Publications by authors named "Xiaolin Wu"

324 Publications

Cerebroprotein Hydrolysate-I Inhibits Hippocampal Neuronal Apoptosis by Activating PI3K/Akt Signaling Pathway in Vascular Dementia Mice.

Neuropsychiatr Dis Treat 2021 17;17:2359-2368. Epub 2021 Jul 17.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People's Republic of China.

Introduction: Vascular dementia (VaD), one of the brain injuries, is difficult to be cured, so it is important to take active neuroprotective treatment after its occurrence. Many studies have shown that apoptosis serves an important role in VaD occurrence; therefore, inhibition of apoptosis may contribute to the recovery of neurological function after VaD occurrence. Cerebroprotein hydrolysate-I (CH-I), a neuropeptide preparation which consists of several amino acids and small molecular peptides as the main active constituent, is extracted using a method similar to cerebrolysin (CBL) which has neuroprotective and neurotrophic effects.

Methods: In the present study, a VaD model which was constructed using bilateral common carotid artery occlusion (BCCAO) in Kunming mice was applied to examine the neuroprotective effects of CH-I.

Results: The results show that CH-I treatment could attenuate the decrease of learning and memory ability, cell apoptosis in the hippocampal CA1 region and inhibit the activation of caspase-3 and caspase-9 in VaD mice. Furthermore, CH-I treatment could also upregulate Bcl-2 protein levels and activate PI3K and Akt.

Discussion: We speculate that CH-I may induce a neuroprotective effect activating PI3K/Akt signaling pathway in VaD mice.
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http://dx.doi.org/10.2147/NDT.S311760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297406PMC
July 2021

Cerebroprotein hydrolysate-I protects senescence-induced by D-galactose in PC12 cells and mice.

Food Sci Nutr 2021 Jul 17;9(7):3722-3731. Epub 2021 May 17.

Institute of Cerebrovascular Diseases Taishan Scholars Construction Project Excellent Innovative Team of Shandong Province Medical Research Center The Affiliated Hospital of Qingdao University Qingdao China.

Cerebroprotein hydrolysate-I (CH-I),a mixture of peptides extracted from porcine brain tissue,has shown a neuroprotective effect, but its role in brain senescence is unclear. In the present study, we established a senescence model of PC12 cells and mice to investigate the effect of CH-I on brain senescence via JAK2/STAT3 pathway. The results showed that CH-I could improve cell viability, inhibit the apoptosis of cells, and reduce the senescence-positive cells induced by D-galactose. In , CH-I improved the learning ability and memory of aging mice, reduced neuronal damage in mice hippocampus. Mechanism studies showed that CH-I could adjust BDNF protein expressions, activate JAK2/STAT3 pathway, and finally enhance telomerase activity. All these findings indicated that CH-I showed a neuroprotective effect against brain senescence. These results might provide further reference and support for the application of CH-I in delaying aging.
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http://dx.doi.org/10.1002/fsn3.2333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269606PMC
July 2021

The BRD4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics.

Cancer Sci 2021 Jul 12. Epub 2021 Jul 12.

Department of Otorhinolaryngology-Head and Neck Surgery, China-Japan Union Hospital, Jilin University, Changchun, China.

Although the role of bromodomain-containing protein 4 (BRD4) in ovarian cancer, pancreatic cancer, multiple lymphoma and many other diseases is well known, its function in cutaneous melanoma is only partially understood. Here, our results show that the BRD4 inhibitor JQ1 promotes the apoptosis of B16 melanoma cells by altering mitochondrial dynamics, thereby inducing mitochondrial dysfunction and increasing oxidative stress. We found that treatment of B16 cells with different concentrations of JQ1 (125 nM or 250 nM), significantly downregulated the expression of protein subunits involved in mitochondrial respiratory chain complexes I, III, IV, and V, increased reactive oxygen species (ROS), induced energy metabolism dysfunction, significantly enhanced apoptosis and activated the mitochondrial apoptosis pathway. At the same time, JQ1 inhibited the activation of AMP-activated protein kinase (AMPK), a metabolic energy sensor. In addition, we found that the mRNA and protein levels of mitochondrial dynamin-related protein 1 (DRP1) increased, whereas the levels of mitochondrial fusion protein 1 (MFN1) and optic atrophy protein 1 (OPA1) decreased. Mechanistically, we determined that JQ1 inhibited the expression of c-Myc and altered mitochondrial dynamics, eventually leading to changes in the mitochondrial function, metabolism, and apoptosis of B16 melanoma cells.
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http://dx.doi.org/10.1111/cas.15061DOI Listing
July 2021

Tracking HIV-1-Infected Cell Clones Using Integration Site-Specific qPCR.

Viruses 2021 Jun 25;13(7). Epub 2021 Jun 25.

Department of Medicine, University of Pittsburgh, 3550 Terrace Street, Scaife Hall-818, Pittsburgh, PA 15261, USA.

Efforts to cure HIV-1 infection require better quantification of the HIV-1 reservoir, particularly the clones of cells harboring replication-competent (intact) proviruses, termed . The digital droplet PCR assays commonly used to quantify intact proviruses do not differentiate among specific repliclones, thus the dynamics of repliclones are not well defined. The major challenge in tracking repliclones is the relative rarity of the cells carrying specific intact proviruses. To date, detection and accurate quantification of repliclones requires in-depth integration site sequencing. Here, we describe a simplified workflow using integration site-specific qPCR (IS-qPCR) to determine the frequencies of the proviruses integrated in individual repliclones. We designed IS-qPCR to determine the frequencies of repliclones and clones of cells that carry defective proviruses in samples from three donors. Comparing the results of IS-qPCR with deep integration site sequencing data showed that the two methods yielded concordant estimates of clone frequencies ( = 0.838). IS-qPCR is a potentially valuable tool that can be applied to multiple samples and cell types over time to measure the dynamics of individual repliclones and the efficacy of treatments designed to eliminate them.
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http://dx.doi.org/10.3390/v13071235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310066PMC
June 2021

CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice.

