Publications by authors named "Lin Ling"

837 Publications

Construction of a Promising Tumor-Infiltrating CD8+ T Cells Gene Signature to Improve Prediction of the Prognosis and Immune Response of Uveal Melanoma.

Front Cell Dev Biol 2021 28;9:673838. Epub 2021 May 28.

Department of Ophthalmology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China.

Background: CD8+ T cells work as a key effector of adaptive immunity and are closely associated with immune response for killing tumor cells. It is crucial to understand the role of tumor-infiltrating CD8+ T cells in uveal melanoma (UM) to predict the prognosis and response to immunotherapy.

Materials And Methods: Single-cell transcriptomes of UM with immune-related genes were combined to screen the CD8+ T-cell-associated immune-related genes (CDIRGs) for subsequent analysis. Next, a prognostic gene signature referred to tumor-infiltrating CD8+ T cells was constructed and validated in several UM bulk RNA sequencing datasets. The risk score of UM patients was calculated and classified into high- or low-risk subgroup. The prognostic value of risk score was estimated by using multivariate Cox analysis and Kaplan-Meier survival analysis. Moreover, the potential ability of gene signature for predicting immunotherapy response was further explored.

Results: In total, 202 CDIRGs were screened out from the single-cell RNA sequencing of GSE139829. Next, a gene signature containing three CDIRGs (, , and ) was identified, which was considered as an independent prognostic indicator to robustly predict overall survival (OS) and metastasis-free survival (MFS) of UM. In addition, the UM patients were classified into high- and low-risk subgroups with different clinical characteristics, distinct CD8+ T-cell immune infiltration, and immunotherapy response. Gene set enrichment analysis (GSEA) showed that immune pathways such as allograft rejection, inflammatory response, interferon alpha and gamma response, and antigen processing and presentation were all positively activated in low-risk phenotype.

Conclusion: Our work gives an inspiration to explain the limited response for the current immune checkpoint inhibitors to UM. Besides, we constructed a novel gene signature to predict prognosis and immunotherapy responses, which may be regarded as a promising therapeutic target.
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http://dx.doi.org/10.3389/fcell.2021.673838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194278PMC
May 2021

Multifunctional nanorods based on self-assembly of biomimetic apolipoprotein E peptide for the treatment of Alzheimer's disease.

J Control Release 2021 Jun 1. Epub 2021 Jun 1.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Targeting a single molecule or a single pathway and poor drug delivery to the brain hamper the therapy of Alzheimer's disease (AD) based on abnormal metabolism of amyloid-β (Aβ). To solve these problems, we designed and synthesized a multi - strategy peptide (MOP), an ingenious apolipoprotein E mimetic peptide, which could reduce Aβ deposition via inhibiting Aβ aggregation and at the same time accelerate Aβ clearance. Meanwhile, MOP could be self-assembled into different nanostructure, thus we constructed a multifunctional delivery system (APND-3) based on MOP self-assembled nanorods (aspect ratios of 3) that was a favorable morphology to enhance the permeation across the blood brain barrier (BBB) to address the poor delivery to brain issues. Besides, the drug delivery system introduces polydopamine (PDA) and COG1410 ligand as a shell to keep the favorable morphology of core and enhance the BBB targeting efficiency. As a result, the delivery system significantly enhances the delivery of MOP to the brain, thus reducing Aβ deposition, mitigating the memory deficits, and ameliorating neurologic damage in AD model mice. Our findings suggest that our drug and carrier integrated multifunctional delivery system has the potential for AD treatment.
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http://dx.doi.org/10.1016/j.jconrel.2021.05.044DOI Listing
June 2021

Preparation and Characterization of Optically Active Polyurethane from Rotatory Binaphthol Monomer and Polyurethane Prepolymer.

Molecules 2021 May 18;26(10). Epub 2021 May 18.

Key Laboratory of Eco-Textile, School of Textiles and Clothing, Jiangnan University, Ministry of Education, 1800 Lihu Road, Wuxi 214122, China.

Optically active polymers are promising multifunctional materials with great application potentials. Herein, environmentally friendly optically active polyurethanes (OPUs) were obtained by introducing rotatory binaphthol monomer to polyurethane. The influence of binaphthol monomer content on the structure, mechanical properties, infrared emissivity, and thermal insulation of OPUs was studied intensively. Structure characterization indicated that the optically active polyurethanes have been successfully synthesized. The OPU synthesized with BIMOL and BDO at the mole ratio of 1:1 presented better thermal resistance. In addition, OPUs showed enhanced tensile strength and stretchability with the increase of BINOL content to a certain extent due to its rigid structural features and high molecular weight. The optically active polyurethanes showed lower infrared emissivity values (8-14 μm) than waterborne polyurethane (WPU), and the infrared emissivity decreased from 0.850 to 0.572 as the content of the BINOL monomer increased. Moreover, OPU4 exhibited the best heat insulation and cooling ability with about a 7 °C temperature difference. The thus-synthesized optically active polyurethanes provide an effective solution for developing highly effective thermal insulation materials.
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http://dx.doi.org/10.3390/molecules26102986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157367PMC
May 2021

Proteomics analysis reveals the importance of transcriptional regulator slyA in regulation of several physiological functions in Aeromonas hydrophila.

J Proteomics 2021 Jul 24;244:104275. Epub 2021 May 24.

Fujian Provincial Key Laboratory of Agroecological Processing and Safety Monitoring, School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, PR China; Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, PR China; Key Laboratory of Marine Biotechnology of Fujian Province, Institute of Oceanology, Fujian Agriculture and Forestry University, Fuzhou 350002, PR China. Electronic address:

