and for lesion and bone segmentation in SPECT, and a DSC of bone segmentation of CT images. These DSCs were larger than that for standard segmentation loss functions by for SPECT segmentation, and for CT segmentation with P-values from a paired t-test.

Conclusions: A ConvNet-based image segmentation method that uses novel loss functions was developed and evaluated. The method can operate in unsupervised, semi-supervised, or fully-supervised modes depending on the availability of annotated training data. The results demonstrated that the proposed method provides fast and robust lesion and bone segmentation for QBSPECT/CT. The method can potentially be applied to other medical image segmentation applications.
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http://dx.doi.org/10.1002/mp.14903DOI Listing
July 2021

FGFR3 phosphorylates EGFR to promote cisplatin-resistance in ovarian cancer.

Biochem Pharmacol 2021 Aug 29;190:114536. Epub 2021 Mar 29.

Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, PR China. Electronic address:

Ovarian cancer is a deadly gynecologic cancer, and the majority of patients with ovarian cancer experience relapse after traditional treatment. Cisplatin (DDP) is a common chemotherapeutic drug for ovarian cancer, but many patients acquire DDP-resistance after treatment with long-term chemotherapy. The mechanisms of drug-resistance in ovarian cancer are not clear, and we thus aim to investigate novel targets for DDP-resistant ovarian cancer. Differential analysis, KEGG pathway enrichment and protein interaction networks were employed to identify the key genes related to DDP-resistance in ovarian cancer. Subsequently, cell viability, apoptosis and migration were measured to assess the effect of fibroblast growth factor receptor 3 (FGFR3) on DDP-resistance. Further, Pearson correlation analysis and co-expression analysis were used to explore the downstream pathways of FGFR3, and the function of FGFR3 and its downstream targets were further demonstrated by in vitro and nude mice experiments. FGFR3 were expressed at high levels in DDP-resistant ovarian cancer cells. FGFR3 silencing suppressed the activation of PI3K/AKT pathway and impeded the drug-resistance and development of tumor cells. Afterwards, we found that FGFR3 was co-expressed with epidermal growth factor receptor (EGFR). FGFR3 overexpression elevated EGFR phosphorylation and activated PI3K/AKT signaling. Furthermore, in nude mice, silencing FGFR3 and inhibiting EGFR phosphorylation were observed to promote the therapeutic effect of DDP. In conclusion, FGFR3 overexpression enhances DDP-resistance of ovarian cancer by promoting EGFR phosphorylation and further activating PI3K/AKT pathway. This study may offer promising targets for DDP-resistant ovarian cancer.
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http://dx.doi.org/10.1016/j.bcp.2021.114536DOI Listing
August 2021

Buildup dynamics of a pulsating dissipative soliton in an all-normal-dispersion PM Yb-doped fiber laser with a NALM.

Opt Lett 2021 Apr;46(7):1612-1615

A pulsating soliton exists in various passively mode-locked fiber lasers. Versatile categories of pulsating solitons have been investigated in a steady regime. However, the formation dynamics of pulsating solitons have not been fully revealed. Herein, we experimentally captured both single pulsating soliton and two pulsating soliton formation processes in an all-normal-dispersion laser. With the help of the time-stretch dispersion Fourier transform technique, the real-time temporal and spectral evolutions of pulsating solitons, during the buildup process, were investigated. It is found that pulsation directly derives from the background noise. In addition, both types of pulsations experience several characteristic stages, including an unstable -switch, spectral shaping, broadening, oscillating, and narrowing, which might be induced by the transient non-balance between the gain and loss of the cavity. We anticipate that the work in this Letter can improve the understanding of pulsating behaviors and bring new insights into the dynamic phenomenon of nonlinear optical systems.
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http://dx.doi.org/10.1364/OL.421697DOI Listing
April 2021

Alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC): a retrospective study of 27 cases.

Arch Gynecol Obstet 2021 10 9;304(4):1043-1053. Epub 2021 Mar 9.

Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

Objective: The aim of the study was to investigate the relative risk factors associated with the prognosis and effective treatments of alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC).

Method: We presented three cases of AFP-producing EOC and performed a brief review to summarize the clinicopathological features and prognostic factors of 24 cases that have been previously reported. We evaluated the correlations among prognostic and clinical parameters, such as stage, pathology and chemotherapy regimens. In addition, a retrospective review of these 27 cases was conducted, and survival curves were estimated using the Kaplan-Meier method.