Cell Rep Med 2021 Jun 1;2(6):100297. Epub 2021 Jun 1.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Targeting solid tumors must overcome several major obstacles, in particular, the identification of elusive tumor-specific antigens. Here, we devise a strategy to help identify tumor-specific epitopes. Glypican 2 (GPC2) is overexpressed in neuroblastoma. Using RNA sequencing (RNA-seq) analysis, we show that exon 3 and exons 7-10 of GPC2 are expressed in cancer but are minimally expressed in normal tissues. Accordingly, we discover a monoclonal antibody (CT3) that binds exons 3 and 10 and visualize the complex structure of CT3 and GPC2 by electron microscopy. The potential of this approach is exemplified by designing CT3-derived chimeric antigen receptor (CAR) T cells that regress neuroblastoma in mice. Genomic sequencing of T cells recovered from mice reveals the CAR integration sites that may contribute to CAR T cell proliferation and persistence. These studies demonstrate how RNA-seq data can be exploited to help identify tumor-associated exons that can be targeted by CAR T cell therapies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233664PMC
June 2021

Exosomal MATN3 of Urine-Derived Stem Cells Ameliorates Intervertebral Disc Degeneration by Antisenescence Effects and Promotes NPC Proliferation and ECM Synthesis by Activating TGF-.

Oxid Med Cell Longev 2021 27;2021:5542241. Epub 2021 May 27.

Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China 266003.

Objective: Low back pain (LBP) is one of the top three causes of disability in developed countries, and intervertebral disc degeneration (IDD) is a major contributor to LBP. In the process of IDD, there is a gradual decrease in nucleus pulposus cells (NPCs) and extracellular matrix (ECM). Exosomes are important exocrine mediators of stem cells that can act directly on cells for tissue repair and regeneration. In this study, we determined the antisenescence, cell proliferation promotion, and ECM modulation effects of human urine-derived stem cell (USC) exosomes (USC-exos) on degenerated intervertebral discs and explored the underlying mechanism.

Methods And Materials: USCs were identified by multipotent differentiation and flow cytometry for mesenchymal stem cell- (MSC-) specific surface protein markers. USC-exos were isolated from the conditioned medium of USCs by ultracentrifugation and then analyzed by transmission electron microscopy (TEM), particle size analysis, and western blotting (WB) for exosome marker proteins. The effects of USC-exos on NPC proliferation and ECM synthesis were assessed by Cell Counting Kit-8 (CCK-8), WB, and immunofluorescence (IF) analyses. The protein differences between normal and degenerative intervertebral discs were mined, and the temporal and spatial variations in matrilin-3 (MATN3) content were determined by WB and IF in the intervertebral disc tissues. The candidate molecules that mediated the function of USC-exos were screened out and confirmed by multiple assays. Meanwhile, the mechanism underlying the candidate protein in USC-exos-induced cell proliferation and regulation of ECM synthesis promoting the activities of NPCs was explored. In addition, the effects of USC-exos on ameliorating intervertebral disc degeneration (IVD) in mice were examined by assessing computed tomography (CT), magnetic resonance imaging (MRI), and histological analyses.

Results: The flow cytometry results showed that USCs were positive for CD29, CD44, and CD73, which are USC surface-specific markers, but negative for CD34 and CD45. In addition, USCs showed osteogenic, adipogenic, and chondrogenic differentiation potential. USC-exos exhibited a cup-shaped morphology, with a mean diameter of 49.7 ± 7.3 nm, and were positive for CD63 and TSG101 and negative for calnexin. USC-exos could promote NPC proliferation and ECM synthesis. The protein content of the matrilin family was significantly reduced in degenerative intervertebral discs, and the decrease in MATN3 was the most significant. USC-exos were found to be rich in MATN3 protein, and exosomal MATN3 was required for USC-exos-induced promotion of NPC proliferation and ECM synthesis, as well as alleviation of intervertebral disc degeneration in IVD rats. In addition, the effects of MATN3 in USC-exos were demonstrated to be achieved by activating TGF-, which elevated the phosphorylation level of SMAD and AKT.

Conclusions: Our study suggests that reduced MATN3 can be considered a characteristic of intervertebral disc degeneration. USC-exos may represent a potentially effective agent for alleviating intervertebral disc degeneration by promoting NPC proliferation and ECM synthesis by transferring the MATN3 protein.
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http://dx.doi.org/10.1155/2021/5542241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175180PMC
May 2021

Global status of dioxin emission and China's role in reducing the emission.

J Hazard Mater 2021 May 31;418:126265. Epub 2021 May 31.

Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.

The global status of dioxin emissions across 150 countries/regions were compiled in this study. China, the major emitter of dioxin and the largest developing country, was chosen as an example to illustrate its emission reductions. The global dioxin emissions were about 97.0 kg TEQ/year, Asia and Africa emitted the most dioxins among the continents. Globally, open burning processes were the most important sources of dioxins. Dioxin emissions in developed countries have remained at low and stable level, while those in developing countries have remained at relatively high level or have continued to increase in recent years. It can be speculated that the global dioxin emissions will increase first and then decrease in the future. Chinese dioxin emissions were stable around 9 kg toxic equivalent (TEQ) in recent years, while 17 subcategories are the key sources of dioxin control in the future. Moreover, according to analysis toward China's dioxin emission trend and sources, there is a large space for dioxins reduction in industries such as metal production, waste incineration and disposal. The results indicated that there is at least 30-70% of reduction scope in China based on three scenarios, and this will reduce the world's annual dioxin emissions by 2.7-6.8%.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126265DOI Listing
May 2021

CRISPR-targeted MAGT1 insertion restores XMEN patient hematopoietic stem cells and lymphocytes.