SlyA is a well-known transcription factor that plays important roles in the regulation of diverse physiological functions including virulence and stress response in various bacterial species. The biological effects of slyA have species-specific characteristics. In this study, a phenotype assay showed that slyA gene deletion in Aeromonas hydrophila (ahslyA) decreased biofilm formation capability but did not affect bacterial hemolytic activity or acid stress response. The differentially expressed proteins between ΔahslyA and wild-type strains were compared by label-free quantitative proteomics to further understand the effects of AhSlyA on biological functions. Bioinformatics assays showed that ΔahslyA may be involved in the regulation of several intracellular metabolic pathways such as galactose metabolism, arginine biosynthesis, and sulfur metabolism. A further phenotypic assay confirmed that AhSlyA plays an important role in the regulation of sulfur and phosphate metabolism. Moreover, ahslyA also directly or indirectly regulated at least eight outer membrane proteins involved in the maintenance of cell permeability. Overall, the results provide insights into the functions of ahslyA and demonstrate its importance in A. hydrophila. BIOLOGICAL SIGNIFICANCE: In this study, we compared the DEPs between the transcriptional regulator slyA-deleted and the wild-type A. hydrophila strains using a label-free quantitative proteomics method. The bioinformatics analysis showed that slyA may be involved in the regulation of several metabolic pathways. Subsequent phenotype and growth assays confirmed that ΔahslyA affected sulfur and phosphate metabolism, and OM permeability. Finally, a ChIP-PCR assay further confirmed that AhSlyA directly binds to the promoters of several candidate genes, including sulfur metabolism-related genes. These results indicated that slyA plays an important regulatory role in pleiotropic physiological functions of A. hydrophila, and these functions may be different from those identified in previous reports from other bacterial species.
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http://dx.doi.org/10.1016/j.jprot.2021.104275DOI Listing
July 2021

L-Theanine regulates glutamine metabolism and immune function by binding to cannabinoid receptor 1.

Food Funct 2021 May 26. Epub 2021 May 26.

Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, China. and National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan 410128, China and Hunan Agricultural University, Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha, Hunan 410128, China.

l-Theanine is a characteristic amino acid in tea with various effects including antioxidant and anti-inflammatory effects. Previously, most studies had reported that l-theanine regulates the immune function in vivo by inhibiting the expression of the inflammatory factors, but how l-theanine regulates the inflammatory factors' pathway is not known. In this study, we innovatively found the binding target of l-theanine in vivo-cannabinoid receptor 1, and demonstrated that l-theanine regulated the immune function and glutamine metabolism by competitively binding cannabinoid receptor 1. Mechanistically, l-theanine competitively binds cannabinoid receptor 1, leading to inhibition of cannabinoid receptor 1 activity, and regulates glutamine metabolism and immune function in normal and E44813-stressed rats. In normal rats, l-theanine inhibits ERK1/2 phosphorylation through Gβy by antagonizing cannabinoid receptor 1, thus affecting GS expression. From the point of view of immune signaling, after LTA antagonizes the activity of cannabinoid receptor 1, it relieves the inhibition of cannabinoid receptor 1 on COX-2 expression, downregulates Pdcd4 expression and NFκB, and ultimately enhances the expression of the anti-inflammatory factor IL-10. In E44813-stressed rats, l-theanine promotes the nuclear translocation of p-ERK1/2 by inhibiting the activity of cannabinoid receptor 1, and finally acts on GS. At the same time, it decreases the expression of the pro-inflammatory factor TNF-α and increases the expression of the anti-inflammatory factor IL-10 in stressed rats through the COX2-Pdcd4-NFκB-IL10 and TNFα pathways. In summary, these results demonstrate that l-theanine regulates glutamine metabolism and immune function by competitively binding to cannabinoid receptor 1.
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http://dx.doi.org/10.1039/d1fo00505gDOI Listing
May 2021

Exploring the Inhibitory Effect of Low-frequency Magnetic Fields on Epileptiform Discharges in Juvenile Rat Hippocampus.

Neuroscience 2021 May 24;467:1-15. Epub 2021 May 24.

School of Life Sciences, Tiangong University, Tianjin 300387, China. Electronic address:

Stimulation with a low frequency electromagnetic field (LF-EMF) has proven to represent a powerful method for the suppression of seizures, as demonstrated in select clinical and laboratory studies. However, the mechanism by which LF-EMF suppresses seizures remains unclear. The purpose of the present study was to explore the modulatory effect of LF-EMF on epileptiform discharges (EDs) using rat hippocampal slices and investigate the underlying mechanisms that mediate these effects. EDs in hippocampal slices was induced by magnesium-free (zero-Mg) artificial cerebrospinal fluid (ACSF) and recorded using an in vitro micro-electrode array (MEA). A small sub-decimeter coil was designed and incorporated in a flexible magnetic stimulation device that allowed electromagnetic fields with different parameters to be delivered to slices. After a stable ED event was recorded, magnetic fields of 0.5 Hz (30 min) with a magnetic intensity of 0.13 mT (5 V voltage input) and 0.25 mT (20 V voltage input) were applied. The results indicated that a high-amplitude 0.5 Hz magnetic field could lead to persistent suppression of ictal discharges (IDs), while low-amplitude magnetic fields did not influence IDs. The persistent suppression of complex ED was prevented if the magnetic fields were applied in the presence of 10 μmol/L bicuculline (BIC), a γ-aminobutyric acid type A (GABA) receptor antagonist, while the application of BIC subsequent to a magnetic field application led to the reappearance of ID. The addition of BIC resulted in EDs that had previously been inhibited by magnetic fields, reappearing. Low-frequency magnetic stimulation was able to inhibit the conversion from interictal discharges (IIDs) or preictal discharges (PIDs) to IDs. This suppression was attributed to the modulation of GABA receptor activity.
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http://dx.doi.org/10.1016/j.neuroscience.2021.05.016DOI Listing
May 2021

Microarray investigation of glycan remodeling during macrophage polarization reveals α2,6 sialic acid as an anti-inflammatory indicator.

Mol Omics 2021 May 18. Epub 2021 May 18.

Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.

Glycosylation is a widely occurring posttranslational modification. Here, we applied a quick, convenient and high-throughput strategy (lectin array) to investigate the variation in glycans on different macrophage subtypes derived from THP-1 and RAW264.7 cells. For THP-1 cells, there were more significant differences in the glycan on M2 macrophages compared to the other two subtypes. In contrast, M1 macrophages exhibited more significant glycan remodeling than the other subtypes for the RAW264.7 cell line. The response of the lectins which recogonize the N-glycan and α2,6 sialic acid was higher during polarization into anti-inflammatory phase (THP-1 derived M2 subtypes), and lower in pro-inflammatory phase (RAW264.7 M1 subtypes). The regulation of several α2,6 sialyltransferase genes was coincident with the regulation of the α2,6 sialic acid on the two cell lines. The lectin response and glycosyltranferase gene expression confirmed that α2,6 sialic acid showed higher expression in the anti-inflammatory phase. This indicated that α2,6 sialic acid was a potential indicator for the anti-inflammatory response.
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http://dx.doi.org/10.1039/d0mo00192aDOI Listing
May 2021

Bioadhesive glycosylated nanoformulations for extended trans-corneal drug delivery to suppress corneal neovascularization.