Results: The patients were aged between 23 and 77 years. The median overall survival was 10 months, and ten (37.04%) patients died within 18 months. We compared the overall mean survival times of all patients in different stages, and the results suggest that the postoperative pathological staging is hardly correlated with prognosis (P = 0.76). There was a correlation between pathology and prognosis (P = 0.0018). The mean survival time was longer for patients who had undergone chemotherapy than for those without chemotherapy (14.88 vs 0.65 months) (P < 0.0001). Moreover, although patients had a good response to the regimens for PEB and TC (P = 0.004), there was no significant difference between PEB and TC (P = 0.386).

Conclusions: AFP-producing EOC is uncommon and regarded as an extremely malignant type of tumor. Patients with chemotherapy may have a longer survival time; additionally, PEB and TC may be an optimal selection for this kind of tumor. Further large-scale studies are needed to confirm our findings.
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http://dx.doi.org/10.1007/s00404-021-06017-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942666PMC
October 2021

A mussel-inspired film for adhesion to wet buccal tissue and efficient buccal drug delivery.

Nat Commun 2021 03 16;12(1):1689. Epub 2021 Mar 16.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Administration of drugs via the buccal route has attracted much attention in recent years. However, developing systems with satisfactory adhesion under wet conditions and adequate drug bioavailability still remains a challenge. Here, we propose a mussel-inspired mucoadhesive film. Ex vivo models show that this film can achieve strong adhesion to wet buccal tissues (up to 38.72 ± 10.94 kPa). We also demonstrate that the adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Additionally, the film with incorporated polydopamine nanoparticles shows superior advantages for transport across the mucosal barrier, with improved drug bioavailability (~3.5-fold greater than observed with oral delivery) and therapeutic efficacy in oral mucositis models (~6.0-fold improvement in wound closure at day 5 compared with that observed with no treatment). We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.
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http://dx.doi.org/10.1038/s41467-021-21989-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966365PMC
March 2021

Effects of mating on reproductive performance of Coccophagus japonicus Compere (Hymenoptera: Aphelinidae).

Sci Rep 2021 Mar 15;11(1):5941. Epub 2021 Mar 15.

Environment and Plant Protection Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou, 571101, China.

Coccophagus japonicus Compere, an endoparasitoid of Parasaissetia nigra Nietner, has great potential for biological control. To assess the influence of mating on the reproductive performance of this parasitoid, we examined the effects of mating on ovarian development, female longevity and number of eggs laid. The results showed that the egg volume in the ovary of C. japonicus first increased and then decreased with increases in the age of female adults. The peak egg volume in the ovary of mated females occurred 2 days earlier than that of virgin females. Within the female age range of 0-15 days, the numbers of eggs at stages I, II, and III first increased and then decreased with increases in the age of female C. japonicus, whereas the number of eggs at stage IV increased. The duration of the coexistence of females and males significantly influenced the length and width of the female ovaries, and the longest ovary tube and the highest number of eggs were obtained with a coexistence duration of 0 days. C. japonicus female longevity decreased with increases in the number of matings, and the number of eggs laid by females within 15 days decreased with increasing delays in mating. In conclusion, mating can shorten the longevity of C. japonicus females, and selecting newly emerged virgin females for mating can significantly improve the number of eggs laid and the breeding efficiency of the parasitoid.
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http://dx.doi.org/10.1038/s41598-021-85351-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971017PMC
March 2021

FGF gene expression in injured tendons as a prognostic biomarker of 1-year patient outcome after Achilles tendon repair.

J Exp Orthop 2021 Mar 11;8(1):20. Epub 2021 Mar 11.

Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.

Purpose: Healing outcome after Achilles Tendon Rupture (ATR) is variable and unsatisfactory. Many ATR patients still exhibit pain, functional deficits and limitations in walking one-year post-surgery. The present study was designed to investigate the association between the expression of healing biomarkers and patient outcome after ATR.

Methods: Tendon biopsies were collected from 25 ATR patients during surgery. At 1-year post surgery, all patients completed questionnaires; Achilles tendon Total Rupture Score (ATRS) and Foot and Ankle Outcome Score (FAOS), and were tested for functional outcomes by heel-rise test. In biopsies, FGF, COL III, FN, COL I and MMP-9 mRNA levels were assessed by quantitative RT-PCR while protein expression was studied by immunohistochemistry (IHC).