Blood 2021 Jun 4. Epub 2021 Jun 4.

National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, United States.

'X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus-infection and N-linked glycosylation defect' (XMEN) disease is a recently described primary immunodeficiency marked by defective T and Natural Killer (NK) cells. Potentially curative hematopoietic stem cell transplant is associated with high mortality rates. We sought to develop an ex vivo targeted gene therapy approach for XMEN patients using CRISPR/Cas9/adeno-associated vector (AAV) to insert a therapeutic MAGT1 gene at the constitutive locus under the regulation of the endogenous promoter. Clinical translation of CRISPR/Cas9/AAV-targeted gene editing (GE) is hampered by low engraftable GE hematopoietic stem/progenitor cells (HSPCs). Here, we optimized GE conditions by transient enhancement of homology-directed repair while suppressing AAV-associated DNA damage response to achieve highly efficient (>60%) genetic correction in engrafting XMEN HSPCs in transplanted mice. Restored MAGT1-glycosylation function in human NK and CD8+ T cells restored NKG2D expression and function in XMEN lymphocytes for potential treatment of infections, and corrected HSPCs for long-term gene therapy, thus offering two efficient therapeutic options for XMEN poised for clinical translation.
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http://dx.doi.org/10.1182/blood.2021011192DOI Listing
June 2021

Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification.

Cancers (Basel) 2021 May 16;13(10). Epub 2021 May 16.

Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne, 50937 Cologne, Germany.

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.
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http://dx.doi.org/10.3390/cancers13102403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156851PMC
May 2021

Digital CRISPR-based method for the rapid detection and absolute quantification of nucleic acids.

Biomaterials 2021 07 11;274:120876. Epub 2021 May 11.

Critical Analytics for Manufacturing Personalized Medicine Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 138602, Singapore; Institute of Bioengineering and Bioimaging, A*STAR, The Nanos, #04-01, 31, Biopolis Way, 138669, Singapore; Mechanobiology Institute, National University of Singapore, T-Lab, #05-01, 5A Engineering Drive 1, 117411, Singapore; Department of Physiology & the Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, 117593, Singapore. Electronic address:

Rapid diagnostics of adventitious agents in biopharmaceutical/cell manufacturing release testing and the fight against viral infection have become critical. Quantitative real-time PCR and CRISPR-based methods rapidly detect DNA/RNA in 1 h but suffer from inter-site variability. Absolute quantification of DNA/RNA by methods such as digital PCR reduce this variability but are currently too slow for wider application. Here, we report a RApid DIgital Crispr Approach (RADICA) for absolute quantification of nucleic acids in 40-60 min. Using SARS-CoV-2 as a proof-of-concept target, RADICA allows for absolute quantification with a linear dynamic range of 0.6-2027 copies/μL (R value > 0.99), high accuracy and low variability, no cross-reactivity to similar targets, and high tolerance to human background DNA. RADICA's versatility is validated against other targets such as Epstein-Barr virus (EBV) from human B cells and patients' serum. RADICA can accurately detect and absolutely quantify EBV DNA with similar dynamic range of 0.5-2100 copies/μL (R value > 0.98) in 1 h without thermal cycling, providing a 4-fold faster alternative to digital PCR-based detection. RADICA therefore enables rapid and sensitive absolute quantification of nucleic acids which can be widely applied across clinical, research, and biomanufacturing areas.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120876DOI Listing
July 2021

Marginal sealing around integral bilayer scaffolds for repairing osteochondral defects based on photocurable silk hydrogels.

Bioact Mater 2021 Nov 18;6(11):3976-3986. Epub 2021 Apr 18.

Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.

Osteochondral repair remains a major challenge in current clinical practice despite significant advances in tissue engineering. In particular, the lateral integration of neocartilage into surrounding native cartilage is a difficult and inadequately addressed problem that determines the success of tissue repair. Here, a novel design of an integral bilayer scaffold combined with a photocurable silk sealant for osteochondral repair is reported. First, we fabricated a bilayer silk scaffold with a cartilage layer resembling native cartilage in surface morphology and mechanical strength and a BMP-2-loaded porous subchondral bone layer that facilitated the osteogenic differentiation of BMSCs. Second, a TGF-β3-loaded methacrylated silk fibroin sealant (Sil-MA) exhibiting biocompatibility and good adhesive properties was developed and confirmed to promote chondrocyte migration and differentiation. Importantly, this TGF-β3-loaded Sil-MA hydrogel provided a bridge between the cartilage layer of the scaffold and the surrounding cartilage and then guided new cartilage to grow towards and replace the degraded cartilage layer from the surrounding native cartilage in the early stage of knee repair. Thus, osteochondral regeneration and superior lateral integration were achieved in vivo by using this composite. These results demonstrate that the new approach of marginal sealing around the cartilage layer of bilayer scaffolds with Sil-MA hydrogel has tremendous potential for clinical use in osteochondral regeneration.
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http://dx.doi.org/10.1016/j.bioactmat.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081879PMC
November 2021

Function of Small Peptides During Male-Female Crosstalk in Plants.

Front Plant Sci 2021 23;12:671196. Epub 2021 Apr 23.

College of Life Sciences, National Key Laboratory of Wheat and Maize Crop Science, Henan Agricultural University, Zhengzhou, China.