J Mater Chem B 2021 05;9(20):4190-4200

State Key Laboratory of Precision Measurement Technology and Instrument, School of Precision Instruments & Opto-Electronics Engineering, Tianjin University, Tianjin 300072, China. and Tianjin Key Laboratory of Biomedical Detection Techniques & Instruments, Tianjin University, Tianjin 300072, China.

Eye-drop formulations as conventional regimens to tackle ocular diseases are far from efficient due to the rapid clearance by eye tears and the blockage of the corneal epithelium barrier. Here, we describe a bioadhesive glycosylated nanoplatform with boric acid pendants as a drug carrier for noninvasive trans-corneal delivery of drugs to treat corneal neovascularization (CNV), a serious corneal disease resulting in significant vision impairment. This biocompatible nanoplatform is formulated from a synthetic amphiphilic boric acid-based copolymer self-assembling to form highly stable micelles with a high loading capacity for dexamethasone (DEX). The nanoplatform is demonstrated to be in contact with the corneal epithelium for a long period under the bioadhesive function of boric acid modules and releases the drug over 96 h in a controlled manner. Our results also suggest that the nanoplatform can be efficiently internalized by corneal epithelial cells in vitro and realize transcytosis in vivo to greatly enhance the transcorneal penetration of the loaded drugs into the pathological corneal stroma. On topical application against rat corneal alkali burn, the nanoformulation presents more robust efficacy on neovascularization suppression and inflammation elimination than free DEX with a negligible effect on normal tissues. This bioadhesive strategy which focuses on extending ocular drug retention and improving trans-corneal drug delivery not only highlights an approach for alternative noninvasive therapy of CNV but also provides a versatile paradigm for other biomedical applications by overcoming protective barriers.
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http://dx.doi.org/10.1039/d1tb00229eDOI Listing
May 2021

mA-related lncRNAs are potential biomarkers for predicting prognoses and immune responses in patients with LUAD.

Mol Ther Nucleic Acids 2021 Jun 9;24:780-791. Epub 2021 Apr 9.

Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China.

Lung adenocarcinoma (LUAD) is the most frequent subtype of lung cancer worldwide. However, the survival rate of LUAD patients remains low. N6-methyladenosine (mA) and long noncoding RNAs (lncRNAs) play vital roles in the prognostic value and the immunotherapeutic response of LUAD. Thus, discerning lncRNAs associated with mA in LUAD patients is critical. In this study, mA-related lncRNAs were analyzed and obtained by coexpression. Univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses were conducted to construct an mA-related lncRNA model. Kaplan-Meier analysis, principal-component analysis (PCA), functional enrichment annotation, and nomogram were used to analyze the risk model. Finally, the potential immunotherapeutic signatures and drug sensitivity prediction targeting this model were also discussed. The risk model comprising 12 mA-related lncRNAs was identified as an independent predictor of prognoses. By regrouping the patients with this model, we can distinguish between them more effectively in terms of the immunotherapeutic response. Finally, candidate compounds aimed at LUAD subtype differentiation were identified. This risk model based on the mA-based lncRNAs may be promising for the clinical prediction of prognoses and immunotherapeutic responses in LUAD patients.
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http://dx.doi.org/10.1016/j.omtn.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094594PMC
June 2021

Study on the dinoflagellate cysts in ballast tank sediments of international vessels in Chinese shipyards.

Mar Environ Res 2021 Apr 28;169:105348. Epub 2021 Apr 28.

College of Marine Ecology and Environment, Shanghai Ocean University, Shanghai, 201306, China; Ballast Water Detecting Lab, Shanghai Ocean University, Shanghai, 201306, China. Electronic address:

The problem of aquatic invasive species caused by discharge of ballast water and sediments from ships' ballast tanks has become extremely prominent. Seventeen sediment samples taken from ballast tanks of different ships docked in two Chinese shipyards were examined to identify the variety of resting dinoflagellate cysts. Twenty-two dinoflagellate cyst taxa were identified in these samples, including 11 photosynthetic and eleven heterotrophic species. These species represent 10 genera with the dominating assemblages of Alexandrium minutum, Scrippsiella acuminata, Lingulodinium polyedra, Protoperidinium sp. and Protoperidinium conicum. The total abundance of the dinoflagellate cysts ranged from 36 to 448 cysts g dry weight, which demonstrated a wide range of diversity for different ships. It was observed that the number of taxa and concentrations of cysts in ballast tank sediments were slightly greater for ships performing short voyage than ships performing longer voyage. The compositions of dinoflagellate cysts in sediments from ships sailing diverse routes were more variable than those sailing same routes. Sediment moisture content proved to be well correlated to the total cyst abundance (r = 0.7422, P < 0.01). Furthermore, nine toxic and harmful species were observed from all sediment samples, which indicated a wide range of distribution and potential risk of harmful algal blooms if being discharged to Chinese waters. As a result, full attention should be drawn to the studies on dinoflagellate cysts in the ballast tank sediments from ships arriving at China, this is of great significance for preventing introduction of toxic and harmful dinoflagellate cysts and protecting native marine biodiversity.
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http://dx.doi.org/10.1016/j.marenvres.2021.105348DOI Listing
April 2021

[Critical quality attribute assessment of big brand traditional Chinese medicine: quality control method of ginkgo leaves extract material based on powder physical properties].

Zhongguo Zhong Yao Za Zhi 2021 Apr;46(7):1622-1628

College of Pharmacy, Fujian University of Traditional Chinese Medicine Fuzhou 350122, China School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China Engineering Research Center of Chinese Medicine Production and New Drug Development, Ministry of Education Beijing 102488, China.

The physical properties of ginkgo leaves extract(GLE) are the critical quality attributes for the control of the manufacturing process of ginkgo leaves preparations. In this study, 53 batches of GLE with different sources from the real world were used as the objects to carry out the research from 3 levels. First, based on micromeritics evaluation method, a total of 29 physical attribute quality parameters in five dimensions were comprehensively characterized, with a total of 1 537 data points. Further, with use of physical fingerprinting technology combined with similarity evaluation, the powder physical properties of 53 batches of GLE showed obvious differences from an overall perspective, and the similarity of the physical fingerprints was 0.876 to 1.000. Secondly, hierarchical clustering analysis(HCA) and principal component analysis(PCA) models were constructed to realize the reliable identification and differentiation of real-world materials produced by GLE from different sources. Multivariate statistical process control(MSPC) model was used to create GLE material Hotelling T~2 and squared prediction error(SPE) control charts. It was found that the SPE score of B_(21) powder exceeded the 99% confidence control limit by 22.495 9, and the SPE scores of A_1 and C_(10) powder exceeded the 95% confidence control limit by 16.099 2, realizing the determination of abnormal samples in the materials of GLE from the production in real world. Finally, the physical quality control method of GLE in the production process of ginkgo leaves preparations was established in this study, providing a reference for the quality control methods of ginkgo leaves preparations in their manufacturing process.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210205.306DOI Listing
April 2021

[Criticalquality attribute assessment of big brand traditional Chinese medicine: visualization method for quality control of Ginkgo Leaves Tablets based on spatial distribution uniformity].