Results: Our analysis confirmed the presence of FGF, COL III, FN, COL I and MMP-9 at mRNA and protein levels in tendon biopsies. FGF gene expression associated positively with improved total ATRS and better functional outcomes. Additionally, FGF mRNA levels were associated with less pain, less running limitations and less loss in physical activity. In addition, higher COL III mRNA expression was associated with more tendon strength.

Conclusion: Our findings indicate that FGF gene expression is associated with improved patient-reported outcome. FGF expression in surgical biopsies could potentially be used to assist the prognostic evaluation of patient outcome and may be used as a predictor for healing. However, further studies are needed to evaluate the role of FGF in Achilles tendon healing.

Level Of Evidence: II.
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http://dx.doi.org/10.1186/s40634-021-00335-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947072PMC
March 2021

Ferroptosis inducer erastin downregulates androgen receptor and its splice variants in castration‑resistant prostate cancer.

Oncol Rep 2021 04 2;45(4). Epub 2021 Mar 2.

Department of Recovery, Nursing School, Jilin University, Changchun, Jilin 130021, P.R. China.

To date, there is no effective therapy available for the treatment of castration‑resistant prostate cancer (CRPC), and patients generally succumb to the disease within 2 to 4 years. In the progression of CRPC, androgen receptor (AR) and its splice variants play critical roles. Hence, it is necessary to develop a drug to inhibit the expression and activity of the full‑length and splice variants of AR for the treatment of CRPC. Erastin, as the first discovered drug to induce ferroptosis, has been studied in various types of cancer. However, there are few studies focusing on the relationship between erastin and AR. In the present study, western blotting, and sulforhodamine B cell viability, glutathione, lipid peroxidation and reactive oxygen species assays were performed to verify the ferroptosis of CRPC cells; reverse transcription‑quantitative polymerase chain reaction, dual‑luciferase reporter, and lentiviral packaging and lentivirus‑infected cell assays were employed to evaluate how erastin affects AR. A mouse xenograft assay was used to determine the underlying mechanism in vivo. Erastin, as a classical inducer of ferroptosis, can suppress the transcriptional activities of both the full‑length and splice variants in AR models in vitro and in vivo. In addition, when erastin was used for CRPC treatment combined with docetaxel, the growth inhibitory efficacy of docetaxel was found to be enhanced. Thus, these findings indicated that ferroptosis inducer erastin has potential in the treatment of CRPC via targeting AR.
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http://dx.doi.org/10.3892/or.2021.7976DOI Listing
April 2021

Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy.

Cancer Immunol Immunother 2021 Sep 19;70(9):2657-2668. Epub 2021 Feb 19.

Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhongshan) University, Guangzhou, 510120, People's Republic of China.

The expression status of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and the infiltration of CD8 T cells in tumor tissues are considered to be related to immunotherapy efficacy and patient prognosis. The purpose of this study is to clarify the prognostic value of the PD-L1/PD-1/CD8 axis, and to develop and validate a comprehensive scoring system based on multiple immune variables to predict cancer survival of upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). The immunohistochemical method was used to detect the expression of PD-L1, PD-1, and CD8 in cancer tissues of UTUC patients after RNU. Then, an immunoscore was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model in the training cohort (n = 120), and it was verified in the validation cohort (n = 54). We found that infiltration of PD-L1 immune cells (ICs), stromal PD-1 tumor-infiltrating lymphocytes (TILs), and intratumoral CD8 TILs was associated with poor overall survival (OS). The immunoscore based on the three immune variables further divided the patients into low- and high-risk groups, and there was a significant difference in the survival rate. A nomogram was constructed by combining tumor-node-metastasis (TNM) stage and immunoscore, and the area under the curve of the receiver-operating characteristic (ROC) (0.78) for predicting 5-year mortality was better than that of the TNM stage (0.70) and immunoscore (0.76). Our results show that the PD-L1/PD-1/CD8 axis-based classifier have potential clinical application to predict cancer survival of UTUC patients after RNU.
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http://dx.doi.org/10.1007/s00262-020-02827-xDOI Listing
September 2021

Effects of Different Planting Densities on Photosynthesis in Maize Determined via Prompt Fluorescence, Delayed Fluorescence and P700 Signals.