Plant peptides secreted as signal molecular to trigger cell-to-cell signaling are indispensable for plant growth and development. Successful sexual reproduction in plants requires extensive communication between male and female gametophytes, their gametes, and with the surrounding sporophytic tissues. In the past decade, it has been well-documented that small peptides participate in many important reproductive processes such as self-incompatibility, pollen tube growth, pollen tube guidance, and gamete interaction. Here, we provide a comprehensive overview of the peptides regulating the processes of male-female crosstalk in plant, aiming at systematizing the knowledge on the sexual reproduction, and signaling of plant peptides in future.
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http://dx.doi.org/10.3389/fpls.2021.671196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102694PMC
April 2021

A rapidly magnetically assembled stem cell microtissue with "hamburger" architecture and enhanced vascularization capacity.

Bioact Mater 2021 Nov 7;6(11):3756-3765. Epub 2021 Apr 7.

Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.

With the development of magnetic manipulation technology based on magnetic nanoparticles (MNPs), scaffold-free microtissues can be constructed utilizing the magnetic attraction of MNP-labeled cells. The rapid construction and vascularization of microtissues with complex hierarchical architectures are of great importance to the viability and function of stem cell microtissues. Endothelial cells are indispensable for the formation of blood vessels and can be used in the prevascularization of engineered tissue constructs. Herein, safe and rapid magnetic labeling of cells was achieved by incubation with MNPs for 1 h, and ultrathick scaffold-free microtissues with different sophisticated architectures were rapidly assembled, layer by layer, in 5 min intervals. The transplantation results showed that in a stem cell microtissue with trisection architecture, the two separated human umbilical vein endothelial cell (HUVEC) layers would spontaneously extend to the stem cell layers and connect with each other to form a spatial network of functional blood vessels, which anastomosed with the host vasculature. The "hamburger" architecture of stem cell microtissues with separated HUVEC layers could promote vascularization and stem cell survival. This study will contribute to the construction and application of structural and functional tissues or organs in the future.
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http://dx.doi.org/10.1016/j.bioactmat.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044908PMC
November 2021

Magnesium Ammonium Phosphate Composite Cell-Laden Hydrogel Promotes Osteogenesis and Angiogenesis .

ACS Omega 2021 Apr 2;6(14):9449-9459. Epub 2021 Apr 2.

Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.

Injectable hydrogels provide an effective strategy for minimally invasive treatment on irregular bony defects in the maxillofacial region. To improve the osteoinduction of gelatin methacrylate (GelMA), we fabricated a three-dimensional (3D) culture system based on the incorporation of magnesium ammonium phosphate hexahydrate (struvite) into GelMA. The optimal concentration of struvite was investigated using the struvite extracts, and 500 μg mL was found to be the most suitable concentration for the osteogenesis of dental pulp stem cells (DPSCs) and angiogenesis of human umbilical vein endothelial cells (HUVECs). We prepared the GelMA composite (MgP) with 500 μg mL struvite. Struvite did not affect the cross-linking of GelMA and released Mg during degradation. The cell delivery system using MgP improved the laden-cell viability, upregulated the expression of osteogenic and angiogenic-differentiation-related genes, and promoted cell migration. Overall, the modifications made to the GelMA in this study improved osteoinduction and demonstrated great potential for application in vascularized bone tissue regeneration.
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http://dx.doi.org/10.1021/acsomega.0c06083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047646PMC
April 2021

Spatial distributions and sources of PAHs in soil in chemical industry parks in the Yangtze River Delta, China.

Environ Pollut 2021 Aug 10;283:117121. Epub 2021 Apr 10.

Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address:

The Yangtze River Delta (YRD) is one of the fastest developing areas in eastern China and contains many chemical industry parks. The profiles and sources of polycyclic aromatic hydrocarbons (PAHs) in soil in chemical industry parks and surrounding areas in the YRD were investigated by analyzing soil samples (n = 64) were collected in the YRD and Rudong chemical park (RD), a typical chemical park in the Yangtze River Delta. The total concentrations of 19 PAHs in the YRD soil samples were 16.3-4694 ng g (mean 688 ng g), and the total concentrations of PAHs in RD were 21.6-246 ng g (mean 75.4 ng g). The PAHs in soil in YRD were dominated by four-ring and five-ring PAHs, and the PAHs in RD were dominated by two-ring and three-ring PAHs. It suggested that PAHs may have been supplied to soil in YRD predominantly through coal combustion and vehicle emissions, PAHs in the soil of RD may be due to the volatilization and leakage of chemical raw material. According to the different distribution characteristics of PAHs, the ratio (1.5) of (2 + 3) rings/4 rings was proposed to identify the chemical source of PAHs. The PAH isomer ratios and principal component analysis/multiple linear regression (PCA/MLRA) results indicated that PAHs concentrations in soil in the YRD and RD are mainly supplied by industrial and traffic emissions. Incremental lifetime cancer risks (ILCRs) indicated that PAHs in soil pose negligible cancer risks to children and adults, but much stronger risks to children than adults.
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http://dx.doi.org/10.1016/j.envpol.2021.117121DOI Listing
August 2021

Effects of air pollution control devices on volatile organic compounds reduction in coal-fired power plants.

Sci Total Environ 2021 Aug 29;782:146828. Epub 2021 Mar 29.

Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Air pollution control devices (APCDs) have been fitted to many coal-fired power plants to decrease the impacts of pollutants generated during coal combustion. APCDs remove conventional pollutants but also decrease volatile organic compound (VOC) emissions. In this study, flue gas samples were collected from different points in seven typical coal-fired power and two industrial boilers, and the VOC concentrations in the flue gas samples were determined by gas chromatography-mass spectrometry (GC-MS). Selective catalytic reduction (SCR) systems and electrostatic precipitators (ESP) can synergistically remove VOCs, the mean removal rate of VOCs by ESP was 42% ± 9%. This was caused by the catalyst in SCR systems and the condensation process in the ESP. Wet flue gas desulfurization (WFGD) affected different VOCs in different ways, increasing the halogenated hydrocarbons and aromatic hydrocarbons concentrations but decreasing the oxygenated VOCs concentrations by 12%. Wet electrostatic precipitators (WESP) increased VOC emissions. By calculating Ozone formation potential (OFP), aromatic hydrocarbons are important contributors to ozone production. The emission factor of the power plant was 0.69 g/GJ, and the Chinese annual emission was about 1.2 × 10 t. VOCs emissions in different regions were affected by factors such as the economy and population. VOC emissions can be decreased by using the most appropriate unit load and improving the VOC removal efficiencies of the APCDs.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146828DOI Listing
August 2021

Early Emergence and Long-Term Persistence of HIV-Infected T-Cell Clones in Children.

mBio 2021 04 8;12(2). Epub 2021 Apr 8.

HIV Dynamics and Replication Program, CCR, National Cancer Institute, Frederick, Maryland, USA.

Little is known about the emergence and persistence of human immunodeficiency virus (HIV)-infected T-cell clones in perinatally infected children. We analyzed peripheral blood mononuclear cells (PBMCs) for clonal expansion in 11 children who initiated antiretroviral therapy (ART) between 1.8 and 17.4 months of age and with viremia suppressed for 6 to 9 years. We obtained 8,662 HIV type 1 (HIV-1) integration sites from pre-ART samples and 1,861 sites from on-ART samples. Expanded clones of infected cells were detected pre-ART in 10/11 children. In 8 children, infected cell clones detected pre-ART persisted for 6 to 9 years on ART. A comparison of integration sites in the samples obtained on ART with healthy donor PBMCs infected showed selection for cells with proviruses integrated in and Our analyses indicate that, despite marked differences in T-cell composition and dynamics between children and adults, HIV-infected cell clones are established early in children, persist for up to 9 years on ART, and can be driven by proviral integration in proto-oncogenes. HIV-1 integrates its genome into the DNA of host cells. Consequently, HIV-1 genomes are copied with the host cell DNA during cellular division. Pediatric immune systems differ significantly from adults, consisting primarily of naive T cells, which have low expression of the HIV-1 coreceptor CCR5. This difference may result in variances in the number or size of infected cell clones that persist in children on ART. Here, we provide the most extensive analysis of the integration landscape of HIV-1 in children. We found that, despite the largely naive cell populations in neonatal immune systems, patterns of HIV-1 integration and the size of infected cell clones are as large and widespread as those in adults. Furthermore, selection for integration events in proto-oncogenes were observed in children despite early ART. If such cell clones persist for the life span of these individuals, there may be long-term consequences that have yet to be realized.
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http://dx.doi.org/10.1128/mBio.00568-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092253PMC
April 2021

Integration in oncogenes plays only a minor role in determining the in vivo distribution of HIV integration sites before or during suppressive antiretroviral therapy.

PLoS Pathog 2021 04 7;17(4):e1009141. Epub 2021 Apr 7.

National Cancer Institute, Frederick, Maryland, United States of America.

HIV persists during antiretroviral therapy (ART) as integrated proviruses in cells descended from a small fraction of the CD4+ T cells infected prior to the initiation of ART. To better understand what controls HIV persistence and the distribution of integration sites (IS), we compared about 15,000 and 54,000 IS from individuals pre-ART and on ART, respectively, with approximately 395,000 IS from PBMC infected in vitro. The distribution of IS in vivo is quite similar to the distribution in PBMC, but modified by selection against proviruses in expressed genes, by selection for proviruses integrated into one of 7 specific genes, and by clonal expansion. Clones in which a provirus integrated in an oncogene contributed to cell survival comprised only a small fraction of the clones persisting in on ART. Mechanisms that do not involve the provirus, or its location in the host genome, are more important in determining which clones expand and persist.
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http://dx.doi.org/10.1371/journal.ppat.1009141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055010PMC
April 2021

Enhancing the oxidative stability of algal oil emulsions by adding sweet orange oil: Effect of essential oil concentration.

Food Chem 2021 Sep 8;355:129508. Epub 2021 Mar 8.

State Key Laboratory of Food Science and Technology, Nanchang University, No. 235 Nanjing East Road, Nanchang 330047, Jiangxi, China; National R&D Center for Freshwater Fish Processing, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.

The effects of sweet orange essential oil (SOEO) concentration (0-12.5% of oil phase) on the physical stability, oxidative stability, and interfacial composition of algal oil-in-water emulsions containing sodium caseinate-coated oil droplets was examined. SOEO addition had no influence on the microstructure and physical stability of the algal oil emulsions. The addition of SOEO enhanced the oxidation stability of algal oil emulsion. As an example, the values of algal oil emulsions with 0 and 10% SOEO were 198 and 100 mmol/kg algal oil after 16 days of accelerated oxidation, respectively. The absorbed protein level was higher in the algal oil emulsion containing 10% SOEO (70%) than in 0% SOEO (57%). This result suggested that the presence of SOEO enhanced the interfacial thickness, possibly by interacting with the casein molecules. A thicker protein layer may have helped to retard the oxidation of the omega-3 oils inside lipid droplets.
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http://dx.doi.org/10.1016/j.foodchem.2021.129508DOI Listing
September 2021

Multiple genetic variations of chronic rhinosinusitis with nasal polyps are associated with respiratory parameters in men with obstructive sleep apnea.

Sleep Breath 2021 Mar 26. Epub 2021 Mar 26.

Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, People's Republic of China.

Purpose: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have a higher risk of obstructive sleep apnea (OSA). However, the relationship between CRSwNP and OSA remains unclear. The aim of this research study was to evaluate the association of multiple single nucleotide polymorphism (SNP) variations in CRSwNP with sleep- and breath-related parameters in men with OSA.