Zhongguo Zhong Yao Za Zhi 2021 Apr;46(7):1616-1621

School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China Engineering Research Center of Chinese Medicine Production and New Drug Development, Ministry of Education Beijing 102488, China.

Spatial distribution uniformity is the critical quality attribute(CQA) of Ginkgo Leaves Tablets, a variety of big brand traditional Chinese medicine. The evaluation of the spatial distribution uniformity of active pharmaceutical ingredients(APIs) in Ginkgo Leaves Tablets is important in ensuring their stable and controllable quality. In this study, hyperspectral imaging technology was used to construct the spatial distribution map of API concentration based on three prediction models, further to realize the visualization research on the spatial distribution uniformity of Ginkgo Leaves Tablets. The region of interest(ROI) was selected from each Ginkgo Leaves Tablet, with length and width of 50 pixels, and a total of 2 500 pixels. Each pixel had 288 spectral channels, and the number of content prediction data could reach 1×10~5 for a single sample. The results of the three models showed that the Partial Least Squares(PLS) model had the highest prediction accuracy, with calibration set determination coefficient R_(pre)~2 of 0.987, prediction set determination coefficient R_(pre)~2 of 0.942, root mean square error of calibration(RMSEC) of 0.160%, and root mean square error of prediction(RMSEP) of 0.588%. The classical least-squares(CLS) model had a greater prediction error, with the RMSEP of 0.867%. Multivariate Curve Resolution-Alternating Least Square(MCR-ALS) model showed the worst predictive ability among the three models, and it couldn't realize content prediction. Based on the prediction results of PLS and CLS models, the spatial distribution map of APIs concentration was obtained through three-dimensional data reconstruction. Furthermore, histogram method was used to evaluate the spatial distribution uniformity of API. The data showed that the spatial distribution of APIs in Ginkgo Leaves Tablets was relatively uniform. The study explored the feasibility of visualization of spatial distribution of Ginkgo Leaves Tablets based on three models. The results showed that PLS model had the highest prediction accuracy, and MCR-ALS model had the lowest prediction accuracy. The research results could provide a new strategy for the visualization method of quality control of Ginkgo Leaves Tablets.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210218.304DOI Listing
April 2021

[Critical quality attribute assessment of big brand traditional Chinese medicine: modular identification of Tongren Niuhuang Qingxin Pills based on efficacy with chemical properties].

Zhongguo Zhong Yao Za Zhi 2021 Apr;46(7):1606-1615

School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China Engineering Research Center of Chinese Medicine Production and New Drug Development, Ministry of Education Beijing 102488,China.

Identification of critical quality attribute(CQA) is crucial in quality control of Tongren Niuhuang Qingxin Pills(TRNHQXP). In this study, 661 active components in TRNHQXP were selected by liquid chromatography-mass spectrometry(LC-MS) and network pharmacology based on reported data and TCMSP, BATMAN-TCM, and TCMID databases, as well as mass spectrometry data, and 1 413 targets of the active components were obtained through SwissTargetPrediction. The 152 potential targets obtained from the intersection of predicted targets with 456 stroke targets underwent functional enrichment analysis by Metascape. The 27 Chinese medicinals in TRNHQXP were divided into four sets according to efficacies. Thirty-seven key targets in the blood-activating and stasis-resolving set and 41 in the tonifying set were screened out. On the basis of these potential key targets, 137 potential key CQA of TRNHQXP for stroke were reversely predicted. This study revealed the possible mechanism of TRNHQXP in treating stroke and established a modular identification method for the potential CQA of big brand traditional Chinese medicine(TCM) based on efficacies and chemical properties. Consequently, the CQA of TRNHQXP were identified by this method, which has provided a reference for the following experimental studies of CQA.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210218.301DOI Listing
April 2021

[Critical quality attribute assessment of big brand traditional Chinese medicine: visualization of blending process for rare medicines in Tongren Niuhuang Qingxin Pills based on spatial distribution uniformity].

Zhongguo Zhong Yao Za Zhi 2021 Apr;46(7):1585-1591

School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 102488, China Engineering Research Center of Chinese Medicine Production and New Drug Development, Ministry of Education Beijing 102488, China.

The spatial distribution uniformity of valuable medicines is the critical quality attribute in the process control of Tongren Niuhuang Qingxin Pills. With the real world sample of the mixed end-point powder of Tongren Niuhuang Qingxin Pills as the research object, hyperspectral imaging technology was used to collect a total of 32 400 data points with a size of 180 pix×180 pix. Spectral angle matching(SAM), classical least squares and mixed tuned matched filtering(MTMF) were used to identify the spatial distribution of rare medicines. MTMF model showed higher identification accuracy, therefore the spatial distribution of the blended intermediates was identified based on the MTMF model. The histogram method was also used to evaluate the spatial distribution uniformity of rare medicines. The results showed that the standard deviation was 4.78, 6.5, 3.48, 1.96, and 3.00 respectively for artificial bezoar, artificial musk, Borneol, Antelope horn and Buffalo horn; the variance was 22.8, 42.3, 12.1, 3.82, and 9.00, and the skewness was 1.26, 1.71, 0.06,-0.86, and 1.04, respectively. The final results showed that the most even blending was achieved in concentrated powder of Borneol, Antelope horn and Buffalo horn, followed by artificial bezoar, and last artificial musk. A visualization method was established for quality attributes of distribution uniformity in blending process of Tongren Niuhuang Qingxin Pills. It could provide evidences of quality control methods in the mixing process of big brand traditional Chinese medicine.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210218.303DOI Listing
April 2021

Glycolysis-Based Genes Are Potential Biomarkers in Thyroid Cancer.

Front Oncol 2021 26;11:534838. Epub 2021 Apr 26.

Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.