Plants (Basel) 2021 Jan 31;10(2). Epub 2021 Jan 31.

Jiangsu Key Laboratory of Crop Genetics and Physiology, Co-Innovation Center for Modern Production Technology of Grain Crops, Key Laboratory of Plant Functional Genomics of the Ministry of Education, Joint International Research Laboratory of Agriculture & Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou 225009, China.

The mutual shading among individual field-grown maize plants resulting from high planting density inevitably reduces leaf photosynthesis, while regulating the photosynthetic transport chain has a strong impact on photosynthesis. However, the effect of high planting density on the photosynthetic electron transport chain in maize currently remains unclear. In this study, we simultaneously measured prompt chlorophyll fluorescence (PF), modulated 820 nm reflection (MR) and delayed chlorophyll fluorescence (DF) in order to investigate the effect of high planting density on the photosynthetic electron transport chain in two maize hybrids widely grown in China. PF transients demonstrated a gradual reduction in their signal amplitude with increasing planting density. In addition, high planting density induced positive J-step and G-bands of the PF transients, reduced the values of PF parameters PI, RC/CS, TR/ABS, ET/TR and RE/ET, and enhanced ABS/RC and N. MR kinetics showed an increase of their lowest point with increasing high planting density, and thus the values of MR parameters V and V were reduced. The shapes of DF induction and decay curves were changed by high planting density. In addition, high planting density reduced the values of DF parameters I, I, and , and enhanced I/I. These results suggested that high planting density caused harm on multiple components of maize photosynthetic electron transport chain, including an inactivation of PSII RCs, a blocked electron transfer between Q and Q, a reduction in PSI oxidation and re-reduction activities, and an impaired PSI acceptor side. Moreover, a comparison between PSII and PSI activities demonstrated the greater effect of plant density on the former.
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http://dx.doi.org/10.3390/plants10020276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910836PMC
January 2021

High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging.

Sci Adv 2021 Feb 3;7(6). Epub 2021 Feb 3.

Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK.

Blood vessels provide supportive microenvironments for maintaining tissue functions. Age-associated vascular changes and their relation to tissue aging and pathology are poorly understood. Here, we perform 3D imaging of young and aging vascular beds. Multiple organs in mice and humans demonstrate an age-dependent decline in vessel density and pericyte numbers, while highly remodeling tissues such as skin preserve the vasculature. Vascular attrition precedes the appearance of cellular hallmarks of aging such as senescence. Endothelial VEGFR2 loss-of-function mice demonstrate that vascular perturbations are sufficient to stimulate cellular changes coupled with aging. Age-associated tissue-specific molecular changes in the endothelium drive vascular loss and dictate pericyte to fibroblast differentiation. Lineage tracing of perivascular cells with inducible PDGFRβ and NG2 Cre mouse lines demonstrated that increased pericyte to fibroblast differentiation distinguishes injury-induced organ fibrosis and zymosan-induced arthritis. To spur further discoveries, we provide a freely available resource with 3D vascular and tissue maps.
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http://dx.doi.org/10.1126/sciadv.abd7819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857692PMC
February 2021

DeepAMO: a multi-slice, multi-view anthropomorphic model observer for visual detection tasks performed on volume images.

J Med Imaging (Bellingham) 2021 Jul 28;8(4):041204. Epub 2021 Jan 28.

Johns Hopkins University, Whiting School of Engineering, Department of Electrical and Computer Engineering, Baltimore, Maryland, United States.