Methods: We included eight CRSwNP SNPs in 2320 participants after strict screening. For each participant, the genetic risk score (GRS) was calculated based on the cumulative effect of multiple genetic variants of CRSwNP. A bivariate correlation analysis was used to assess the relationship between CRSwNP genetic polymorphisms and polysomnography parameters in men with OSA. Logistic regression analyses were used to assess the relationship between the risk of OSA and CRSwNP genetic polymorphisms.

Results: In moderate OSA, rs28383314 was related to the oxygen desaturation index, and rs4807532 was positively associated with the microarousal index (r = 0.09, P = 0.03 and r = 0.11, P = 0.01, respectively). The CRSwNP GRS was positively correlated with the oxygen desaturation index and cumulative time percentage with SpO < 90% in moderate OSA (r = 0.13, P < 0.001 and r = 0.1, P = 0.01, respectively). There was no association between the CRSwNP GRS and the risk of OSA (OR = 1.007; 95% CI, 0.973-1.042; P = 0.702).

Conclusion: In men with moderate OSA, single CRSwNP genetic variations correlated with sleep-related parameters, and the cumulative effects of CRSwNP genetic variations were associated with the hypoxic index. CRSwNP may be a predisposing condition for sleep disorders in men with moderate OSA.
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http://dx.doi.org/10.1007/s11325-021-02356-6DOI Listing
March 2021

Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR/Cas9 with 53BP1 inhibition for enhanced homology-directed repair.

Gene Ther 2021 Jun 12;28(6):373-390. Epub 2021 Mar 12.

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

X-linked chronic granulomatous disease is an immunodeficiency characterized by defective production of microbicidal reactive oxygen species (ROS) by phagocytes. Causative mutations occur throughout the 13 exons and splice sites of the CYBB gene, resulting in loss of gp91 protein. Here we report gene correction by homology-directed repair in patient hematopoietic stem/progenitor cells (HSPCs) using CRISPR/Cas9 for targeted insertion of CYBB exon 1-13 or 2-13 cDNAs from adeno-associated virus donors at endogenous CYBB exon 1 or exon 2 sites. Targeted insertion of exon 1-13 cDNA did not restore physiologic gp91 levels, consistent with a requirement for intron 1 in CYBB expression. However, insertion of exon 2-13 cDNA fully restored gp91 and ROS production upon phagocyte differentiation. Addition of a woodchuck hepatitis virus post-transcriptional regulatory element did not further enhance gp91 expression in exon 2-13 corrected cells, indicating that retention of intron 1 was sufficient for optimal CYBB expression. Targeted correction was increased ~1.5-fold using i53 mRNA to transiently inhibit nonhomologous end joining. Following engraftment in NSG mice, corrected HSPCs generated phagocytes with restored gp91 and ROS production. Our findings demonstrate the utility of tailoring donor design and targeting strategies to retain regulatory elements needed for optimal expression of the target gene.
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http://dx.doi.org/10.1038/s41434-021-00251-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232036PMC
June 2021

The Associations Between Sleep Architecture and Metabolic Parameters in Patients With Obstructive Sleep Apnea: A Hospital-Based Cohort Study.

Front Neurol 2021 10;12:606031. Epub 2021 Feb 10.

Department of Otolaryngology-Head & Neck Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.

The associations between objective sleep architecture and metabolic parameters have been rarely studied in patients with obstructive sleep apnea (OSA). Here, we evaluated the associations between objective sleep measures derived polysomnography (PSG) and metabolic parameters. A total of 2,308 subjects with suspected OSA were included. We measured common metabolic parameters such as body mass index (BMI) and glucose, insulin, blood pressure, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels. All subjects underwent full-night PSG. PSG sleep parameters included total sleep time (TST), time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep, sleep efficiency, and the microarousal index (MAI). The TST correlated with the BMI, glucose level, and systolic blood pressure. The SWS/TST ratio correlated with BMI and glucose, TC, and TG levels. The REM/TST ratio correlated with BMI, glucose, insulin, and TG levels, and diastolic blood pressure. We found significant relationships between sleep efficiency and BMI, glucose levels, and TG levels. The MAI was significantly correlated with all metabolic parameters. After adjustment for age, gender, smoking status, alcohol use, apnea hypopnea index, and oxygen desaturation index (ODI), multiple linear regression analysis showed that the MAI was independently associated with glucose level, TC, HDL, and LDL. REM/TST ratio was positively associated with diastolic blood pressure but negatively associated with glucose metabolism. Though some independent correlation between sleep and metabolic parameters was confirmed, only weak associations were observed, suggesting a clinically negligible influence of sleep structure. Further prospective studies are warranted to confirm our findings.
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http://dx.doi.org/10.3389/fneur.2021.606031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919522PMC
February 2021

Endoplasmic reticulum stress and autophagy are involved in adipocyte-induced fibrosis in hepatic stellate cells.

Mol Cell Biochem 2021 Jun 26;476(6):2527-2538. Epub 2021 Feb 26.

Institute of Cerebrovascular Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.

Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF β/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.
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http://dx.doi.org/10.1007/s11010-020-03990-6DOI Listing
June 2021

Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem/progenitor cells.

Blood 2021 May;137(19):2598-2608

Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Lentivector gene therapy for X-linked chronic granulomatous disease (X-CGD) has proven to be a viable approach, but random vector integration and subnormal protein production from exogenous promoters in transduced cells remain concerning for long-term safety and efficacy. A previous genome editing-based approach using Streptococcus pyogenes Cas9 mRNA and an oligodeoxynucleotide donor to repair genetic mutations showed the capability to restore physiological protein expression but lacked sufficient efficiency in quiescent CD34+ hematopoietic cells for clinical translation. Here, we report that transient inhibition of p53-binding protein 1 (53BP1) significantly increased (2.3-fold) long-term homology-directed repair to achieve highly efficient (80% gp91phox+ cells compared with healthy donor control subjects) long-term correction of X-CGD CD34+ cells.
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http://dx.doi.org/10.1182/blood.2020008503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120141PMC
May 2021

Tumor suppressive microRNA-485-5p targets PRRX1 in human skin melanoma cells, regulating epithelial-mesenchymal transition and apoptosis.