While increased glycolysis has been identified as a cancer marker and attracted much attention in thyroid cancer (THCA), the prognostic role of it remains to be further elucidated. Here we aimed to determine a specific glycolysis-associated risk model to predict THCA patients' survival. We also explored the interaction between this signature and tumor immune microenvironment and performed drug screening to identify specific drugs targeting the glycolysis-associated signature. Six genes (CHST6, POM121C, PPFIA4, STC1, TGFBI, and FBP2) comprised the specific model, which was an independent prognostic indicator in THCA patients determined by univariate, LASSO and multivariate Cox regression analyses. The receiver operating characteristic (ROC) curve analysis confirmed the excellent clinical performance of the prognostic signature. According to the specific gene signature, patients were categorized into high- and low-risk subgroups. The high-risk group was characterized by decreased immune score and elevated tumor purity, as well as worser survival prognosis compared to the low-risk group. We also validated the expression of these genes in clinical samples and experiments. Lastly, we identified potential drugs targeting the glycolysis-associated signature. The derived glycolysis-related signature is an independent prognostic biomarker for THCA patients and might be used as an efficacy of biomarker for drug-sensitivity prediction.
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http://dx.doi.org/10.3389/fonc.2021.534838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107473PMC
April 2021

Emerging open microfluidics for cell manipulation.

Chem Soc Rev 2021 May;50(9):5333-5348

Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China.

Cell manipulation is the foundation of biochemical studies, which demands user-friendly, multifunctional and precise tools. Based on flow confinement principles, open microfluidics can control the movement of microscale liquid in open space. Every position of the circuit is accessible to external instruments, making it possible to perform precise treatment and analysis of cells at arbitrary target positions especially at the single-cell/sub-cell level. Benefiting from its unique superiority, various manipulations including patterned cell culture, 3D tissue modelling, localized chemical stimulation, online cellular factor analysis, single cell sampling, partial cell treatment, and subcellular free radical attack can be easily realized. In this tutorial review, we summarize two basic ideas to design open microfluidics: open microfluidic networks and probes. The principles of mainstream open microfluidic methods are explained, and their recent important applications are introduced. Challenges and developing trends of open microfluidics are also discussed.
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http://dx.doi.org/10.1039/d0cs01516dDOI Listing
May 2021

Metabolism-Based Capture and Analysis of Circulating Tumor Cells in an Open Space.

Anal Chem 2021 May 26;93(18):6955-6960. Epub 2021 Apr 26.

Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China.

The level of circulating tumor cells (CTCs) in blood is a predictor of metastatic cancer progress, serving as an important biomarker for cancer diagnosis, prognosis, and therapy. Currently, there are mainly two conventional strategies to distinguish CTCs, including biological property-based affinity capture and physical property-based label-free isolation. Although great progress has been made in this field, the ability to distinguish CTCs still needs to be improved further due to the cell heterogeneity. Herein, a metabolism-based isolation approach was applied to identify tumor cells according to the "Warburg effect", and a bifunctional open-space platform with fluid walls was developed for real-time monitoring and in situ capture/analysis of tumor cells. A drop-on-demand inkjet printing technique was introduced to create a single cell-containing droplet array with high throughput and high encapsulation rate, and the homogeneous crystalline matrix spots ejected from the inkjet also provided high-quality and reproducible lipid profiling. This platform could combine both microscopic image and mass data, and it has been proven to be capable of isolating and identifying CTCs in complex blood samples, making it a promising tool for evaluating the efficacy of therapy and monitoring the disease progression.
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http://dx.doi.org/10.1021/acs.analchem.0c05155DOI Listing
May 2021

LncRNA-LINC01089 inhibits lung adenocarcinoma cell proliferation and promotes apoptosis via sponging miR-543.

Tissue Cell 2021 Mar 24;72:101535. Epub 2021 Mar 24.

Department of Thoracic Surgery, Taizhou Hospital of Wenzhou Medical University, China. Electronic address:

LINC01089, a newly discovered long non-coding RNA (lncRNA), has been reported to inhibit the progression of various types of cancers. This study aimed to characterize LINC01089 in the pathogenesis of lung adenocarcinoma (LUAD). LINC01089 expression in LUAD tissues or/and cells and its association with the overall survival of LUAD patients was analyzed in The Cancer Genome Atlas (TCGA)-LUAD database, by qRT-PCR or by Kaplan-Meier's curve. Databases of StarBase, LncBase, and DEmiRNA were used to predict and confirm the interaction between LINC01089 and potential LINC01089-targeted microRNAs (miRNAs). The expressions of these miRNAs in LUAD tissues or/and cells were determined by qRT-PCR, and dual-luciferase reporter assay was performed to validate lncRNA-miRNA interaction. The expressions of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and Cleaved caspase-3 in LUAD cells were analyzed by Western blot. LINC01089 improved overall survival of LUAD patients and was low-expressed in LUAD. Upregulating LINC01089 expression reduced LUAD cell viability, inhibited colony formation, enhanced apoptosis, accompanied by downregulated Bcl-2 and miR-543 and upregulated Bax and Cleaved caspase-3. MiR-543 was determined as a target gene of LINC01089, and was high-expressed in LUAD tissues. Upregulating miR-543 expression induced the opposite effects to LINC01089 upregulation on these cellular biological behaviors and the expressions of Bcl-2, Bax and Cleaved caspase-3. Moreover, the effects of miR-543 upregulation and LINC01089 upregulation were mutually counteracted by each other. LINC01089 inhibited lung adenocarcinoma cell proliferation and promoted apoptosis via sponging miR-543.
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http://dx.doi.org/10.1016/j.tice.2021.101535DOI Listing
March 2021

Epithelium-Penetrable Nanoplatform with Enhanced Antibiotic Internalization for Management of Bacterial Keratitis.

Biomacromolecules 2021 May 21;22(5):2020-2032. Epub 2021 Apr 21.

State Key Laboratory of Precision Measurement Technology and Instrument, School of Precision Instruments & Opto-Electronics Engineering, Tianjin University, Tianjin 300072, China.