We propose a deep learning-based anthropomorphic model observer (DeepAMO) for image quality evaluation of multi-orientation, multi-slice image sets with respect to a clinically realistic 3D defect detection task. The DeepAMO is developed based on a hypothetical model of the decision process of a human reader performing a detection task using a 3D volume. The DeepAMO is comprised of three sequential stages: defect segmentation, defect confirmation (DC), and rating value inference. The input to the DeepAMO is a composite image, typical of that used to view 3D volumes in clinical practice. The output is a rating value designed to reproduce a human observer's defect detection performance. In stages 2 and 3, we propose: (1) a projection-based DC block that confirms defect presence in two 2D orthogonal orientations and (2) a calibration method that "learns" the mapping from the features of stage 2 to the distribution of observer ratings from the human observer rating data (thus modeling inter- or intraobserver variability) using a mixture density network. We implemented and evaluated the DeepAMO in the context of -DMSA SPECT imaging. A human observer study was conducted, with two medical imaging physics graduate students serving as observers. A -fold cross-validation experiment was conducted to test the statistical equivalence in defect detection performance between the DeepAMO and the human observer. We also compared the performance of the DeepAMO to an unoptimized implementation of a scanning linear discriminant observer (SLDO). The results show that the DeepAMO's and human observer's performances on unseen images were statistically equivalent with a margin of difference ( ) of 0.0426 at , using 288 training images. A limited implementation of an SLDO had a substantially higher AUC (0.99) compared to the DeepAMO and human observer. The results show that the DeepAMO has the potential to reproduce the absolute performance, and not just the relative ranking of human observers on a clinically realistic defect detection task, and that building conceptual components of the human reading process into deep learning-based models can allow training of these models in settings where limited training images are available.
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http://dx.doi.org/10.1117/1.JMI.8.4.041204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840951PMC
July 2021

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells.

Front Pharmacol 2020 14;11:615824. Epub 2021 Jan 14.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.
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http://dx.doi.org/10.3389/fphar.2020.615824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841342PMC
January 2021

Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: A retrospective multicenter study (TSU-02 study).

Oncoimmunology 2021 01 4;10(1):1861737. Epub 2021 Jan 4.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.

Locally advanced upper urinary tract urothelial carcinoma (UTUC) exhibits high recurrence and metastasis rates even after radical nephroureterectomy. Adjuvant immunotherapy can be a reasonable option, and a simple, low-cost, and effective biomarker is further needed. Stromal tumor-infiltrating lymphocytes (sTILs) has been demonstrated as a prognostic and predictive biomarker in various tumor types, but not yet in locally advanced UTUC. In this multicenter, real-world and retrospective study, we tried to investigate the prognostic role of sTIL and its correlation with the PD-L1/PD-1/CD8 axis by reviewing the clinicopathologic variables of 398 locally advanced UTUC patients at four high-volume Chinese medical centers. sTIL density was evaluated with standardized methodology on H&E sections, and patients were stratified by the cutoff of sTIL (50%). Results showed that high sTIL indicated improved survival (CSS, = .022; RFS, = .015; DFS, = .004), and was an independent predictor of better CSS (, 0.577; 95% CI, 0.391-0.851; = .006), RFS (, 0.613; 95% CI 0.406-0.925; = .020) and DFS (, 0.609; 95% CI, 0.447-0.829; = .002). A strongly positive correlation between sTIL density and the expression level of PD-1/PD-L1/CD8 axis was observed. We also found that aristolochic acid (AA) exposure was associated with increased sTIL and elevated PD-L1 expression, indicating that AA-related UTUC might be a distinct subgroup with unique tumor microenvironment characteristics. Our results show that sTIL can be an easily acquired biomarker for prognostic stratification in locally advanced UTUC.
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http://dx.doi.org/10.1080/2162402X.2020.1861737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801121PMC
January 2021

Mesoporous silica nanoparticles combined with AKR1C3 siRNA inhibited the growth of castration-resistant prostate cancer by suppressing androgen synthesis in vitro and in vivo.

Biochem Biophys Res Commun 2021 02 12;540:83-89. Epub 2021 Jan 12.

Nursing School of Jilin University, Changchun, 130012, China. Electronic address:

Intracrine androgen synthesis plays a critical role in the development of castration-resistant prostate cancer (CRPC). Aldo-keto reductase family 1 member C3 (AKR1C3) is a vital enzyme in the intracrine androgen synthesis pathway. In this study, mesoporous silica nanoparticles (MSNs) were employed to deliver small interfering RNA targeting AKR1C3 (siAKR1C3) to downregulate AKR1C3 expression in CPRC cells. The optimal weight ratio of MSNs/siAKR1C3 was determined by a gel retardation assay. Prostate cancer cells such as VCaP cells, which intracrinally express AKR1C3, and LNCaP-AKR1C3 cells stably transfected with AKR1C3 were used to investigate the antitumour effect of MSNs-siAKR1C3. Fluorescence detection and Western blot analyses were applied to confirm the entrance of MSNs-siAKR1C3 into the cells. A SRB (Sulforhodamine B) assay was employed to assess the cell viability, and a radioimmunoassay was used to measure the androgen concentration. Moreover, real-time PCR (RT-PCR), Western blot analysis and ELISA were used to determine the transcription and expression of prostate-specific antigen (PSA), AKR1C3 and androgen receptor (AR). Meanwhile, a reporter gene assay was performed to determine the AR activity. Additionally, a castrated nude mouse xenograft tumour model was produced to verify the inhibitory effect of MSNs-siAKR1C3 in vivo. The results showed that the optimal weight ratio of MSNs/siAKR1C3 was 140:1, and the complex could effectively enter cells, downregulate AKR1C3 expression, reduce the androgen concentration, inhibit AR activation, and inhibit CRPC development both in vitro and in vivo. These results indicate that decreasing intracrine androgen synthesis and inactivating AR signals by MSNs-siAKR1C3 may be a potential effective method for CRPC treatment.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.074DOI Listing
February 2021

Accelerated Bone Regeneration by MOF Modified Multifunctional Membranes through Enhancement of Osteogenic and Angiogenic Performance.

Adv Healthc Mater 2021 03 14;10(6):e2001369. Epub 2021 Jan 14.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.

Owing to the insufficient guidance of new bone formation in orthopedic and craniomaxillofacial surgery, construction of a guided bone regeneration membrane to support vascularized bone regeneration remains a challenge. Herein, an electrospun asymmetric double-layer polycaprolactone/collagen (PCL/Col) membrane modified by metal-organic framework (MOF) crystals is developed. The optimization of the PCL/Col weight ratio (1:1 and 1:1.5) enables the composite membrane with a balanced tensile strength (only fell by 49.9% in wet conditions) and a controlled degradation rate (completely degraded at 12 weeks). The MOF crystals can provide a pH-responsive release of Zn ions. In vitro experiments indicate that the barrier layer functions to prevent the infiltration of fibrous connective tissue. The MOF crystal layer functions to enhance osteogenesis and angiogenesis in vitro. Using a rat calvarial defect model, the MOF crystals exhibit a sign of osteoinductivity along with blood vessel formation after 8 weeks post-surgery. Strikingly, when assessed in a chick chorioallantoic membrane model, the MOF modified membrane demonstrates a significant angiogenic response, which can be envisaged as its outstanding merits over the commercially Col membrane. Therefore, the MOF crystals represent an exciting biomaterial option, with neovascularization capacity for bone tissue engineering and regenerative medicine.
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http://dx.doi.org/10.1002/adhm.202001369DOI Listing
March 2021

Gene variations in autism spectrum disorder are associated with alteration of gut microbiota, metabolites and cytokines.

Gut Microbes 2021 Jan-Dec;13(1):1-16

State Key Laboratory of Reproductive Medicine, Center of Global Health, Nanjing Medical University, Nanjing, China.

The genetic variations and dysbiosis of gut microbiota are associated with ASD. However, the role of the microbiota in the etiology of ASD in terms of host genetic susceptibility remains unclear. This study aims to systematically explore the interplay between host genetic variation and gut microbiota in ASD children. Whole-exon sequencing was applied to 26 ASD children and 26 matched controls to identify the single nucleotide variations (SNVs) in ASD. Our previous study revealed alteration in gut microbiota and disorder of metabolism activity in ASD for this cohort. Systematic bioinformatic analyses were further performed to identify associations between SNVs and gut microbiota, as well as their metabolites. The ASD SNVs were significantly enriched in genes associated with innate immune response, protein glycosylation process, and retrograde axonal transport. These SNVs were also correlated with the microbiome composition and a broad aspect of microbial functions, especially metabolism. Additionally, the abundance of metabolites involved in the metabolic network of neurotransmitters was inferred to be causally related to specific SNVs and microbes. Furthermore, our data suggested that the interaction of host genetics and gut microbes may play a crucial role in the immune and metabolism homeostasis of ASD. This study may provide valuable clues to investigate the interaction of host genetic variations and gut microbiota in the pathogenesis of ASD.
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http://dx.doi.org/10.1080/19490976.2020.1854967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808426PMC
January 2021

Nanoscale Zeolitic Imidazolate Framework-8 Activator of Canonical MAPK Signaling for Bone Repair.