Cell Biol Int 2021 Jul 18;45(7):1404-1414. Epub 2021 May 18.

School of Traditional Chinese Medicine, Jilin Agriculture University, Changchun, Jilin, PR China.

Melanoma is one of the most aggressive skin cancers. Existing evidence has reported the aberrant expression of microRNAs (miRNAs) in melanoma, but their putative targets and underlying downstream effects remain to be further understood. Herein, we explored the suppressive role of miR-485-5p in melanoma progression. Initial bioinformatics analyses showed that the PRRX1 gene was differentially expressed in melanoma, while miR-485-5p was predicted to be a potential regulatory miRNA binding to PRRX1 mRNA. We confirmed that PRRX1 was upregulated, while miR-485-5p was downregulated in human melanoma samples compared with adjacent normal skin tissues. We then showed that PRRX1 was a target gene of miR-485-5p by dual-luciferase reporter gene assay. Moreover, a reduction in the expression of PRRX1 and downregulation of important proteins of the transforming growth factor-beta (TGFβ) signaling pathway was observed after miR-485-5p overexpression. Furthermore, miR-485-5p overexpression or PRRX1 knockdown suppressed epithelial-mesenchymal transition, cell viability, migration, and invasion, and promoted cell apoptosis in melanoma cells. Our study demonstrates the tumor-suppressive functions of miR-485-5p in the development of human melanoma, providing a potential target for therapy.
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http://dx.doi.org/10.1002/cbin.11575DOI Listing
July 2021

Verification of CRISPR editing and finding transgenic inserts by Xdrop indirect sequence capture followed by short- and long-read sequencing.

Methods 2021 07 12;191:68-77. Epub 2021 Feb 12.

Samplix ApS, Mileparken 28, Herlev, Denmark. Electronic address:

Validation of CRISPR-Cas9 editing typically explores the immediate vicinity of the gene editing site and distal off-target sequences, which has led to the conclusion that CRISPR-Cas9 editing is very specific. However, an increasing number of studies suggest that on-target unintended editing events like deletions and insertions are relatively frequent but unfortunately often missed in the validation of CRISPR-Cas9 editing. The deletions may be several kilobases-long and only affect one allele. The gold standard in molecular validation of gene editing is direct sequencing of relatively short PCR amplicons. This approach allows the detection of small editing events but fails in detecting large rearrangements, in particular when only one allele is affected. Detection of large rearrangements requires that an extended region is analyzed and the characterization of events may benefit from long-read sequencing. Here we implemented Xdrop™, a new microfluidic technology that allows targeted enrichment of long regions (~100 kb) using just a single standard PCR primer set. Sequencing of the enriched CRISPR-Cas9 gene-edited region in four cell lines on long- and short-read sequencing platforms unravelled unknown and unintended genome editing events. The analysis revealed accidental kilobases-large insertions in three of the cell lines, which remained undetected using standard procedures. We also applied the targeted enrichment approach to identify the integration site of a transgene in a mouse line. The results demonstrate the potential of this technology in gene editing validation as well as in more classic transgenics.
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http://dx.doi.org/10.1016/j.ymeth.2021.02.003DOI Listing
July 2021

Exosomes Derived from Human Urine-Derived Stem Cells Inhibit Intervertebral Disc Degeneration by Ameliorating Endoplasmic Reticulum Stress.

Oxid Med Cell Longev 2020 7;2020:6697577. Epub 2020 Dec 7.

Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China 266003.

Objective: This study is aimed at determining the effects of human urine-derived stem cell-derived exosomes (USCs-exos) on pressure-induced nucleus pulposus cell (NPC) apoptosis and intervertebral disc degeneration (IDD) and on the ERK and AKT signaling pathways.

Methods: The NPCs were obtained from patients with herniated lumbar discs. Western blot analysis (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine endoplasmic reticulum (ER) stress levels of NPCs under stress. Human USCs were identified using an inverted microscope, three-line differentiation experiments, and flow cytometry. A transmission microscope, nanoparticle size analysis, and WB procedures were used to identify the extracted exosomes and observe NPC uptake. A control group, a 48 h group, and a USCs-exos group were established. The control group was untreated, and the 48 h group was pressure-trained for 48 h, while the USCs-exos group was pressure-trained for 48 h and treated with USCs-exos. WB, qRT-PCR, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis were used to determine the ER stress levels in stress conditions and after exosomal treatment. The AKT and ERK pathways were partially detected. Magnetic Resonance Imaging (MRI) and computed tomography (CT) were used to evaluate cell degeneration while exosomal effects on the intervertebral disc (IVD) tissue were determined by hematoxylin and eosin (HE) staining, Safranin O-fast green staining, immunohistochemical staining (IHC), nuclear magnetic resonance (NMR), spectrometric detection, and total correlation spectroscopy (TOCSY). IVD metabolites were also identified and quantified.

Results: After pressure culture, ER stress markers (GRP78 and C/EBP homologous protein (CHOP)) in the NPCs were significantly elevated with time ( < 0.05). Human USCs are short and spindle-shaped. They can successfully undergo osteogenic, adipogenic, and chondrogenic differentiation. In this study, these stem cells were found to be positive for CD29, CD44, and CD73. The exosomes were centrally located with a diameter of 50-100 nm. CD63 and Tsg101 were highly expressed while the expression of Calnexin was suppressed. The exosomes can be ingested by NPCs. USCs-exos significantly improved ER stress responses and inhibited excessive activation of the unfolded protein response (UPR) as well as cell apoptosis and disc degeneration through the AKT and ERK signaling pathways ( < 0.05).