A standardized regimen for addressing the adverse effects of bacterial keratitis on vision remains an intractable challenge due to poor epithelial penetration and a short corneal retention time. In this study, a new strategy is proposed to implement the direct transport of antibiotics to bacteria-infected corneas topical administration of an epithelium-penetrable biodriven nanoplatform, thereby enabling the efficacious treatment of bacterial keratitis. The nanoplatforms were composed of amphiphilic glycopolymers containing boron dipyrromethene and boronic acid moieties with stable fluorescence characteristics and the ability to potentiate epithelial penetration deep into the cornea. The boronic acid-derived nanoplatforms enabled efficient cellular internalization through the high affinity of boric acid groups for the diol-containing bacterial cell wall, resulting in enhanced drug penetration and retention inside the pathogenic bacteria. The bacterial cells formed agglomerations after incorporating the nanoplatforms along with a special mechanism to release the encapsulated cargo in response to bacteria. Compared with the drug alone, this smart system achieved enhanced bacterial mortality and attenuated inflammation associated with -induced keratitis in rats, demonstrating a paradigm for targeted ocular drug delivery and an alternative strategy for managing bacterial keratitis or other bacterial infections by heightening corneal permeability and transcorneal bioavailability.
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http://dx.doi.org/10.1021/acs.biomac.1c00139DOI Listing
May 2021

Puromycin-Modified Silica Microsphere-Based Nascent Proteomics Method for Rapid and Deep Nascent Proteome Profile.

Anal Chem 2021 04 15;93(16):6403-6413. Epub 2021 Apr 15.

Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, P.R. China.

Nascent proteome is crucial in directly revealing how the expression of a gene is regulated on a translation level. In the nascent protein identification, puromycin capture is one of the pivotal methods, but it is still facing the challenge in the deep profiling of nascent proteomes due to the low abundance of most nascent proteins. Here, we describe the synthesis of puromycin-modified silica microspheres (PMSs) as the sorbent of dispersive solid-phase microextraction and the establishment of the PMS-based nascent proteomics (PMSNP) method for efficient capture and analysis of nascent proteins. The modification efficiency of puromycin groups on silica microspheres reached 91.8% through the click reaction. After the optimization and simplification of PMSNP, more than 3500 and 3900 nascent proteins were rapidly identified in HeLa cells and mouse brains within 13.5 h, respectively. The PMSNP method was successfully applied to explore changes in the translation process in a biological stress model, namely, the lipopolysaccharide-stimulated HeLa cells. Biological functional analyses revealed the unique characters of the nascent proteomes and exhibited the superiority of the PMSNP in the identification of low abundance and secreted nascent proteins, thus demonstrating the sensitivity and immediacy of the PMSNP method.
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http://dx.doi.org/10.1021/acs.analchem.0c05393DOI Listing
April 2021

The mediating role of daytime sleepiness between problematic smartphone use and post-traumatic symptoms in COVID-19 home-refined adolescents.

Child Youth Serv Rev 2021 Jul 8;126:106012. Epub 2021 Apr 8.

Centre for Educational and Health Psychology, Sichuan University, Chengdu, China.

Background: COVID-19 was first recognized in late 2019 in China, at which time school closures forced most students to isolate at home or maintain social distance, both of which increased smartphone use, daytime sleepiness and post traumatic disorder (PTSD) risks. However, to date, no research has fully explored these behavioral risks or the consequences.

Methods: Two thousand and ninety home-confined students from two Chinese high schools participated in an online-based questionnaire battery that assessed their sociodemographic characteristics, COVID-19 related exposures, daytime sleepiness, problematic smartphone use, and PTSD. The subsequent data were subjected to mediation analysis, and structural equation models (SEM) were employed to explore the variable relationships.

Results: The problematic smartphone use, daytime sleepiness and PTSD prevalence were respectively 16.4%, 20.2% and 6.9%. The number of COVID-19 related exposure was directly associated with problematic smartphone use and PTSD symptoms. Problematic smartphone use was found to be a mediator between COVID-19 related exposure and PTSD symptoms, and daytime sleepiness was found to partially mediate the associations between problematic smartphone use and PTSD.

Conclusions: The more exposure associated with the pandemic, the more psychological and behavioral problems the adolescents had. The relatively high rate of problematic smartphone use in home isolated adolescents possibly increased the risk of daytime sleepiness and psychological problems. Therefore, targeted improvements are needed to reduce the risk of psychological problems and daytime sleepiness in adolescents.
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http://dx.doi.org/10.1016/j.childyouth.2021.106012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028598PMC
July 2021

[Effect of delayed cord clamping and umbilical cord milking on cerebral hemodynamics in preterm infants: a randomized double-blind controlled trial].

Authors:
Ling Lin Hao Peng

Zhongguo Dang Dai Er Ke Za Zhi 2021 Apr;23(4):332-337

Department of Pediatrics, Suining Central Hospital, Suining, Sichuan 629000, China.

Objective: To compare the effect of delayed cord clamping (DCC) versus umbilical cord milking (UCM) on cerebral blood flow in preterm infants.

Methods: This was a single-center, prospective, double-blind, randomized controlled trial. A total of 46 preterm infants, with a gestational age of 30-33 weeks, who were born in Suining Central Hospital from November 2, 2018 to November 15, 2019 were enrolled and randomly divided into DCC group and UCM group, with 23 infants in each group. The primary outcome indexes included cerebral hemodynamic parameters[peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistance index (RI)] measured by ultrasound within 0.5-1 hour, (24±1) hours, (48±1) hours, and (72±1) hours after birth. Secondary outcome indexes included hematocrit, hemoglobin, red blood cell count, and serum total bilirubin levels on the first day after birth and the incidence rate of intraventricular hemorrhage during hospitalization.

Results: A total of 21 preterm infants in the DCC group and 23 in the UCM group were included in the statistical analysis. There was no significant difference in PSV, EDV, and RI between the two groups at all time points after birth ( > 0.05). There was also no significant difference between the two groups in the hematocrit, hemoglobin, red blood cell count and total bilirubin levels on the first day after birth, and the incidence rate of intraventricular hemorrhage during hospitalization ( > 0.05).

Conclusions: DCC and UCM have a similar effect on cerebral hemodynamics in preterm infants with a gestational age of 30-33 weeks.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050552PMC
April 2021

Transporter proteins in Zymomonas mobilis contribute to the tolerance of lignocellulose-derived phenolic aldehyde inhibitors.

Bioprocess Biosyst Eng 2021 Apr 10. Epub 2021 Apr 10.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.