ACS Appl Mater Interfaces 2021 Jan 23;13(1):97-111. Epub 2020 Dec 23.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.

Zeolitic imidazolate framework-8 (ZIF-8) is an important type of metal organic framework and has found numerous applications in the biomedical field. Our previous studies have demonstrated that nano ZIF-8-based titanium implants could promote osseointegration; however, its osteogenic capacity and the related mechanisms in bone regeneration have not been fully clarified. Presented here is a nanoscale ZIF-8 that could drive rat bone mesenchymal stem cell (rBMSC) differentiation into osteoblasts both in vitro and in vivo, and interestingly, nano ZIF-8 exhibited a better osteogenic effect compared with ionic conditions of Zn at the same concentration of Zn. Moreover, the cellular uptake mechanisms of the nanoparticles were thoroughly clarified. Specifically, nano ZIF-8 could enter the rBMSC cytoplasm probably via caveolae-mediated endocytosis and macropinocytosis. The intracellular and extracellular Zn released from nano ZIF-8 and the receptors involved in the endocytosis may play a role in inducing activation of key osteogenic pathways. Furthermore, through transcriptome sequencing, multiple osteogenic pathways were found to be upregulated, among which nano ZIF-8 primarily phosphorylated ERK, thus activating the canonical mitogen-activated protein kinase pathway and promoting the osteogenesis of rBMSCs. Taken together, this study helps to elucidate the mechanism by which nano ZIF-8 regulates osteogenesis and suggests it to be a potential biomaterial for constructing multifunctional composites in bone tissue engineering.
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http://dx.doi.org/10.1021/acsami.0c15945DOI Listing
January 2021

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases.

Front Cell Dev Biol 2020 26;8:602269. Epub 2020 Nov 26.

Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom.

The bone marrow (BM) vascular niche microenvironments harbor stem and progenitor cells of various lineages. Bone angiogenesis is distinct and involves tissue-specific signals. The nurturing vascular niches in the BM are complex and heterogenous consisting of distinct vascular and perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease. Therefore, this review provides an overview of the current understanding of the BM vascular niches for hematopoietic stem cells and their malfunction during aging, bone loss diseases, arthritis and metastasis.
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http://dx.doi.org/10.3389/fcell.2020.602269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726257PMC
November 2020

3D printing of metal-organic framework incorporated porous scaffolds to promote osteogenic differentiation and bone regeneration.

Nanoscale 2020 Dec;12(48):24437-24449

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China.

Bone substitute biomaterials, whose compositions and structures both play vital roles in bone defect healing, hold promising prospects in the clinical treatment of bone defects. Three-dimensional (3D) printed porous scaffolds incorporating osteoinductive components are considered as ideal bone grafts, because of the accurate control of structure parameters and the capacity to enhance bone tissue regeneration. Our previous studies demonstrated that nanoscale zeolitic imidazolate framework-8 (nanoZIF-8), a subclass of metal organic frameworks (MOFs), presented minimal cytotoxicity, inhibited bacterial activities, and promoted osteogenesis both in vitro and in vivo. However, the application of nanoZIF-8 in the 3D printed scaffold system remains unknown. In this study, nanoZIF-8 was incorporated into composite scaffolds composed of polycaprolactone (PCL) and dicalcium phosphate dihydrate (DCPD) via extrusion-based 3D printing technology. The results revealed that the composite scaffolds possessed increased mechanical strength and exhibited homogeneous structure with highly interconnected macropores. In vitro studies indicated that scaffolds showed biocompatibility to bone mesenchymal stem cells (BMSCs), significantly up-regulated the expression of osteogenesis-related genes and proteins, and facilitated the extracellular matrix mineralization. In vivo results showed that 3D printed porous scaffolds promoted new bone formation and enhanced micro-architecture at the critical defect sites (Φ10 mm) in rabbits, compared with the blank control group. Moreover, composite scaffolds significantly improved calvarial defect healing in comparison with scaffolds without nanoZIF-8 incorporation. In summary, nanoZIF-8 modified 3D printed porous composite scaffolds demonstrated great potential in the treatment of critical-sized bone defects, proving the effectiveness of MOF incorporation in 3D printed composite scaffolds to promote osteogenesis in the field of bone tissue engineering.
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http://dx.doi.org/10.1039/d0nr06297aDOI Listing
December 2020
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