Conclusion: Through the AKT and ERK signaling pathways, USCs-exos significantly inhibit ER stress-induced cell apoptosis and IDD under pressure conditions. It is, therefore, a viable therapeutic strategy.
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http://dx.doi.org/10.1155/2020/6697577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787770PMC
December 2020

The Translation from Bioactive Ion Concentration Screening to Application for Preventing Peri-implantitis.

ACS Appl Mater Interfaces 2021 Feb 19;13(4):5782-5794. Epub 2021 Jan 19.

Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai 200011, China.

Peri-implantitis is a typical pathological condition characterized by the destructive inflammation in the soft tissue and the progressive loss of supporting bones. As the current effective treatments and preventive measures are inconsistent and unpredictable, the use of biomaterials as carriers of bioactive ion coatings is a promising approach. However, the translation from lab to large-scale production and clinical applications is difficult due to a technology barrier. Determining the effective dosage of each ion to achieve an application of the screening is challenging. Here, we selected zinc and strontium ions to provide multiple effects on antibacterial activity and osteogenesis. The optimal coating with effective release concentrations of the two ions was obtained after the two-step screening from testing. The results showed that this type of bioactive ion usage leads to an enhanced osseointegration during the immediate implantation in a periodontitis-affected environment and prevents soft tissue inflammation and bone resorption in an inflammatory environment. The new biologically active ion screening method could verify the effectiveness of this clinical translation and its potential for large-scale production and could determine the effective dosage of each ion for a specific application.
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http://dx.doi.org/10.1021/acsami.0c19698DOI Listing
February 2021

Elevated lymphotoxin-α (TNFβ) is associated with intervertebral disc degeneration.

BMC Musculoskelet Disord 2021 Jan 13;22(1):77. Epub 2021 Jan 13.

Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.

Background: Intervertebral disc degeneration (IVDD) is a primary cause of degenerative disc diseases; however, the mechanisms underlying the degeneration remain unclear. The immunoinflammatory response plays an important role in IVDD progression. The inflammatory cytokine lymphotoxin-α (LTα), formerly known as TNFβ, is associated with various pathological conditions, while its role in the pathogenesis of IVDD remains elusive.

Methods: Real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and enzyme-linked immunosorbent assays were used to assess the levels of LTα in human nucleus pulposus (NP) tissues between degeneration and control groups. The plasma concentrations of LTα and C-reactive protein (CRP) were compared between healthy and IVDD patients. Rat primary NP cells were cultured and identified via immunofluorescence. Methyl-thiazolyl-tetrazolium assays and flow cytometry were used to evaluate the effects of LTα on rat NP cell viability. After NP cells were treated with LTα, degeneration-related molecules (Caspase-3, Caspase-1, matrix metalloproteinase (MMP) -3, aggrecan and type II collagen) were measured via RT-qPCR and WB.

Results: The levels of both the mRNA and protein of LTα in human degenerated NP tissue significantly increased. Plasma LTα and CRP did not differ between healthy controls and IVDD patients. Rat primary NP cells were cultured, and the purity of primary NP cells was > 90%. Cell experiments showed inversely proportional relationships among the LTα dose, treatment time, and cell viability. The optimal conditions (dose and time) for LTα treatment to induce rat NP cell degeneration were 5 μg/ml and 48 ~ 72 h. The apoptosis rate and the levels of Caspase-3, Caspase-1, and MMP-3 significantly increased after LTα treatment, while the levels of type II collagen and aggrecan were decreased, and the protein expression levels were consistent with their mRNA expression levels.

Conclusions: This study demonstrated that elevated LTα is closely associated with IVDD and that LTα may induce NP cell apoptosis and reduce important extracellular matrix (ECM) proteins, which cause adverse effects on IVDD progress. Moreover, the optimal conditions for LTα treatment to induce NP cell degeneration were determined.
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http://dx.doi.org/10.1186/s12891-020-03934-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807514PMC
January 2021

Circulating MicroRNAs in Relation to Esophageal Adenocarcinoma Diagnosis and Survival.

Dig Dis Sci 2021 Jan 6. Epub 2021 Jan 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Background And Aims: Tissue miRNA can discriminate between esophageal adenocarcinoma (EA) and normal epithelium. However, no studies have examined a comprehensive panel of circulating miRNAs in relation to EA diagnosis and survival.

Methods: We used all 62 EA cases from the US Multi-Center case-control study with available serum matched 1:1 to controls. Cases were followed for vital status. MiRNAs (n = 2064) were assessed using the HTG EdgeSeq miRNA Whole Transcriptome Assay. Differential expression analysis of miRNAs in relation to case-control status was conducted. In cases, Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. P values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Predictive performance was assessed using cross-validation.

Results: Sixty-eight distinct miRNAs were significantly upregulated between cases and controls (e.g., miR-1255b-2-3p fold change = 1.74, BH-adjusted P = 0.01). Assessing the predictive performance of these significantly upregulated miRNAs yielded 60% sensitivity, 65% specificity, and 0.62 AUC. miR-4253 and miR-1238-5p were associated with risk of mortality after EA diagnosis (HR = 4.85, 95% CI: 2.30-10.23, BH-adjusted P = 0.04 and HR = 3.81, 95% CI: 2.02-7.19, BH-adjusted P = 0.04, respectively).

Conclusions: While they require replication, these findings suggest that circulating miRNAs may be associated with EA diagnosis and survival.
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http://dx.doi.org/10.1007/s10620-020-06740-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257775PMC
January 2021
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