Transporter proteins are of great importance for improving the tolerance of fermentation strains to lignocellulose-derived furans and phenolic inhibitors. Different from the documented transporter proteins responsible for the tolerance of furfural and 5-hydroxymethyl-furfural (HMF), transporters responsible for that of varied phenolic aldehyde inhibitors were less investigated and elucidated. Here, an interesting phenomenon was found that no phenolic alcohols were accumulated from phenolic aldehydes degradation in Zymomonas mobilis. A transcriptional profiling of transporter genes was established in Z. mobilis ZM4 under phenolic aldehydes stress using DNA microarray. Six transporter proteins were identified as the potential candidates responsible for the tolerance of phenolic aldehydes including ABC transporter (ZMO0799 and ZMO0800), MFS transporter (ZMO1288 and ZMO1856), and RND transporter (ZMO0282 and ZMO0798). Furthermore, the analysis showed that the key transporters were significantly correlated with oxidoreductases and transcriptional regulators. This work would provide several important transporter genes serving as synthetic biology tools for improving the robustness of biorefinery strains.
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http://dx.doi.org/10.1007/s00449-021-02567-xDOI Listing
April 2021

T cell reactivity to regulatory factor X4 in type 1 narcolepsy.

Sci Rep 2021 Apr 9;11(1):7841. Epub 2021 Apr 9.

Department of Psychiatry and Behavioral Sciences, Stanford University Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.

Type 1 narcolepsy is strongly (98%) associated with human leukocyte antigen (HLA) class II DQA1*01:02/DQB1*06:02 (DQ0602) and highly associated with T cell receptor (TCR) alpha locus polymorphism as well as other immune regulatory loci. Increased incidence of narcolepsy was detected following the 2009 H1N1 pandemic and linked to Pandemrix vaccination, strongly supporting that narcolepsy is an autoimmune disorder. Although recent results suggest CD4+ T cell reactivity to neuropeptide hypocretin/orexin and cross-reactive flu peptide is involved, identification of other autoantigens has remained elusive. Here we study whether autoimmunity directed against Regulatory Factor X4 (RFX4), a protein co-localized with hypocretin, is involved in some cases of narcolepsy. Studying human serum, we found that autoantibodies against RFX4 were rare. Using RFX4 peptides bound to DQ0602 tetramers, antigen RFX4-86, -95, and -60 specific human CD4+ T cells were detected in 4/10 patients and 2 unaffected siblings, but not in others. Following culture with each cognate peptide, enriched autoreactive TCRαβ clones were isolated by single-cell sorting and TCR sequenced. Homologous clones bearing TRBV4-2 and recognizing RFX4-86 in patients and one twin control of patient were identified. These results suggest the involvement of RFX4 CD4+ T cell autoreactivity in some cases of narcolepsy, but also in healthy donors.
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http://dx.doi.org/10.1038/s41598-021-87481-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035403PMC
April 2021

Corrigendum: High-Dose Intravenous Immunoglobulin in Severe Coronavirus Disease 2019: A Multicenter Retrospective Study in China.

Front Immunol 2021 22;12:671443. Epub 2021 Mar 22.

Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

[This corrects the article DOI: 10.3389/fimmu.2021.627844/full.].
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http://dx.doi.org/10.3389/fimmu.2021.671443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020904PMC
March 2021

Overexpression of Dioxygenase Encoding Gene Accelerates the Phenolic Aldehyde Conversion and Ethanol Fermentability of Zymomonas mobilis.

Appl Biochem Biotechnol 2021 Apr 7. Epub 2021 Apr 7.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.

NADH-dependent reductase enzyme catalyzes the phenolic aldehyde conversion and correspondingly improves the ethanol fermentability of the ethanologenic Zymomonas mobilis. This study constructed the transcriptional landscape of mono/dioxygenase genes in Z. mobilis ZM4 under the stress of the toxic phenolic aldehyde inhibitors of 4-hydroxybenzaldehyde, syringaldehyde, and vanillin. One specific dioxygenase encoding gene ZMO1721 was differentially expressed by 3.07-folds under the stress of 4-hydroxybenzaldehyde among the eleven mono/dioxygenase genes. The purified ZMO1721 shared 99.9% confidence and 48.0% identity with the oxidoreductase in Rhodoferax ferrireducens T118 was assayed and the NADH-dependent reduction activity was confirmed for phenolic aldehyde vanillin conversion. The ZMO1721 gene was then overexpressed in Z. mobilis ZM4 and the 4-hydroxybenzaldehyde conversion rate was accelerated. The cell growth, glucose consumption, and ethanol productivity of Z. mobilis ZM4 were also improved by ZMO1721 overexpression. The genes identified on improving phenolic aldehyde tolerance and ethanol fermentability in this study could be used as the synthetic biology tools for modification of ethanologenic strains.
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http://dx.doi.org/10.1007/s12010-021-03551-7DOI Listing
April 2021

Identification of potential candidate proteins for reprogramming spinal cord-derived astrocytes into neurons: a proteomic analysis.

Neural Regen Res 2021 Nov;16(11):2257-2263

Department of Anatomy and Histoembryology, Fujian Medical University, Fuzhou, Fujian Province, China.

Our previous study has confirmed that astrocytes overexpressing neurogenic differentiation factor 1 (NEUROD1) in the spinal cord can be reprogrammed into neurons under in vivo conditions. However, whether they can also be reprogrammed into neurons under in vitro conditions remains unclear, and the mechanisms of programmed conversion from astrocytes to neurons have not yet been clarified. In the present study, we prepared reactive astrocytes from newborn rat spinal cord astrocytes using the scratch method and infected them with lentivirus carrying NEUROD1. The results showed that NEUROD1 overexpression reprogrammed the cultured reactive astrocytes into neurons in vitro with an efficiency of 13.4%. Using proteomic and bioinformatic analyses, 1952 proteins were identified, of which 92 were differentially expressed. Among these proteins, 11 were identified as candidate proteins in the process of reprogramming based on their biological functions and fold-changes in the bioinformatic analysis. Furthermore, western blot assay revealed that casein kinase II subunit alpha (CSNK2A2) and pinin (PNN) expression in NEUROD1-overexpressing reactive astrocytes was significantly increased, suggesting that NEUROD1 can directly reprogram spinal cord-derived reactive astrocytes into neurons in vitro, and that the NEUROD1-CSNK2A2-PNN pathway is involved in this process. This study was approved by the Animal Ethics Committee of Fujian Medical University, China (approval No. 2016-05) on April 18, 2016.
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http://dx.doi.org/10.4103/1673-5374.310697DOI Listing
November 2021

Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China.

Open Life Sci 2021 18;16(1):150-159. Epub 2021 Feb 18.

Department of Endocrinology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250, East Street, Licheng District, Quanzhou, 362300, Fujian, China.

The purpose of this study was to assess the relationship between 25-hydroxyvitamin D (25(OH)D), urinary iodine concentration (UIC), and type 2 diabetes mellitus (T2DM) risk and complications and to establish a model to predict T2DM in the general population. A total of 567 adults (389 T2DM patients and 178 controls) were enrolled, and the levels of 25(OH)D, iodine, and blood biochemical parameters were measured. Pearson's correlation analysis showed an inverse correlation between 25(OH)D level, UIC, and T2DM risk. Low 25(OH)D level was a risk factor for developing T2DM (OR, 0.81; 95% CI, 1.90-2.63; = 0.043) after adjustment for multiple risk factors. 25(OH)D level and UIC were inversely correlated with short-term and long-term glucose levels. 25(OH)D deficiency was also associated with a high incidence of T2DM complicated with thyroid dysfunction. A prediction model based on 25(OH)D, iodine status, and other risk factors was established and recommended to screen high-risk T2DM in the general population and provide early screening and timely treatment for them.
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http://dx.doi.org/10.1515/biol-2021-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968538PMC
February 2021

Prognostic and clinicopathological value of circPVT1 in human cancers: A meta-analysis.

Cancer Rep (Hoboken) 2021 Apr 1:e1385. Epub 2021 Apr 1.

Department of Orthopedics, The Second Xiangya Hospital Central South University, Changsha, China.

Background: Circular RNA PVT1 (circPVT1) is significantly upregulated in various human cancers and is related to poor clinical outcome of cancer patients. However, the prognostic and clinicopathological value of circPVT1 in diverse human cancers remains controversial and inconclusive.

Aim: The objective of our study is to evaluate the prognostic and clinicopathological role of circPVT1 for cancer patients.

Methods And Results: PubMed, Embase, Web of Science, and Cochrane Library were searched for eligible studies by October 1, 2020. The correlation between circPVT1 expression, and overall survival (OS) and clinical parameters was assessed by pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses, heterogeneity, and publication bias were conducted to further enhance reliability. Twelve studies (1282 patients) were selected for this meta-analysis, including 11 on prognosis and 10 on clinicopathological parameters. Elevated expression of circPVT1 was associated with a worse OS in cancer patients (HR, 2.009; 95% CI, 1.667-2.408, 1.892; P < .001). For clinicopathological value, upregulation of circPVT1 was closely related to poor clinical parameters lymph node metastasis (OR = 2.019; 95% CI, 1.026-3.976; P = .042; I = 77.5%; P = 0.000), late clinical stage (OR = 3.594; 95% CI, 1.828-7.065; P < .001; I = 71.7%; P = 0.001), distant metastasis (OR = 4.598; 95% CI, 1.411-14.988; P = .011; I = 78.1%; P = 0.001), and chemoresistant (OR = 6.400; 95% CI, 2.107-19.441; P = .001; I = 49.6%; P = 0.159).

Conclusion: High expression of circPVT1 is correlated with unfavorable prognosis of cancer patients, indicating that circPVT1 can function as a potential prognostic biomarker in human cancer.
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http://dx.doi.org/10.1002/cnr2.1385DOI Listing
April 2021

SPTBN1 inhibits inflammatory responses and hepatocarcinogenesis via the stabilization of SOCS1 and downregulation of p65 in hepatocellular carcinoma.

Theranostics 2021 20;11(9):4232-4250. Epub 2021 Feb 20.

Department of Medicine and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Spectrin, beta, non-erythrocytic 1 (SPTBN1), an adapter protein for transforming growth factor beta (TGF-β) signaling, is recognized as a tumor suppressor in the development of hepatocellular carcinoma (HCC); however, the underlying molecular mechanisms of this tumor suppression remain obscure. The effects on expression of pro-inflammatory cytokines upon the inhibition or impairment of SPTBN1 in HCC cell lines and liver tissues of and wild-type (WT) mice were assessed by analyses of quantitative real-time reverse-transcription polymerase chain reaction (QRT-PCR), enzyme linked immunosorbent assay (ELISA), Western blotting and gene array databases from HCC patients. We investigated the detailed molecular mechanisms underlying the inflammatory responses by immunoprecipitation-Western blotting, luciferase reporter assay, chromatin immunoprecipitation quantitative real time PCR (ChIP-qPCR), immunohistochemistry (IHC) and electrophoretic mobility shift assay (EMSA). The proportion of myeloid-derived suppressor cells in liver, spleen, bone marrow and peripheral blood samples from WT and mice were measured by fluorescence-activated cell sorting (FACS) analysis. Further, the hepatocacinogenesis and its correlation with inflammatory microenvironment by loss of SPTBN1/SOCS1 and induction of p65 were analyzed by treating WT and mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Loss of SPTBN1 in HCC cells upregulated the expression of pro-inflammatory cytokines including interleukin-1α (IL-1α), IL-1β, and IL-6, and enhanced NF-κB transcriptional activation. Mechanistic analyses revealed that knockdown of SPTBN1 by siRNA downregulated the expression of suppressor of cytokine signaling 1 (SOCS1), an E3 ligase of p65, and subsequently upregulated p65 accumulation in the nucleus of HCC cells. Restoration of SOCS1 abrogated this SPTBN1 loss-associated elevation of p65 in HCC cells. In human HCC tissues, SPTBN1 gene expression was inversely correlated with gene expression of IL-1α, IL-1β and IL-6. Furthermore, a decrease in the levels of SPTBN1 gene, as well as an increase in the gene expression of IL-1β or IL-6 predicted shorter relapse free survival in HCC patients, and that HCC patients with low expression of SPTBN1 or SOCS1 protein is associated with poor survival. Heterozygous loss of SPTBN1 ( ) in mice markedly upregulated hepatic expression of IL-1α, IL-1β and IL-6, and elevated the proportion of myeloid-derived suppressor cells (MDSCs) and CD4CD25Foxp3 regulatory T cells (Foxp3Treg) cells in the liver, promoting hepatocarcinogenesis of mouse fed by DDC. : Our findings provided evidence that loss of SPTBN1 in HCC cells increases p65 protein stability via the inhibition of SOCS1 and enhances NF-κB activation, stimulating the release of inflammatory cytokines, which are critical molecular mechanisms for the loss of SPTBN1-induced liver cancer formation. Reduced SPTBN1 and SOCS1 predict poor outcome in HCC patients.
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http://dx.doi.org/10.7150/thno.49819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977457PMC
February 2021